SAMJ Vol 105, No 5 (2015) by HMPG

MAY 2015

VOL. 105 NO. 5

Antimicrobial resistance 325, 357 The menacing bread tag 342 Recommendations for treatment of URTIs 345 Community- v. healthcare-acquired bloodstream infections 359, 363 Rheumatic heart disease in Africa 361, 384 Severity-of-illness score to predict death of TB patients in the ICU 393 Diabetes management in children 397, 400, 405 Current role of splenectomy for ITP 408 CME: Antibiotic stewardship 413-422

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MAY 2015

VOL. 105 NO. 5

GUEST EDITORIAL

SAMJ

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The World Health Organization Global Action Plan for antimicrobial resistance M Mendelson, M P Matsoso

EDITOR-IN-CHIEF Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA)

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EDITOR’S CHOICE

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB

CORRESPONDENCE 328

VIM-2 carbapenemase-producing Pseudomonas aeruginosa in a patient from Port Elizabeth, South Africa S Govender, T Masunda, J Black

328

Paediatric chemoprophylaxis for child contacts of patients with drug-resistant tuberculosis: Are current guidelines effective in preventing disease? N Padayatchi, N Naidu

329

Tracking antenatal HIV prevalence in South Africa P Nkomo, A Goga

330

Outcomes in treatment with darunavir/ritonavir in ART-experienced paediatric patients G Kindra, N Sipambo, H Moultrie, L Fairlie

331

Better menstrual management options for adolescents needed in South Africa: What about the menstrual cup? M Beksinska, J Smit, R Greener, V Maphumulo, Z Mabude

332

Masterly inactivity: A forgotten precept F Mai

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman HMPG CEO AND PUBLISHER Hannah Kikaya | Email: hannah.kikaya@ hmpg.co.za MANAGING EDITOR Ingrid Nye TECHNICAL EDITORS Emma Buchanan Paula van der Bijl NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za

IZINDABA 333 334 337 338 339

Lifesaving water quality solution ‘ignored’ Little-used medical technology could help thousands see, hear and feel better SAMA pitches in to help victims of adverse medical events Tygerberg Hospital keeps more hearts beating with pioneering service Government inability to harness high-tech radiology blurs NHI vision

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OBITUARY Philippe Emile Agnes Schuermans

PRODUCTION MANAGER (CMC) Emma Jane Couzens DTP & DESIGN (CMC) Carl Sampson HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@samedical.org JOURNAL ADVERTISING Charles William Duke Benru de Jager Reneé van der Ryst

SAMJ FORUM

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ISSUES IN PUBLIC HEALTH The simple bread tag – a menace to society? R Karro, P Goussard, J Loock, R Gie

345

RECOMMENDATIONS Updated recommendations for the management of upper respiratory tract infections in South Africa* A J Brink, M F Cotton, C Feldman, H Finlayson, R L Friedman, R Green, W Hendson, M H Hockman, G Maartens, S A Madhi, G Reubenson, E J Silverbauer, I L Zietsman

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HEALTHCARE DELIVERY Description of an internal medicine outreach consultant appointment in western KwaZulu-Natal, South Africa, 2007 to mid-2014* R I Caldwell, B Gaede, C Aldous

PROFESSIONAL ADVERTISING Ladine van Heerden | Tel. 012 481 2121 Email: ladinev@samedical.org

357

EDITORIALS

359

Key to antimicrobial stewardship success: Surveillance by diagnostic microbiology laboratories W Lowman

361

Rheumatic fever and rheumatic heart disease in Africa A M Cilliers

Antibiotic administration in the critically ill – in need of intensive care! M Mer, J Lipman

RESEARCH 363

EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR

Community- versus healthcare-acquired bloodstream infections at Groote Schuur Hospital, Cape Town, South Africa R McKay, C Bamford

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ONLINE SUPPORT Gertrude Fani | Tel. 072 463 2159 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Adv. Y Lemmer, Prof. E L Mazwai, Dr M Mbokota, Mr G Steyn, Dr G Wolvaardt Production and distribution services supplied and managed by Media Outsourcing, a wholly owned subsidiary of Cape Media Corporation. Tel. 021 681 7000 ISSN 0256-9574 Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

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A prospective observational study of bacteraemia in adults admitted to an urban Mozambican hospital* M Preziosi, T F Zimba, K Lee, M Tomas, S Kinlin, C Nhatave-Paiva, R Bene, T Paunde, H Lopes, S Kalkhoff, V Prathap, K Akrami, E V Noormahomed, R T Schooley, E Aronoff-Spencer

375

Kaposi’s sarcoma, a South African perspective: Demographic and pathological features* R D Mohanlal, S Pather

379

Ocular surface squamous neoplasia among HIV-infected patients in Botswana* K T Steele, A P Steenhoff, G P Bisson, O Nkomazana

384

Rheumatic fever and rheumatic heart disease among children presenting to two referral hospitals in Harare, Zimbabwe* P Gapu, M Bwakura-Dangarembizi, G Kandawasvika, D Kao, C Bannerman, J Hakim, J A Matenga

389

Validation of a severity-of-illness score in patients with tuberculosis requiring intensive care unit admission* C F N Koegelenberg, C A Balkema, Y Jooste, J J Taljaard, E M Irusen

393

Outcomes of TB/HIV co-infected patients presenting with antituberculosis drug-induced liver injury* S Naidoo, D Evans, E Jong, K Mellet, R Berhanu

397

The poor children of the poor: Coping with diabetes control in a resource-poor setting* F P R de Villiers

400

The success of various management techniques used in South African children with type 1 diabetes mellitus* K L Kalweit, N Briers, S A S Olorunju

405

Self-monitoring of blood glucose measurements and glycaemic control in a managed care paediatric type 1 diabetes practice* B Davey, D G Segal

408

Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP* K R Antel, E Panieri, N Novitzky

CONTINUING MEDICAL EDUCATION

413

GUEST EDITORIAL Practical solutions to the antibiotic resistance crisis M Mendelson

414

REVIEW Role of antibiotic stewardship in extending the age of modern medicine M Mendelson

419

ARTICLES Diagnosis of bacterial infection* T H Boyles, S Wasserman

419

Optimising the administration of antibiotics in critically ill patients* G A Richards, I A Joubert, A J Brink

420

Twitter: A tool to improve healthcare professionals’ awareness of antimicrobial resistance and antimicrobial stewardship* D A Goff, D van den Bergh

421

Use of vaccines as a key antimicrobial stewardship strategy* A J Brink, G A Richards

421

Role of infection control in combating antibiotic resistance* A C Whitelaw

422

CASE REPORT A lady with a broken heart: Apical ballooning syndrome* C Rush, M Ntsekhe

*Full article available online only.

CONTENTS LISTED IN Index Medicus (Medline). Excerpta Medica (EMBASE). Biological Abstracts (BIOSIS). Science Citation Index (SciSearch). Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions R1 248.00 p.a. Foreign subscriptions R2 832.00 p.a. Single copies R104.00 local, R236.00 foreign Members of the Association receive the SAMJ only on request, as part of their membership benefit. Subscriptions: Tel. 012 481 2071 E-mail: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. Suites 9 & 10, Lonsdale Building, Gardner Way, Pinelands, 7405 Tel. 072 635 9825 E-mail: publishing@hmpg.co.za Website: www.samedical.org Please submit all letters and articles for publication online at www.samj.org.za © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works License. http://creativecommons.org/licenses/bync/3.0 Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAMJ. For more information on our plagiarism policy, please visit http://www.samj.org.za/ index.php/samj/about/editorialPolicies Printed by Creda Communications

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GUEST EDITORIAL

The World Health Organization Global Action Plan for antimicrobial resistance If our overuse and misuse of antibiotics is not halted now, about 10 million people will die annually from drug-resistant bacterial infections within 35 years.[1] The hammer blow will fall hardest on Africa and Asia, accounting for 4.1 and 4.7 million deaths, respectively, and the world’s economy will lose more than 7% of its gross domestic product (USD210 trillion) by 2050. These numbers should make people sit up, listen and change behaviour. But more often than not, it has to be personal to achieve this. So imagine that you or someone close to you is in need of a hip replacement to allow them to walk again, pain free. As Smith and Coast[2] point out, if no antibiotics were available to prevent a surgical site infection, which would happen 40 - 50% of the time without antibiotic prophylaxis, and 30% of those not receiving prophylaxis would die from the resulting surgical site infection, would you choose to have that operation, or allow someone you love to have it? The same questions could be asked for patients embarking on cancer chemotherapy with the risk of neutropenic sepsis, people requiring transplantation, or indeed any number of other treatments that we have come to take for granted that rely on antibiotics. This is not a futuristic scenario … it is being played out right here, right now, in South Africa (SA) and other countries across the globe. Decisions to withhold surgery based purely on the patient being colonised by pan-resistant bacteria are being made, and people are dying of untreatable infections in our hospitals and communities. Quite simply, our abuse of antibiotics is destroying modern medicine as we know it. Unless the international community can alter its path, we will lose the ‘miracle of antibiotics’. In May this year, the World Health Assembly debates the international response to this crisis, a Global Action Plan (GAP) on antimicrobial resistance (AMR).[3] Adoption of the GAP would see the culmination of a year of intense consultation between the tripartite alliance comprising the World Health Organization, the Food and Agriculture Organization and the World Organization for Animals, with governments and all relevant stakeholders. Its overall goal is to ensure the continuity of successful treatment and prevention of infectious diseases. At its heart lies access: access to the means of preventing infection in the first place, i.e. safe water, sanitation, and vaccines; and access to affordable, qualityassured antimicrobials, and the diagnostics needed to ensure that they are prescribed appropriately. Access, not excess! The draft GAP has five specific strategic objectives: (i) to improve awareness and understanding of AMR through effective communication, education and training; (ii) to strengthen knowledge and evidence base through surveillance and research; (iii) to reduce the incidence of infection through effective sanitation, hygiene, and infection prevention measures, which include vaccination and heightened infection control in health facilities; (iv) to optimise the use of antimicrobials in humans and animals; and (v) to develop the economic case for sustainable investment in new medicines, diagnostics, vaccines and other interventions for the needs of all countries. The GAP will provide a framework for national operational action plans that should be in place within 2 years of its endorsement. They should reflect engagement of the whole of society, be sustainable, incorporate incremental targets for implementation, and above all promote access, not excess, and prevention of infection first. The GAP applies equally to human and animal health. Approximately 80% of all antimicrobials used in countries such as the USA are used in animal feed,[4] and it is becoming increasingly clear that bacterial resistance in livestock is influencing infection and colonisation with the same bacteria in humans.[5,6]

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There is a lack of data concerning levels of resistance, particularly in low- and middle-income countries (LMICs), which is hampering progress.[7] International collaboration to support health systems strengthening, surveillance and reporting is written into the GAP, and is also a focus of parallel initiatives. Two of the work streams of the Global Health Security Agenda[8] (Prevent-1; Prevention of AMR, and Detect-1, National Laboratory Systems) directly support the GAP. Similarly, a Laboratory Twinning Initiative driven by the Commonwealth and Public Health England,[9] which seeks to strengthen public health laboratories in LMICs, has the potential to stimulate regional collaboration, as recently demonstrated by Caribbean countries.[10] In many respects, by having a definitive strategy and binding commitments signed by government departments and stakeholders, SA’s national plan is ahead of the curve (Department of Health, Anti microbial Resistance National Strategy Framework, 2014 - 2024 – to be placed on http://www.health.gov.za shortly). However, as one of the BRICS nations that are collectively responsible for three-quarters of the 36% increase in antibiotic prescribing that has occurred globally in the past 10 years,[11] it is time for us to put our own house in order. To save antibiotics and the future of modern medicine, we must adopt a quote by Mahatma Gandhi: ‘You must be the change you wish to see in the world.’ Each and every one of us, prescribers and recipients alike, need to understand the gravity of the situation, the fact that overuse and misuse of antibiotics is driving resistance, and put a stop to inappropriate prescribing. Marc Mendelson Division of Infectious Diseases and HIV Medicine, Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa, and Faculty of Health Sciences, University of Cape Town marc.mendelson@uct.ac.za Malebona Precious Matsoso National Department of Health, Pretoria, South Africa 1. Review on Antimicrobial Resistance. December 2014. http://amr-review.org (accessed 2 January 2015). 2. Smith R, Coast J. The true cost of antimicrobial resistance. BMJ 2013;346:f1493. [http://dx.doi.org/10.1136/bmj.f1493] 3. World Health Organization. Draft Global Action Plan for Antimicrobial Resistance. http://apps.who.int/gb/ebwha/ pdf_files/EB136/B136_20-en.pdf (accessed 13 March 2015). 4. United States Food and Drug Administration. Summary Report on Antimicrobials Sold or Distributed for Use in Food-producing Animals. Department of Health and Human Services, 2009. 5. Rinsky JL, Nadimpalli M, Wing S, et al. Livestock-associated methicillin and multidrug resistant Staphylococcus aureus is present among industrial, not antibiotic-free livestock operation workers in North Carolina. PLoS One 8(7):e67641. [http://dx.doi.org/10.1371/journal.pone.0067641] 6. Voss A, Loeffen F, Bakker J, Klassen C, Wulf M. Methicillin-resistant Staphylococcus aureus in pig farming. Emerg Infect Dis 2005;11(12):1965-1966. 7. World Health Organization. Antimicrobial resistance: Global report on surveillance, 2014. http://www. who.int/drugresistance/documents/surveillancereport/en/ (accessed 1 March 2015). 8. United States Department of Health and Human Services. The Global Health Security Agenda. http://www. globalhealth.gov/global-health-topics/global-health-security/ghsagenda.html (accessed 15 March 2015). 9. The Commonwealth. Commonwealth and Public Health England to strengthen public health laboratories. http://thecommonwealth.org/media/news/commonwealth-and-public-health-englandstrengthen-public-health-laboratories (accessed 6 March 2015). 10. Caribbean Public Health Agency. http://carpha.org/Media-Centre/CARPHA-Events/AMR-Workshop (accessed 17 March 2015). 11. Van Boeckel TP, Sandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: An analysis of national pharmaceutical sales data. Lancet Infect Dis 2014;14(8):742-750. [http://dx.doi.org/10.1016/ S1473-3099(14)70780-7]

S Afr Med J 2015;105(5):325. DOI:10.7196/SAMJ.9644

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EDITOR’S CHOICE

CME: Practical solutions to the antibiotic resistance crisis

Approximately 700 000 people die annually from antibiotic-resistant infections worldwide, and this will rise to 10 million per year by 2050 if our current overuse and misuse of antibiotics is not curtailed. Moreover, if antibiotics are lost, each and every medical procedure that relies on antibiotics to prevent or treat infection will be affected, changing the face of modern medicine as we know it. Far from being a futuristic fantasy, this is already being played out in South African hospitals, leading to closure of wards, cancellation of operating lists, and patients being sent home without operations that they need because of colonisation with multidrug- or pandrug-resistant bacteria. Welcome to the postantibiotic era! This edition of CME focuses on the practical measures that we can take to make antibiotic prescribing appropriate and what needs to be done to prevent infection in the first place, thereby negating their need. These interventions, along with heightened surveillance and reporting of resistance patterns and antibiotic usage, form the battle strategy to defend the efficacy of antibiotics. The antibiotic pipeline, which in terms of new classes of antibiotic has been dry for the past 28 years and for antibiotics against Gram-negative infections is not projected to yield a new antibiotic for the next 10 - 15 years, cannot be relied on to save the day. On the contrary, no antibiotic has lasted more than 16 years without resistance developing to it. The emphasis is therefore on preserving what we have through antibiotic stewardship, an intervention that ensures appropriate, optimal antibiotic prescribing, without doing harm to the patient.

SAMJ: Antimicrobial resistance

Ninety years ago, having just discovered penicillin, Alexander Fleming fretted about antimicrobial resistance (AMR). His concerns were well founded – last year, the World Health Organization (WHO) declared that AMR ‘threatens the achievements of modern medicine. A post-antibiotic era – in which common infections and minor injuries can kill – is a very real possibility for the 21st century.’[1] As will be appreciated, some clinical isolates of Mycobacterium tuberculosis, Neisseria gonorrhoeae, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, and species of Enterobacter, Salmonella and Shigella, are now resistant to most antibiotics.[2] Antibiotics are used around the world in livestock and fish farming, often in crowded,

Fig. 1. Deaths attributable to antimicrobial resistance every year by 2050.[4] unclean conditions, to facilitate faster growth and guarantee a cheap food supply. Resistant bacteria can be transferred to humans through contact with livestock, through the food chain, and through waste water from these operations, as well as via wastewater from hospitals and pharmaceutical plants.[3] By 2050, it is reckoned, over 4 million deaths in Africa will be attributable to AMR (Fig. 1).[4] Since 1987 there has been a relative ‘discovery void’, with only 12 new antibiotics approved since 2000.[5] Because the development of antibiotics, from discovery to human trials, is difficult and expensive, the current stock of antibiotics needs to be conserved and any new ones preserved. Last year the Glaxo CEO stated that pharma was unlikely to spend research funds on discovery of new antibiotics if they were to sit on the shelf for fear of development of AMR upon their use. Fortunately, ‘several small companies, seeking to fill the gap, have had new antibiotics approved, and the world’s fourth-largest drug company recently announced its return to the effort. However, major disincentives remain, including the difficulty of conducting large clinical trials to compare drugs in patients with antibioticresistant infections.’[2] In May this year, the World Health Assembly debates the international response to the AMR crisis, namely a Global Action Plan (GAP) for AMR.[6] Adoption of the GAP will follow a year of consultation between a tripartite alliance (comprising the WHO, the Food and Agriculture Organization (FAO) and the World Organization for Animals (OIE)) with governments and all relevant stakeholders. In this issue of SAMJ we emphasise the crisis of AMR, and seek to warn against administering antibiotics simply because we are unsure of a diagnosis or to satisfy patient

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demand, especially when the infection may be viral and not bacterial. This is why we are pleased to offer the Working Group of the Infectious Diseases Society of Southern Africa’s updated recommendations for the management of upper respiratory tract infections in South Africa,[7] and devote this month’s CME to antibiotic stewardship. In this regard, two editorials are key reading,[8,9] as is the research article by McKay et al.[10] on community- versus healthcareacquired bloodstream infections at Groote Schuur Hospital, Cape Town,[10] in which local surveillance data are used to support empirical choices of antimicrobials following assessment of whether the infection is community or healthcare acquired. As the Lowman editorial[8] confirms, ‘good ol’ cloxacillin (a far superior drug to vancomycin in the treatment of S. aureus) is still a perfectly suitable option in the right patient. Similarly, with a <5% ESBL rate for Enterobacteriaceae associated with community-acquired BSIs, the third- and fourth-generation cephalosporins still have an important role to play.’

Diabetes in children

For children with type 1 diabetes, certain fundamental behaviours are associated with better glycaemic control: frequency of blood glucose (BG) testing (requiring sufficient BG test strips), frequency of insulin injections, absence of insulin omission, adherence to meal planning, and patient-initiated dose adjustments, based on BG testing. Three articles[11-13] deal with management of diabetes in children and point out the sharp contrast between the status of patients in the public and private sectors. In the public sector children often cope without adult assistance and, lacking a sufficiency of BG test strips, are unable

EDITOR’S CHOICE

to undertake any more than rudimentary BG monitoring; in the private sector they receive education and dietary and exercise advice and have access to the most up-to-date management techniques. Davey and Segal[13] insist that restricted access to BG test strips – so often the case in the public sector – should not be allowed to handicap any patient’s diabetes control efforts.

The simple bread tag – a menace to society

Karro et al.[14] alert us to the dangers of the small rectangle of jagged plastic securing the bag containing a loaf of sliced bread. Three infants in whom a bread tag had lodged in the laryx or subglottis had to be rescued by bronchoscopy. Made of thin plastic, the tags tend to be radiolucent on X-ray and may even be missed on both flexible nasopharyngoscopy and direct laryngoscopy. The authors advise that until redesigned in a safer format, the tags should be removed from the bag of bread and stored out of reach of young children, or donated to Bread Tags for Wheelchairs – The Wheelchair Foundation,[15] which recycles them to buy wheelchairs.

Idiopathic thrombocytopenic purpura (ITP)

First-line treatment of ITP is with oral glucocorticoids, with splenectomy employed as second-line treatment. Newer drugs such as rituximab and thrombopoeitin agonists have brought the role of splenectomy into question, particularly as a lethal late complication may be postsplenectomy sepsis. Antel et al.[16] in their article ‘Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP’ confirm that splenectomy should remain the second-line treatment for ITP in most patients, including those with HIV-associated ITP.

Ocular surface squamous neoplasia

Emerging evidence suggests that ocular surface squamous neoplasia (OSSN) that requires surgery may be emerging as an AIDS-defining

illness in sub-Saharan Africa. A study of OSSN among HIV-infected patients in Botswana[17] shows that the annual incidence of OSSN increased significantly from 3 cases per 100 000 in 1998 to 7/100 000 in 2004. The authors report on some 500 patients, more than half of whom had AIDS (CD4 counts <200 cells/µL). JS 1. Antimicrobial resistance: Global report on surveillance 2014. www.who.int/iris/.../9789241564748_ eng.pdf (accessed 23 March 2015). 2. Nathan C, Cars O. Antibiotic resistance – problems, progress, and prospects. N Engl J Med 2014;371:1761-1763. [http://dx.doi.org/10.1056/NEJMp1408040] 3. The dangers of hubris on human health. http://reports.weforum.org/global-risks-2013/risk-case-1/ the-dangers-of-hubris-on-human-health (accessed 23 March 2015). 4. Review on Antimicrobial Resistance. http://amr-review.org/sites/default/files/AMR%20Review%20 Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20 nations_1.pdf (accessed 15 April 2015). 5. Frontier Pharma: Antibiotics – identifying and commercializing first-in-class innovation. http:// gbiresearch.com/report-store/market-reports/frontier-pharma/frontier-pharma-antibioticsidentifying-and-commercializing-firstinclass-innovation (accessed 23 March 2015). 6. Mendelson M, Matsoso P. The World Health Organization Global Action Plan for antimicrobial resistance. S Afr Med J 2015;105(5):325. [http://dx.doi.org/10.7196/SAMJ.9644] 7. Brink AJ, Cotton MF, Feldman C, et al. Updated recommendations for the management of upper respiratory tract infections in South Africa. S Afr Med J 2015;105(5):345-352. [http://dx.doi.org/10.7196/SAMJ.8716] 8. Lowman W. Key to antimicrobial stewardship success: Surveillance by diagnostic microbiology laboratories. S Afr Med J 2015;105(5):359-360. [http://dx.doi.org/10.7196/SAMJ.9615] 9. Mer M, Lipman J. Antibiotic administration in the critically ill – in need of intensive care! S Afr Med J 2015;105(5):357-359. [http://dx.doi.org/10.7196/SAMJ.9665] 10. McKay R, Bamford C. Community- versus healthcare-acquired bloodstream infections at Groote Schuur Hospital, Cape Town, South Africa. S Afr Med J 2015;105(5):363-369. [http://dx.doi. org/10.7196/SAMJ.8183] 11. De Villiers FPR. The poor children of the poor: Coping with diabetes control in a resource-poor setting. S Afr Med J 2015;105(5):397-399. [http://dx.doi.org/10.7196/SAMJ.8496] 12. Kalweit KL, Briers N, Olorunju SAS. The success of various management techniques used in South African children with type 1 diabetes mellitus. S Afr Med J 2015;105(5):400-404. [http://dx.doi. org/10.7196/SAMJ.9334] 13. Davey B, Segal DG. Self-monitoring of blood glucose measurements and glycaemic control in a managed care paediatric type 1 diabetes practice. S Afr Med J 2015;105(5):405-407. [http://dx.doi. org/10.7196/SAMJ.7686] 14. Karro R, Goussard P, Loock J, Gie R. The simple bread tag – a menace to society. S Afr Med J 2015;105(5):342-344. [http://dx.doi.org/10.7196/SAMJ.8996] 15. Bread Tags for Wheelchairs – the Wheelchair Foundation. http://wheelchairfoundation.org/blog/ breadtags-for-wheelchairs/ (accessed 16 April 2015). 16. Antel KR, Panieri E, Novitzky N. Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP. S Afr Med J 2015;105(5):408-412. [http://dx.doi.org/10.7196/SAMJ.8987] 17. Steele KT, Steenhoff AP, Bisson GP, Nkomazana O. Ocular surface squamous neoplasia among HIVinfected patients in Botswana. S Afr Med J 2015;105(5):379-383. [http://dx.doi.org/10.7196/SAMJ.8524]

This month in the SAMJ ... Marc Mendelson*†‡ is Professor of Infectious Diseases at University of Cape Town, President of the Federation of Infectious Diseases Societies of Southern Africa and co-chair of the South African Antibiotic Stewardship Programme. He has worked in partnership with the Department of Health to develop the South African Antimicrobial Resistance Strategic Framework and is now continuing the work towards its implementation. *Mendelson M, Matsoso P. The World Health Organization Global Action Plan for antimicrobial resistance. S Afr Med J 2015;105(5):325. [http://dx.doi.org/10.7196/SAMJ.9644] †

Mendelson M. Practical solutions to the antibiotic resistance crisis. S Afr Med J 2015;105(5):413. [http://dx.doi.org/10.7196/SAMJ.9642]

‡

Mendelson M. Role of antibiotic stewardship in extending the age of modern medicine. S Afr Med J 2015;105(5):414-418. [http://dx.doi.org/10.7196/SAMJ.9635]

Warren Lowman* is a clinical microbiologist with Vermaak and Partners Pathologists. He also holds an honorary lecturer’s post in the Department of Clinical Microbiology and Infectious Diseases at the University of the Witwatersrand and is a consultant clinical microbiologist at the Wits Donald Gordon Medical Centre. He is a current Exco member of the South African Society of Clinical Microbiology (SASCM) and chairs two subcommittees within SASCM. He serves in an advisory capacity to a number of other national clinical microbiology-related committees and is driven by the need to improve the clinical application and integration of microbiological diagnostic services in medical care. This guides his interests in hospital-related clinical microbiology, which span many facets from infection prevention and control to antimicrobial susceptibility testing to antimicrobial therapeutics. He believes that his passion for ‘bugs’ is dwarfed only by the scope and complexity of the microbial world, which ensures that there is never a dull moment. *Lowman W. Key to antimicrobial stewardship success: Surveillance by diagnostic microbiology laboratories. S Afr Med J 2015;105(5):359-360. [http://dx.doi.org/10.7196/SAMJ.9615]

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VIM-2 carbapenemase-producing Pseudomonas aeruginosa in a patient from Port Elizabeth, South Africa

To the Editor: We report on the emergence of a multidrug-resistant Pseudomonas aeruginosa isolate in a public hospital in Port Elizabeth, Eastern Cape Province, South Africa (SA), where the lack of anti biotic stewardship may have been a contributing factor. A 76-year-old woman was admitted in February 2014 following a non-pathological hip fracture. She received no perioperative antibiotic prophylaxis and 4 days after hip replacement surgery she was started on cloxacillin (500 mg intravenous infusion 8-hourly) with suspected wound sepsis. Dislocation of the prosthetic joint necessitated a joint revision, after which she was discharged despite suffering from postoperative hip pain and bleeding from the surgical site. The antibiotic susceptibility profiles of P. aeruginosa isolated from superficial swab specimens prior to discharge revealed susceptibility to colistin only and resistance to ampicillin, amoxicillin-clavulanic acid, piperacillin-tazobactam, cefixime, cefuroxime, cefoxitin, cefotaxime, ceftazidime, cefepime, ertapenem, nitrofurantoin, trimethoprim-sulfamethoxazole, imipinem, meropenem, tigecycline, amikacin, gentamycin and ciprofloxacin. The Verona integron-mediated (VIM-2) carbapenemase encoding blaVIM-2 gene was also detected in the P. aeruginosa isolate by polymerase chain reaction and gene sequencing. Following a deterioration of the surgical wounds, the patient was readmitted and started on cloxacillin (1 g intravenous infusion 6-hourly). Deep tissue specimens confirmed the P. aeruginosa prosthetic joint infection, and 3 months after the initial admission her prosthesis was removed and colistin (9 mU loading dose followed by 4.5 mU 12-hourly) and rifampicin were started. The colistin was stopped after 10 days because of nephrotoxicity. During the period of colistin administration, 7/17 doses were missed which contributed to the selection of colistin-resistant P. aeruginosa isolates. The patient’s condition deteriorated with other complications such as gas gangrene on the right foot, pulmonary oedema, renal dysfunction and cellulits of the left shin and she died after 19 weeks in hospital. The blaVIM-2 gene is located within the class 1 integron (In 56), which is also known to carry other genes that encode aminoglycoside-modifying enzymes.[1] P. aeruginosa VIM-2-producing isolates have caused nosocomial infections worldwide.[2] In SA, VIM has been found in Klebsiella spp. and Providencia spp. in the Gauteng region and P. aeruginosa in a Cape Town hospital, and Acinetobacter baumannii was reported in Pretoria.[3-5] To our knowledge this was the first report of the detection of a VIM-2-producing P. aeruginosa isolate in a patient from a Port Elizabeth public hospital. Sharlene Govender, Tinashe Masunda

Department of Biochemistry and Microbiology, Nelson Mandela Metropolitan University, Port Elizabeth, Eastern Cape, South Africa sharlene.govender@nmmu.ac.za

John Black

Department of Infectious Diseases, Livingstone Hospital, Port Elizabeth, Eastern Cape, South Africa, and Department of Medicine, University of Cape Town, Cape Town, South Africa 1. Strateva T, Yordanov D. Pseudomonas aeruginosa – a phenomenon of bacterial resistance. J Med Microbiol 2009;58(9):1133-1148. [http://dx.doi.org/10.1099/jmm.0.009142-0] 2. Touati M, Diene SM, Dekhil M, Djahoudi A, Racherache A, Rolain JM. Dissemination of a class I integron carrying VIM-2 carbapenemase in Pseudomonas aeruginosa clinical isolates from a hospital intensive care unit in Annaba, Algeria. Antimicrob Agents Chemother 2013;57(5):2426-2427. [http:// dx.doi.org/10.1128/AAC.00032-13] 3. Perovic O. Antimicrobial resistance: Update on carbapenemase-producing Enterobacteriaceae. Communicable Diseases Communiqué 2014;13(9). 4. Jacobson RK, Minenza N, Nicol M, Bamford C. VIM-2 metallo-β-lactamase-producing Pseudomonas aeruginosa causing an outbreak in South Africa. J Antimicrob Chemother 2012;67(7):1797-1798. [http://dx.doi.org/10.1093/jac/dks100] 5. Kock MM, Bellomo AN, Storm N, Ehlers MM. Prevalence of carbapenem resistance genes in Acinetobacter baumannii isolated from clinical specimens obtained from an academic hospital in South Africa. Southern African Journal of Infectious Diseases 2013;28(1):28-32.

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Paediatric chemoprophylaxis for child contacts of patients with drug-resistant tuberculosis: Are current guidelines effective in preventing disease?

To the Editor: The World Health Organization (WHO) estimates that there were 480 000 new cases of multidrug-resistant tuberculosis (MDR-TB) in 2013.[1] Alarmingly, 40% of MDR-TB cases for which second-line drug susceptibility test results were reported originated in South Africa (SA).[1] This has important implications in vulnerable populations, such as children, where infection with drug-resistant strains of TB are usually attributable to transmission rather than acquisition of resistance.[2] In high-burden settings, it is estimated that there are at least two child contacts who are either HIV-infected or younger than 5 years of age for every MDR-TB source case.[3,4] The growing spread of MDRTB, the protracted and toxic nature of current treatment regimens and the associated morbidity and mortality all emphasise the need for effective preventive therapy. There is limited evidence on optimal paediatric chemoprophylaxis to prevent disease in child contacts of MDR-TB cases, and the subject remains controversial. We have examined recently adapted paediatric chemoprophylactic guidelines and evaluated their effectiveness in the context of drug-resistant TB. We highlight a critical gap in research that is urgently needed to guide policy. The 2013 South African Guidelines for the Management of Tuberculosis in Children make the following recommendations, following exclusion of TB disease: (i) isoniazid preventive therapy (IPT; 10 - 15 mg/kg/day for 6 months) in all child contacts that are HIV infected or <5 years of age; (ii) rifampicin (15 mg/kg/day for 4 months) in isoniazid mono-resistant index cases; and (iii) high-dose isoniazid (15 - 20 mg/kg for 6 months) for neonates born to mothers with infectious drug-resistant TB.[5] While IPT significantly reduces the risk of drug-susceptible TB disease, and possibly TB strains with low-level isoniazid resistance, its applicability in the prevention of MDR-TB disease is questionable. Indeed, Kritski et al.[6] found that isoniazid had no protective effect in adult and child contacts of MDR-TB patients. In addition, Sneag et al.[7] described the failure of chemoprophylaxis with standard antituberculosis agents in five child contacts of MDR-TB patients. There are no randomised chemoprophylaxis clinical trials for child contacts of MDR-TB patients. A prospective study in the Federal States of Micronesia found that of 110 adult and child MDR-TB contacts, administered a tailored (based on the susceptibility pattern of the source case) 12-month, multidrug prophylactic regimen, none developed TB disease.[8] Two studies conducted in SA report similar findings. Schaaf et al. [3] prospectively followed up 105 child contacts of adult MDR-TB patients for 30 months. Only 5% (2/41) of children who received an individualised, multidrug prophylactic regimen developed TB disease compared with 20% (13/64) of children who were monitored without preventive therapy. Most recently, Seddon et al.[9] demonstrated that a three-drug prophylactic regimen consisting of high-dose isoniazid, ofloxacin and ethambutol for 6 months was both effective and well tolerated in child contacts of MDR-TB; only 3.2% of children (6/186) developed incident TB. Although there is a growing number of observational studies suggesting that MDR-TB chemoprophylaxis may be beneficial in MDR-TB-exposed children, there is still a lack of international consensus on the management of child contacts of MDR-TB patients. The WHO does not advocate the use of second-line agents as chemoprophylaxis for contacts of MDR-TB patients.[5] Likewise, the UK National Institute for Health and Clinical Excellence recommends close follow-up rather than intervention.[4] In contrast, several US institutions support the use of a regimen containing two drugs to which the source case is susceptible.[4] Such discordance is largely attributable to the potential adverse effects associated with antiMDR-TB drugs. Both Bamrah et al.[8] and Seddon et al.[9] have reported good drug tolerability, however, with only 0 - 5.5% of patients experiencing adverse effects necessitating treatment interruption.

May 2015, Vol. 105, No. 5

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Available in 10s and 20s References: 1. Burnett I, Schachtel B, Sanner K, Bey M, Grattan T, Littlejohn S. Onset of Analgesia of a Paracetamol Tablet Containing Sodium Bicarbonate: A Double-Blind, Placebo-Controlled Study in Adult Patients with Acute Sore Throat. Clin Ther 2006;28(9):1273-1278. 2. Grattan TJ, Burnett I, Sindet-Pedersen S, et al. PK/PD investigation of a novel paracetamol tablet containing sodium bicarbonate. J Clin Pharmacol 2004;44:1188. S0 GRAND-PA速 PARACETAMOL TABLETS. Reg. No. 36/2.7/0223. Each tablet contains Paracetamol 500 mg; Sodium Bicarbonate 630 mg; preserved with Potassium Sorbate 0.05% m/m; Sodium content 173 mg per tablet; Sugar free. For full prescribing information, refer to package insert. GlaxoSmithKline South Africa (Pty) Ltd. Reg no. 1948/03013 5/07. 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460, Fax:+27 (0)11 745 7000. For any product safety issues please contact Tel:+27 (0)11 745 6001.

CORRESPONDENCE

The lifetime risk of progression to active TB disease is 5 - 15% in people with latent infection.[10] Given that this figure rises sharply to 50% in children younger than 12 months,[11] and that inadequate chemotherapy may result in significant morbidity, the management of children with latent TB (including MDR-TB) is fundamental to TB control. In the absence of a randomised clinical trial, observational studies strongly indicate that appropriate MDR-TB chemoprophylaxis should be considered when TB disease has been excluded, there is significant exposure to a close drugresistant TB contact and the risk of disease progression is high. More research is urgently required to conclusively guide policy. Acknowledgments. NP and NN are supported by the Centre for the AIDS Programme of Research in South Africa (CAPRISA). Research reported in this publication was supported by the South African Medical Research Council.

Nesri Padayatchi, Naressa Naidu

South African Medical Research Council (SAMRC)/Centre for the AIDS Programme of Research in South Africa (CAPRISA) HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa nesri.padayatchi@caprisa.org 1. World Health Organization. Global Tuberculosis Report 2014. Geneva: World Health Organization, 2014. http://www.who.int/tb/publications/global_report/en/ (accessed 16 February 2015). 2. Seddon JA, Hesseling AC, Marais BJ, Jordaan A, Victor T, Schaaf HS. The evolving epidemic of drug-resistant tuberculosis among children in Cape Town, South Africa. Int J Tuberc Lung Dis 2012;16(7):928-933. [http://dx.doi.org/10.5588/ijtld.11.0679] 3. Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: A 30-month follow-up. Pediatrics 2002;109(5):765-771. [http://dx.doi.org/10.1542/peds.109.5.765] 4. Seddon JA, Godfrey-Faussett P, Hesseling AC, Gie RP, Beyers N, Schaaf HS. Management of children exposed to multidrug-resistant Mycobacterium tuberculosis. Lancet Infect Dis 2012;12(6):469-479. [http://dx.doi.org/10.1016/S1473-3099(11)70366-8] 5. Department of Health South Africa. Guidelines for the Managment of Tuberculosis in Children. South Africa: National Department of Health, 2013. http://www.kznhealth.gov.za/family/NationalChildhood-TB-Guidelines-2013-ZA.pdf (accessed 16 February 2015). 6. Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 1996;153(1):331-335. [http://dx.doi. org/10.1164/ajrccm.153.1.8542139] 7. Sneag DB, Schaaf HS, Cotton MF, Zar HJ. Failure of chemoprophylaxis with standard antituberculosis agents in child contacts of multidrug-resistant tuberculosis cases. Pediatr Infect Dis J 2007;26(12):11421146. [http://dx.doi.org/10.1097/INF.0b013e31814523e4] 8. Bamrah S, Brostrom R, Setlik L, Fred D, Kawamura M, Mase S. An ounce of prevention: Treating MDR-TB contacts in a resource limited setting. Presented at the International Union of Tuberculosis and Lung Disease Conference, 11-15 November 2010, Berlin, Germany. 9. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: A prospective cohort study. Clin Infect Dis 2013;57(12):1676-1684. [http://dx.doi.org/10.1093/cid/cit655] 10. Mandell GL, Bennet JL, Dolin R. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000. 11. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: A critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8(4):392-402.

S Afr Med J 2015;105(4):328-329. DOI:10.7196/SAMJ.9500

Tracking antenatal HIV prevalence in South Africa

Acknowledgement. This work was supported by funds from the South African Medical Research Council.

Palesa Nkomo

Medical Research Council Health Systems Research Unit, Pretoria, South Africa palesa.nkomo@mrc.ac.za

To the Editor: South Africa (SA) has been conducting annual crosssectional anonymous unlinked antenatal HIV seroprevalence surveys in sentinel sites (ANCHSS) for more than 20 years.[1] These sites are randomly selected using probability proportional to size sampling (PPS) methods as this combines a random approach with a bias towards larger clinics, resulting in a self-weighted sample.[1] Firsttime antenatal attendees are enrolled into the ANCHSS, and blood for unlinked anonymous antenatal HIV testing (UAT) is drawn at the same time as first antenatal booking bloods. Without refuting the usefulness of ANCHSS for tracking the antenatal HIV epidemic, five main concerns have recently been raised:[2] (i) high cost of ANCHSS implementation; (ii) high cost of duplicate HIV testing – every pregnant woman is tested anonymously for HIV infection using laboratory enzyme-linked immunoassay tests and is also routinely tested for HIV infection using clinic-based rapid tests; (iii) timing – the survey mainly measures HIV prevalence once during pregnancy; (iv) ethical – anonymous results are not returned to pregnant women; and (v)

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representativeness – sentinel sites may not be representative of the entire pregnant population. Consequently new methods for antenatal HIV surveillance need investigation. Since the inception of the SA programme to prevent HIV transmission from mother to child (PMTCT), more than 95% of the healthcare system integrates PMTCT HIV testing into routine antenatal care.[3,4] Furthermore, the district health information system (DHIS), which gathers aggregate data from each facility in each district, has been updated to include routine data elements on HIV testing and HIV test results in general and among pregnant women. Data on second tests during pregnancy have also recently been added to the DHIS. A growing consensus has posited that, in the context of antiretroviral therapy, PMTCT expansion and DHIS strengthening, alternative surveillance methods and data sources are increasingly available and should be explored to address the concerns associated with UAT-based ANCHSS.[2] The World Health Organization developed guidelines for countries to evaluate the utility of routine data from PMTCT programmes ‘for HIV sentinel surveillance among pregnant women’ as outlined above.[2] These guidelines recognise the denominator and double counting problems with DHIS data, which require rectification.[5] This then begs the following questions: (i) should time and energy be invested in studying SA DHIS data and comparing these with SA ANCHSS data? (ii) should the quality of routine antenatal HIV testing procedures be assessed? and (iii) should SA ANCHSS be stopped? We answer ‘yes’ to the first two questions, as strong routine monitoring systems are critical for management and planning. In addressing the third question, we believe that if routine data are used to monitor antenatal HIV prevalence, intermittent, periodic ANCHSS may still be needed to corroborate results. However, ANCHSS should be changed to linked, named testing to circumvent duplication and ethical issues. As our previous national work has shown that >95% of mothers accept named testing, uptake of antenatal HIV testing would not be significantly reduced by named, linked testing.[6]

Ameena Goga

Medical Research Council Health Systems Research Unit, Pretoria, South Africa, and Department of Paediatrics, University of Pretoria 1. National Department of Health, South Africa. The 2012 National Antenatal Sentinel HIV & Herpes Simplex Type-2 Prevalence Survey in South Africa. http://www.health-e.org.za/wp-content/ uploads/2014/05/ASHIVHerp_Report2014_22May2014.pdf (accessed 8 April 2015). 2. World Health Organization. Guidelines for Assessing the Utility of Data from Prevention of MotherTo-Child Transmission (PMTCT) Programmes for HIV Sentinel Surveillance Among Pregnant Women. http://apps.who.int/iris/bitstream/10665/85512/1/9789241505611_eng.pdf (accessed 8 April 2015). 3. Department of Health, South Africa. National Consolidated Guidelines for the Prevention of MotherTo-Child Transmission of HIV (PMTCT) and the Management of HIV in Children, Adolescents and Adults. http://www.sahivsoc.org/upload/documents/HIV%20guidelines%20_Jan%202015.pdf (accessed 8 April 2015). 4. Woldesenbet S, Goga A, Jackson D, et al. Mother-To-Child Transmission of HIV (PMTCT). Evaluation of the Early Infant Diagnosis Service in Primary Health Care Facilities in South Africa: Report on Results of Situational Assessment. http://www.mrc.ac.za/healthsystems/SituationalAssessment2012. pdf (accessed 8 April 2015). 5. Health Systems Trust. Health Systems Barometer, 2013/2014. http://www.health-e.org.za/wp-content/ uploads/2014/10/DHB_2013-14.pdf (accessed 8 April 2015) 6. Goga AE, Dinh TH, Jackson DJ for the SAPMTCTE study group. Early (4-8 Weeks Post-delivery) Population-level Effectiveness of WHO PMTCT Option A, South Africa, 2011. South African Medical Research Council, National Department of Health of South Africa and PEPFAR/US Centers for Disease Control and Prevention. 2013. http://www.mrc.ac.za/healthsystems/SAPMTCTE2011.pdf (accessed 8 April 2015).

S Afr Med J 2015;105(4):329. DOI:10.7196/SAMJ.9472

May 2015, Vol. 105, No. 5

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Outcomes in treatment with darunavir/ritonavir in ARTexperienced paediatric patients

To the Editor: Increasing development of resistant mutations to first- and second-line antiretroviral (ART) regimens among children is a matter of concern, as limited third-line paediatric ART preparations are available in the public sector.[1,2] There are various explanations for this increase,[3] including drug interactions leading to reduced bioavailability as seen in tuberculosis (TB) co-infection.[4,5] In children <3 years of age, a first-line ART regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) with the protease inhibitor (PI) lopinavir, boosted with ritonavir (LPV/r), is recommended.[6,7] Many children may have resistance mutations to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) because of prior exposure to nevirapine during prophylaxis for prevention of mother-to-child transmission.[8,9] In a review of children failing first-line ART in resource-poor countries, at least 54% had major PI mutations.[2] It is therefore imperative for paediatric formulations of new antiretrovirals to be developed and be accessible for these children.[10,11] Darunavir, a PI, boosted with ritonavir (DRV/r), has been shown to be effective in viral suppression in PI-experienced patients and has a low side-effect profile.[12] The drug has been tested clinically in South Africa (SA) and found to be safe and effective in PI-experienced paediatric participants.[13,14] DRV has since been registered for paediatric use in SA in children aged ≥3 years,[14] but is available only in the private sector and at the discretion of the paediatric third-line committee in the public sector. We conducted a retrospective chart analysis of the outcomes of patients receiving DRV/r at Harriet Shezi Clinic (HSC), a paediatric ART clinic based at Chris Hani Baragwanath Hospital, Johannesburg, SA. Five of the 1 128 children currently on follow-up at HSC received DRV/r as part of their antiretroviral regimen from September 2010 to March 2014. DRV was obtained for these children from the manufacturer through a compassionate use programme with the permission of the SA Medicines Control Council (MCC). Permission to study the children was obtained from the bioethics committee of the University of the Witwatersrand (M130760) in 2013. Informed consent was obtained from the caregivers for use of DRV, as it was not registered in the country at the time. Sociodemographic, laboratory, anthropometric and clinical information for the five patients was extracted from the clinic database. Standard-of-care viral loads and CD4 counts conducted by the National Health Laboratory Service were assessed. Genotype resistance testing was done by the Division of Virology, Stellenbosch University, using the Stanford University HIV Drug Resistance Database for interpretation of the resistance tests. The median age of initiating first-line PI-based ART in the five children was 3.8 months (range 1.4 - 57.7), and all had World Health Organization stage 3 HIV infection or higher. The median time to virological failure after first-line ART initiation was 30.4 months (range 15.4 - 50.6). All had at least three major PI mutations, V82A, M46L and I54V, which reduced susceptibility to LPV/r. Notably, four of the five patients were on concomitant TB treatment and therefore received double-dose LPV/r; the fifth child was on suboptimal ART for socioeconomic reasons. The median age at DRV/r initiation was 50.3 months (range 38.5 106.7). The baseline median weight-for-age z-score (WAZ) was –0.79 (range –0.65 - –0.94), and the median height-for-age z-score (HAZ) was –0.88 (range –0.82 - –0.97). WAZ and HAZ scores remained constant over 24 months.

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Median time to virological suppression on DRV/r was 6 months (range 3 - 12). There were viral rebounds in three of the five patients, but all remained suppressed at 24 months. CD4 counts remained constant. There was no hospitalisation or any significant morbidity on DRV/r. We found that it was feasible to use DRV/r in a public healthcare setting and achieve virological suppression by 24 weeks. Despite viral rebounds the children managed to resuppress and maintain suppression at 24 months of follow-up, with adequate adherence counselling. These findings are similar to the ARIEL study, which included children with a similar drug resistance profile;[13] virological suppression was observed in 56% of the ARIEL participants at 24 weeks and in 81% by week 48.[14] While lipid profiles were not monitored, which is one of our limitations, there were no major safety concerns. We recommend that paediatric preparations of DRV be readily available at tertiary paediatric healthcare facilities so that children failing an LPV/r-based regimen can be treated at the discretion of the treating physician and without resort to a third-line committee. We would like to highlight the importance of adequate super-boosting of LPV/r in children co-treated for TB to ensure that virological suppression is maintained during co-treatment. Acknowledgements. We thank the children, their caregivers and the staff of HSC. We also thank Hermien Gous and Angela Oosthuizen for organising the darunavir and for adherence counselling, Gert van Zyl and his laboratory at Stellenbosch University for genotyping, Shobna Sawry for Therapy Edge access, and Merleesa Govender for the MCC applications. Disclosure statement. The authors declare no conflicts of interest. Darunavir was obtained from Janssen from their compassionate use programme.

Gurpreet Kindra

Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa gurpreetkindra@gmail.com

Nosisa Sipambo

Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa, and Chris Hani Baragwanath Hospital, Johannesburg

Harry Moultrie

Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa

Lee Fairlie

Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa, and Chris Hani Baragwanath Hospital, Johannesburg 1. Taylor BS, Hunt G, Abrams EJ, et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Res Hum Retroviruses 2011;27(9):945-956. [http://dx.doi.org/10.1089/AID.2010.0205] 2. Sigaloff KC, Calis JC, Geelen SP, van Vugt M, de Wit TF. HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: A systematic review. Lancet Infect Dis 2011;11(10):769-779. [http://dx.doi.org/10.1016/S14733099(11)70141-4] 3. Arage G, Tessema GA, Kassa H. Adherence to antiretroviral therapy and its associated factors among children at South Wollo Zone hospitals, Northeast Ethiopia: A cross-sectional study. BMC Public Health 2014;14(1):365. [http://dx.doi.org/10.1186/1471-2458-14-365. 4. McIlleron H, Ren Y, Nuttall J, et al. Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther 2011;16(3):417421. [http://dx.doi.org/10.3851/IMP1757] 5. Frohoff C, Moodley M, Fairlie L, et al. Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment. PLoS One 2011;6(2):e17273. [http:// dx.doi.org/10.1371/journal.pone.0017273] 6. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Recommendations for a public health approach: 2010 revision. http://www.who.int/hiv/pub/ paediatric/infants2010/en/ (accessed 28 May 2014). 7. Department of Health, South Africa. The South African Antiretroviral Treatment Guidelines 2013. http://www.sahivsoc.org/upload/documents/2013%20ART%20Treatment%20Guidelines%20 Final%2025%20March%202013%20corrected.pdf (accessed 28 May 2014). 8. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med 2010;363(16):1510-1520. [http://dx.doi.org/10.1056/NEJMoa1000931]

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9. Hunt GM, Coovadia A, Abrams EJ, et al. HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine. AIDS 2011;25(12):1461-1469. [http://dx.doi. org/10.1097/QAD.0b013e3283492180]. 10. Eley BS, Meyers T. Antiretroviral therapy for children in resource-limited settings: Current regimens and the role of newer agents. Paediatr Drugs 2011;13(5):303-316. [http://dx.doi.org/10.2165/11593330000000000-00000] 11. Boyd MA, Hill AM. Clinical management of treatment-experienced, HIV/AIDS patients in the combination antiretroviral therapy era. Pharmacoeconomics 2010;28(Suppl 1):17-34. [http://dx.doi. org/10.2165/11587420-000000000-00000] 12. McKeage K, Scott LJ. Darunavir: in treatment-experienced pediatric patients with HIV-1 infection. Paediatr Drugs 2010;12(2):123-131. [http://dx.doi.org/10.2165/11204530-000000000-00000] 13. Violari A, Bologna R, Kimutai R, et al. ARIEL: 24-week safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients aged 3 to <6 years. http://www.hivandhepatitis.com/2011_ conference/croi2011/posters/ARIEL.pdf (accessed 28 May 2014). 14. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in treatmentexperienced pediatric patients aged 3 to <6 years: Week 48 analysis of the ARIEL trial. Presented at the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, Malaysia, 30 June - 3 July 2013. Abstract MOAB0102. http://pag.ias2013.org/abstracts.aspx?aid=1116 (accessed 28 May 2014).

S Afr Med J 2015;105(4):330-331. DOI:10.7196/SAMJ.9211

Better menstrual management options for adolescents needed in South Africa: What about the menstrual cup?

To the Editor: Providing forms of menstrual management to women and girls in need has been on the South African (SA) government’s agenda for the past 4 years.[1] A sanitary pads campaign launched in 2014 reported that almost nine million SA girls aged 13 - 19 miss time at school because of lack of sanitary products.[2] In 2010, the World Health Organization reported that the lack of school toilets with privacy and facilities for menstrual hygiene contributes to sporadic attendance and drop-out among young women in Africa.[3] Several other SA initiatives have focused on disposable sanitary towels, as the environmental impact of menstrual waste on sewage systems is considerable.[4] Menstrual pads, tampons and rags routinely block pipes and joints, which is costly, takes time to resolve and imposes health hazards.[4] The menstrual cup (MCup) is a non-absorbent reusable barrier cup that collects menstrual blood, is typically made of flexible medical-grade silicone, and has been approved by the US Food and Drug Administration. Unlike tampons, there have been no reports of toxic shock syndrome or other infectious sequelae resulting from use. Many studies on MCups indicate that women found the device acceptable.[5-11] To date only one of these studies has been conducted in Africa.[11] This recent randomised cross-over trial conducted in KwaZulu-Natal Province, SA, compared the acceptability and performance of the MPower MCup (Fig. 1) among 110 women

with those of sanitary towels or tampons. In comparison with the menstrual hygiene product used most often, the MCup was rated better in respect of comfort, quality, menstrual blood collection capacity, appearance and preference. Participating students and working women were comfortable using the MCup in their place of work/study. Owing to the high-volume capacity of MCups, many of the women preferred to wait until they got home to wash their cups, as the MCup can be emptied and wiped out during the day and washed later. Although MCups are made in SA (Fig 1.), and can be ordered on the internet or through a limited number of pharmacies, they have not been provided or mentioned in most of the SA menstrual management campaigns to date. Like many other MCups the SA MPower MCup comes in two sizes, the smaller size being recommended for adolescents. The cost of tampons for one woman per year has been calculated as approximately the same as one MCup at current SA retail prices.[12] In SA the MPower MCup retails for R265.00, while a box of 32 tampons costs approximately R40.00. As the lifespan of one MCup is typically 5 years, MCup use would represent a considerable cost saving over time. Mags Beksinska

Jennifer Smit

Ross Greener, Virginia Maphumulo, Zonke Mabude

Maternal, Adolescent and Child Health Research, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Durban, South Africa 1. Matlala A, Mabuza K. Zuma promises free towels for women. The Sowetan, 10 January 2011. http:// www.sowetanlive.co.za/news/2011/01/10/zuma-promises-free-towels-for-women (accessed 3 February 2014). 2. South African Government News Agency. Campaign brings sanitary dignity for school girls. SANews. gov.za, 18 September 2014. http://www.sanews.gov.za/south-africa/campaign-brings-sanitary-dignityschool-girls (accessed 14 November 2014). 3. Brocklehurst C, Bartram J. Swimming upstream: Why sanitation, hygiene and water are so important to mothers and their daughters. Bull World Health Organ 2010;88(7):482-482. [http://dx.doi. org/10.2471/BLT.10.080077] 4. Marni S, Kjellén M, Pensulo C. Girls’ and women’s unmet needs for menstrual hygiene management (MHM): The interactions between MHM and sanitation systems in low-income countries. Journal of Water, Sanitation and Hygiene for Development 2013;3(3):283-297. [http://dx.doi.org/10.2166/ washdev.2013.101] 5. Liswood R. Internal menstrual protection: Use of a safe and sanitary menstrual cup. Obstet Gynecol 1959;13(5):539-543. 6. Karnaky KJ. Internal menstrual protection with the rubber menstrual cup. Obstet Gynecol 1962;19(5):688-691. 7. Pena EF. Menstrual protection: Advantages of the menstrual cup. Obstet Gynecol 1962;19(5):684-687. 8. Parker J, Bushell RW, Behrman SJ. Hygienic control of menorrhagia: Use of rubber menstrual cup. Int J Fertil 1964;9:619-621. 9. Cheng M, Kung R, Hannah M, Wilansky D, Shime J. Menses cup evaluation study. Fertil Steril 1995;64(3):661-663. 10. Stewart K, Greer R, Powell M. Women’s experience of using the Mooncup. J Obstet Gynaecol 2010;30(3):285-287. [http://dx.doi.org/10.3109/01443610903572117] 11. Beksinska M, Smit J, Greener R, et al. Acceptability and performance of the menstrual cup in South Africa: A randomized cross-over trial comparing the menstrual cup to tampons or sanitary pads. J Women’s Health 2015;24(2):151-158. [http://dx.doi.org/10.1089/jwh.2014.5021] 12. Howard C, Rose CL, Trouton K, et al. FLOW (finding lasting options for women): Multicentre randomized controlled trial comparing tampons with menstrual cups. Can Fam Physician 2011;57(6):e208-215.

S Afr Med J 2015;105(4):331. DOI:10.7196/SAMJ.9205

Fig. 1. The MPower cup.

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CORRESPONDENCE

Masterly inactivity: A forgotten precept

To the Editor: When I was a medical student at the University of Cape Town, South Africa, in the mid-1950s a wise old professor introduced me to the treatment concept of masterly inactivity. Sometimes just waiting and seemingly doing nothing is the favoured therapeutic modality. Over a lifetime in medicine, I have seen many occasions when this approach was successful, and other times when physicians, including myself, have broken this rule with unfortunate and antitherapeutic results. For many years, I practised inpatient and outpatient liaison psychiatry. I used to joke, perhaps a little cynically and certainly with exaggeration, that I got most of my therapeutic successes by stopping rather than prescribing psychotropic medications. This happened especially when a patient had been prescribed two or more psychotropic drugs the combined adverse effects of which were more unpleasant than the symptoms of the original illness. For the past ten years I have worked in the income security programmes of the federal government of Canada, appraising the applications of Canadians who apply for disability pensions and deciding on their eligibility. This task involves a detailed review of medical reports and files that often extend over many years. It provides a unique chronological perspective of each patient’s long-term medical history. I must admit that on many occasions I shake my head sadly when I see a physician ordering yet another magnetic resonance imaging scan or carrying out yet another medical procedure that will not have a meaningful or useful outcome. Often this approach will reinforce a patient’s illness behaviour and cost overstretched healthcare systems additional needless dollars. I believe that our patients and our society pay a huge price for this shortsighted approach. Why do doctors do this? There are several explanations. We have all been taught to practise defensive medicine. If you don’t carry out a test or do a procedure, and the patient sues, you could be in legal trouble. Other than to follow sound clinical judgement and evidencebased guidelines, there is no easy answer to this society-imposed measure. In addition, many patients demand that something, anything, be done to ease their complaint. They believe that action, any action, is better than waiting for the body’s built-in remedies to do their bit. Managing the exigent patient requires tact, information and expertise. Perhaps this is where the word ‘masterly’ registers. ‘Inactivity’ does not mean doing nothing. Our bodies have many natural resources for coping with and counteracting disease processes,

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both physiological and psychological. Waiting can promote these healing resources; by waiting, the doctor becomes a collaborator rather than an adversary competing with the body’s natural defences. This is particularly the case with use of antibiotics. Waiting a few days gives time for the immunological defences to be provoked that may make antibiotics unnecessary. These ideas must be conveyed to the patient in a way that he or she can understand. The fear of missing a treatable organic disease is ingrained during our training and may be another explanation as to why we have forgotten the masterly inactivity precept. To counteract this attitude, we need an equally ingrained fear of perpetuating illness behaviour by ordering unnecessary tests or carrying out poorly indicated medical procedures. This is not to say that an investigation or a test should not be done when there is a clear indication, or when the likelihood of discovering useful information or achieving success is high, or the need is urgent. To delay the diagnosis of breast cancer, for example, is not going to improve the patient’s prospects. The Choosing Wisely Canada initiative (www.choosingwiselycanada.org) fits with this approach to patient management. It makes specific recommendations about the use of antibiotics for respiratory illness in children, for example, or about the use of imaging tests in back pain. In my personal life, I have noticed how some of my medical problems, such as pain from my arthritic knees, improve if I wait a few days or weeks. I was actually able to cancel an arthroscopy that had been recommended by my physician. Perhaps, after all, there is an upside to having long waiting times for certain procedures. Physicians are counselled to ‘First do no harm’. In our actioninspired society I sometimes wonder if we have not thrown out the ‘nature healing’ baby with the ‘do something’ bath water. Acknowledgements. Reprinted from F Mai, ‘Masterly inactivity: a forgotten precept’, Canadian Medical Association Journal 2014;186(4):312. ©Canadian Medical Association 2014. This work is protected by copyright and the making of this copy was with the permission of the Canadian Medical Association Journal (www.cmaj.ca). Any alteration of its content or further copying in any form whatsoever is strictly prohibited unless otherwise permitted by law. The Royalty Fee has been waived.

François Mai

Adjunct Professor, Department of Psychiatry, Faculty of Medicine, Queen’s University, Kingston, Canada maifse@gmail.com S Afr Med J 2015;105(4):332. DOI:10.7196/SAMJ.9303

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Lifesaving water quality solution ‘ignored’ A filtration unit that can deliver cheap, safe drinking water to 200 people for 3 years, giving dysfunctional rural municipalities more than enough time to fix broken pipes and polluted water sources and/or increase their maintenance capacity, is being ignored by South Africa (SA)’s health officials. With infants in poor rural communities at daily risk of diarrhoea and even cholera – as epitomised by the 80 deaths of babies from a malfunctioning and decaying water reticulation system in the former Ukahlamba District of Barkly East in April 2008[1] – the potential for a repeat occurrence remains high. A recent national report commissioned by the Department of Water and Sanitation (DWS) concludes that poor operation and maintenance of the water supply, treatment and reticulation infrastructure is resulting in ‘significant losses’ of water (loss of life omitted), which if corrected can reverse current water shortages. The May 2013 strategic overview by the then Department of Water Affairs (DWA) found that there was no surplus water in SA, that available water resources were at their limit, and that climate change would worsen the situation. Poorly maintained reticulation systems aside, many rural communities rely on untreated raw water from rivers, springs or boreholes, with many of these sources (particularly but not only in the Eastern Cape) contaminated as a result of lack of proper land management and ‘source protection’. In a survey carried out after the Duzi Canoe Marathon in 2012, 40% of the field was found to have gone down with chronic diarrhoea. Tests showed that the levels of human faecal contamination of the Umsunduzi River were 115 000 parts per 100 mL (the internationally accepted count being 150/100 mL). The Umgungundlovu District through which the Umsunduzi runs has the highest diarrhoea rate in the country. A DWS study, ‘Support to the implementation and maintenance of reconciliation strategies for towns in the southern planning region’ by one of the country’s leading strategic resource planning and management consultancies, Umvoto Africa, has shown that most of the water supply problems and restrictions experienced in many towns and villages in the Eastern and Western Cape could be avoided by proper management of existing schemes. A shortage of appropriately qualified engineers correlates closely with municipalities with the

Yonele Jamta, age 4, who lost her 22-month-old brother Siviwe, and Pamela Fuma, age 2, playing at one of Barkly East’s formerly deadly communal taps in 2008. Photo: Nigel Louw, Daily Dispatch.

poorest water safety and supply and sanitation records.

Globally leading technology on hand

The applicable LifeStraw technology, available for the past 9 years and winner of ten top international awards for excellence in design and technology (including Time Magazine’s Invention of the Year, 2005, and Popular Science’s A Water Purifier for the Masses), outperforms any similar device on the SA market, exceeding the World Health Organization’s criteria of the ‘highly protective’ category for microbiological performance. The community model uses two 25-litre chambers, the upper of which can be filled with river, puddle, rain or even turbid surface water. A lever on the lower chamber enables expulsion of all the filtered dirty water, at least once a week. Already the prevalence of infant and child diarrhoea at one of four modest NGO-sponsored projects, a crèche in Masiphumelele township in Kommetjie, Cape Town, serving 106 small children (34 HIV/AIDS-infected), has dropped by 100%. Only one of the crèche babies was still suffering from diarrhoea this March, 2 months after implementation. Lifestraws are also in use at the Ikamva Labantu Crèche in Khayelitsha (Cape Town), in Hluhluwe (northern KwaZulu-Natal) and in the Makadesh squatter community in Pretoria. The company is marketed in SA as

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Aqua4Life. CEO Nico Germishuizen, who holds the southern African distribution rights for LifeStraw (manufactured by Swiss-based global health solutions company Vestergaard, which also produces the popular long-lasting insecticidal PermaNet malaria bed nets), said that he was still awaiting data on the impact of the devices in the other three areas.

Kenya’s success story

In Kenya’s Western Province, where Vester gaard has been operating for 6 years, family (smaller) water purifiers were provided to 877 505 households in 2011 alone, with ongoing provision and back-up safe water education and training in 300 schools. The impact on providing safe water to 125 000 schoolchildren (data not yet collated and interpreted) hardly needs much imagination. Germishuizen told Izindaba that a comm unity unit costs about ZAR5 000, which works out at about 5c per litre over 3 years, after which the unit is replaced by the funding entity. Ironically, the introduction of the product to the local market is a spin-off of his environmental health and safety business losing mining contracts in the downscaling aftermath of the Marikana mine police killings. ‘I was looking for another income stream and came across this company looking for new operators in this terrain,’ he says. His company donates one unit to provide a child with safe, free drinking water for a year for every unit sold, ‘banks’ this ‘unit’, and then

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distributes a community water purifier to preidentified high-risk communities, a result of Vestergaard’s ‘Follow the Litres’ project.

The cost of implementing charity projects

Germishuizen is sitting with an excess of units in stock because, as he puts it, the appetite for community social investment in SA is on the wane. ‘We know of several projects that are available, but people at the helm of charities are seeing millions spent with very little benefit to their causes.’ He puts this down to the ‘8020 syndrome’, where 80% of donations go to overheads and 20% trickle down to project implementation. He’s finding his work cut out to convince NGOs (and governments and local authorities) that the equation for his service is exactly the other way around, because of the efficacy and robustness of the product. His company is BEE compliant (partnering with a Department of Trade and Industry-sponsored empowerment outfit that supplies only paper soap to schools and communities and desperately needed a more product-legitimate partner). However Aqua4Life remains on ‘the outer fringes’ and currently relies on the private sector to ‘do what we need to do’. ‘From time to time we get international funding, which helps a lot,’ Germishuizen said. He described his franchise and parent company as a ‘profitfor-good outfit in the humanitarian channel’, adding: ‘Yes, at the end of the day we’re a business, but we do good.’ Their main partner in the fight for clean water and sanitation is Rotary International Club of Sea Point’s Dr Tony Davidson, who helps identify projects and implementation strategies, with back-up by top Vestergaard executives. Germishuizen said it was ‘in the nature of things’ that babies had to die before publicity

was generated and action taken (remedial action after the Eastern Cape Ukahlamba tragedy took months), adding that while provinces and municipalities ‘get their act together, we can supply a solution that can buy them 9 - 15 years of time’. Asked about competing products of similar quality in SA, he said there were none. Seemingly similar local products all worked on carbon-activated filters that ‘only take out the rancid taste of chlorine or fluoride and some other stuff, but not the stuff that makes you sick’. His filters, of which there are varying sizes ranging from a backpacking flask to the community unit, were SA Bureau of Standards approved. He challenged any local company to test their product against the LifeStraw units for efficacy and safety.

In a survey carried out after the Duzi Canoe Marathon in 2012, 40% of the field was found to have gone down with chronic diarrhoea. Tests showed that the levels of human faecal contamination of the Umsunduzi River were 115 000 parts per 100 mL (the internationally accepted count being 150/100 mL). The Umgungundlovu district through which the Umsunduzi runs has the highest diarrhoea rate in the country.

Blue Drop success exaggerated

The much-touted DWA Blue Drop incentivebased water quality regulation strategy[2] was introduced in 2008 after alarming reports

found 68% of municipalities unable to say whether or not they met drinking water quality standards, with supplies to 37% of households interrupted for at least one day (2003 data).[2] While unique in the international regulatory domain, the private sector however claims that the strategy is being subject to a strong government ‘spin element’, with water quality actually deteriorating nationally. In 2009, 23 water supply systems obtained the Blue Drop certification (which includes compliance with water quality standards and verifying the existence of a water safety plan). In 2010, nine lost it and 24 gained it for the first time, bringing the total to 38 (less than 5% of the 787 systems assessed). The three top performers were Johannesburg, Cape Town and the small rural town of Bitou (in the Plettenberg Bay area of the Western Cape). Eutrophication (nutrient enrichment of water, often by farm fertiliser run-off, which causes algal blooms) is cited as a ‘growing concern’, with about one-third of the total volume of water held in strategic storage approaching the point where it is no longer ‘fit for purpose’ without significant and costly management intervention. Much remains to be done to fulfil people’s constitutional right to ‘sufficient food and water’. An obstinate refusal to look to the private sector for what would be a costeffective medium- to long-term solution will almost certainly aggravate matters. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(5):333-334. DOI:10.7196/SAMJ.9684 1. Bateman C. Incompetent maintenance/inept response; 80 more E Cape babies die. S Afr Med J 2008;98(6):429-430. 2. Wikipedia. Water supply and sanitation in South Africa. en.wikipedia.org/wiki/Water_supply_and_sanitation_in_ South_Africa (accessed 13 April 2015).

Little-used medical technology could help thousands see, hear and feel better ‘If you look hard and long, you can find us. If you listen hard and long, you can hear any of us, call any of us that you wish.’ (Tamora Pierce, Wild Magic) South Africa (SA) has the home-grown expertise and technology to drastically improve the eyesight, hearing and nutri tion of most of the tens of thousands of

its citizens who suffer unnecessarily from severe impairment in these areas. That’s the inescapable conclusion Izindaba came to after tracking down and interviewing four of the country’s leading innovators in these fields. Their highly mobile, cost-saving, ground-breaking devices and adapt able products are only now gaining slow purchase after languishing for years in the backwaters of resistance, suspicion and bureaucratic apathy.

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Hearing

A dramatic diagnostic innovation is a device called the KUDUwave 5000 Portable Diag nostic Audiometer, which detects impending partial or total hearing loss suffered by (among other patient groups) between 30% and 47% of people under going treatment for multidrugresistant tuberculosis (MDR-TB) (about 10 000 at present).[1] The existing MDR-TB hearing loss percentages translate to about 4 000 people

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Medical device innovator Dr Dirk Koekemoer.

on the verge of mild to profound hearing loss as a result of side-effects of the toxic but lifesaving kanamycin, a drug used in the MDRTB treatment cocktail. With the new alternative MDR-TB drug bedaquiline now being cautiously and slowly rolled out to decentralised MDR-TB treatment clinics nationwide, the timely use of a portable audiometer to diagnose early hearing loss enables a drug switch with far better outcomes. The cost of surviving MDRTB before bedaquiline and another effective new MDR-TB drug delamanid (the first new TB drugs in 40 years) became available this year was a near-even chance of mild to profound hearing loss – if the patient was among the estimated 48% who survived MDR-TB at all. Hundreds of the surviving MDR-TB patients remain at risk of imminent deafness due to the (some clinicians say overly) cautious roll-out of bedaquiline – and the National Drug-Resistant TB Directorate’s financially conservative pur chase of just 120 portable audiometers (which cost ZAR45 000 each, excluding VAT, as opposed to ZAR250 000 for existing sparsely distributed stationary audio booths). There are 4 500 primary healthcare clinics in SA, with 350 either treating MDR-TB or being set up to do so. The audiometer is light and portable (carried in a small suitcase, it consists of a headset, computer tablet and software), and can detect ototoxicity by measuring the ear’s ability to detect very high frequencies. It is best used in an open space (as opposed to the closed traditional booth), an additional benefit given the airborne cross-patient infectiousness of MDR-TB. The data can be transmitted directly by a nurse with basic proficiency via easy training or an audiometrist to an audiologist, who can interpret, properly diagnose, and recommend

or adjust treatment. Far from taking work away from specialists it will probably create more, but vastly improve efficiency and increase the number of diagnoses. Medical device innovator, medical doctor and software developer Dirk Koekemoer believes that his device (should the national health department quickly expand its current pilot project to all existing clinics) has the potential to save the hearing of at least 2 000 MDR-TBinfected people. ‘If you pick up the ototoxicity, you can stop the meds [kanamycin] immediately and save their hearing – it’s all about how well you can apply the KUDUwave and thus identify the kanamycin toxicity.’ There are about 1 600 audiologists in SA; of these about 400 work in the public sector, creating a heavy workload. Koekemoer said that deafness is the most common chronic disability in the world, with an estimated 3 million South Africans needing hearing aids and other hearing services, for all sorts of reasons. ‘I think they should have bought 250 KUDUwaves at the outset – I mean I have 200 just lying here now, but Dr Norbert Ndjeka [MDR-TB Directorate chief] needs to motivate and get a budget passed – there’s simply nobody else in the world with similar equipment,’ he emphasised.

Engineer, medical technologist and software developer Dirk Koekemoer believes that his device (should the national health department quickly expand its current pilot project to all existing clinics) has the potential to save the hearing of at least 2 000 MDR TB-infected people. Since realising during testing in 2006 that he had 16 medical devices that could examine a patient ‘better than a GP – and automate primary healthcare from screening to diag nostics and treatment’, he’s had his share of frustrations. ‘You develop something, work out how to do things, market this new principle, process and equipment to government – and in the end they [seem to] understand it. Then they put out a tender for traditional equip ment – and you don’t get the tender. I’ve learnt to identify the champions in government and seed them – then they finally go for it. Otherwise you have to find the money yourself through NGOs.’ Illustrating the utility of the device, he said there was one audiologist in Zambia using his devices to fit hearing aids and assist ‘thousands of people via the internet’. ‘The impact is huge, not just from a humanitarian perspective but also on the professionals that use the equipment’. One ‘now massive’ private

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practice in SA had 20 units distributed via small-town pharmacies across the country. ‘All I know is that there are 350 decentralised [public sector] TB sites going up across the country and each one needs one.’ Koekemoer said that on 24 March (World TB Day) this year, he watched with government officials as 250 self-selected patients ‘self-screened’ (under supervision) on the KUDUwave in Kanana township near Orkney in North West Province over a 4-hour period. A total of 40 were automatically referred to an audiologist (via an SMS to their phone).

Nutrition

The National Department of Health introduced an integrated nutrition programme in 1995 to counter, among other things, the partly HIVdriven 11.4% of deaths of SA children under 5 years old attributed to low birth weight.[2,3] However, there have been copious challenges and widely varying success rates, and an estimated 15% of infants are still being born with a low birth weight. This is in spite of the massive and sustained roll-out of antiretroviral (ARV) drugs, which has dramatically slowed HIV incidence. Resistance to breastfeeding remains widespread (before the hugely successful introduction of prevention of mother-to-child transmission (PMTC) drugs, breastfeeding was the surest way of transmitting HIV to your child). Providing proper nutrition to anyone undergoing ARV treatment is vital, given that drug-induced nausea can cause vomiting and reduce overall food intake. Overall, the most easily preventable yet most prominent detrimental health conditions associated with malnutrition are nutrient deficiencies. The impact of anaemia caused by low iron levels among preschool children (21.4%) and pregnant women (50%),[2,3] and of deficiencies in various vitamins and calcium (causing visual impairment/blindness and beriberi, respectively), is overwhelming.[4] UNICEF puts the main causes of malnutrition

The KUDUwave portable audiometer.

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down to ‘household food insecurity, inadequate child and maternal care, and insufficient essential human services such as health, education, water and environmental sanitation and housing’.

Not only does surgical removal of cataracts improve the self-care and potential earning capacity of the mostly elderly patients, but the impact on HIV/AIDSorphaned children is enormous. In SA each elderly caregiver looks after an estimated average of 4.6 children. Enter Profs Spinnler Benade and Maretha Opperman, head and vice-head of the Cape Peninsula University of Technology’s Functional Food Research Unit. With several patented nutritional supplements to their name, they now have a formulation in biscuit and porridge form that addresses specific nutritional deficiencies in vulnerable SA populations. Working backwards from the epidemiological data, they’ve come up with a premix of red palm oil-derived beta-carotene and five different forms of vitamin E and vital minerals. The 25 g biscuit is aimed at children up to the age of 5, and the porridge at any older vulnerable person. Public funding would enable quick and effective free distribution to vulnerable groups (pregnant women and children). Already some goldmines have expressed interest in on-site distribution of the porridge to their workers. Unpublished clinical trials involving 80 preschool children in Bethelsdorp near Port Elizabeth, with the biscuit being administered once daily, five days a week for 6 months, have shown dramatic and unprecedented drops in vitamin E deficiencies. Opperman says that the prevalence of vitamin E deficiencies was unexpected in this group. ‘Vitamin E is essential for weight gain, optimal growth and development of the nervous system, and because of poor diets low in fruit, vegetables and healthy oils, vitamin E deficiency is a reality’. She added: ‘We know the biscuit and porridge concept works, as has been proven in several clinical trials – this model provides an excellent opportunity for government and the private sector to become involved to address these nutrition problems in disadvantaged communities. The long-term effects of such an involvement by different stakeholders could be a good investment in terms of health, nutrition and development.’

Seeing

Sixteen months into his Stellenbosch University ophthalmology registration, Dr Will Mapham, his generalist skills honed in the public sector

healthcare cauldron of the Eastern Cape’s deep rural hospitals and now working at Tygerberg Hospital, has come up with a versatile eyetest cell-phone application. It will turbo-charge referral times and improve diagnoses and treatment, especially for its target patient group, far-flung, mostly indigent rural people. The Vula Eye Health mobile app enables health workers to conduct eye tests, take an accurate history and photos of the eyes, and communicate with specialists via its ‘eyeMessage’ system, hugely assisting appropriate ref errals.[5] It doesn’t take much to imagine its potential when you witness the impact of cataract surgery on sight restoration and a person’s life – given that cataracts cause 66% of all blindness in SA (the incidence of blindness due to cataracts is calculated at 1 000 people per year, 80% of whom are indigent). Not only does surgical removal of cataracts improve the selfcare and potential earning capacity of the mostly elderly patients, but the impact on HIV/AIDSorphaned children is enormous. In SA each elderly caregiver looks after an estimated average of 4.6 children, while in Zimbabwe about 71% of grandparents older than 60 years care for HIV/ AIDS-orphaned children. Mapham has intimate knowledge of what a difference near-gold-standard annual cataract surgery rates make. He was a referring medical officer to Port Elizabeth Provincial Hospital’s Drs Mark Jacoby and Danie Louw, who have since come to within a few dozen of the international gold-standard cataract surgery rate of 2 000 surgical procedures per 1 million blind people.[6] (The SA downward-revised local target is 1 500, set in 2010 when research showed that most units were failing even to get close to this level.) A measure of the PE surgical pair’s success is that their cataract patient profile has changed from mostly blinding cataracts to early cataracts requiring a less invasive procedure with quicker healing and similar quality of restored sight. This strongly underlines the value of Mapham’s cell-phone referral application. Mapham first made his name as a young medical officer when he helped recruit dozens of interns, community service doctors and medical officers to less popular deep rural Eastern Cape coastal area rural hospitals by touting the benefits of the unique generalist learning curve and unmatched rural leisure lifestyle on campuses and at major medical events.[7] His cell-phone app was made possible by a R1 million South African Breweries research grant to develop, programme, test, market and explore high-tech innovations. In 2008 he published ‘Mobile phones: Changing healthcare one SMS at a time’[5] in the SA Journal of HIV Medicine. He says that his inspiration for the app came from working

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A victim of blinding cataract will soon see again.

in the Eastern Cape and Swaziland,[8] where people had limited or no access to eye clinics. ‘I came across people who had been blind for many years and needed cataract surgery to restore their vision. Hopefully this will enable people to get the help they need as soon as possible, rather than suffering with preventable blindness for long periods of time,’ he adds. He previously spent time in New York and Washington, USA, where he designed mobile phone applications for healthcare. It is to be hoped that the right government officials, national and provincial, will take note of this quartet of healthcare innovators who have the products and tools to make their delivery task so much easier and cheaper. The private sector certainly is … Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(5):334-336. DOI:10.7196/SAMJ.9682 1. Harris T, Heinze B. Open access guide to audiology and hearing aids for otolaryngologists tuberculosis (TB), aminoglycoside and HIV-related hearing loss. https://vula.uct.ac.za/access/ content/group/27b5cb1b-1b65-4280-9437-a9898ddd4c40/ Tuberculosis%20_TB_,%20HIV%20and%20aminoglycoside%20 related%20hearing%20loss%20_ototoxicity.pdf (accessed 13 April 2015). 2. UNICEF. The State of the World’s Children 2009. http://www. unicef.org/sowc09/ (accessed 12 April 2015). 3. World Bank. Nutrition at a glance: South Africa. http://siteresources. worldbank.org/NUTRITION/Resources/281846-1271963823772/ southafrica.pdf (accessed 12 April 2015). 4. Wikipedia. Malnutrition in South Africa. http://en.wikipedia.org/ wiki/Malnutrition_in_South_Africa (accessed 12 April 2015). 5. www.vulamobile.com, Mapham WE. Mobile phones: Changing healthcare, one SMS at a time. Southern African Journal of HIV Medicine 2008; Spring. 6. Bateman C. PE eye department carves up cataract surgery record book. S Afr Med J 2012;102(4):213-214. 7. Bateman C. Miracles in the land of non-accountability. S Afr Med J 2004;94(12):941-942. 8. Pons J, Mapham WE, Newsome B, et al. The potential impact of a cataract surgery programme on the care of orphans and vulnerable children in Swaziland. S Afr Med J 2012;102(3):140141.

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SAMA pitches in to help victims of adverse medical events The South African Medical Association (SAMA) is inves tigating setting up a fund to compensate patients who fall victim to unavoidable adverse events (through no fault of their treating physician), while working with government to improve the overall quality of care in both the public and private sectors.

Another legal ‘driver’ was the 1997 Contingency Fees Act, which permits attorneys to offer clients ‘free’ legal help in pursuing a suit against a medical practitioner (in fact 25% of the settlement or double their usual fee, whichever is the lesser). SAMA Chairperson Dr Mzukisi Groot boom emphasised that this would in no way affect legitimate medical negligence claims, but form part of an overall strategy to address a crisis that threatened the very existence of higher-risk specialist care in South Africa (SA) – something that would negatively impact on patients. Identifying and compassionately addressing genuinely unavoidable accidents and adverse outcomes, while teaching doctors to communicate openly and honestly with their patients, would help reduce the expensive rising tide of pending claims. SA, while seriously short of specialists, nevertheless had some of the best and most sought-after practitioners in the world, with ground-breaking and/or lifesaving procedures an almost everyday occurrence. He cited Dr Graham Howarth, Africa representative for the global Medical Protection Society (MPS), to which most doctors in South Africa belong, as recently saying that an extrapolation of the annual indemnity fee hikes necessary to counter rising claims over the next 5 - 10 years ‘begs the question of whether anyone will be left in the private sector to deliver babies [for example] at all’. Grootboom said that private obstetricians would this year pay the highest annual indemnity subscriptions at ZAR450 000 per annum, which came on top of their equipment, office and administration overheads. The ‘very real danger’ existed that this could induce them and other high-risk

consultants to avoid certain procedures and/ or move to the public sector (where the state pays for their indemnity cover), which he described as ‘simply shifting the problem elsewhere’, hiking the taxpayer-footed legal bill, which could potentially cripple or at least severely curtail overall public healthcare delivery. The rising curve in MPS settlements involving local obstetricians graphically illustrates the problem; the payout in 2013 was ZAR13 million, up from ZAR2 million in 2003 (the latter involving a single claim).

Claims out of kilter with negligence trends – SAMA

Echoing what national health minister Dr Aaron Motsoaledi said in Gauteng at an early March medicolegal summit called to address the escalating crisis, Grootboom said that the local explosion in medicolegal claims was not in keeping with generally known trends of negligence. Recent amendments to the Road Accident Fund legislation made damages claims for personal injury sustained in motor vehicle accidents now a far less lucrative source of income for lawyers, who had shifted their target to doctors and hospitals. Another legal ‘driver’ was the 1997 Contingency Fees Act, which permits attorneys to offer clients ‘free’ legal help in pursuing a suit against a medical practitioner (in fact 25% of the settlement or double their usual fee, whichever is the lesser). Motsoaledi accused some (unnamed) chief health executives at his public hospitals of being in cahoots with lawyers to cash in on the lucrative litigation. ‘They and others in the health sector are members of syndicates which have permeated our hospitals, sharing information which leads to the looting of funds meant for members of the public,’ he charged at the indemnity summit. Gauteng, KwaZulu-Natal and the Eastern Cape currently have claims against them worth billions; Gauteng alone faces medical negligence claims estimated at ZAR1.268 billion. The Black Lawyers Association (BLA) strongly attacked Motsoaledi’s ‘fingerpointing’, saying that he should be more introspective and examine the true cause of the massive lawsuits channelled against his department. It bemoaned SAMA’s apparent support for the minister at the medicolegal summit, saying that it amounted to ‘an

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orchestrated assault on the rights of the downtrodden and victims of malpractice in public healthcare’ and that both the BLA and SAMA should campaign for higher professional standards among their members when treating members of the public.

A ‘no-fault’ compensation scheme has already been suggested by top health science academics in order to limit the costs of medical negligence and its impact on NHI. This would limit legal costs for provincial health departments and private practitioners by reducing the number of court cases.

National Health Insurance delivery under threat

Over the past 13 years the overall indemnity insurance paid by private doctors to protect themselves against medical negligence claims has risen by 573%, pushing up their fees and encouraging those not contemplating the financially safer haven of the state sector to look overseas for opportunities – or simply give up their practices. The annual MPS subscription for a private neurosurgeon in SA will this year reach ZAR338 520, while plastic, bariatric, orthopaedic, non-spinal and fertility surgeons will pay ZAR140 860 per annum. The greatest number of claims, with the highest damages paid, are in obstetrics, neurosurgery, spinal surgery, trauma and orthopaedics, all highly sought-after and understaffed disciplines with severe work pressure. Grootboom said it was entirely possible that newly qualified doctors would steer clear of such specialisation unless the situation was quickly mitigated or corrected, further undermining the government’s ability to deliver universal healthcare via National Health Insurance (NHI). He said he was fully aware there were other drivers behind the rising litigation (such as diminished supervision of juniors, a lack of necessary nursing skills, equipment and drugs, and insufficient and thinly spread medical expertise, especially in more rural areas). However, by improving best practice skills and straightforward communication with patients, and working with government to diminish risk

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to patients, SAMA hoped that doctors could better live up to their dictum of, ‘first do no harm’ and avoid having to practise defensively in a hostile, pressurised and uncertain climate. A ‘no-fault’ compensation scheme has already been suggested by top health science academics in order to limit the costs of medical negligence and its impact on NHI. This would limit legal costs for provincial health departments and private practitioners by reducing the number of court cases. Such a system does not rule out court action for those dissatisfied with their compensation, but rather creates a short cut for patients who prefer not to go through protracted and expensive legal battles.

Ubuntu approach vital for resolution

Motsoaledi said at the medicolegal sum mit that unless something was done about the increasing rates of medical negligence claims, ‘the whole system will suffer immeasurable damage’. He recently appointed an independent ombudsman to look into patient complaints, while the Office of Health Standards Compliance, tasked with setting and monitoring minimum standards for all hospitals (public and private) in advance of the NHI, is also expected to have some impact on the crisis. Howarth of the

MPS commented in an article published recently in the SAMJ: ‘I think it points to the kind of future we’d have if people are not very careful. Private patients, providers, public patients and providers, politicians and policy pundits all have a vested interest in solving the problem – there is not a medical answer – it has to enter public debate.’ Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(5):337-338. DOI:10.7196/SAMJ.9683

Tygerberg Hospital keeps more hearts beating with pioneering service A pioneering life- and costsaving radial angiography service in Tygerberg Hospital’s cardiology department, the only one of its kind in Africa, is giving hundreds more patients unprecedented access to accurate diagnosis and treatment. Built around medical advances that allow both angiography and the often ensuing strategic placement of coronary stents to be done via the radial artery in the arm instead of the traditional and more risky femoral artery in the groin, the custom-built, six-seater radial angiography lounge has helped reduce procedure and recovery times. Every year this gives more than 200 extra referred patients access to diagnostic and therapeutic procedures that could potentially save their lives – and saves the hospital an estimated ZAR1.5 million in what would otherwise have been overnight accommodation, food and linen costs. Private hospitals have already shown interest in emulating both the facility and the service, while the more proactive medical aids are fast sitting up and paying attention.

Patient diagnostic, treatment and discharge times halved

Tygerberg Hospital cardiologist and chair of the pivotal philanthropic SUNHEART Foundation Dr Alfonso Pecoraro says that the radial angiography suite looks like a dialysis unit but enables patients to undergo and recover from a diagnostic angiogram in 3 hours, and from a stent in 6. ‘The suite is right alongside the theatre, so they literally walk in, get on the table to have the procedures done, and walk

Medtronic MD Mike Howe-Ely, SUNHEART Director Anton Doubell, former Western Cape Minister of Health Theuns Botha and patient Caureen Amelia Petersen.

out. Patients can read or use their laptops to keep occupied if they have nothing else to do while we prep them before or monitor them afterwards,’ he said. The product of SUNHEART and private investment partner Medtronic, the suite should increase throughput of patients by approximately 15% (the cardiology unit performs about 1 700 procedures per annum). SUNHEART is the brainchild of Tygerberg’s five cardiologists, Charles Kyriakakis, Pecoraro, Anton Doubell, Hellmuth Weich and Philip Herbst, whose ambition it is to change the cardiology landscape by creating access to ‘advanced cardiac care for all’ through innovative measures and procedures. Medtronic is a Minneapolis (USA)-based global leader in medical technology.

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General cardiology awareness and train ing is also being spread to several of the Western Cape’s more rural district hospitals via cardiology satellite outreach facilities that enable staff to be trained in basic cardiology and proper diagnostic work-ups, resulting in a dramatic decline in inappropriate referrals to Tygerberg Hospital. Says Pecoraro: ‘The net amount of patients we see has increased, but it’s mitigated by the faster turn-around and correct patient profile. Our training commitments have also increased, but hopefully the savings we show will result in more funding.’ He said that with the World Health Organization predicting that diseases of lifestyle in Africa will have overtaken HIV/AIDS as the leading cause of death within 15 years, the radial angiography

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and stent service was ‘massively necessary’. ‘As we move towards the Western diet and the Western way of living, South African (SA) statistics on debilitating heart conditions are soaring while they are stabilising in the Western world.’ According to Prof. Doubell, Head of the Tygerberg Cardiology Division and Director of SUNHEART, more than 50 000 patients in SA annually require advanced cardiac care such as coronary angiography. ‘As we shift to a valuebased healthcare culture, the need for innovative solutions that result in high-quality, costeffective healthcare is more important than ever before,’ he added. SUNHEART’s first sponsored research project, the screening of large numbers of schoolchildren for rheumatic heart disease, was launched last year in collaboration with the British Society of Echocardiography. ‘More than 1 500 children have been screened for rheumatic heart disease during 2014,’ says Herbst, study leader for Echo in Africa.

Training for proper referral vital

Pecoraro said that rural cardiovascular training platforms, supported by radial angiography suites in major referral hospitals, had proved themselves in Canada, where the population was ‘also geographically challenged’. He said that SUNHEART was already helping several private hospital executives with ideas on planning their own suites and that he believed it would not be long before the big healthcare funders ‘insist that this is the way it should be done’. Stents had revolutionised cardiovascular care. ‘For the right patient it works very well, complication rates are low and usually there’s a very good outcome.’ Dr Jonny Broomberg, CEO of Discovery Health, said it was ‘inspiring to see this type of innovation and a strong focus on value and patient centeredness in our public healthcare

system. We hope this example can be followed by other public and private hospitals, especially if this technique continues to enhance clinical outcomes, reduce cost and improve affordability and cost-effectiveness.’ Tygerberg’s cardiology division is widely considered a premier training facility for young cardiologists, from both SA and the rest of the African continent. The renovation of the unit’s lecture room has created an ultra-modern lecture facility, boosting teaching and training activities in the unit further. An additional fully funded training fellowship has also contributed to an increase in the trainee output from the unit. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(5):338-339. DOI:10.7196/SAMJ.9555

Government inability to harness hightech radiology blurs NHI vision Almost runaway techno logical advances have put radiology at the cutting edge of diagnostic and therapeutic healthcare, increasing its reach beyond the wildest dreams of its oldest living practitioners. Yet the government’s inability to pragmatically leverage willing private sector information technology (IT) skills and capacity has left South Africa (SA) way short of what it could potentially offer most of its patients. With just 1.48 radiologists per 100 000 people in SA and universal healthcare cover

Dr Richard Tuft, executive director of the RSSA.

age now a longstanding non-negotiable government priority, public/private colla boration is at the core of any success. Izindaba has learnt that a powerful vendorneutral archiving and storage IT portal with the potential to deliver cost-effective, high-quality image reporting across primary, secondary and tertiary healthcare platforms has been on offer to government for the past 6 months – without any official ‘uptake’. Developed by the Radiological Society of South Africa (RSSA), the portal has been met with major enthusiasm and ‘head office’ lobbying by public sector radiology department chiefs – yet the private sectormanaged fee-for-service instrument remains effectively on ice when it comes to 80% of the population. This while some tertiary hospitals (according to reliable Izindaba sources) sit with an annual tally of more than 100 000 black and white unreported (i.e. uninterpreted) X-rays, illustrating what an enormous difference such a referral system could make to healthcare outcomes. Any healthcare facility with a picture archiving and communication system (PACS) and sufficient bandwidth could send images to the central RSSA-managed portal for inter pretation and feedback by a radiologist – empowering the state team managing the patient to render far better care.

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Approached for comment, the executive director of the RSSA, Dr Richard Tuft, said the single-format portal was of international digital technology standard and ‘solves the problem of different technology being used to store and read images’. ‘We want to use the capacity of the private sector to help out the state with the reporting of images. It’s been demonstrated internationally to improve healthcare outcomes. We have this expandable virtual and potential system – but no client!’ Asked about the fee-for-service charges, he declined to give figures except to say it was ‘not a particularly high’ rate. ‘We have to pay the consulting radiologists whether they’re in the public or private sector, pay for the technology, manage the system and pay for quality control via random peer review,’ he added.

Radiology’s message to government – ‘we want to help out’

Tuft said that quality was paramount, with the consulting radiologist able to interpret whether he or she was seeing pathology. Asked what he’d do if he had a ‘magic wand’ to change things, he replied: ‘I think the biggest thing would be for the Department of Health to accept that the private sector is not automatically going to oppose the NHI – large groupings are very keen to actively assist but are

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being excluded from the process. With fibreoptic networks now commonplace, technology and IT have to be absolutely paramount if the NHI is to have any chance [of succeeding]’. Tuft said there is enormous expertise, proficiency and willingness ‘out there’, yet the government seemed ‘almost trying to reinvent the wheel in every possible area. We’re all working in the same direction in the same country,’ he added. The RSSA had a ‘very active’ National Health Insurance standing committee that was already helping government with basic specifications for health departments at different levels of government.

With just 1.48 radiologists per 100 000 people in SA and universal healthcare coverage now a longstanding nonnegotiable government priority, public/private collaboration is at the core of any success. Just over 2 years ago, Izindaba witnessed the planning and early implementation of a major telemedicine project in the Eastern Cape, initiated and guided by the province’s former Director-General of Health, the tech- and business-savvy Dr Siva Pillay. It has since fallen apart, through inadequate equipment provisioning, lack of installation or maintenance, poor IT support and/or lack of ongoing training. Substandard contractors awarded shaky tenders remain a nation-wide problem. Pillay himself, considered a maverick by the union-friendly and historically corrupt Eastern Cape health department, was ousted 2 years ago and is now practising medicine and running his many and varied business enterprises in the Port Elizabeth area.

What’s possible …

With radiologists (interpreting images) and radiographers (capturing images) hav ing to upskill themselves virtually on a month-tomonth basis, cross-sectional imag ing today enables pinpoint diagnoses, allowing clinicians to focus treatment as never before. Taking a patient into theatre to ‘cut and see what we find’ is ancient history. Now an abnormality is detected via any one of a number of radiological techniques, and an image-guided biopsy is done instead. Interventional radiology is cutting edge, enabling (for example) a neurologist intravascular access to treat lifethreatening conditions such as an aneurysm, using minimally invasive techniques. Tuft said that ‘in theory’ there should be no limits to the availability of technology in SA

and that broader bandwidths, while initially expensive, were getting cheaper all the time. However, Prof. Zarina Lockhat, head of radiology at the University of Pretoria and Steve Biko Academic Hospital, painted a somewhat more complex and challenging picture.

Life in the public sector

While agreeing that technological advances in radiology had changed the face of medicine (she singled out ultrasound, computed tomography (CT) and magnetic resonance imaging), the expense of ‘each piece of equipment just goes higher and higher’, while ‘whatever system you have, maintenance and daily care of equipment is a big issue, I find’. She said that the main criterion was funding. ‘Yes, telemedicine should be rou tine, not just images but biochemical results, confidential patient profiles, blood results, the list is end less.’ Better funding would enable the more rural district hospitals to be linked to the far better-equipped tertiary referral hospitals and enable them to buy the equipment and bandwidth necessary to transmit the data. ‘The private sector has got it right, but often transmits less than they would like. For just one CT scan you need to send a minimum of about 500 images. The information and detail you can see to make diagnoses depends on the number of images you have. It can work, but you also need trained personnel – and it’s hard (if not impossible in teleradiology) to separate radiology/radiography from IT. Most centres have dedicated IT staff and PACS administrators – they’re a crucial part of the radiology department. You also need electronic medical records, the digitisation of hospital departments – it all has to be integrated,’ she added. Lockhat said that her department had attempted teleradiology, but data transfer was extremely costly and became unsustainable for ‘certain peripheral hospitals’. Asked what a rural medical officer was supposed to do, she said that data security remained a major issue, but they could still anonymise the data, using iPads, computers or cell phones to transmit. ‘There are some groups who can give you an opinion on line, some are free, some charge a rate … There are medicolegal implications, but if it’s urgent you (the specialist) can give verbal reports on the phone. It’s quite risky, but if you have an intracerebral hemorrhage or other gross pathology it’s not a problem – the risk comes in with the more subtle pathology.’ The limited technology rural doctors were saddled with enabled advice and feedback on

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basic chest X-rays and ultrasound. When it came to more complex pathology, the best route remained patient referral to a central hospital. ‘You can only go up to a certain point; it’s not just the equipment you need, but the relevant specialist to interpret that modality.’ She emphasised that the entire focus of telemedicine was to support rural areas. ‘Tech and IT have to be number one priority for medical care generally. Images are part of it, but if a clinician wants to discuss a case with another clinician they need to send all the data possible, not just radiology images.’ Her top solutions to the current challenges were better funding and an increase in posts for radiologists and radiographers nationally, and more training of ultrasonographers – although this did not solve the ongoing outflow of her staff to the private sector. ‘Those in academic medicine and those who want to do research generally stay, though,’ she emphasised. Steve Biko Academic Hospital is 9 years into a digital system, putting it years ahead of many of its peers, although all SA’s tertiary teaching hospitals are now digital, enabling many student exams to be run digitally.

Some tertiary hospitals (according to reliable Izindaba sources) sit with an annual tally of more than 100 000 black and white unreported (i.e. uninterpreted) X-rays. Lockhat said that all the heads of department at every academic hospital in SA met regularly to discuss challenges and solutions, in order to create ‘a common vision and goal, and to co-ordinate teaching programmes’. She pointed to advanced ‘post-processing and reconstruction’ soft ware in radiology as an example of astoundingly fast advances in her field. ‘You can improve detailed imaging of anatomy and pathology. There are a host of software packages: for example cardiac, neurological, virtual colonography, onco logy tumour tracking, CT and MRI soft ware creating exquisitely detailed images and colour reconstructions with extremely fast acquisition times. It’s here that the magic lies.’ Chris Bateman chrisb@hmpg.co.za S Afr Med J 2015;105(5):339-340. DOI:10.7196/SAMJ.9465

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OBITUARY

Philippe Emile Agnes Schuermans (1943 - 2014)

Philippe was born in Ghent, Belgium, on 8 July 1943. His father was a stockbroker and private banker in that city. However, his grandfather and ancestors prior to his grandfather’s generation had been general practitioners, and he was determined to follow

the same profession, but in Africa. Schooled at the Jesuit St Barbara College in Ghent, he completed a classical education of mostly Latin and Greek in 1962 and then enrolled at the Free University of Gent in the faculty of medicine, from which he graduated with distinction in 1969. In his final year of studies he was granted permission to also study for a diploma in Tropical Medicine at the Tropical Institute of Antwerp. Following his marriage in that same year he commenced his career at a Catholic mission hospital in Rwanda, where he had existing family ties through an uncle who was a missionary priest in that country. In Rwanda Philippe enjoyed seven years of very fruitful and rewarding work in three different mission hospitals. He was also the founding member of the NGO BUFMAR (Bureau des Formations Medicales Agréées du Rwanda), which was founded in 1975 and is still operational today. BUFMAR serves as a central depot for medicines and medical equipment and also manufactures some basic products such as rehydration drips, ointments, and antimalaria and deworming tablets.

Because of the lack of schooling facilities for his children, Philippe moved back to Belgium in 1976, where he started a private practice in the village of Gierle near Antwerp. However, his calling to work in Africa never left him, and it prompted him to take up a post as a contract doctor in Zaire. That soon thereafter led him to continue his career in South Africa. He arrived in South Africa in 1983 and was joined by his wife and five children shortly thereafter. The next 25 years were filled with service at various hospitals throughout KwaZulu-Natal. Most were in rural areas, where his calling to help the most needy was best fulfilled. One of these hospitals was Mbongolwane Hospital. There Philippe played a key role in the creation of an orphanage that today provides a home for approximately 40 children. He passed away peacefully on 27 May 2014 at the Zululand Homes for the Aged after a brief battle with cancer. Jean Schuermans Pietermaritzburg, South Africa jean.schuermans@gmail.com

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ISSUES IN PUBLIC HEALTH

The simple bread tag – a menace to society? R Karro, P Goussard, J Loock, R Gie Dr Ryan Karro, MB ChB, FCORL (SA), is currently a specialist in private practice and holds a sessional post in state practice. At the time of writing the article he was a senior registrar in the Department of Otorhinolaryngology, Tygerberg Hospital and Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa. Dr Pierre Goussard, MB ChB, MMed, Cert Pulmonol Paed (SA), PhD, is a senior specialist in the Paediatric Pulmonology Unit, Department of Child Health and Paediatrics, Tygerberg Hospital and Faculty of Health Sciences, Stellenbosch University. Prof. James Loock, MB ChB, FCS (SA) ORL, is Head of Otorhinolaryngology, Tygerberg Hospital and Faculty of Health Sciences, Stellenbosch University. Prof. Robert Gie, MB ChB, MMed (Paed), FCPaed (SA), is Head of Paediatric Pulmonology, Department of Child Health and Paediatrics, Tygerberg Hospital and Faculty of Health Sciences, Stellenbosch University. Corresponding author: R Karro (rkarro@iname.com)

Foreign bodies (FBs) are potentially life-threatening when inhaled by a child, depending on where they lodge. Symptoms can range from acute upper airway obstruction to mild, vague respiratory complaints. Between 80% and 90% of inhaled FBs occlude the bronchi, while the larynx is a less common site. The commonest inhaled paediatric FBs are organic, e.g. seeds or nuts. Plastic FBs are less common and more difficult to diagnose. They are generally radiolucent on lateral neck radiographs and are often clear and thin. We report three cases of an unusual plastic laryngeal FB, the bread tag. Plastic bread tags were first reported in the medical literature as an ingested gastrointestinal FB in 1975. Since then, over 20 cases of gastrointestinal complications have been described. We report what is to our knowledge the first paediatric case of an inhaled bread tag, and also the first case series, briefly discuss the symptoms and options for removal of laryngeal FBs, and highlight the dangers of the apparently harmless bread tag. Images of the bread tags in situ and after their removal are included. S Afr Med J 2015;105(5):342-344. DOI:10.7196/SAMJ.8996

Foreign bodies (FBs) are potentially life-threatening when inhaled by a child, depending on where they lodge. Symptoms can range from acute upper airway obstruction (UAO) to mild, vague respiratory complaints. An inhaled FB is one of the most common causes of accidental death in children under 1 year of age. The risk of inhalation remains high up to the age of 3 years.[1] The increased incidence of inhalation in this age group is due to the young child’s inherent curiosity in exploring the environment orally, faster respiratory rate and work of breathing, and under-developed teeth. The commonest inhaled paediatric FBs are organic, e.g. seeds or nuts. Plastic FBs are less common and more difficult to diagnose. They are generally radiolucent on a chest radiograph and are often clear and thin. These features also contribute to plastic FBs being missed on flexible nasopharyngoscopy and direct laryngoscopy.[2] The majority (80 90%) of inhaled FBs occlude the bronchi, while the larynx is a less common site.[2] Three children presented at Tygerberg Children’s Hospital, Cape Town, South Africa, between January 2011 and June 2012 with an unusual yet ubiquitous plastic laryngeal FB: the common bread tag.

Case series Case 1

The first patient was a 4-year-old girl brought in by her mother, who had seen her ingesting a bread tag earlier that day. She had obvious dysphonia and inspiratory stridor but no respiratory distress. The chest radiograph showed features highly suggestive of an FB in the subglottis (Fig. 1), and flexible nasendoscopy revealed the bread tag lodged sagittally between the vocal cords with surrounding oedema (Fig. 2). An urgent procedure was done to remove the bread tag under general anaesthesia via a combination of flexible and rigid bronchoscopy. This proved to be challenging, as the bread tag was broken in half (Fig. 3) and its sharp points were embedded in the subglottic mucosa. Following removal, the child was kept intubated overnight. Upon extubation, she had no further stridor and was subsequently discharged without any respiratory sequelae.

Fig. 1. Chest radiograph with bread tag seen in subglottis (arrow).

Case 2

The second patient was a 15-month-old boy referred to our unit with a 5-day history of UAO non-responsive to medical management. He was initially seen at a day hospital with UAO, nebulised and sent home. Two days later he returned with worsening symptoms. According to his mother, the

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Fig. 2. FB in situ before removal.

symptoms had been of sudden onset. There was no history of choking or coughing.

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paediatric intensive care unit overnight. By the following day the stridor had resolved, and she was discharged a day later.

The bread tag

Fig. 3. An incomplete bread tag after removal.

Fig. 4. Another bread tag after removal, partly folded.

He had a previous history of mild asthma, controlled on metered-dose inhalers. On arrival, he was not acutely distressed and looked deceptively well. His oxygen saturation was 94%, although he had inspiratory and expiratory stridor, a sternal tug and a pulsus paradoxus. A chest radiograph showed what looked like an FB in the subglottis and some segmental collapse of the right upper zone. Flexible bronchoscopy carried out as an urgent procedure revealed an incomplete bread tag (Fig. 4) wedged firmly between the vocal cords. This was removed with the flexible bronchoscope and the child was monitored overnight in the high-care unit while receiving three doses of dexamethasone. The following day he was well and was discharged.

Case 3

The third patient was an 8-month-old girl who was referred to our unit from a district hospital, with a history of the grandmother having found the child with a piece of plastic in her mouth: ‘She suddenly swallowed it, choked and became blue.’ After being shaken the child started to breathe again, but subsequently developed noisy breathing. On arrival, she was not distressed but had obvious inspiratory stridor. Flexible bronchoscopy was performed as an urgent procedure, and an intact bread tag was found lodged in the subglottis. It proved too difficult to remove in one piece, so it was pushed down into the right main bronchus and then removed piecemeal via a combination of rigid and flexible bronchoscopy. The child was given a single dose of intravenous dexamethasone 4 mg and monitored in the

Plastic bread tags, otherwise known as occlupanids (from the Latin occlu, to close, and pan, bread), were developed by Floyd G Paxton, founder of Kwik Lok, USA, in 1952.[3] They have the obvious advantage of being easily reusable. They were first reported in the medical literature as an ingested gastrointestinal FB in 1975.[3] Since then over 20 cases of gastrointestinal complications have been described, ranging from bowel obstruction to perforation,[3] with at least three reported deaths.[4] Rosow et al.[5] reported the first case of an inhaled bread tag, which lodged in the subglottis of an adult. We have reported what is to our knowledge the first paediatric case of an inhaled bread tag, and also the first case series.

Laryngeal FBs

In a retrospective study by Bloom et al.[2] of 185 aspirated FBs, nine (5%) were found to be laryngeal. A laryngeal FB can either lodge at the glottic level or wedge in the subglottis. The subglottis, being the narrowest part of the paediatric larynx, is classically where these laryngeal FBs lie. The unique feature of a subglottic FB is that it is usually small enough to fit through the vocal cords, but often has sharp edges that embed in the subglottic mucosa.[6] The confined subglottic space adds to the difficulty of removal and the development of ensuing oedema. Symptoms of laryngeal FBs differ from other tracheobronchial FB aspirations, and they are often more difficult to diagnose. Laryngeal FBs can be separated into two categories: large, conforming items that obstruct the laryngeal inlet causing immediate respiratory distress, and sharp, thin, aerodynamic FBs causing partial obstruction.[2] Partial laryngeal obstruction can cause variable and sometimes subtle symptoms mimicking other causes of upper airway obstruction. These symptoms include dysphonia, cough, stridor, wheeze and dyspnoea. Additionally, thin laryngeal FBs are frequently radiolucent on a chest radiograph without the typical lung features of unilateral air trapping or mediastinal shift, making diagnosis with standard imaging difficult.[2] General practitioners and emergency room doctors need to have a high index of suspicion in the face of a nonspecific history and a normal plain radiograph.

How are they removed?

In two of our three cases, the bread tag was broken in half exposing the clasping

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teeth, which impacted in the subglottic mucosa. This made removal difficult and traumatic. Virtually all inhaled FBs can be extracted via bronchoscopy, with success rates of over 98%.[7] Rigid bronchoscopy is the standard technique for removal, but flexible bronchoscopy, often the technique used to remove an FB in an awake adult, is becoming increasingly used. In children it is generally used for the initial diagnostic procedure and thereafter may be used for the removal, depending on the individual circumstance and expertise. It is considered to be less traumatic than rigid bronchoscopy and can be particularly useful for retrieving FBs lodged more distally in the tracheobronchial tree. Rigid bronchoscopes are advantageous in that they are bigger in diameter, allowing larger FB removal, aspiration of thick secretions and better patient ventilation.[7] Rigid endoscopes also have excellent optical visualisation and a wider array of ancillary instrumentation.[8] Generally, teams should be trained in both rigid and flexible bronchoscopy. In our three patients a combination of both techniques was used, but in the third case the rigid endoscope proved to be most useful for removing the larger intact bread tag.

The dangers of bread tags

The dangers of bread tags have been highlighted by previous authors. Some have suggested redesigning them to make them less hazardous, for example enlarging them, thereby minimising the chance of their being swallowed,[4] removing the sharp edges, or manufacturing them out of a radio-opaque material.[7] Others have called for complete cessation of their manufacture.[9-11] Bread tags are often made of brightly coloured plastic and are therefore attractive to young children. They appear harmless, and most parents, and indeed most doctors, are probably unaware that they are dangerous.[10] We agree with those who call for complete elimination of bread tags and replacing them with a safer option.[10,11] While bread tags are still in circulation, we advise that they should be removed from the bread packet as soon as they are brought into the home and stored safely out of reach of young children. Alternatively, they can be donated to a worthy cause such as ‘bread tags for wheelchairs’,[12] a local non-profit organisation that raises funds from recycling the bread tags to buy wheelchairs for those who cannot afford them.

Conclusion

We hope that this series of three cases of laryngeal obstruction by an apparently

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harmless household object, the plastic bread tag, will draw the attention of the medical fraternity and indeed the public to the potential menace that these ubiquitous items represent. These tags should be redesigned in a safer format, or removed from use. 1. Cohen S, Avital A, Godfrey S, et al. Suspected foreign body inhalation in children: What are the indications for bronchoscopy? J Pediatr 2009;155(2):276-280. [http://dx.doi.org/10.1016/j. jpeds.2009.02.040] 2. Bloom DC, Christenson TE, Manning SC, et al. Plastic laryngeal FBs in children: A diagnostic challenge. Int J Pediatr Otorhinolaryngol 2005;69(5):657-662. [http://dx.doi.org/10.1016/j. ijporl.2004.12.006] 3. Lehmer LM, Ragsdale BD, Daniel J, et al. Plastic bag clip discovered in partial colectomy accompanying proposal for phylogenic plastic bag clip classification. BMJ Case Rep 2011, published online 5 September 2011. [http://dx.doi.org/10.1136/bcr.02.2011.3869] 4. Sutton G. Hidden dangers of sliced bread. BMJ 1984;28:1995. [http://dx.doi.org/10.1136/ bmj.288.6435.1995-b]

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5. Rosow DE, Chen S. Office removal of a subglottic bread clip. Case Rep Otolaryngol Volume 2013 (2013), Article ID 480676, 3 pages. [http://dx.doi.org/10.1155/2013/480676] 6. Halvorson DJ, Merritt RM, Mann C, Porubsky ES. Management of subglottic foreign bodies. Ann Otol Rhinol Laryngol 1996;105(7):541-544. [http://dx.doi.org/10.1177/000348949610500709] 7. Rodrigues AJ, Oliveira EQ, Scordamaglio PR, et al. Flexible bronchoscopy as the first-choice method of removing foreign bodies from the airways of adults. J Bras Pneumol 2012;38(3):315-320. [http:// dx.doi.org/10.1590/S1806-37132012000300006] 8. Swanson KL, Prakash UBS, Midthun DE. Flexible bronchoscopic management of airway foreign bodies in children. Chest 2002;121(5):1695-700. [http://dx.doi.org/10.1378/chest.121.5.1695] 9. Beer TW. Fatalities from bread tag ingestion. Med J Aust 2002;176(10):506. 10. Ellul J, Hodgkinson PD. Problems with a plastic bread bag clip. Arch Emerg Med 1987;6(2):156-157. [http://dx.doi.org/10.1136/emj.6.2.156] 11. Tang A, Kong AB, Walsh D, Verma R. Small bowel perforation due to a plastic bread bag clip: The case for clip redesign. Aust NZ J Surg 2005;75(5):360-362. [http://dx.doi.org/10.1111/j.14452197.2005.03356.x] 12. http://www.breadtagsforwheelchairs.co.za (accessed 7 April 2015).

Accepted 18 March 2015.

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RECOMMENDATIONS

Updated recommendations for the management of upper respiratory tract infections in South Africa A J Brink, M F Cotton, C Feldman, H Finlayson, R L Friedman, R Green, W Hendson, M H Hockman, G Maartens, S A Madhi, G Reubenson, E J Silverbauer, I L Zietsman Dr Adrian Brink is a consultant clinical microbiologist at Ampath National Laboratory Services, Milpark Hospital, Johannesburg, South Africa; Prof. Mark Cotton is head of the Division of Paediatric Infectious Diseases, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Children’s Hospital, Cape Town, South Africa; Prof. Charles Feldman is head of the Division of Pulmonology, Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; Prof. Heather Finlayson is a consultant at the Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Children’s Hospital, Cape Town; Dr Ray Friedman is an otorhinolaryngologist at Mediclinic Sandton and Netcare Linksfield Clinic, Johannesburg; Prof. Rob Green is head of the Department of Paediatrics and Child Health, University of Pretoria, South Africa; Dr Willy Hendson is a consultant in Paediatric Cardiology, Department of Paediatrics and Child Health, Rahima Moosa Mother and Child Hospital, Faculty of Health Sciences, University of the Witwatersrand; Dr Maurice Hockman is an otorhinolaryngologist at Netcare Linksfield Hospital, Johannesburg; Prof. Gary Maartens is head of the Division of Clinical Pharmacology, Department of Medicine, University of Cape Town; Prof. Shabir Madhi is Executive Director of the National Institute for Communicable Diseases and Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand; Dr Gary Reubenson is a consultant in the Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand and Rahima Moosa Mother and Child Hospital, Johannesburg; Dr Eddie Silverbauer is a consultant clinical microbiologist at Ampath National Laboratory Services, Sunninghill and Waterfall hospitals, Johannesburg; and Dr Inge Zietsman is a consultant clinical microbiologist at Ampath National Laboratory Services, Sandton, and Morningside Clinic, Johannesburg. The authors constitute the Working Group of the Infectious Diseases Society of Southern Africa. Corresponding author: A J Brink (brinka@ampath.co.za)

Background. Inappropriate use of antibiotics for non-severe upper respiratory tract infections (URTIs), most of which are viral, significantly adds to the burden of antibiotic resistance. Since the introduction of pneumococcal conjugate vaccines in South Africa in 2009, the relative frequency of the major bacterial pathogens causing acute otitis media (AOM) and acute bacterial rhinosinusitis (ABRS) has changed. Recommendations. Since URTIs are mostly viral in aetiology and bacterial AOM and ABRS frequently resolve spontaneously, these recommendations include diagnostic criteria to assist in separating viral from bacterial causes and hence select those patients who do not require antibiotics. Penicillin remains the drug of choice for tonsillopharyngitis and amoxicillin the drug of choice for both AOM and ABRS. A dose of 90 mg/kg/d is recommended for children, which should be effective for pneumococci with high-level penicillin resistance and will also cover most infections with Haemophilus influenzae. Amoxicillin-clavulanate (in high-dose amoxicillin formulations available for both children and adults) should be considered the initial treatment of choice in patients with recent antibiotic therapy with amoxicillin (previous 30 days) and with resistant H. influenzae infections pending the results of studies of local epidemiology (β-lactamase production ≥15%). The macrolide/azalide class of antibiotics is not recommended routinely for URTIs and is reserved for β-lactam-allergic patients. Conclusion. These recommendations should facilitate rational antibiotic prescribing for URTIs as a component of antibiotic stewardship. They will require updating when new information becomes available, particularly from randomised controlled trials and surveillance studies of local aetiology and antibiotic susceptibility patterns. S Afr Med J 2015;105(5):345-352. DOI:10.7196/SAMJ.8716

1. Background

The initial and subsequent revised upper respiratory tract infection (URTI) guideline for South Africa (SA) was published in 2004 and in 2008 in the SAMJ and the South African Journal of Epidemiology and Infection, respectively.[1,2] In 2014, new multidisciplinary experts were invited to join the original working group of the Infectious Diseases Society of Southern Africa to prepare the current recommendations. The methods used are similar to those described before, and the process was done electronically, including review from international experts. There is a worldwide increase in antibiotic resistance, and studies suggest that this is contributed to by inappropriate use of antibiotics, particularly for URTIs.[3] Viral infections cause the majority of URTIs. All clinicians should know the natural history of the ‘common cold’ so that a deviation from normal can be managed effectively. Most

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important is an appreciation that clear nasal secretions frequently become purulent without signifying secondary bacterial disease, and that coughing is a normal accompaniment (Fig. 1). The organisms responsible for most bacterial URTIs are similar in all age groups. Streptococcus pneumoniae (the pneumococcus) was previously the most common bacterial cause of acute otitis media (AOM) and sinusitis. Haemophilius influenzae has replaced pneumococci as the most frequently isolated pathogen following routine vaccination of children with pneumococcal conjugate vaccines (PCVs) (PCV-7 was introduced in SA in 2009 and replaced by PCV-13 in 2011).[4] Systematic reviews suggest that in high-income countries the benefit of antibiotics for acute pharyngotonsillitis, AOM and acute bacterial rhinosinusitis (ABRS) is extremely limited.[5-7] For example, 13 (95% confidence interval (CI) 9 - 22) adults with ABRS require antibiotics

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to benefit one.[5] However, there are few data from low- and middle-income countries, where rheumatic fever and suppurative complications such as mastoiditis are more common. Through simple recommendations of antibiotics with a relatively narrow spectrum, patients ought to be well managed, serious complications avoided and the propensity to select for resistance minimised. The most frequently recommended initial antibiotics of choice for URTIs therefore remain penicillin and amoxicillin. The recommendations for duration of therapy differ: ABRS and acute pharyngo tonsillitis should be treated for 5 and 10 days, respectively, and AOM for 5 or 7 days. Recent evidence suggests that a shorter duration of antibiotic treatment is associated with less emergence of resistant pathogens.[8] Duration will always depend on clinical response, and in some patients antibiotic duration may

need to be shortened or prolonged. However, 10 days of oral penicillin is required to eradicate group A β-haemolytic streptococci (GABHS) (S. pyogenes) in patients with pharyngotonsillitis. The recommendations for frequency of administration vary according to the site of infection and the pharmacokinetic/ pharmacodynamic (PK/PD) profiles of the drugs used. In AOM a twice-daily dose of amoxicillin has the same clinical efficacy as amoxicillin administered three times a day. For optimal clinical success, the antibiotic dosage must be tailored to the individual. A common cause of treatment failure and antibiotic resistance is suboptimal dosing. For example, in AOM 5 mL is erroneously prescribed as a standard dose for a child weighing 5 - 15 kg, instead of individualising doses by body mass. Dosages in this guideline include both the registered standard doses and higher doses,

Nasal stuffiness and throat irritation

Low-grade fever, malaise, myalgia

and/or

Sneezing and watery nasal discharge

and/or

Mucopurulent secretions 1 - 3 days later

Coughing in 60 - 80% of cases (does not imply bacterial disease)

Persists up to 10 days in 35% of cases

which are recommended where high-level antibiotic resistance is reported (see Tables 6 and 7). All paediatric doses are given as mg/ kg per dose, followed by frequency of daily administration. Recommendations have been made based on surveillance of appropriate pathogens and relevant publications.[4,9,10] For S. pneumoniae, an important pathogen causing AOM and ABRS, resistance to β-lactam antibiotics can be overcome by increasing antibiotic dosage. For example, a higher dose of amoxicillin of 90 mg/ kg/d is recommended for AOM and ABRS. Amoxicillin should be effective for H. influenzae not producing β-lactamases. Because of concerns of high-level macrolide resistance among isolates of S. pneumoniae in some areas of practice in SA, this class is reserved for patients with severe β-lactam antibiotic allergy. Furthermore, in terms of PK/PDs and clinical studies that include microbiological efficacy results, all macrolides, including azithromycin, are ineffective in eradicating H. influenzae. Recommendations for initial antibiotics of choice as well as alternative choices of antibiotics are given. The first-line antibiotics penicillin or amoxicillin remain the agents of choice. The indications for alternative antibiotics may include the following: • Allergy or intolerance to first-line agents • Recent prior use of first-line agents • Complicated and/or severe initial presentation • High-risk cases likely or known to be infected with highly resistant organisms • Failed initial therapy. These recommendations are based on best practice, taking into account unique local circumstances.

2. Acute pharyngotonsillitis

Acute pharyngotonsillitis is an inflammatory condition of the pharyngeal wall, often divided into pharyngitis and tonsillitis. Respiratory viruses, including adenoviruses, Coxsackie

Persists up to 10 days in 31% of cases

Fig. 1. Natural history of the common cold.

Table 1. Diagnostic and treatment criteria for acute pharyngotonsillitis 1. Symptoms suggestive of acute pharyngitis/tonsillitis are sore throat, fever, difficulty in swallowing, halitosis, etc. However, clinicians’ ability to differentiate GABHS pharyngitis from other causes is limited. Therefore: 2. The prescence of coryza, cough, conjunctivitis, hoarseness, anterior stomatitis, discrete ulcerative lesions or diarrhoea makes GABHS unlikely, and no antibiotics are recommended. 3. If none of the above symptoms is present, two alternative approaches are recommended: • A throat swab for GABHS: if positive, prescribe antibiotics* • No throat swab for GABHS: empiric antibiotic therapy for patients aged 3 - 21 years† 4. Tender anterior cervical lymphadenopathy, pharyngeal erythema or exudate increases the likelihood of GABHS pharyngitis. *A delay in antibiotic prescription pending availability of culture results does not reduce efficacy in ARF prevention. † Throat swabs for GABHS confirmation may be not be feasible in many SA settings owing to increased direct and indirect financial expenditure and additional healthcare visits.

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Table 2. Penicillin recommendations for acute pharyngotonsillitis Children Penicillin VK, 250 mg twice daily for 10 days (<27 kg) or 500 mg twice daily for 10 days (>27 kg) (given 30 minutes before food) Benzathine penicillin (intramuscular injection) 3 - 5 years: 600 000 U >5 years: 1.2 MU* Adolescents and adults Penicillin VK, 500 mg twice daily for 10 days (given 30 minutes before food) Benzathine penicillin (intramuscular injection) 1.2 MU* *1.2 MU as a single dose. To minimise the discomfort of parenteral administration, the medication should be given at room temperature. For patients receiving 1.2 million U, 300 000 U can be given as procaine penicillin. Alternatively, dilute benzathine penicillin with 1% lidocaine.

A virus, influenza virus, parainfluenza virus and Epstein-Barr virus (EBV), are the major cause of pharyngitis. Bacteria, especially GABHS (S. pyogenes), account for 5 - 30% of cases.[11] Correctly performed throat culture has a sensitivity of 90 - 95% for detecting GABHS. Non-infectious causes of pharyngitis include allergy and exposure to irritating substances. Most cases of viral and bacterial acute pharyngitis are self-limiting, including those caused by GABHS, so the primary reason for considering antibiotic therapy is to prevent acute rheumatic fever (ARF). Of note, as approximately two-thirds of patients with ARF have no preceding sore throat, antibiotics have only a limited ability to reduce the incidence of ARF. Patients with rheumatic heart disease or prior episode(s) of ARF should receive secondary penicillin prophylaxis, but require antibiotic therapy for acute pharyngitis (suggestive of GABHS) initially (Table 1).

2.1 Antibiotic recommendations for streptococcal pharyngotonsillitis

The treatment of choice is penicillin (Table 2). 2.1.1 Penicillin Penicillin reduces the risk of ARF and provides some symptom relief in GABHS.[12] A single dose of intramuscular benzathine penicillin is adequate, but oral therapy may be preferred if compliance is considered likely. The mixture of benzathine penicillin and procaine penicillin gives a less painful injection.[13] Alternatively, a dilution of benzathine penicillin with 1% lidocaine has been shown to be well tolerated.[14] When given by mouth, penicillin can be given twice or three times daily instead of four times a day. Penicillin should be given 30 minutes before a meal, as food reduces its absorption. A 10-day course is recommended. An important point in favour of continued use of penicillin is the lack of resistance by GABHS, as opposed to the use of erythromycin and other macrolides, where widespread use promotes resistance.[15,16] An additional advantage of penicillin is its

Table 3. Amoxicillin recommendations for acute pharyngotonsillitis Children* Amoxicillin 50 mg/kg/d once daily (maximum 1 000 mg) for 10 days Adolescents and adults* moxicillin 500 - 1 000 mg twice daily (alternatively, 50 mg/kg/d once daily (maximum A 3 000 mg)) for 10 days *Dose to the closest increment of 125 mg.

Table 4. Recommendations for β-lactam allergy in acute pharyngotonsillitis Children Azithromycin 10 - 20 mg/kg/d once daily for 5 days Clarithromycin 15 mg/kg/d, divided into two doses, for 10 days Adolescents and adults Azithromycin 500 mg once daily for 3 days Clarithromycin 500 mg twice daily or 500 mg modified-release once daily for 10 days

narrow spectrum of activity, which reduces the risk of selection of resistance. 2.1.2 Amoxicillin Amoxicillin is an alternative to penicillin VK and has the advantage of no food restrictions (Table 3). However, a rash can occur when pharyngotonsillitis is caused by EBV infection, which can lead to an erroneous diagnosis of penicillin allergy or, rarely, a severe skin reaction. However, recent evidence suggests that this rash is much less common with amoxicillin (~30% risk in confirmed EBV infection) than with ampicillin. Several trials have demonstrated non-inferiority of oncedaily amoxicillin to twice-daily amoxicillin or penicillin V.[17,18] Once-daily regimens may improve patient adherence. 2.1.3 Alternative antibiotic choices 2.1.3.1 Short-course therapy (5 days) Short-course therapy with several antibiotics including the cephalo sporins (cefuroxime, cefprozil, cefpodoxime) has been shown to be non-inferior to a 10-day course of penicillin

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VK.[6] However, whether shorter courses provided similar reduction in ARF is unknown. Furthermore, cephalosporins are broaderspectrum agents than penicillin/amoxicillin and have a greater propensity to select for resistance. A 10-day course of penicillin or amoxicillin is therefore recommended. 2.1.3.2 Antibiotics for β-lactam allergy Macrolide/azalide resistance in GABHS is a major concern, and use of these agents should therefore be restricted to penicillin-allergic patients (Table 4).

2.2 Symptom relief

The mainstay of the management of acute pharyngitis is symptom atic. This includes adequate analgesia and antipyretics for the relief of fever-related symptoms (generally paracetamol or ibuprofen), and sufficient hydration.

3. Acute otitis media

AOM is a common childhood illness – 75% of children have at least one episode by 3

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years of age. However, AOM is often misdiagnosed (Table 5). The main bacterial causes of AOM are S. pneumoniae, non-typeable H. influenzae, and Moraxella catarrhalis. Since the introduction in RSA of PCV-7 in 2009, followed by PCV-13 in 2011, the relative frequency of these three major middle ear pathogens has changed. H. influenzae has replaced S. pneumoniae as the most frequently isolated middle ear pathogen.[4] Up to 12.2% (range 9.5 - 15.5%) of H. influenzae isolated from respiratory tract infections in SA produce β-lactamase, and this is even more frequent if the child was recently on antibiotics, resulting in resistance to penicillins.[10] As otitis media may be part of neonatal sepsis, any neonate with AOM and fever requires evaluation for sepsis. Causative organisms in neonatal AOM include coliforms, group B β-haemolytic streptococci and Staphylococcus aureus.

3.1 Treatment of AOM

As AOM is often viral in aetiology, with even bacterial AOM frequently resolving spontaneously, antibiotics may be deferred for 48 hours while symptomatic therapy is administered, except for AOM cases associated with a bulging tympanum and a temperature of >38°C, where, although this is controversial, immediate treatment is recommended. In addition, if symptoms persist or worsen, antibiotics should be started. A useful approach is to provide a prescription to be filled only if no improvement by 48 hours; this approach is reasonable where good follow-up is possible in children ≥2 years of age. However, in patients with limited access to healthcare and because of the risks of a serious infection with S. pneumoniae and/ or H. influenzae, we recommend that treatment commence from the first visit, provided the AOM is correctly diagnosed. Antibiotics should be considered especially in the following cases: • Recurrent AOM • Immunocompromised patients • Neonates • Structural ENT or immunological abnormalities • Fever (temperature >38°C) or pain >48 hours • Day-care attendees or siblings of children attending day-care centres. Risk factors for resistant S. pneumoniae infections include age (≤2 years), attendance at day-care centres or siblings of children attending day-care centres, not vaccinated with PCVs, prior AOM within the past

6 months, and antibiotic treatment within the past 3 months. These influence the choice and dosage of antibiotics. Risk factors for resistant H. influenzae infections have not been elucidated, but a recent course of antibiotics that are not resistant to β-lactamases (i.e. amoxicillin) increases the risk for β-lactamase-producing H. influenzae. Paracetamol (10 - 15 mg/kg 4 - 6-hourly) or ibuprofen (5 - 10 mg/ kg 8-hourly) can be given for symptom relief (avoid under- and overdosing). Although decongestants are widely prescribed for rhinitis, their use in AOM is controversial and generally discouraged. If used, topical nasal application for a maximum of 3 days is preferable.

3.2 AOM with tympanostomy tubes (AOMT)

AOM with otorrhoea in patients with tympanostomy tubes is considered a separate clinical entity, since in a child with glue ear a biofilm disease is present, so acute otitis in this situation represents acute exacerbation of a chronic process. This is a common problem, and culture of otorrhoea fluid will often show significant growth of bacteria such as Pseudomonas aeruginosa and S. aureus in addition to the usual pathogens. As β-lactams do not cover the entire spectrum of organisms cultured, a topical otological formulation of ciprofloxacin is an efficacious therapeutic option for managing AOMT, avoiding oral treatment.[19] The advantages of topical antibiotics administered correctly, rather than systemic antibiotics, include significantly higher tissue levels, substantially reduced adverse effects and, perhaps most importantly, considerably less likelihood of antimicrobial resistance.

3.3 Antibiotic choices for AOM

The initial antibiotic treatment of choice, except in neonates, is amoxicillin. Amoxicillin-clavulanate is recommended as the initial antibiotic treatment of choice for suspected resistant H. influenzae, particularly if there is history of prior antibiotic use (preceding 30 days) with an antibiotic that was not β-lactamase stable (e.g amoxicillin), or if local data show a high proportion (≥15%) of resistance to amoxicillin (mediated by β-lactamase production). 3.3.1 Amoxicillin The recommended dosage of amoxicillin is 80 - 90 mg/kg/d. This higher dose is associated with a better eradication of H. influenzae and

Table 5. Diagnostic criteria for AOM 1. AOM is defined as an acute upper respiratory tract infection, affecting one or both ears (often associated with infection in the rest of the upper respiratory tract), presenting with: • Otalgia (holding, tugging, rubbing of the ear in a non-verbal child) • Hearing loss • Pyrexia, with nausea and dizziness that may develop concurrently 2. Symptom presentation varies with age. However, as typical symptoms overlap with other conditions, a clinical history alone is not sufficient to predict whether AOM is present. The middle ear mucositis develops an effusion, in this case suppuration, as evidenced by a tympanic membrane that may become: • Red • Oedematous • Immobile • Bulging 3. Hence, to confirm the diagnosis, middle ear effusion and inflammation of the eardrum have to be identified by visualisation of the tympanic membrane (TM). Signs of these are fullness, bulging, cloudiness and redness of the TM. Pneumotoscopy and tympanometry are very useful in determining the presence of a middle ear effusion. Other causes of a ‘red’ TM include crying, otitis externa, myringitis and barotrauma. AOM is as a consequence frequently misdiagnosed. Similarly, over-diagnosis is common.

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overcomes high-level penicillin-resistant pneumococci, particularly prevalent for: • Age ≤2 years • Day-care attendees or siblings of children attending day-care centres • AOM in previous 6 months • Antibiotic administration during 30 days preceding the AOM episode. 3.3.2 Amoxicillin-clavulanate The addition of a β-lactamase inhibitor (clavulanate) extends the spectrum of amoxicillin to include β-lactamase-producing H. influenzae and M. catarrhalis. A high-dose amoxicillin-clavulanate preparation (90 mg/ kg amoxicillin and a constant amount of clavulanate of 6.4 mg/kg) is available in a paediatric formulation. This gives dosages adequate to also eradicate S. pneumoniae that are susceptible to or have high-level resistance to penicillin. This formulation may not be available in all SA sectors. In order to achieve the higher dose, additional amoxicillin can be added to standard-dose amoxicillin-clavulanate formulations to achieve an amoxicillin concentration of 80 - 90 mg/kg, which is better than simply doubling the doses of standard preparations (additional clavulanate is not required, and maintaining the clavulanate dose lowers the risk of gastrointestinal side-effects). Similarly, if the high-dose amoxicillinclavulanate formulation (2 000 mg amoxicillin-125 mg clavulanate) that is registered for adults is not available, additional amoxicillin (1 000 mg) can be added to a standard-dose amoxicillin-clavulanate formulation (e.g. 875 mg amoxicillin-125 mg clavulanate).

3.3.3 Oral cephalosporins

Cefuroxime axetil and cefpodoxime are the only oral cephalo sporins that give middle ear fluid (MEF) levels sufficiently above

the minimum inhibitory concentration (MIC) for both penicillinsensitive and some intermediate-resistant S. pneumoniae and for H. influenzae.[20] Considering the high prevalence of β-lactam resistance in many areas of SA, these cephalosporins should be prescribed at the higher dosages detailed below if used to treat AOM. Based upon PK/PD findings and clinical trials of AOM, cefuroxime axetil and cefpodoxime are expected to fail in many cases of penicillin-intermediate and resistant pneumococcal strains, while cefprozil (15 mg/kg twice daily) should not be used empirically in this setting, as it is only effective against penicillin-susceptible pneumococci. [21] Cefaclor, cefixime and loracarbef are less active in vitro against S. pneumoniae and are not recommended. 3.3.4 Parenteral cephalosporins The MEF concentration of ceftriaxone exceeds the MICs for AOM pathogens for >50 hours after a single 50 mg/kg intramuscular injection. However, a 3-day regimen is clinically superior, particularly in non-responsive AOM caused by penicillin-resistant S. pneumoniae.[22] Ceftriaxone use should be reserved for failure of high-dose amoxicillin-clavulanate, for severe presentations, or if oral administration is unreliable. These scenarios may require specialist consultation. 3.3.5 Macrolides/azalides The erm gene mutation causing high-level resistance to macrolides, which cannot be overcome by dose increase, has been identified in the majority of erythromycin-resistant S. pneumoniae strains in some sectors in SA.[23] Macrolides are therefore not recommended for routine empirical antibiotic therapy of S. pneumoniae infections and are reserved for type 1 β-lactam hypersensitivity. Furthermore, in terms of PK/PDs

Table 6. Antibiotic recommendations for children with AOM or ABRS Initial antibiotic treatment Recommended drug of choice Amoxicillin (80 - 90 mg/kg/d divided into 2 doses) <2 years 7 days >2 years 5 days OR Amoxicillin-clavulanate* (90 mg/kg/d amoxicillin-6.4 mg/ kg/d clavulanate divided into 2 doses) Cefuroxime† (30 mg/kg/d divided into 2 doses) Cefpodoxime† (16 mg/kg/d divided into 2 doses) <2 years 7 days >2 years 5 days

Failure of initial antibiotic treatment after 48 - 72 hours Alternative treatment if penicillin allergy (non-type 1) Azithromycin (10 mg/kg once daily) for 3 days Clarithromycin (15 - 30 mg/ kg/d divided into 2 doses) for 5 days Erythromycin estolate (40 mg/ kg/d divided into 4 doses) for 5 days

Recommended drug of choice Amoxicillin-clavulanate* (90 mg/kg/d amoxicillin-6.4 mg/kg/d clavulanate divided into 2 doses) <2 years 7 - 10 days > 2years 5 - 7 days OR Ceftriaxone§ (50 mg/kg/d IM or IV once daily) for 3 days

Alternative treatment if penicillin allergy (type 1) Levofloxacin‡ (20 mg/kg/d once daily or divided into 2 doses) for 5 days

Alternative treatment Ceftriaxone§ (50 mg/kg/d IM or IV once daily) for 3 days Clindamycin (90 - 150 mg/kg/d divided into 3 doses) with or without a second- or third-generation cephalosporin† for 5 - 7 days Failure of antibiotic therapy, severe toxicity and/or progression beyond the middle ear Refer for further evaluation and management

IM = intramuscular; IV = intravenous. *If the high-dose amoxicillin-clavulanate formulation (90 mg/kg/d amoxicillin-6.4 mg/kg/d clavulanate) is not available, standard-dose amoxicillin-clavulanate (e.g. 45 mg/kg/d amoxicillin-6.4 mg/ kg/d clavulanate divided into 2 doses) plus additional amoxicillin (40 - 45 mg/kg/d divided into 2 doses) can be used. Amoxicillin-clavulanate may be considered first-line therapy in patients with: • Recent amoxicillin therapy (previous 30 days) • Concurrent conjunctivitis[7] • Complicated initial presentations, e.g. periorbital oedema in cases of ABRS • Suspected resistant H. influenzae pending local epidemiology (% β-lactamase production) • Additional risk factors for AOM caused by β-lactamase-producing pathogens may include immunocompromised patients and/or neonates. † Cephalosporins are alternative β-lactamase-stable agents available for the treatment of AOM. The higher dosages of cephalosporins recommended would cover for most pneumococcal isolates of intermediate resistance to penicillin, but not necessarily for pneumococcal isolates with high-level resistance. The particular choice of cephalosporins would depend on physician or patient preference, availability and cost. The cephalosporins (second or third generation) may also be used as alternative treatment for non-type 1 β-lactam allergies (refer to section 5, β-lactam allergy). ‡ For children with a complicated and/or severe initial presentation and a history of immediate type 1 hypersensitivity response to penicillin, levofloxacin is recommended as an alternative to amoxicillin-clavulanate or ceftriaxone (refer to section 5, β-lactam allergy). Confirmed β-lactam type 1 hypersensitivity (positive skin test) is the only scenario in which levofloxacin in URTIs in children is recommended. § Ceftriaxone may also be used as first-line therapy in complicated initial presentations, e.g. periorbital oedema in cases of ABRS, preferably in consultation with an otorhinolaryngologist.

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Table 7. Antibiotic recommendations for adults with ABRS or AOM Initial antibiotic treatment Recommended drug of choice Amoxicillin (1 g 8-hourly) for 5 days OR Amoxicillin-clavulanate* (2 000 mg amoxicillin-125 mg clavulanate 12-hourly) for 5 days Cefuroxime† (1 000 mg 12-hourly) for 5 days Cefpodoxime† (400 mg 12-hourly) for 5 days

Failure of initial antibiotic treatment after 48 - 72 hours Alternative treatment if penicillin allergy Telithromycin (800 mg once daily) for 5 days Gemifloxacin (320 mg once daily) for 5 days Levofloxacin (500 mg 12-hourly or 750 mg once daily) for 5 days Moxifloxacin (400 mg once daily) for 5 days

Recommended drug of choice Amoxicillin-clavulanate* (2 000 mg amoxicillin-125 mg clavulanate 12-hourly) for 5 - 7 days Telithromycin (800 mg once daily) for 5 - 7 days Gemifloxacin (320 mg once daily) for 5 - 7 days Levofloxacin (500 mg 12-hourly or 750 mg once daily) for 5 - 7 days Moxifloxacin (400 mg once daily) for 5 - 7 days Clindamycin‡ (450 mg 8-hourly) for 5 - 7 days Ceftriaxone§ for 3 days (IV/IM)

Failure of antibiotics, severe toxicity and/or progression outside of the sinuses Refer to otorhinolaryngologist for further evaluation and management

IV = intravenous; IM = intramuscular. *If the high-dose amoxicillin-clavulanate formulation (2 000 mg amoxicillin-125 mg clavulanate) is not available, the standard-dose amoxicillin-clavulanate formulation (875 mg amoxicillin-125 mg clavulanate 12-hourly) plus additional amoxicillin (1 000 mg 12-hourly) can be used. Amoxicillin-clavulanate may be considered first-line therapy in patients with: • Recent amoxicillin therapy (previous 30 days) • Recurrent ABRS • Suspected resistant H. influenzae pending local epidemiology (% β-lactamase production) • Additional risk factors for ABRS caused by β-lactamase-producing pathogens may include immunocompromised patients, including pregnant patients and diabetics. † The higher dosages of cephalosporins recommended would cover for most pneumococcal isolates of intermediate resistance to penicillin, but not necessarily for pneumococcal isolates with highlevel resistance. The particular choice of cephalosporins would depend on physician or patient preference, availability and cost. The cephalosporins (second or third generation) may also be used as alternative treatment for non-type 1 β-lactam allergies (refer to section 5, β-lactam allergy). ‡ Clindamycin use is restricted to confirmed pneumococcal ABRS unresponsive to β-lactam antibiotics or as additional therapy to provide for anaerobic and S. aureus cover, despite the lack of clinical evidence at this time of the safety or efficacy of combination therapy for ABRS. § Ceftriaxone or the respiratory fluoroquinolones may also be used as first-line therapy in complicated initial presentations, e.g. periorbital oedema, preferably in consultation with an otorhinolaryngologist.

and clinical studies with microbiological results, all macrolides, including azithromycin, are not effective in eradication of H. influenzae.

3.6.2 Adults For adults, AOM and ABRS have identical treatment (Table 7).

3.3.6 Trimethoprim-sulfamethoxazole (TMP-SMX) The high rate of resistance of S. pneumoniae and H. influenzae in SA precludes using TMP-SMX. High bacteriological failure rates have been noted in double-tap studies.[24]

3.7 Antibiotic recommendations for AOMT

3.4 Duration of therapy for AOM

Most antibiotics are clinically effective for uncomplicated AOM in regimens of 5 days, since eradication of organisms takes place within 72 hours.[25] However, therapy beyond 72 hours is required for adequate eradication of potentially pathogenic bacteria colonising the nasopharynx, which otherwise predispose to relapses of AOM. Further studies are needed to determine the optimal duration of therapy in children <2 years of age or with non-responsive AOM.[20,26] Until then, therapy for 7 days is recommended for AOM in the following groups: • Age ≤2 years • Recurrent or chronic AOM • Complicated AOM.

3.5 Failure to respond to antibiotics in AOM

For clinical failure (e.g. persistent fever) after 48 - 72 hours of appropriate, compliant initial antibiotic therapy, consider referral to an otorhinolaryngologist for tympanocentesis and MEF culture. This is relevant in areas with a high prevalence of antibiotic-resistant S. pneumoniae, as are the majority of major urban centres in SA.

3.6 Antibiotic recommendations for AOM

3.6.1 Children Antibiotic recommendations for children are set out in Table 6.

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The recommended topical formulation contains ciprofloxacin 0.3% and dexamethasone 0.1% in an otic suspension, applied four drops twice daily for 7 days. The technique of application of the drops is essential to the success of this treatment regimen. Aural toilet by suctioning must be performed before instilling the drops into the external auditory canal, and must be followed by tragal pressure to push the drops through the tympanostomy tubes into the middle ear. A disposable nasal aspirator may be used for suctioning at home.

4. Acute bacterial rhinosinusitis

ABRS is usually preceded by a viral URTI. Allergy, trauma, dental infection or other factors leading to inflammation of the nose and paranasal sinuses may also predispose individuals to ABRS. The most common bacterial isolates from the maxillary sinuses in ABRS are similar to AOM, namely S. pneumoniae, H. influenzae and M. catarrhalis. However, both the prevalence of H. influenzae and the proportion of β-lactamase-producing H. influenzae have markedly increased in URTIs, including ABRS in children and adults, since the widespread use of PCV. The diagnostic criteria for ABRS are set out in Table 8. Antibiotic therapy must be capable of eradicating S. pneumoniae, which, as in AOM, causes most of the serious sequelae. Other streptococci, anaerobic bacteria and S. aureus occur in a small percentage of cases. Chlamydophila pneumoniae and other ‘atypical’ pathogens should be considered in patients with chronic sinusitis. Fungi are rarely associated with sinusitis and may be seen in allergic sinusitis and immunocompromised hosts. However, their clinical

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Table 8. Diagnostic criteria for ABRS 1. Rhinosinusitis (all-cause including viral) is diagnosed when the following signs and symptoms are present: One of either: • Anterior or postnasal discharge With or without: • Facial pain/pressure • Change in sense of smell 2. Acute bacterial rhinosinusitis requiring antibiotics is only diagnosed if: Symptoms >10 days and <3 months Worsening of above symptoms (‘second sickening’) occurs in <10 days 3. Acute viral rhinosinusitis (often associated with the common cold) is diagnosed if: Symptoms <10 days Non-severe symptoms No ‘second sickening’ occurred

The duration of antibiotic treatment for ABRS is classically 10 days, based on published clinical trials in which pre- and post-treatment sinus aspirates were performed. However, evidence for moxifloxacin and telithromycin suggests that a shorter course of 5 - 7 days is clinically and/or bacteriologically equivalent to a 10-day course. Recent adult studies also show that bacteriological eradication occurs within 72 hours with moxifloxacin (400 mg once daily) or with high-dose, short-course

4.3.2 Adults Antibiotic recommendations for adults with ABRS or AOM are set out in Table 7.

5. Beta-lactam allergy

Severe lasting purulence or fever

4.1 Duration of antibiotic treatment for ABRS

4.3 Antibiotic recommendations for ABRS

4.3.1 Children Antibiotic recommendations for children with AOM or ABRS are set out in Table 6.

• Nasal obstruction

significance in immune-competent patients is unclear. Multiple factors play a role in antibiotic selection for ABRS. S. pneumoniae may be associated with serious intracranial and extrasinus complications, and hence requires adequate coverage in initial therapy. Cover for H. influenzae (and M. catarrhalis in children) should be considered. Prior antibiotic use is a major risk factor for antibiotic-resistant strains. Because recent antibiotic exposure increases the risk of carriage and infection with resistant organisms, the choice and dosage of antibiotic therapy must take into account a history of recent antibiotic use. Other factors to consider are the severity of disease, its rate of progression, and varying rates of resistance in SA. Regarding whether antibiotics are necessary for ABRS, recent meta-analyses of antibiotics v. placebo showed only marginal benefit.[5] Overall, 13 (95% CI 9 - 22) adults require antibiotics to benefit one patient.

with high prevalence of antibiotic-resistant S. pneumoniae, as are most major urban centres in SA.

levofloxacin (750 mg once daily for 5 days). This higher dose of levofloxacin improves its PK/PD profile, and in a comparative trial of this dose v. levofloxacin 500 mg once daily for 10 days, clinical and microbiological efficacy was similar. A recent meta-analysis examined the efficacy and safety of short v. longer courses of antibiotic therapy for adults with ABRS in 12 randomised controlled trials (RCTs).[5] No statistical difference in efficacy was noted between short-course (3 - 7 days) v. longcourse (6 - 10 days) antibiotic therapy (odds ratio (OR) 0.95; 95% CI 0.81 - 1.12). In addition, no differences in microbiological efficacy (OR 1.30; 95% CI 0.62 - 2.74), relapse rates (OR 0.95; 95% CI 0.63 - 1.37) or adverse effects (OR 0.88; 95% CI 0.71 - 1.09) were found. However, if only the studies that compared 5 days (short course) v. 10 days (long course) were included (five RCTs), adverse effects were significantly fewer for short-course treatment (OR 0.79; 95% CI 0.63 - 0.98). Data for children are inconclusive, however, as shorter courses of therapy have not been studied. The recommended duration of therapy for uncomplicated ABRS in adults is therefore 5 days.

4.2 Failure to respond to antibiotics in ABRS

For clinical failure (e.g. persistent fever) after 48 - 72 hours of appropriate, compliant antibiotic therapy, consider referral to an otorhinolaryngologist for further evaluation. A computed tomography scan, fibreoptic endoscopy or sinus aspiration and culture may be necessary. This is relevant in areas

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The high prevalence of penicillin nonsusceptibility and cross-resistance in S. pneumoniae has complicated the management of penicillin-allergic patients and limited the choice of alternative agents, particularly in children. Clinicians should differentiate an immediate type 1 IgE-mediated hypersensitivity reaction from other less dangerous types of hypersensitivity. Classic signs of type 1 hypersensitivity are anaphylaxis, angiooedema, urticarial rash and bronchospasm. If a type I hypersensitivity reaction to penicillin has occurred, all β-lactam antibiotics should be avoided unless there is no alternative drug available, when penicillin desensitisation can be attempted as an inpatient. Patients with other types of hypersensitivity reactions, usually a maculopapular rash on amoxicillin, should avoid all penicillins but may tolerate other β-lactam antibiotics such as cephalosporins. The first-generation cephalosporins should be avoided as they have a higher risk of cross-reactivity with penicillin, but this risk is much lower for second- or thirdgeneration cephalosporins (reported to be only 0.1%).[27,28] Consensus opinion suggests that if the previous reaction to penicillin was a maculopapular rash, it is relatively safe to use second- or third-generation cephalosporins, and use would depend on the patient’s social circumstances and access to followup. However, in patients with a remote history of a rash on penicillin, it is often difficult to differentiate a maculopapular rash from an urticarial rash – all β-lactam antibiotics should be avoided if urticaria occurred on penicillins, as this is a type 1 reaction. In this setting, skin testing before using a cephalosporin is recommended, as a positive reaction to penicillin indicates type 1 hypersensitivity.[5] In the latter patients, including children with a complicated and/or severe initial presentation and a history/confirmation of immediate type 1 hypersensitivity response to penicillin, levofloxacin is recommended

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as an alternative to amoxicillin-clavulanate or ceftriaxone. Owing to possible selection of resistance among pneumococci and other pathogens associated with widespread use, this is the only scenario in which levofloxacin in URTIs in children is recommended. Although levofloxacin’s safety profile in children has been studied extensively, the incidence of musculoskeletal events (arthritis or arthralgia and tendinopathy) involving weight-bearing joints was increased in levofloxacin-treated children.[5,29-31] Experience with moxifloxacin in children is relatively limited. Endorsement. These recommendations are endorsed by the Infectious Diseases Society of Southern Africa, the Southern African Society for Paediatric Infectious Diseases and the Federation of Infectious Diseases Societies of Southern Africa. Disclaimer. This statement is published for educational purposes only. The recommendations are based on currently available scientific evidence together with the consensus opinion of the authors. Adherence to these recommendations is voluntary and does not account for individual variation among patients; the recommendations are not intended to supplant physician judgement with respect to particular patients or special clinical situations. In addition, the recommendations do not indicate an exclusive diagnostic workup or course of treatment or serve as a standard of medical care. Review panel. R Dagan (Professor of Paediatric and Infectious Diseases, Soroka University Medical Center and Faculty for Health Sciences, BenGurion University, Beer-Sheva, Israel), K P Klugman (Professor of Infectious Diseases, Department of Global Health, The Rollins School of Public Health, Emory University, Atlanta, USA), M Mendelson (Head of the Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa). Author disclosures. A J Brink: GlaxoSmithKline/Aspen speaker’s bureau (SB); Sanofi Aventis SB, research grant (RG), research support (RS); MSD SB; Pfizer SB; M F Cotton: ViiV advisory board (AB); GlaxoSmithKline/Aspen RG; Gilead RG, Bristol-Myers Squibb grant investigator (GI); C Feldman: Abbott AB, SB; Astra-Zeneca SB; Sanofi Aventis SB; MSD AB SB; Pfizer AB SB; GlaxoSmithKline/Aspen AB, SB, Sandoz consultant (C); R L Friedman: Sanofi Aventis C, SB; GlaxoSmithKline/Aspen educational support (ES), SB; Takeda AB, ES; H Finlayson: none; R Green: AstraZeneca AB, ES, SB; Cipla AB, ES, SB; GlaxoSmithKline/Aspen, ES, SB; MSD AB, ES, SB; Mylan AB, ES, SB; Pfizer SB; Wyeth AB, ES, SB; H Hendson: none; M H Hockman: Sanofi Aventis AB, SB, ES; MSD AB, SB; Pfizer SB; Roche ES SB; GlaxoSmithKline/Aspen ES, SB, RS; Schering-Plough ES, SB; G Maartens: none; S A Madhi: Pfizer AB, GI, research contractor (RC), RG, SB; Sanofi Pasteur RC, SB; GlaxoSmithKline AB, GI, RC, RG, SB; Novartis RC, RG, AB; G Reubenson: Abbvie SB; Pfizer SB, ES; Sanofi Aventis research relationship (RR), ES; E J Silverbauer: none; I L Zietsman: GlaxoSmithKline/Aspen SB; Sanofi Aventis SB; MSD SB, ES; Pfizer ES. 1. Brink AJ, Cotton MF, Feldman C, et al. for the Working Group of the Infectious Diseases Society of South Africa. Guideline for the management of upper respiratory tract infections. S Afr Med J 2004;94(6):475-483.

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2. Brink AJ, Cotton MF, Feldman C, et al. for the Working Group of the Infectious Diseases Society of Southern Africa. Updated guideline for the management of upper respiratory tract infections in South Africa: 2008. S Afr J Epidemiol Infect 2008;23(4):27-40. 3. Jacobs MR. World trends in antimicrobial resistance among common respiratory tract pathogens in children. Pediatr Infect Dis J 2003;22(8):S109-S119. [http://dx.doi.org/10.1097/00006454-200303000-00005] 4. Hockman MH. The effect of Prevnar vaccination on otitis media in Gauteng, South Africa. Presented at the 11th European Symposium on Paediatric Cochlear Implantation (ESPCI), Istanbul, Turkey, 18-21 May 2013. 5. Chow AW, Benninger MS, Brook I, et al. IDSA Clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012;54(8):1041-1045. [http://dx.doi.org/10.1093/cid/cir1043] 6. Van Driel ML, De Sutter AIM, Keber N, Habraken H, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database Syst Rev 2013, Issue 4. Art. No.: CD004406. [http://dx.doi.org/10.1002/14651858.CD004406.pub3] 7. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics 2013;131(3):e964-e999. [http://dx.doi.org/10.1542/peds.2012-3488] 8. Pechere JC. Parameters important in short antibiotic courses. J Int Med Res 2000;28(Suppl 1):3A-12A. 9. Huebner RE, Wasas AD, Hockman M, Klugman KP, for the ENT Study Group. Bacterial aetiology of non-resolving otitis media in South African children. J Laryngol Otol 2003;117(3):169-172. [http:// dx.doi.org/10.1258/002221503321192430] 10. Zietsman IL, Brink AJ. National surveillance of private sector respiratory tract pathogens in South Africa, 2010. S Afr J Epidemiol Infect 2011;26(2):51-53. 11. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 Update by the Infectious Diseases Society of America. Clin Infect Dis 2012;55(10):1-17 [http://dx.doi.org/10.1093/cid/cis629] 12. Arguedas A, Mohs E. Prevention of rheumatic fever in Costa Rica. J Pediatr 1992;121(4):569-572. [http://dx.doi.org/10.1016/S0022-3476(05)81146-1] 13. Bass JW. A review of the rationale and advantages of various mixtures of benzathine penicillin G. Pediatrics 1996;97(6):960-963. 14. Amir J, Ginat S, Cohen YH, Marcus TE, Keller N, Varsano I. Lidocaine as a diluent for administration of benzathine penicillin G. Pediatr Infect Dis J 1998;17(10):890-893. [http://dx.doi. org/10.1097/00006454-199810000-00008] 15. Dicuonzo G, Fiscarelli E, Gherardi G, et al. Erythromycin-resistant pharyngeal isolates of Streptococcus pyogenes recovered in Italy. Antimicrob Agents Chemother 2002;46(12):3987-3990. [http://dx.doi. org/10.1128/AAC.46.12.3987-3990.2002] 16. Reinert RR, Lutticken R, Bryskier A, Al-Lahham A. Macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes in the pediatric population in Germany during 2000-2001. Antimicrob Agents Chemother 2003;47(2):489-493. [http://dx.doi.org/10.1128/AAC.47.2.489-493.2003] 17. Clegg HW, Ryan AG, Dallas SD, et al. Treatment of streptococcal pharyngitis with once-daily compared with twice-daily amoxicillin. Pediatr Infect Dis J 2006;25(9):761-767. [http://dx.doi.org/10.1097/01. inf.0000235678.46805.92] 18. Lennon DR, Farrell E, Martin DR, Stewart JM. Once-daily amoxicillin versus twice-daily penicillin V in group A β-haemolytic streptococcal pharyngitis. Arch Dis Child 2008;93(6):474-478. [http://dx.doi. org/10.1136/adc.2006.113506] 19. Dohar J, Giles W, Roland P, et al. Topical ciprofloxacin/dexamethasone superior to oral amoxicillin/ clavulanic acid in acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2006;118(3):e561-e569. [http://dx.doi.org/10.1542/peds.2005-2033] 20. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J 1996;15(3):255-259. [http://dx.doi.org/10.1097/00006454-199603000-00015] 21. Nicolau DP, Sutherland CA, Arguedas A, Dagan R, Pichichero ME. Pharmacokinetics of cefprozil in plasma and middle ear fluid in children undergoing treatment for acute otitis media. Pediatr Drugs 2007;9(2):119-123. [http://dx.doi.org/10.2165/00148581-200709020-00005] 22. Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologic efficacy of a three-day intramuscular ceftriaxone regimen in nonresponsive acute otitis media. Pediatr Infect Dis J 1998;17(12):1126-1131. [http:// dx.doi.org/10.1097/00006454-199812000-00005] 23. McGee L, Klugman KP, Wasas A, Capper T, Brink AJ and the Antibiotics Surveillance Forum of South Africa. Serotype 19F multiresistant pneumococcal clone harboring two erythromycin resistance determinants [erm(B) and mef(A)] in South Africa. Antimicrob Agents Chemother 2001;45(5):15951598. [http://dx.doi.org/10.1128/AAC.45.5.1595-1598.2001] 24. Leiberman A, Leibovitz E, Piglansky L, et al. Bacteriologic and clinical efficacy of trimethoprimsulfamethoxazole for treatment of acute otitis media. Pediatr Infect Dis J 2001;20(3):260-264. [http:// dx.doi.org/10.1097/00006454-200103000-00009] 25. Ingvarsson L, Lundgren K. Penicillin treatment of acute otitis media in children: A study of the duration of treatment. Acta Otolaryngol 1982;94(3-4):283-287. [http://dx.doi.org/10.3109/00016488209128915] 26. Leibovitz E, Dagan R. Otitis media therapy and drug resistance. Infect Med 2001;18(4):263-270. 27. Pichichero NE. Use of selected cephalosporins in penicillin allergic patients: A paradigm shift. Diagn Microbiol Infect Dis 2007;57(Suppl 7):13s-18s. [http://dx.doi.org/10.1016/j.diagmicrobio.2006.12.004] 28. Joint task force on practice parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: An updated practice parameter. Ann Allergy Asthma Immunol 2010;105(4):259-273. [http://dx.doi.org/10.1016/j.anai.2010.08.002] 29. Arguedas A, Dagan R, Pichichero M, et al. An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media. Pediatr Infect Dis J 2006;25(12):1102-1109. [http://dx.doi.org/10.1097/01.inf.0000202138.12950.3c] 30. Bradley JS, Jackson MA. The use of systemic and topical fluoroquinolones. Pediatrics 2011;128(4):e1034-1045. [http://dx.doi.org/10.1542/peds.2011-1496] 31. Noel GJ, Bradley JS, Kauffman RE, et al. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. Pediatr Infect Dis J 2007;26(10):879-891. [http://dx.doi.org/10.1097/INF.0b013e3180cbd382]

Accepted 2 February 2015.

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HEALTHCARE DELIVERY

Description of an internal medicine outreach consultant appointment in western KwaZulu-Natal, South Africa, 2007 to mid-2014 R I Caldwell, B Gaede, C Aldous Doc Caldwell spent more than 25 years in private practice as a specialist physician in Pietermaritzburg, South Africa, and then took up a post at Grey’s Hospital as outreach physician for internal medicine. He now does outreach on a sessional basis, and has a part-time position with the School of Clinical Medicine, University of KwaZulu-Natal, as undergraduate liaison between Pietermaritzburg and Durban. Bernhard Gaede was recently appointed Head of the Department of Family Medicine at UKZN. Prior to this he was Director of the Centre for Rural Health at UKZN for 4 years after working for more than a decade at Emmaus Hospital in the Drakensberg. Areas of interest and research have included the healthcare system, communitylevel care (including home-based care and traditional medicine), human rights and medical anthropology. Recent interests include health professional education and establishment of a decentralised teaching platform. Colleen Aldous is a senior lecturer in the School of Clinical Medicine at UKZN. She is a medical scientist with a PhD in science education and is involved in postgraduate research mentorship across several medical disciplines including surgery, orthopaedics, dermatology, paediatrics, opthalmology, general medicine and psychology. Her own research interest is human genetics, and she is a member of the national steering committee and working group reviewing National Department of Health policy guidelines for human genetics services. Corresponding author: R I Caldwell (ric@caldwells.co.za)

This is a description of an internal medicine outreach appointment in western KwaZulu-Natal Province (KZN), South Africa (SA), from 2007 to mid-2014, facilitated by the transport services of the Red Cross Air Mercy Service (AMS) and funded by the KZN Department of Health. The hospital visits represented ‘multifaceted’ as opposed to ‘simple’ outreach. The AMS database of outreach visits was analysed according to frequencies of visits, number of patient contacts and number of contacts with medical personnel. A brief history of the outreach visits is given and their nature described. From January 2007 to the end of June 2014, the outreach physician undertook 481 hospital visits and visited seven hospitals (out of 21) more than 40 times each. A total of 3 340 medical personnel contacts were made, and 5 239 patients were seen. Other internal medicine specialists undertook an additional 199 visits, during which they made 1 157 personnel contacts and saw 2 020 patients. The combined total was therefore 680 visits undertaken, 4 497 medical personnel contacts made and 7 259 patients seen. The appointment of a dedicated outreach consultant for a particular discipline together with a reliable air and road transport system was successful in providing access to specialist care in rural settings. This strategy could be recommended throughout SA. Further studies would be required in order to assess outcomes. S Afr Med J 2015;105(5):353-356. DOI:10.7196/SAMJ.9173

There is worldwide inequality between specialist services available to different sections of the population. This differential between urban and rural populations is starkly exemplified in KwaZulu-Natal Province (KZN), South Africa (SA).[1,2] Outreach by specialists has been employed for years as a means of addressing equity of services.[3] Such visits have been classified broadly as either simple or multifaceted outreach, with only the latter having had a significant impact on health outcomes.[3,4] ‘Multifaceted’ visits represent heterogeneous activities and interactions between specialists and primary care practitioners that can include clinical service, in-service training for the staff, clinical audits or governance and even research. ‘Simple’ visits refer to mere displacement of an outpatient clinic to the visited site. This is a description of an internal medicine outreach appointment in western KZN from 2007 to mid-2014, facilitated by the transport services of the Red Cross Air Mercy Service (AMS) and funded by the KZN Department of Health (KZN-DOH). The area covered by the outreach, the western half of the province, was designated as a pilot area for liaison between Grey’s Hospital, Pietermaritzburg (PMB), and 21 district hospitals (Fig. 1). The population was approximately 3 million, most of whom relied on the public health service. The outreach service was supported by the creation of full-time permanent posts for outreach for the major specialties by KZN-

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DOH, based at Grey’s Hospital, in 2006. A limited outreach service in the area had been in existence for more than 25 years, but the formal agreement in 1998 between KZN-DOH and the AMS put air transportation on a firm foundation, and made regular day visits to distant destinations possible. In the PMB Department of Internal Medicine there were 14 consultants. The aim was that if each doctor ‘adopted’ a hospital to visit regularly, or if subspecialists rotated through different hospitals, the outreach physician, by undertaking frequent monthly visits, was able to ensure that all 21 hospitals received internal medicine outreach. Each hospital required a regular monthly visit from the major specialties, but with only one specialty per visit, so as not to dilute the personnel available to receive that visit. The visit was structured, with clinical and teaching rounds and a formal tutorial for all medical staff. Arms-length-organised air and road transportation was the key to the outreach. The single turbo-prop Swiss Pilatus aeroplanes were robust and reliable, the pilots were numerous and competent, and the AMS was an experienced professional medical transport provider. Road transport was just as important, as statistics confirmed, and the AMS provided PMB with its own vehicle and driver. Based on the experience gained by the hospital visits of the first author, a brief history of the outreach visits is given and their nature described. A data collection sheet, designed by internal medicine outreach, recorded visiting and visited personnel (doctors and medical students,

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programme. The doctors at remote peripheral hospitals could thus receive regular training from, and liaison with, different specialties. In the planning of the hospital visit, various activities were identified as part of what the outreach visit should include. These components included an early-morning meeting, which incorporated a teaching session. This was to be followed by a booked outpatients clinic, where doctors from the local hospital and a nurse/interpreter were required to be present. A further component included a problem ward round of selected cases presented by the doctors concerned, where diagnosis, management and need for referral were to be covered.

Description of the hospital visits By air

Fig. 1. KZN health districts, showing the Grey’s Hospital catchment area.

the latter mainly on electives), patients seen, and their clinical details including the need for referral. The teaching session and problems encountered on the visit, and actions necessary, were also included. These forms were faxed to the AMS and filed in the Department of Internal Medicine at Grey’s Hospital. Visits were also recorded in a separate log, noting whether they were by air or road, as were cancellations, which occurred mainly due to bad weather. This log provided details on the number of visits per year and per hospital, and the number of flights v. road trips. AMS staff also maintained a log of all flights from their base in Durban, and of road trips done from PMB. As part of the review of the outreach service, the database of outreach visits from the AMS was analysed according to frequencies of visits, number of patient contacts and number of contacts with medical personnel. Permission

for access to the database of the visits supported by AMS was obtained.

Setting up the outreach programme

During the setting up of the outreach service, all district hospitals in the catchment area of Grey’s Hospital were visited by the outreach specialist in order to assess the needs, staffing situation and infrastructure. All hospitals were scheduled for regular visits by specialists, eight of which were allocated to the outreach specialist while 13 were distributed to other available consultants in the Department of Internal Medicine. Visits were scheduled for particular days of the month: for example, Dundee Hospital was visited on the first Tuesday of every month. The same hospital would receive visits from consultants in other specialties on other regular days of the month as part of the AMS outreach

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Outreach doctors awaited the AMS plane at PMB Airport at 07h30 from its Durban base. Arrival time at the remote hospitals depended on the flight plan. Flying time direct to Dundee, for instance, was 40 minutes, but it was much longer if the route was via Richards Bay and Ulundi to pick up and drop off other medical personnel. Road transport, provided by the relevant hospital, picked up the doctor at the airstrip for transfer. This journey might be short (for example, Dundee Hospital was very close to the airstrip), or longer (Charles Johnson Memorial Hospital was a 45-minute drive from the same airstrip). Arrival time at a hospital therefore ranged from 09h30 to as late as 11h00. Return flights from airstrips were usually from 15h30 onwards, depending on the need to pick up other doctors before sunset, as many strips are very basic and do not have landing lights. Expected landing time at PMB Airport was therefore from 16h30 onwards. Bad weather could result in the need to overfly to Durban, necessitating that personnel be driven back to PMB, which resulted in a very late but safe return.

By road

Road transport was necessary when there was no suitable airstrip for the hospital concerned, or if the distance from Grey’s Hospital was short. Initially the AMS provided a vehicle for PMB, with one of the doctors driving, but subsequently a permanent professional driver was employed. The vehicle left from Grey’s Hospital, the departure time dependent on the required arrival time. For example, a 06h00 start was required to achieve an 08h00 arrival at Church of Scotland Hospital (COSH), Tugela Ferry, in time for the teaching meeting. Return time varied according to the needs of the visit, usually by lunchtime with an 08h00 arrival. The drop-off back at Grey’s Hospital was therefore usually by 16h00 or earlier.

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Table 1. Trips and hospital visits by the outreach physician year by year, January 2007 to end of June 2014 Year

Hospital visits, n

Flights, n

By road, n

Trips, n

2007

2008

2009

2010

2011

Table 2. Number of visits by the outreach physician per hospital, January 2007 to end June 2014 Order

Hospital

Visits, n

COSH (Tugela Ferry)

Vryheid

Dundee

Charles Johnson Memorial (Nqutu)

Estcourt

2012

Emmaus

2013

Rietvlei

2014 (to end June)

Christ the King (Ixopo)

Totals

481

195

314

509

Greytown

Richmond

Madadeni (Newcastle)

From January 2007 to the end of June 2014, the outreach physician undertook 481 hospital visits and made 509 trips. The discrepancy is explained by 41 Durban trips to attend KZN Pharmacotherapeutic Committee (KZN-PTC) meetings, by the fact that on occasion more than one hospital was visited per trip, and by the inclusion of occasional flights that had to be aborted prior to reaching the destination. Table 1 shows the yearly breakdown of such trips. The number of return flights (195) and road trips (314) is recorded.

St Apollinaris (Creighton)

Newcastle

East Griqualand & Usher (Kokstad)

Fort Napier (PMB)

Ladysmith

Town Hill (PMB)

Frequency of visits per hospital

Tayler Bequest (Matatiele)

Table 2 shows that with regular monthly visits, the outreach physician was able to visit four hospitals (out of 21) more than 50 times each, and a further three 40 or more times each.

Montebello

Appelsbosch

Niemeyer (Utrecht)

Multifaceted versus simple outreach

Total

Hospital and other visits

The hospital visits represented multifaceted as opposed to simple outreach, and Table 3 shows the breakdown of personnel involved (doctors, medical students, nurses) and patients seen from 2007 to June 2014. A total of 3 340 medical personnel contacts were made, and 5 239 patients were seen.

Involvement of the rest of the Department of Internal Medicine

During this same period, other internal medicine specialists under足 took 199 visits, giving a total of 680. A total of 4 497 medical personnel contacts were made, and 7 259 patients were seen. Table 4 details hospital visits by other physicians over this period.

Discussion

The internal medicine outreach programme in Area 2 of KZN had a large quantitative effect on access to specialist care. In 7.5 years the outreach physician undertook nearly 500 hospital visits, including almost 200 flights and more than 300 road trips, and undertook more than 3 000 medical personnel contacts and more than 5 000 patient consultations. Other specialists in the department provided a further 199 visits and saw 2 020 patients. Much of the total output could therefore be attributed to the appointment of a dedicated outreach co-ordinator. The PMB Department of Internal Medicine was fortunate in having a large enough consultant complement to allow the outreach physician to focus on this field rather than to be involved in clinical work at the tertiary hospital. Nevertheless, the appointment was a full-time one, requiring contribution to the running and welfare of the department.

355

481

Table 3. Visits, personnel contacts and patients seen, January 2007 to end June 2014 Order

Hospital

Visits, n

Personnel contacts, n

Patients seen, n

COSH

892

605

Vryheid

247

1 102

Dundee

283

676

Charles Johnson Memorial

279

444

Estcourt

385

320

Emmaus

336

552

Rietvlei

295

498

Christ the King

242

602

Greytown

158

276

Richmond

Madadeni

12 - 21

Others (<10 visits each)

102

481

3 340

5 239

Totals

The outreach physician was therefore on the call roster, did ward rounds at Edendale Hospital, a PMB regional/district hospital, initiated a telemetry link to peripheral hospitals, and became co-ordinator of

May 2015, Vol. 105, No. 5

FORUM

Table 4. Other physician visits, 2007 to mid-2014 Hospital

Visits, n

Personnel contacts, n

Patients seen, n

Vryheid

Dundee

Charles Johnson Memorial

100

Estcourt

Emmaus

Rietvlei

121

Greytown

197

328

Richmond

Madadeni

176

174

St Apollinaris

East Griqualand & Usher

296

748

Ladysmith

Tayler Bequest

Appelsbosch

191

265

Totals

199

1 157

2 020

the elective medical student programme for internal medicine, such students often attending outreach visits. The incumbent was appointed as the outreach representative, for all specialties, on the KZN-PTC in Durban and organised two internal medicine weekend mini-symposia, held at Grey’s Hospital in 2009 and 2011. The very existence of an outreach programme presupposed an efficient, independent transport system, such as that provided by the AMS. The variable reliability of transport provided by recipient hospitals between hospital and airstrip emphasised this. It was air transport that made outreach feasible when a large geographical area was involved, scattered with numerous hospitals. This was of course the case with the catchment area of Grey’s Hospital, and indeed for the whole of KZN. Air travel was more effective for the overall outreach service, as it could transport eight to nine individuals per flight, provide several pick-up and drop-off points, and therefore serve several hospitals on one round trip. There were two planes available on most travel days. However, flight visits were inefficient per individual specialist/ hospital, as timing of arrivals and returns was unpredictable, exacerbated by occasional bad weather. The importance of safe road transport by the transport provider cannot be overstated. (The outreach physician undertook more road than air trips, and for him this was a more efficient means of transport.) Road travel usually implied a single destination and fewer passengers, a disadvantage for overall hospital provision. However, it allowed a predictable early start and arrival time, and return as soon as the visit was completed. Nevertheless, road visits

could involve long and potentially dangerous journeys, with less capacity than journeys by air. The hospital visit varied from hospital to hospital, the nature of the visit largely depending on the requirements, management and culture of the individual hospital. Some hospitals provided a large personnel contact and few patients, some the opposite, and some in between. Simple outreach was never employed, and the comparison between Vryheid Hospital and COSH visits illustrated how variable the multifaceted category could be:[3,4] at Vryheid there were few medical personnel and very many patients per visit, while at COSH many personnel and relatively few patients were encountered. At Vryheid there was a great need for a booked specialist outpatient clinic, to obviate or to facilitate referral. COSH had three senior medical officers with more than 65 years’ continuous combined service, stability regarding medical managers and therefore less reliance on visiting consultants. There were many doctors at the teaching meeting, and a smaller patient load on problem ward rounds. Limitations within the outreach programme included cancellation of visits, bad weather being the most common cause; inefficient transport from airstrip to hospital and vice versa; a relatively short time at the facility compared with the time taken for the travelling itself; ill-preparedness on the part of the recipient hospital; and lack of availability of some consultants, although the majority did participate. Occasionally the outreach physician undertook 2- or 3-day trips during which he visited several hospitals and stayed overnight at bed-and-breakfast accommodation organised

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by the AMS. These road trips maximised time at a facility and reduced time spent travelling. However, comparative costs had to be considered, given that AMS provided an ‘air service for multiple personnel’ with built-in overheads. Moreover, not many consultants would find it acceptable, or even feasible, to spend longer periods away from their home base. The considerable output achieved by the appointment of an outreach physician would on its own be a recommendation for this strategy throughout SA.[3,4] How much this improved quality of care and outcomes was more difficult to determine, when an intervention was only on a monthly basis. More statistics would be required, preferably on a prospective basis, to enable outcomes to be compared and the effect of referrals and follow-up monitored.[5] Reducing unnecessary use of services and influencing referral patterns favourably were clear aims of the outreach. Patients seen by the outreach specialist were those who might otherwise have required referral to the relevant regional or tertiary hospital. Only a minority of patients seen were referred, indicating that the intervention itself obviated the need for referral.[6] The specialist could also expedite any future appointment. Enabling peripheral hospital doctors to liaise with an individual specialist personally, rather than deal with an impersonal voice on the phone, encouraged them to make contact with the outreach physician on a regular, sometimes frequent, basis.[4] More needed to be done in terms of establishing and enforcing protocols, employing morbidity-mortality meetings, etc. in order to make care more efficient. [4]

Conclusion

This study showed that the appointment of a dedicated outreach consultant for a particular discipline, together with a capable transport system, was successful in providing access to specialist care. This strategy could be recommended throughout SA. However, further studies, preferably prospective, would be required in order to assess outcomes and improvements in quality of care.[4,5] 1. Tudor Hart J. ‘The inverse care law.’ Lancet 1971;1(7696):405-412. 2. Clarke DL, Aldous C. Surgical outreach in rural South Africa: Are we managing to impart surgical skills? S Afr Med J 2014;104(1):57-60. [http://dx.doi.org/10.7196/SAMJ.7252] 3. Gruen RL, Weeramanthri TS, Knight SE, Bailie RS. Specialist outreach clinics in primary care and rural hospital settings. Cochrane Database Syst Rev 2004;(1):CD003798. [http://dx.doi. org/10.1002/14651858.CD003798.pub2] 4. Gaede B, McKerrow NH. Outreach programme: Consultant visits to rural hospitals. CME 2011;29(2):57-58. 5. Gruen RL, Weeramanthri TS, Bailie RS. Outreach and improved access to specialist services for indigenous people in remote Australia: The requirements for sustainability. J Epidemiol Community Health 2002;56(7):517-521. [http://dx.doi.org/10.1136/jech.56.7.517] 6. Gruen RL, Bailie RS, Wang Z, Heard S, O’Rourke IC. Specialist outreach to isolated and disadvantaged communities: A population based study. Lancet 2006;368(9530):130-138. [http:// dx.doi.org/10.1016/ S0140-6736(06)68812-0]

Accepted 24 November 2014.

EDITORIAL

Antibiotic administration in the critically ill – in need of intensive care! Infections and infectious dis eases remain a leading cause of morbidity and mortal ity worldwide. Sepsis claims 10 000 lives globally every day.[1] Antimicrobials, a major weapon in our armamentarium to combat infections, are arguably the most poorly prescribed of all medications. Antibiotics represent at least 30% of acute care hospitals’ drug expendi ture. They are prescribed to 20 - 50% of inpa tients and to a greater extent in intensive care unit (ICU) patients. Of note they are prone to misuse, with 22 - 65% of prescriptions either not indicated or inadequate to treat the infec tion.[2,3,4] The consequences of this misuse are unnecessary costs and side-effects, resistant micro-organisms and failure of treatment.[2,5,6] The Prevalence of Infection in South Africa (PISA) study, which evaluated antimicrobial prescription practices at specialist and superspecialist level in state/academic and the pri vate sectors among critically ill patients in South Africa (SA), revealed startling results – approximately 80% of such patients were receiving antimicrobial therapy, the appropri ate choice of antimicrobial occurred in just over 40% of patients, antibiotics were modi fied appropriately in just over 10% of patients, and the duration of therapy was appropriate in just over a quarter of the patients.[3] A recent commentary aptly suggested that the major reason that antibiotics are prescribed inappropriately is that there is a lack of knowledge about infectious diseases and antimicrobial therapy, and health care providers are afraid not to prescribe antibiotics.[7] This is particularly true in the critical care setting, where antimicrobial management represents an ongoing challenge. Critically ill patients constitute a unique population and differ from the non-critically ill in terms of antibiotic administration and dosing. A greater understanding of antibiotic dosing in these patients is essential for all involved in their care. This editorial aims to focus on some of the important principles and strategies aimed at optimising antimicrobial use among critically ill patients. In a recent study measuring serum β-lactam antibiotic concentrations in patients in the ICU, it was found that almost threequarters of antibiotic prescriptions needed to be altered to achieve therapeutic targets (plasma concentrations too low) without toxicity (plasma concentrations too high).[8] The reason for the inaccuracy of a ‘one size fits all’ dosing in the ICU, apart from

patients’ weights, involves the distinct patho physiological changes that occur in ICU patients and their management. The main alterations in this regard relating to antibiotic concentrations are: (i) increased volume of distribution of drugs; (ii) increased cardiac output; (iii) increased hepatic and renal blood flow (and hence increased metabolism and excretion); and (iv) low serum protein levels, and hence altered protein binding of drugs (Fig. 1).[9,10] These changes often lead to subtherapeutic concentrations. This may be further compounded by the fact that ICU patients frequently have renal dysfunction and require renal replacement therapies (RRTs), which further complicates the resultant serum antibiotic concentration(s). Depending on the dose prescribed of both drug and RRT, there could potentially be under- or over-dosing.[8] Patients with sepsis tend to need, and to be given, fluid in the initial resuscitative phase of the disease. Leaky capillaries, often compounded by hypoproteinaemia, predispose these patients to extravascular fluid extravasation. This will have little effect on lipophilic agents (e.g. fluoroquinolones) as their typical volume of distribution (Vd; the space into which the drug diffuses) is very large, and the relative increase in Vd too small to produce an overall Vd change. [11] Hydrophilic antibiotics, which primarily occupy the intravascular space, will also distribute into this increased extravascular water, and due to a relatively small initial Vd, this increase will produce a markedly large change (increase) in the Vd of such antibiotics. This increased Vd means that administering the same dose of a hydrophilic

antibiotic to a patient with leaky capillaries will result in a lower concentration of the antibiotic in the serum, and particularly a lower maximal concentration. Marik[12] demonstrated that the sicker the patient (and the higher the APACHE II score), the larger the Vd of amikacin. This phenomenon (i.e. increased Vd, needing larger doses for the same serum concentration in critically ill patients) has been validated by others. Practical implications for dosing. As first dose give a large, loading dose of antibiotic, particularly those with hydrophilic tend encies (aminoglycosides, glycopeptides, β-lactams and colistin.) Remember this is independent of altered clearances (i.e. renal dysfunction) (Fig. 2). Di Giantomasso et al.[13] have demon strated an increased organ blood flow early in sepsis. Clinically this means that in the presence of normal renal function, an increased renal blood flow will translate into an increased glomerular filtration rate and hence an increased creatinine clearance. This clinical phenomenon has now been termed augmented renal clearance (ARC).[14] In such circumstances all renally eliminated drugs will have increased clearances. ARC has now been documented in >60% of patients with ‘normal’ serum creatinine admitted to multidisciplinary ICUs.[15] The practical implication is that with standard dosing, ARC results in subtherapeutic concentrations of drugs that have renal elimination (unless higher doses are administered) (Fig. 1). Practical implications for dosing. Younger patients without renal dysfunction often manifest ARC and hence clear renally eliminated drugs quickly. Shorten the dosing interval, e.g.

Plasma concentrations in sepsis

Hyperdynamic circulation

Leaky capillaries and/or altered protein binding

Normal organ function

End organ dysfunction (e.g. renal or hepatic)

Unchanged Vd

Decreased CL

Normal plasma concentrations

High plasma concentrations

Extracorporeal circuits

Increased extravascular water

Augmented renal CL

Increased Vd

Altered CL and increased Vd of sepsis

These often coexist

Low plasma concentrations

Plasma concentrations high or low

Fig. 1. Pathophysiological changes of sepsis affecting antibiotic concentrations. (Vd = volume of distribution; CL = clearance.)

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EDITORIAL

Renally cleared antibiotic

Loading dose

Hydrophilic agent Small Vd (Vd increased by sepsis)

Lipophilic agent Large Vd (Vd unchanged by sepsis)

• Loading dose required

• No loading dose Independent of following step Maintenance dose

Augmented renal clearance

Normal renal function

Acute kidney injury

• Dose increase

• No dose change

• Dose reduction

Fig. 2. Loading doses should be thought of as independent of maintenance dosing. (Vd = volume of distribution.)

instead of daily aminoglycosides use 18-hourly; instead of a bi-daily dose of β-lactam administer same dose 8-hourly. Increased total daily dose (aminoglycosides, glycopeptides, β-lactams), extended infusions (β-lactams) and therapeutic drug monitoring (TDM) may also be employed. Highly protein-bound drugs are usually kept within the vascular compartment owing to the size of the protein-drug complex. In such circumstances, and depending on a number of other factors, there is usually a small amount of circulating drug that is not protein bound. This component (free drug, f) represents the active constituent of the drug and crosses various membranes such as vascular, kidney and meninges. Protein binding of <70% is usually of little clinical consequence, but commonly used antibiotics such as ertapenem, teicoplanin, ceftriaxone, flucloxacillin and daptomycin are highly protein bound (>80% protein binding). In a pragmatic trial of 7 000 adult patients requiring fluid resuscitation who were admit ted to ICUs in Australia and New Zealand, 40% of patients arrived in the ICU with albumin concentrations of ≤25 g/L.[16] As albumin is the primary binding site for most drugs, if hypoalbuminaemic patients are administered highly protein-bound drugs, there will initially be a much higher than normal f. If the drug is renally excreted and the patient has normal or near normal renal function, this high free fraction will soon pass through the kidney (via glomerular filtration) and be eliminated from the body at a rate much higher than occurs with the ‘normal’ high protein binding.[17] In such circumstances the half-life of these drugs is much shorter than expected. Clinically this has the effect of shortening the duration of action of

these drugs. ARC further exaggerates this effect in that the antibiotic half-life and duration of action are even shorter (Fig. 1). Practical implications for dosing. For highly protein-bound drugs in the ICU, shorten the frequency of dosing, e.g. instead of daily ceftriaxone administer a bi-daily dose; similarly for ertapenem, teicoplanin and daptomycin, higher than ‘standard’ doses are suggested. Larger loading doses (aminoglycosides, glycopeptides, β-lactams), extended infusions (β-lactams) and TDM may also be employed. For renally eliminated antibiotics there are reasonably good texts for dosage adjustments in patients with renal dysfunction, and to a lesser extent this is also the case with hepatic dysfunction. RRT alters clearances markedly, and this complicates dosage administration enormously.[18-23] ICUs order their RRT modalities differently (CVVH, CVVHD, CVVHDF, SLEDD) and even the settings within these modalities differ (predilution, post-dilution, dialysate rates). Clearances of urea, creatinine, fluids and in fact medium and small molecules all vary in these different modalities. It is therefore not surprising that clearances of the unbound component of antibiotics will differ accordingly. In the clinical scenario a prescription of continuous RRT does not necessarily imply a 24-hour clearance time, as there is often ‘downtime’ of such artificial kidneys relating to entities such as kidney clotting and set-up times for new circuits. This complicates the clinical clearances even further (Fig. 1). It is for this reason that some units routinely employ TDM to prescribe antibiotics more accurately, including β-lactam TDM.[1,24,25,26]

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This is standard practice, for example, at the Royal Brisbane and Women’s Hospital. Practical implications for dosing. Search for an article measuring antibiotic concentrations with the RRT settings most similar to your own and use this article to adjust your dos ing, or ask your laboratory to set up β-lactam TDM. Note too that if continuous RRT filter downtime is prolonged (nurses busy, long set-up time) clearances will be far less than continuous 24-hour continuous RRT. There is a global problem of increasing anti biotic resistance, with the minimum inhibitory concentration (MIC) of many organisms rising. While it is beyond the scope of this editorial to address single or double Gram-negative anti biotic cover, or how to deal with increasing resistance patterns optimally, it is important to recognise that increasing the dose of some antibiotics can overcome rising MICs. How to deliver β-lactam antibiotics optimally has received much attention in recent literature (i.e. via a bolus or prolonged infusions, be they continuous infusion or extended infusions). There is some emerging evidence that delivery of β-lactam antibiotics may be further enhanced by administration as a prolonged infusion.[27,28] Where continuous infusions are employed, an initial bolus dose should be given prior to the initiation of the infusion. It should be noted that, to date, continuous infusions have not been shown to improve clinical outcomes. Our personal advice is to use extended infusions. Finally, we would like to conclude by addressing the issue of β-lactam TDM. TDM in general can be used to prevent toxicity or improve efficacy. Measurement of aminoglycoside and vancomycin serum concentrations, which are generally universally available, usually fall into the former category. As β-lactams have a high therapeutic range with infrequent toxicity, it was conventionally deemed that TDM of these drugs was unnecessary. More recently we have realised how we have been underdosing such drugs, and the need for TDM of these antibiotics has come to the fore.[1,24,25,26] A better understanding of antibiotic dosing in the critically ill will go a long way to enhancing the longevity of what is becoming an increasingly scarce resource. There are no new antibiotic classes nearing clinical production. We believe that correct antibiotic dosing will limit the increasing burden of antimicrobial resistance, minimise therapeutic failures and, most importantly, improve patient outcomes. M Mer Divisions of Critical Care and Pulmonology, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

EDITORIAL

J Lipman Director, Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia, and Professor and Head of Anaesthesiology and Critical Care, University of Queensland, Queensland, Australia Corresponding author: M Mer (mervyn.mer@wits.ac.za) 1. Global Sepsis Alliance. Stop Sepsis. Save Lives. www.globalsepsisalliance.org (accessed 11 January 2015). 2. Von Gunten V, Reymond JP, Boubaker K, et al. Antibiotic use: Is appropriateness expensive? J Hosp Infect 2009;71(2):108-111. [http://dx.doi.org/10.1016/j.jhin.2008.10.026] 3. Paruk F, Richards G, Scribante J, et al. Antibiotic prescription practices and their relationship to outcome in South Africa: Findings of the prevalence of infection in South African intensive care units (PISA) study. S Afr Med J 2012;102(7):613-616 4. Roberts JA, Paul SK, Akova M, et al. DALI: Defining antibiotic levels in intensive care unit patients: Are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 2014;58(8):10721083. [http://dx.doi.org/10.1093/cid/ciu027] 5. Dellit TH, Owens RC, McGowan JE, et al. Infectious Disease Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44(2):159-177. [http://dx.doi.org/10.1086/510393] 6. Paterson DL, Lipman J. Returning to the pre-antibiotic era in the critically ill: The XDR problem. Crit Care Med 2007;35(7):1789-1791. [http://dx.doi.org/10.1097/01.CCM.0000269352.39174.A4] 7. Nouwen JL. Controlling antibiotic use and resistance. Clin Infect Dis 2006; 42(6):776-777. [http:// dx.doi.org/10.1086/500328] 8. Roberts JA, Ulldemolins M, Roberts MS, et al. Therapeutic drug monitoring of β-lactams in critically ill patients: Proof of concept. Int J Antimicrob Agents 2010;36(4):332-339. [http://dx.doi.org/10.1016/j. ijantimicag.2010.06.008] 9. Udy AA, Roberts JA, De Waele JJ, Paterson DL, Lipman J. What’s behind the failure of emerging antibiotics in the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance. Int J Antimicrob Agents 2012;39(6):455-457. [http://dx.doi.org/10.1016/j. ijantimicag.2012.02.010] 10. Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med 2013;39(12):2070-2082. [http://dx.doi.org/10.1007/s00134-013-3088-4] 11. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient – concepts appraised by the example of antimicrobial agents. Adv Drug Deliver Rev 2014;77:3-11. [http://dx.doi.org/10.1016/j.addr.2014.07.006] 12. Marik PE. Aminoglycoside volume of distribution and illness severity in critically ill septic patients. Anaesth Intensive Care 1993;21(2):172-173. 13. Di Giantomasso D, May CN, Bellomo R. Vital organ blood flow during hyperdynamic sepsis. Chest 2003;124(3):1053-1059. [http://dx.doi.org/10.1378/chest.124.3.1053]

14. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance. Clin Pharmacokinet 2010;49(1):1-16. [http://dx.doi.org/10.2165/11318140-000000000-00000] 15. Udy AA, Baptista JP, Lim NL, et al. Augmented renal clearance in the ICU: Results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations. Crit Care Med 2014;42(3):520-527. [http://dx.doi.org/10.1097/ CCM.0000000000000029] 16. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:22472256. [http://dx.doi.org/10.1056/NEJMoa040232] 17. Joynt GM, Lipman J, Gomersall CD, Young RJ, Wong EL, Gin T. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother 2001;47(4):421-429. [http:// dx.doi.org/10.1093/jac/47.4.421] 18. Eyler RF, Mueller BA. Antibiotic dosing in critically ill patients with acute kidney injury. Nat Rev Nephrol 2011;7(4):226-235. [http://dx.doi.org/10.1038/nrneph.2011.12] 19. Kielstein JT, Burkhardt O. Dosing of antibiotics in critically ill patients undergoing renal replacement therapy. Curr Pharm Biotechnol 2011;12(12):2015-2019. [http://dx.doi. org/10.2174/138920111798808275] 20. Roberts DM, Roberts JA, Roberts MS, et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: A multicentre pharmacokinetic study. Crit Care Med 2012;40(5):1523-1528. [http://dx.doi.org/10.1097/CCM.0b013e318241e553] 21. Blot S, Lipman J, Roberts DM, et al. The influence of acute kidney injury on antimicrobial dosing in critically ill patients: Are dose reductions always necessary? Diagn Microbiol Infect Dis 2014:79(1):7784. [http://dx.doi.org/10.1016/j.diagmicrobio.2014.01.015] 22. Roberts JA, Roberts DM. Antibiotic dosing in critically ill patients with septic shock and on continuous renal replacement therapy: Can we resolve this problem with pharmacokinetic studies and dosing guidelines? Crit Care 2014;18(3):156. [http://dx.doi.org/10.1186/cc13939] 23. Kumar A, Singh NP. Antimicrobial dosing in critically ill patients with sepsis-induced acute kidney injury. Indian J Crit Care Med 2015;19(2):99-108. [http://dx.doi.org/10.4103/0972-5229.151018] 24. McWhinney B, Wallis S, Hillister T, Roberts JA, Lipman J, Ungerer JPJ. Analysis of twelve beta-lactam antibiotics in human plasma by HPLC with ultraviolet detection. J Chromatogr B 2010;878(22):20392043. [http://dx.doi.org/10.1016/j.jchromb.2010.05.027] 25. Udy AA, De Waele JJ, Lipman J. Augmented renal clearance and therapeutic monitoring of β-lactams. Int J Antimicrob Agents 2015;45(4):331-333. [http://dx.doi.org/10.1016/j.ijantimicag.2014.12.020] 26. Wong G, Brinkman A, Benefield RJ, et al. An international, multi-centre survey of β-lactam antibiotics therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother 2014;69(5):1416-1423.[http://dx.doi.org/10.1093/jac/dkt523] 27. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and pipericillin/tazobactam: A systematic review and meta-analysis. Clin Infect Dis 2013;56(2):272-282. [http://dx.doi.org/10.1093/cid/cis857] 28. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: A multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013;56(2):236-244. [http://dx.doi.org/10.1093/cid/cis856]

S Afr Med J 2015;105(4):357-359. DOI:10.7196/SAMJ.9665

Key to antimicrobial stewardship success: Surveillance by diagnostic microbiology laboratories The important role of laboratories in enhancing antimicrobial stewardship activities through improved diagnostics and provision of surveillance data is globally recognised.[1] Consider the aim of an antimicrobial stewardship programme: ‘optimize clinical outcomes while minimizing the unintended consequences of antimicrobial use’. [2] The clinical microbiology laboratory plays a critical role in achieving these aims through the provision of culture and susceptibility data that are both patient-specific (optimisation of clinical outcomes) and informative for surveillance activities that guide empirical antimicrobial selection (minimising unintended consequences of antimicrobial use). For this reason, the World Health Organization (WHO) included the strengthening of surveillance and laboratory capacity in its 2011 World Health Day six-point plan to combat antimicrobial resistance (AMR).[3] South African laboratories in the public and private sectors have the means to provide surveillance data and, through a collaborative approach, the capacity to create antimicrobial resistance maps. In line with the WHO’s recommendations and under the auspices of the South African Society of Clinical Microbiology, efforts are currently underway to improve national AMR surveillance data for typical healthcareassociated pathogens. The generation and provision of these data is, however, only half of the challenge. The analysis and interpretation thereof is equally important, as highlighted in this month’s SAMJ by McKay and Bamford[4] in their study comparing community- with healthcare-acquired bloodstream infections at Groote Schuur Hospital (GSH), Cape Town, a tertiary public sector hospital.

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The study is a retrospective description of bloodstream isolates submitted to the GSH laboratory over a 1-year period. Using predefined criteria, the isolates were classified as community or healthcare acquired and a comparative analysis of resistance patterns was undertaken. The issue of differing resistance patterns in the community v. hospital is a well-established and much-publicised phenomenon.[5] The article serves to reinforce these established differences, highlighting the profound resistance associated with hospital pathogens: (i) a 47.6% difference in the methicillinresistant Staphylococcus aureus (MRSA) rate; and (ii) a ~35% difference in extended-spectrum β-lactamase (ESBL) production by Enterobacteriaceae. The authors have provided substantive local surveillance data to support their recommendations for empirical antimicrobial prescribing based on an assessment of whether the infection is community or healthcare acquired. They have therefore highlighted a crucial element that, for various reasons relating to surveillance capacity, has unfortunately not been available in similar published local AMR surveillance data.[6-8] This element is the clinical and epidemiological context that is required for interpretation of the data. Unfortunately without this context the data become blurred and the issue of resistance is magnified disproportionately. Aggregated data (which is what we have seen to date) give an indication of whether overall resistance is on the increase or decrease, but do not provide sufficient information to guide practice at a local level. Nearly three-quarters of all bloodstream infections (BSIs) from GSH, as McKay and Bamford show, were healthcare acquired; when

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EDITORIAL

aggregated these data roughly translate into a 33% MRSA rate and a 30% ESBL rate. Compare this with the 0% MRSA rate and 4% ESBL rate for community-acquired infections at the same hospital, and the importance of making the distinction between community- and healthcare-acquired BSIs becomes obvious. Aggregated data without context are therefore inadvertently detrimental to antimicrobial stewardship initiatives, as the perceived threat of resistance compels many prescribers to go straight for the ‘big-gun’ antibiotics. While AMR is a very real threat to the prospects of treating infections, as McKay and Bamford confirm, good ol’ cloxacillin (a far superior drug to vancomycin in the treatment of S. aureus[9]) is still a perfectly suitable option in the right patient. Similarly, with a <5% ESBL rate for Enterobacteriaceae associated with community-acquired BSIs, the third- and fourth-generation cephalosporins still have an important role to play. Importantly, McKay and Bamford have indicated that their surveillance data are being constructively utilised at GSH, as suggested recommendations ‘are in line with contemporary hospital antibiotic recommendations’. As an example, the intensive care units (ICUs) account for almost three-quarters of all Acinetobacter baumannii bloodstream infections, supporting the decision to include colistin or tobramycin as empirical treatment options for ICU patients with suspected Gram-negative sepsis. The dissemination and utilisation of surveillance data is crucial if they are to impact on patient management and outcomes. Unfortunately this aspect is often sorely neglected, requiring a collaborative effort from clinical, laboratory and hospital staff. For the general practitioner serving the community, it would require close liaison with the microbiology laboratory with provision of practice-specific surveillance data. Local hospital AMR surveillance data should ideally go a step further through stratification of susceptibility data by ward/unit. In their study McKay and Bamford stratified by discipline rather than by individual wards and demonstrated some distinct differences in organism profile, although no major differences in susceptibility profiles. Ward-specific surveillance data have been shown to be a more useful tool for empirical antimicrobial selection, owing to distinct within-hospital antimicrobial susceptibility differences between wards/units.[10] For example, one cannot compare the cardiology ICU with the surgical ICU, or the haematology-oncology unit with the rest of the general medical unit. Nevertheless, the stratification data presented in this paper are illuminating and could potentially be stratified further for additional enhancement of antimicrobial stewardship efforts. McKay and Bamford’s study raises some additional challenges and areas of focus for hospitals, laboratories and prescribers. Classification of infections into community v. healthcare acquired is becoming more difficult, and the term ‘healthcare associated’ has been widely used to account for an increasingly complex healthcare environment that includes patients from long-term care facilities, rehabilitation centres, dialysis centres, etc.[11,12] The definitions used in different studies vary considerably.[12] This lack of standardisation is a major stumbling block to adequate risk assessment. Similarly, the cited risk factors for likelihood of a multidrug-resistant organism that are often used to guide empirical antimicrobial selection lack specificity and are generally used too loosely.[13-15] Distinctive epidemiological criteria upon which to base antimicrobial choices are desperately required, and local surveillance data are crucial in addressing this need. Enhanced surveillance data based on standardised definitions, with subsequent analysis at a local (facility/practice) level, could potentially identify risk factors with better diagnostic accuracy. This would enable hospitals (facilities) to develop facility-specific guidelines for antimicrobial prescribing. Development of such sitespecific guidelines is particularly challenging in the private sector, where hospitals are governed by corporate processes and policies. However, hospitals are not all the same, varying significantly in

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their case mix, which influences risk factors, and crucially in their microbiological ‘ecosystem’. This type of enhanced surveillance would require substantial investment in personnel and IT infrastructure. Laboratories face the challenge of providing accurate, reliable and standardised data. As indicated in McKay and Bamford’s study, piperacillin-tazobactam (a valuable agent) susceptibility data were not reported because of methodological limitations. Similarly, ESBL production was not tested but inferred from the cefepime result, a limitation acknowledged by the authors. Many laboratories would not use cefepime but rather ceftriaxone to infer ESBL production, whereas others would confirm it with phenotypic testing. It is evident that this methodological variance can have a major impact on the generation and interpretation of collated surveillance data, highlighting the need for some form of standardisation, if not in methods then at least in reporting. In the private sector there are usually two or three laboratories serving a hospital, each with its own subtle differences in practice and reporting. Ultimately the onus is on the hospital to collate these data and provide meaningful surveillance reports. Notwithstanding the important antimicrobial stewardship initia tives undertaken by various stakeholders as part of a commitment to address AMR, the success of antimicrobial stewardship (if measured according to the aims thereof) begins with the microbiology labora tory. The message is very clear, as McKay and Bamford have subtly suggested in their concluding remarks – the onus is on diagnostic microbiology laboratories to provide good-quality, clinically relevant and stratified surveillance data. Warren Lowman Vermaak and Partners Pathologists, Johannesburg, South Africa, Wits Donald Gordon Medical Centre, Johannesburg, and Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg Corresponding author: W Lowman (warren.lowman@wits.ac.za) 1. Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance – the need for global solutions. Lancet Infect Dis 2013;13(12):1057-1098. [http://dx.doi.org/10.1016/S1473-3099(13)70318-9] 2. Dellit TH, Owens RC, McGowan JE jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007;44(2):159-177. [http://dx.doi.org/10.1086/510393] 3. World Health Organization. Policy Package to Combat Antimicrobial Resistance 2011. http://www. who.int/world-health-day/2011/policybriefs/en/ (accessed 4 March 2015). 4. McKay R, Bamford C. Community- versus healthcare-acquired bloodstream infections at Groote Schuur Hospital, Cape Town, South Africa. S Afr Med J 2015;105(5):363-369. [http://dx.doi.org/10.7196/SAMJ.8183] 5. Rodriguez-Bano J, Lopez-Prieto MD, Portillo MM, et al. Epidemiology and clinical features of community-acquired, healthcare-associated and nosocomial bloodstream infections in tertiary-care and community hospitals. Clin Microbiol Infect 2010;16(9):1408-1413. [http://dx.doi.org/10.1111/ j.1469-0691.2009.03089.x] 6. Brink A, Moolman J, da Silva MC, Botha M, National Antibiotic Surveillance Forum. Antimicrobial susceptibility profile of selected bacteraemic pathogens from private institutions in South Africa. S Afr Med J 2007;97(4):273-279. 7. Brink A, Feldman C, Richards G, Moolman J, Senekal M. Emergence of extensive drug resistance (XDR) among Gram-negative bacilli in South Africa looms nearer. S Afr Med J 2008;98(8):586-592. 8. Perovic O, Singh-Moodley A, Duse A, et al. National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010 - 2012. S Afr Med J 2014;104(8):563568. [http://dx.doi.org/10.7196/samj.7617] 9. Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, et al. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis 2011;11(3):208-222. [http://dx.doi.org/10.1016/S1473-3099(10)70285-1] 10. Kuster SP, Ruef C, Zbinden R, et al. Stratification of cumulative antibiograms in hospitals for hospital unit, specimen type, isolate sequence and duration of hospital stay. J Antimicrob Chemother 2008;62(6):1451-1461. [http://dx.doi.org/10.1093/jac/dkn384] 11. Lenz R, Leal JR, Church DL, Gregson DB, Ross T, Laupland KB. The distinct category of healthcare associated bloodstream infections. BMC Infect Dis 2012;12:85. [http://dx.doi.org/10.1186/1471-2334-12-85] 12. Henderson KL, Muller-Pebody B, Johnson AP, Wade A, Sharland M, Gilbert R. Community-acquired, healthcareassociated and hospital-acquired bloodstream infection definitions in children: A systematic review demonstrating inconsistent criteria. J Hosp Infect 2013;85(2):94-105. [http://dx.doi.org/10.1016/j.jhin.2013.07.003] 13. Chalmers JD, Rother C, Salih W, Ewig S. Healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: A systematic review and meta-analysis. Clin Infect Dis 2014;58(3):330339. [http://dx.doi.org/10.1093/cid/cit734] 14. Xie J, Ma X, Huang Y, et al. Value of American Thoracic Society guidelines in predicting infection or colonization with multidrug-resistant organisms in critically ill patients. PloS One 2014;9(3):e89687. [http://dx.doi.org/10.1371/journal.pone.0089687] 15. Nseir S, Grailles G, Soury-Lavergne A, Minacori F, Alves I, Durocher A. Accuracy of American Thoracic Society/Infectious Diseases Society of America criteria in predicting infection or colonization with multidrug-resistant bacteria at intensive-care unit admission. Clin Microbiol Infect 2010;16(7):902908. [http://dx.doi.org/10.1111/j.1469-0691.2009.03027.x]

S Afr Med J 2015;105(5):359-360. DOI:10.7196/SAMJ.9615

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EDITORIAL

Rheumatic fever and rheumatic heart disease in Africa Acute rheumatic fever (ARF), with its varied and potentially devas tating cardiac complication of rheumatic heart disease (RHD), has largely been eradicated from developing countries, but continues to be a scourge mainly in poorly resourced areas of the world and also among the indigenous populations of some wealthy countries such as New Zealand and Australia.[1] The disease is particularly prevalent in populations where there is overcrowding and high levels of poverty. Efforts have been made to commit to the elimination of ARF/RHD in South Africa (SA) and the rest of Africa. The Drakensberg Declaration, which initiated and promoted the Awareness, Surveillance, Advocacy and Prevention (ASAP) programme to raise public awareness, establish surveillance programmes, advocate for support and promote prevention, was adopted at the 1st All Africa Workshop on Rheumatic Fever and Rheumatic Heart Disease held in the Drakensberg, SA, in 2005.[2] The ASAP programme has unfortunately not been expanded on a national scale so far. Subsequent attempts at solutions to controlling ARF and RHD globally have included the establishment of registers to track disease outcomes and outline strategies related to the ASAP proposal to improve disease control in low-income countries.[3] Information about levels of ARF/RHD is scarce and poorly documented in less-developed areas of the world such as Africa.[4] The prevalence of RHD in SA has been reported occasionally since the landmark study by McClaren et al.[5] in 1975, which showed an overall prevalence rate of RHD (using clinical examination to establish the diagnosis) of 6 - 9/1 000 among schoolchildren in Soweto, Johannesburg. A prospective clinical registry of valvular heart disease using echocardiography to make the diagnosis during 2006/2007 among individuals older than 14 years at Chris Hani Baragwanath Academic Hospital in Soweto revealed an incidence of 23.5/100 000 patients with RHD presenting for the first time.[6] Recent information from the past decade concerning the prevalence of RHD in sub-Saharan Africa has emanated from echocardiography screening studies in asymptomatic schoolchildren. Marijon et al.[7] showed a very high prevalence rate of 30.4/1 000 in Mozambique in 2007. A similarly high prevalence rate of 15/1 000 in a much larger cohort of Ugandan schoolchildren was reported in 2012.[8] Two very recent cardiac clinic hospital-based study cohorts from Africa, using echocardiography to confirm diagnoses, showed RHD to be the most important heart condition in patients aged 10 - 19 years (affecting 62.1%) in Cameroon,[9] while RHD was present in 22.4% of children undergoing echocardiography at a centre in Malawi.[10] In contrast, a recent publication from SA[11] has shown a dramatic decline in the number of children younger than 14 years with ARF and RHD presenting to the paediatric cardiology department at Chris Hani Baragwanath Academic Hospital over the 17-year period 1993 2010. The referral population has not changed despite an increase in the number of patients referred to the unit during this period. The population served by this large tertiary care hospital is largely poor and includes the massive periurban population of Soweto, patients referred by secondary hospitals in southern and eastern Gauteng Province, and patients from North West Province. The majority of patients with ARF/RHD were found to have originated from outside Soweto, but the addresses provided could not be validated. Many patients who present with severe disease requiring surgery to repair or replace damaged heart valves are suspected to originate from rural areas, and they include people from beyond SA’s borders who have made the informal settlements in and around Gauteng their home.[11]

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A similar downward trend has been observed at a central hospital complex in Limpopo Province, where a decline in the prevalence of RHD among children up to 13 years old has also been documented. A record review of paediatric echocardiography reports for the period 2001 - 2012 showed that the number of cases decreased from 36 per year for the first 4 years of the study to an average of 14 and six per year in the middle and final 4 years of the study, respectively. During the same time period the number of cases of congenital heart disease diagnosed each year remained relatively constant. This information suggests a decreasing prevalence of childhood RHD in Limpopo Province.[12] Anecdotally, numbers of children presenting to large tertiary hospitals with ARF/RHD have declined in Free State Province, but not in KwaZulu-Natal and rural parts of the Eastern Cape (personal communications, Prof. Stephen Brown, Dr Ebrahim Hoosen and Dr Lungile Pepeta, respectively). Several sociopolitical changes in SA could have contributed to the documented decline in the numbers of children with ARF/RHD in Gauteng and Limpopo provinces. These include an improvement in the socioeconomic status of the broader population since the new political dispensation in 1994, less overcrowding in dwellings, free healthcare for children under the age of 6 years, more widespread availability of primary healthcare facilities, and easy access to penicillin for the treatment of all sore throats.[12] The latter resulted in a dramatic decline in the incidence of ARF in Costa Rica and Cuba, as has been well documented.[13,14] Information on the incidence and prevalence rates of ARF and RHD in SA and the rest of Africa is needed to ensure targeting of susceptible populations with prevention and treatment programmes. Research opportunities should therefore continue to be created to allow for a pan-African survey of the frequency and origins of patients with ARF/RHD presenting to the larger central and secondary hospitals in SA and other parts of Africa, to assess the need for control strategies in vulnerable areas. Other methods of detection, such as screening for RHD with echocardiography in schoolchildren, are excellent ways to seek out affected individuals so that secondary prophylaxis can be instituted. Echocardiographic screening is, however, a very costly undertaking requiring expensive equipment, specialised expertise, reliable and relevant diagnostic echocardiographic criteria that can easily be replicated, and time spent by physicians and technical echocardiographic personnel away from their hospital commitments. The eradication of ARF/RHD is a complex process that needs to be addressed at various levels. These include education of vulnerable communities about the disease, provision of easy access to medical care, and increasing the availability of free penicillin to treat group A streptococcal pharyngitis and for secondary prophylaxis against further attacks of ARF in patients with established RHD. Just as important is to address poverty and overcrowding, which are associated with high levels of ARF and RHD, as improvement in socioeconomic conditions has also been shown to promote the control of ARF.[15] Improvement of economic circumstances in disadvantaged communities is therefore also an important component of the management of ARF/RHD. Until such communities are economically empowered, ARF/RHD will continue to be a problem despite interventions to control the disease. All these interventions may prove to be a challenge in some parts of SA and in countries in the rest of Africa.

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EDITORIAL

A M Cilliers Paediatric Cardiology Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg

7. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007;357(5):470-476. [http://dx.doi.org/10.1056/NEJMoa065085] 8. Beaton A, Okello E, Lwabi P, et al. Echocardiography screening for rheumatic heart disease in Ugandan schoolchildren. Circulation 2012;125(25):3127-3132. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.112.092312] 9. Jingi AM, Noubiap JJ, Kamden P, et al. The spectrum of cardiac disease in the West Region of Cameroon: A hospital-based cross-sectional study. Int Arch Med 2013;6(1):44. [http://dx.doi. org/10.1186/1755-7682-6-44] 10. Kennedy N, Miller P. The spectrum of paediatric cardiac disease presenting to an outpatient clinic in Malawi. BMC Res Notes 2013;6:53 [http:dx.doi.org/10.1186/1756-0500-6-53] 11. Cilliers AM. Rheumatic fever and rheumatic heart disease in Gauteng on the decline: Experience at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. S Afr Med J 2014;104(9):632-634. [http://dx.doi:10.7196/SAMJ.8318] 12. Sutton C. Ascertainment of rheumatic heart disease in children in the Limpopo Province of South Africa. Abstracts of Proceedings of the 15th Annual SA Heart Congress, Durban 2014. SA Heart, Journal of the South African Heart Association 2014;11(4):204. 13. Arguiedas A, Mohs E. Prevention of rheumatic fever in Costa Rica. J Pediatr 1992;121(4):569-572. [http://dx.doi.org/10.1016/S0022-3476(05)81146-1] 14. Nordet P, Lopez R, Duenas A, Sarmiento L. Prevention and control of rheumatic fever and rheumatic heart disease: The Cuban experience (1986-1996-2002). Cardiovasc J Afr 2008;19(3):135-140. 15. DiSciascio G, Taranta A. Rheumatic fever in children. Am Heart J 1980;99(5);635-658. [http://dx.doi. org/10.1016/0002-8703(80)90739-5]

Corresponding author: A M Cilliers (antoinette.cilliers@wits.ac.za) 1. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005;5(11):685-694. [http://dx.doi.org/10.1016/S1473-3099(05)70267-X] 2. Mayosi B, Robertson K, Volmink J, et al. The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006;96(3):246. 3. Carapetis JR, Zuhlke LJ. Global research priorities in rheumatic fever and rheumatic heart disease. Ann Pediatr Cardiol 2011;4(1):4-12. [http://dx.doi:10.4103/0974-2069.79616] 4. Tibazarwa KB, Volmink JA, Mayosi BM. Incidence of acute rheumatic fever in the world: A systematic review of population-based studies. Heart 2008;94(12):1534-1540. [http://dx.doi:10.1136/ hrt.2007.141309] 5. McLaren MJ, Hawkins DM, Koornof HJ, et al. Epidemiology of rheumatic heart disease in black school children of Soweto, Johannesburg. BMJ 1975;3(5981):474-478. 6. Sliwa K, Carrington M, Mayosi BM, et al. Incidence and characteristics of newly diagnosed rheumatic heart disease in urban African adults: Insights from the Heart of Soweto study. Eur Heart J 2010;31(6):719-727. [http://dx.doi:10.1093/eurheart/eurheart/ehp530]

S Afr Med J 2015;105(5):361-362. DOI:10.7196/SAMJ.9433

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Month 20xx, Vol. xxx, No. x

RESEARCH

Community- versus healthcare-acquired bloodstream infections at Groote Schuur Hospital, Cape Town, South Africa R McKay,1 MSc; C Bamford,2,3 MB ChB, FCPath, MMed S chool of Population and Public Health, University of British Columbia, Vancouver, Canada Division of Medical Microbiology, University of Cape Town, South Africa 3 National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa 1 2

Corresponding author: C Bamford (colleen.bamford@nhls.ac.za)

Background. Bloodstream infections (BSIs) cause considerable morbidity and mortality. The epidemiology of bacterial infections differs in community and hospital settings. Regular surveillance and reporting of pathogens and antimicrobial susceptibility can assist in appropriate management of BSIs. Objectives. To describe the distribution of organisms and of antibiotic susceptibility among isolates from blood cultures at a tertiary academic hospital during a 1-year period, stratifying by place of infection acquisition. Methods. This was a retrospective descriptive study of bloodstream isolates from cultures from adults (>13 years of age) routinely submitted between 1 October 2011 and 30 September 2012 to the clinical laboratory at Groote Schuur Hospital, Cape Town, South Africa. Community-acquired infections were compared with healthcare-acquired infections, defined as infections developing at least 48 hours after admission or within 3 months of admission to a healthcare facility. Frequencies and proportions of infecting organisms are presented, along with susceptibility results for selected pathogens. The hospital-acquired isolates were stratified by ward (emergency, general medical or general surgical ward or intensive care unit (ICU)) to determine organism frequency and susceptibility patterns by hospital ward. Results. Among adults, 740 non-duplicate pathogens were isolated from BSIs. Nearly three-quarters of infections were healthcare acquired. Enterobacteriaceae and non-fermentative Gram-negative bacilli were predominant among healthcare-acquired pathogens (39.2% and 28.5%, respectively), while Enterobacteriaceae and Gram-positive organisms were the most common among community-acquired pathogens (39.2% and 54.3%, respectively). The majority of community-acquired Enterobacteriaceae were highly susceptible to antibiotics (gentamicin 95.6%, ceftriaxone 96.1% and ciprofloxacin 92.2%), whereas 64.6% of healthcare-associated isolates were susceptible to gentamicin, 58.5% to ceftriaxone and 70% to ciprofloxacin. All community-acquired Staphylococcus aureus isolates v. 52.4% of healthcare-acquired isolates were susceptible to cloxacillin. The susceptibility of healthcare-acquired Pseudomonas aeruginosa and Acinetobacter baumanii complex isolates was <80% to all antibiotics with the exception of colistin. Klebsiella spp., S. aureus and Escherichia coli were the commonest causes of healthcareacquired infections in all areas outside of the ICUs, whereas Acinetobacter was common in the ICUs and rare in all other areas. Conclusion. The distinction between community- and healthcare-acquired infections is critical in antibiotic selection because narrowspectrum agents can be utilised for community-acquired infections. The considerable antibiotic resistance of healthcare-acquired pathogens highlights the importance of infection prevention and control. This type of surveillance could be incorporated into routine laboratory practice. S Afr Med J 2015;105(5):363-369. DOI:10.7196/SAMJ.8183

Bloodstream infections (BSIs) cause considerable morbidity and mortality.[1,2] Estimates suggest that 10 - 13% of community-onset BSIs are fatal,[3,4] while 23% of nosocomial BSIs resulted in death in one study in the USA.[4] A paediatric cohort study in Kenya reported a case fatality rate of 24% for community-acquired and 53% for hospital-acquired bacteraemia.[5] A systematic review of admissions to hospital in various regions of Africa estimated that 13.5% of adults and 8.2% of children had community-acquired BSIs,[6] indicating these are a common cause of illness and account for a substantial proportion of all healthcare admissions. Rapid diagnosis, identification of the causative bacteria and appropriate treatment are essential in mitigating the morbidity and mortality associated with BSIs. The epidemiology of bacterial infections differs in community and hospital settings. The predominant bacteria causing communityacquired infections are Gram-positive organisms, while hospitalacquired infections are more frequently caused by Gram-negative bacteria.[4] This distinction has relevance to empirical treatment of suspected bacterial infection.

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In the past decade, an additional category of healthcare-associated infection has been recognised, to cover infections in patients who have had recent contact with the healthcare system.[7] Healthcareassociated infections are typically similar to hospital-acquired infections in terms of pathogens and susceptibility patterns. We have therefore chosen to combine hospital-acquired and healthcareassociated infections as healthcare-acquired infections. Increasing antibiotic resistance complicates treatment of infections, in some cases seriously diminishing the options for effective therapy,[8] and is often associated with worse outcomes.[9] Laboratory-based surveillance data for BSIs in South Africa (SA) are available; however, these data do not distinguish between community- and hospitalacquired infection.[10] Regular surveillance and reporting of BSIs and antibiotic susceptibility, including differentiation of community- and healthcare-acquired infections, can assist in managing infections appropriately and in adapting local antibiotic stewardship policies.[11,12] Groote Schuur Hospital (GSH) is a large tertiary academic and teaching hospital in Cape Town, SA. In this hospital, blood cultures are generally collected when a patient has clinical features of sepsis,

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RESEARCH

typically before commencing or changing antibiotic therapy. However, there are no explicit guidelines or policies around indications for taking of blood cultures, and practices may vary from clinician to clinician. This report describes the distribution of organisms isolated in blood cultures at GSH during a 1-year period. Additionally, we describe the distribution of antibiotic resistance among some groups of pathogens. We adapted routine laboratory practices to allow for classification of infections as healthcare or community acquired and applied this stratification to analysis of pathogens and antibiotic susceptibility results. Guidelines to clinicians on antimicrobial therapy of bloodstream and other infections are provided by means of an annually updated and freely available booklet. At the time of the study, prior authorisation of most second-line antibiotics was required.

Methods

Study design

This was a retrospective assessment of bacterial isolates collected at GSH over a 12-month period.

Data

All microbiology testing was conducted at the GSH National Health Laboratory Service microbiology laboratory, which uses the BACTEC 9240 automated blood culture system (Becton Dickinson, USA). Identification and susceptibility testing was carried out using various standard methods employed in the laboratory. In the majority of cases standard biochemical tests and disc diffusion and gradient diffusion susceptibility tests were used for Gram-positive organisms, whereas a method of direct inoculation of the ID-GNB and the AST-N064 cards of the Vitek 2 system was used for Gram-negative organisms.[13] However, alternative methods were used if needed. Susceptibility results were interpreted according to the Clinical Laboratory Standards Institute (CLSI) criteria for the relevant year.[14,15] While the appropriate breakpoints for cephalosporins were utilised, the laboratory at this time, in line with the contemporary national practice, continued to accept the suggestion of the Vitek Advanced Expert System to report extended-spectrum β-lactamase (ESBL)producing Enterobacteriaceae as resistant to all cephalosporins. In addition, ESBL production was not reported on the laboratory information system (LIS) owing to limitations in the design and setup of the interface linking the Vitek instrument and the LIS. Hence, for the purposes of this analysis, ESBL production was assumed if Enterobacteriaceae isolates were reported as resistant to cefepime. Staphylococcus aureus isolates with an inducible clindamycin resistance phenotype were reported as resistant to clindamycin. Culture result data were extracted for every bloodstream isolate from GSH recorded in the laboratory database for the period 1 October 2011 - 30 September 2012. To limit the data to single infection episodes, duplicates (defined as instances of an additional culture submitted from the same patient, isolating the same organism, within 14 days of a previous culture) were excluded.[5,16] As part of regular practice, local microbiologists prospectively categorised each case of BSI after collecting relevant information from the attending clinician; this information was then recorded in a separate database, linkable by unique laboratory number. Healthcare-acquired infections were defined as those in patients admitted to (any) hospital for at least 48 hours before developing signs and symptoms of infection, or who had been admitted to a healthcare facility within the 3 months preceding the date of blood culture. In addition, infections in patients living in a long-term care facility or receiving dialysis, chemotherapy or home-based intravenous therapy were also

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included as healthcare-acquired infections.[7] Community-acquired isolates were defined as those occurring before admission, or within the first 48 hours of admission in patients without recent hospitalisation in the past 3 months. Classification of isolates as contaminants was based on recognition of the organism as one commonly considered to be a contaminant (i.e. on the identity of the organism), provided this was supported by the treating clinician’s clinical assessment and decision not to provide therapy targeted to the isolate.[17] In the majority of cases in our hospital only a single blood culture is submitted per episode of sepsis. However, if multiple cultures were submitted, the number of positive blood culture bottles or sets was also used to determine whether an isolate was categorised as a contaminant or not. Isolates for which no clinical information was available, usually owing to early discharge of the patient, were also classified as contaminants. Additional study variables included the date on which the blood sample was taken, the age and gender of the patient, and the hospital ward where the patient was located. Ethical approval for the study was granted through the University of Cape Town’s Faculty of Health Sciences Human Research Ethics Committee and the University of British Columbia’s Clinical Research Ethics Board.

Analysis

We used descriptive methods to assess the distribution of blood stream organisms and resistance patterns. Antibiotic susceptibility results were recorded in this database as susceptible, intermediate or resistant. Results are presented as the proportion of susceptible isolates out of the number of valid test results for that antibiotic and organism (or group of organisms). We further stratified the organism and susceptibility results by wards, grouped into categories of emergency, general medical, intensive care units (ICUs), maternity and surgery. Fisher’s exact tests were used to compare the proportions, with p<0.05 considered statistically significant. Data preparation and analysis were conducted in SAS software for Windows, version 9.3 (SAS Institute, USA).

Results

Study sample

There were 1 730 blood culture records from adults >13 years of age in the database; of these, 799 were considered pathogens and 931 contaminants. One hundred and forty-three pathogens were removed as duplicates. After including multiple organisms isolated from individual blood cultures (87 additional pathogens), our dataset contained 740 pathogens, isolated from 653 episodes of BSI in 533 patients. There were 981 organisms isolated from 931 blood cultures that were considered contaminants.

Demographics

Seventy-three per cent of the 653 episodes of illness (n=472) and 73% of the 740 organisms isolated (n=543) were healthcare acquired. The mean patient age was 49.6 years (standard deviation (SD) 19.8) for those with community-acquired infections, and 45.5 years (SD 16.8) for those with healthcare-acquired infections (Table 1).

Microbiology

Among community-acquired isolates, Gram-positive organisms were most common (54.3%, n=107), while there were 77 Enterobacteriaceae isolates (39.1%) (Table 2). Non-fermenting Gram-negative bacilli and fungi were rare. Streptococcus pneumoniae was the most frequently isolated organism (21.3%, n=42), followed by Escherichia coli (19.8%, n=39) and S. aureus (15.2%, n=30).

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Table 1. Demographics of patients with BSIs at GSH, 1 October 2011 - 30 September 2012 Adults (≥13 years) (N=653) Community acquired

Healthcare acquired

Total,* n (%)

181 (27.7)

472 (72.3)

Males, n (%)

75 (44.4)

270 (60.3)

Age (years), mean (SD)

49.6 (19.8)

45.5 (16.8)

*Total is number of BSI episodes; some patients had more than one episode, and if these were considered distinct, they were counted separately.

Table 2. Distribution of organisms causing BSIs among adults at GSH, 1 October 2011 - 30 September 2012

Community acquired (N=197, 26.6%) n (%)

Healthcare acquired (N=543, 73.4%) n (%)

Gram-negative bacilli

Enterobacteriaceae

77 (39.1)

214 (39.4)

Enterobacter

5 (2.5)

38 (7.0)

E. coli

39 (19.8)

54 (9.9)

K. pneumoniae

14 (7.1)

86 (15.8)

Salmonella spp.

9 (4.6)

1 (0.2)

Other*

10 (5.1)

35 (6.4)

5 (2.5)

154 (28.4)

A. baumanii complex

1 (0.5)

87 (16.0)

P. aeruginosa

4 (2.0)

37 (6.8)

Other

30 (5.5)

4 (2.0)

Staphylococci

35 (17.8)

99 (18.2)

S. aureus

30 (15.2)

63 (11.6)

Non-fermentative Gram-negative bacilli

†

Other Gram-negatives‡ Gram-positive

Coagulase-negative staphylococci

5 (2.5)

36 (6.6)

61 (31.0)

11 (2.0)

β-haemolytic streptococci

13 (6.6)

S. pneumoniae

42 (21.3)

4 (0.7)

Streptococci

Other α-haemolytic streptococci Enterococci Other

6 (3.0)

7 (1.3)

5 (2.5)

41 (7.6)

6 (3.0)

4 (2.0)

24 (4.4)

Candida spp.

1 (0.5)

24 (4.4)

Cryptococcus neoformans

3 (1.5)

Fungi

*Includes Citrobacter, Morganella, Pantoea, Proteus, Providencia, Raoultella and Serratia. † Includes Stenotrophomonas maltophilia. ‡ Includes anaerobes and fastidious Gram-negative bacilli.

Gram-negative bacilli constituted the largest group of healthcare-acquired isolates (68.0%, n=369) (Table 2). Gram-positive organisms and fungi accounted for 27.8% and 4.4%, respectively. Among the Gram-negative bacilli, Enterobacteriaceae predominated (39.4%, n=214), while non-fermenting Gramnegative bacilli constituted 28.4% (n=154). The most commonly isolated healthcare-

acquired organisms were Acinetobacter baumanii complex (16.0%, n=87), Klebsiella spp. (15.8%, n=86), S. aureus (11.6%, n=63) and E. coli (9.9%, n=54).

Antibiotic susceptibility

Community-acquired isolates Community-acquired bloodstream patho gens demonstrated minimal resistance to

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most first-line antibiotic agents used for treatment. All S. aureus isolates (n=30) were susceptible to cloxacillin, and 28 and 29 were susceptible to erythromycin and clindamycin, respectively (Fig. 1). The majority of S. pneumoniae isolates (35/42, 83%) were fully susceptible to penicillin (minimum inhibitory concentration (MIC) ≤0.06 µg/mL) while the remainder (7/42, 17%) had MICs in the range of 0.12 - 2 µg/ mL, meaning that they would be categorised as resistant in cases of meningitis, but susceptible for infections outside the central nervous system. All S. pneumoniae isolates were susceptible to ceftriaxone according to meningitis breakpoints (MIC ≤0.5 µg/mL). The majority of Enterobacteriaceae were susceptible to gentamicin (95.6%), ceftriaxone (96.1%) and ciprofloxacin (92.2%) (Fig. 2). The proportion of ESBLproducing Enterobacteriaceae was just under 5%, and 79.1% were susceptible to amoxicillin/clavulanate. Healthcare-acquired isolates Resistance was higher among healthcareacquired pathogens. Just over half of S. aureus isolates were susceptible to cloxacillin and to clindamycin (52.4% and 55.6%, respectively) (Fig. 3). No vancomycin resistance was detected in the 41 enterococcal isolates. Among the Enterobacteriaceae, only 41.4% were susceptible to amoxicillin/ clavulanate, 64.6% to gentamicin and 70% to ciprofloxacin (Fig. 3). ESBL production occurred in 39.6%. More than 99% were susceptible to the carbapenems, including ertapenem, meropenem and imipenem. Susceptibility to amikacin was 85.4%. Susceptibility to piperacillin/tazobactam was not reported owing to incomplete testing as a result of limitations of the Vitek 2 Gram-negative susceptibility card in use at the time (Product Correction/Field Safety Notice Vitek® 2 Piperacillin/Tazobactam Memo, communication from bioMerieux, 5 April 2011). Pseudomonas aeruginosa showed relatively low susceptibility rates to most agents tested, ranging from 44.4% for imipenem and ciprofloxacin to 72.2% for ceftazidime (data not shown). Colistin was the only agent that retained high levels of susceptibility (91.7%). Susceptibility rates for piperacillin/tazobactam could not be reported for P. aeruginosa isolates for the same reason as above. A. baumanii complex also demonstrated low levels of susceptibility: only tobramycin and colistin retained susceptibility rates above 70% (72.1% and 96.6%, respectively) (data not shown).

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Healthcare acquired

Community acquired

100 90 80 Susceptible, %

70 60 50 40 30 20 10 0

Cloxacillin

Clindamycin

Erythromycin

Co-trimoxazole

Vancomycin

Fig. 1. Antibiotic susceptibility of S. aureus isolated from BSIs among adults (≥13 years) at GSH, 1 October 2011 - 30 September 2012 (community-acquired S. aureus n=30, healthcare-acquired S. aureus n=63).

Community acquired

Healthcare acquired

100 90 80 Susceptible, %

70 60 50 40 30 20 10 0

xim

e on iax

n illi

Am f Ce

lin

cil

a ot ef /c

e at

lav

an ul

e ap

n pe

e op er

ic ox

ici

m ta en

cin

a ox ofl r p

er uc ) d o t pr tan Am L B sis ES re (% cin

ika

Fig. 2. Antibiotic susceptibility of Enterobacteriaceae isolated from BSIs among adults (≥13 years) at GSH, 1 October 2011 - 30 September 2012.

Ward stratification The ward distribution of healthcareacquired organisms is shown in Table 3. Half (n=271, 49.9%) of all healthcare-acquired isolates were associated with ICUs. Of these, nearly a quarter were identified as A. baumanii complex (n=65, 24.0%), while just over one-tenth were K. pneumoniae (n=33, 12%). In contrast, 28% of isolates were associated with general surgical wards (n=153, 28.2%), with equal numbers of

E. coli and K. pneumoniae predominating (n=26, 17.0%). Fewer healthcare-associated isolates were associated with emergency (n=34, 6.3%) and general medical wards (n=76, 14.0%), but among these, the predominant organisms were S. aureus (emergency n=8, 23.5%; general medical n=18, 23.7%), K. pneumoniae (emergency n=8, 23.5%; general medical n=10, 13.2%) and E. coli (emergency n=7, 20.6%; general medical n=11, 14.5%) (Table 3). The number

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of healthcare-acquired isolates associated with the maternity wards was very small (n=9), so no further analysis of these isolates is presented. The susceptibility profiles of selected pathogens isolated from different wards are shown in Figs 4 - 6. There were no statistically significant differences in the proportions susceptible to antibiotics in different wards, apart from E. coli isolates in the emergency ward (n=7), which were significantly more susceptible (100%) to ciprofloxacin than isolates from the ICUs (40%, n=10), and Acinetobacter isolates in the ICUs (n=65), which were significantly less susceptible to tobramycin (67.7%) and to amikacin (39%) than those associated with surgical wards (n=14, 100% and 78% susceptibility, respectively) (p<0.05 for all comparisons).

Discussion

Three-quarters of BSIs in adults at GSH are healthcare acquired. Although this may be partially expected at a tertiary hospital receiving many patients referred from other institutions, and therefore fewer community-acquired infections, this high proportion does illustrate the potential for reduction in numbers of BSIs through preventive measures, e.g. prompt removal of unnecessary intravenous lines and urinary catheters, and through improved hand hygiene. The predominance of Gram-positive organisms among community-acquired infections and Gram-negative organisms among healthcare-acquired infections was confirmed in this study. Overall the most prevalent organisms responsible for community-acquired (S. pneumoniae, E. coli, S. aureus and K. pneumoniae) and healthcareacquired (Acinetobacter spp., Klebsiella spp., S. aureus, E. coli, enterococci, Enterobacter spp., P. aeruginosa, and coagulase-negative staphylococci) BSIs in our study were generally consistent with other recent studies.[18,19] Klebsiella spp., S. aureus and E. coli were the commonest causes of healthcare-acquired infections in all areas outside the ICUs, whereas Acinetobacter was common in the ICUs and rare in all other areas. Community-acquired bloodstream patho gens in this hospital remain largely susceptible to the first-line antibiotics, but anti biotic resistance is relatively common among healthcare-acquired bloodstream pathogens. Given that more than 50% of S. aureus isolates are resistant to cloxacillin, empirical vancomycin is appropriate for serious healthcare-acquired S. aureus infections. Likewise, with 40% of healthcare-acquired

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was not possible to investigate the proportion of isolates susceptible to the previously used combination of piperacillin-tazobactam and amikacin. In the ICUs, colistin or tobramycin may be needed for Acinetobacter

Enterobacteriacae being ESBL producers, the use of ertapenem for suspected Gramnegative sepsis in this hospital seems justified. Amikacin is one possible alternative (85% susceptibility), but unfortunately it

100

Susceptible, %

Cloxacillin

Clindamycin Erythromycin

Co-trimoxazole Vancomycin

Emergency n=8

General medical Intensive care n=18 n=20

Surgery n=17

Fig. 3. Antibiotic susceptibility of S. aureus causing healthcare-acquired BSIs among adults (≥13 years) at GSH, 1 October 2011 - 30 September 2012, according to ward groups.

infections. These conclusions are in line with contemporary hospital antibiotic recommendations. Compared with a previous report that included data from GSH from 2010,[10] a lower proportion of healthcare-acquired S. aureus were susceptible to cloxacillin (52.4% v. 69%) and clindamycin (55.6% v. 71%) in the present study. The proportion of susceptible A. baumanii isolates was also lower in the present study with regard to ceftazidime (20.7% v. 49%), imipenem (18.4% v. 26%), meropenem (18.6% v. 23%) and gentamicin (39.1% v. 47%). The likely reasons for these differences are the stratification of isolates into community- and healthcare-acquired infections, as well as the exclusion of contaminants and duplicates.[10] Our results confirm the low susceptibility rates for P. aeruginosa and A. baumannii that have been reported in SA national surveillance data and in studies from other countries (although numbers of isolates may be low for confident comparisons) and reinforce the reliance on colistin as the sole agent that retains activity against most strains.[20] The ward-stratified results suggest that the distribution of organisms

Table 3. Distribution of organisms causing healthcare-acquired BSIs among adults (≥13 years) at GSH, 1 October 2011 30 September 2012, according to ward groups Hospital ward groups Emergency n (%) Enterobacteriaceae

General medical n (%)

Intensive care n (%)

Maternity n (%)

Surgery n (%)

Total n (%)

17 (7.9)

28 (13.1)

83 (38.8)

1 (0.5)

85 (39.7)

214 (39.4)

E. cloacae complex

-15

3 (3.9)

16 (5.9)

15 (9.8)

34 (6.3)

E. coli

7 (20.6)

11 (14.5)

10 (3.7)

26 (17.0)

54 (9.9)

K. pneumoniae

8 (23.5)

10 (13.2)

33 (12.2)

1 (11.1)

26 (17.0)

78 (14.4)

Serratia marcescens

10 (3.7)

2 (1.3)

12 (2.2)

Other

2 (5.9)

4 (5.3)

14 (5.2)

16 (10.5)

36 (6.6)

3 (8.8)

8 (10.5)

110 (40.6)

8 (88.9)

25 (16.3)

154 (28.4)

Gram-negative non-fermenting bacilli A. baumanii complex

4 (5.3)

65 (24.0)

4 (44.4)

14 (9.2)

87 (16.0)

P. aeruginosa

3 (8.8)

2 (2.6)

20 (7.4)

1 (11.1)

11 (7.2)

37 (6.8)

Stenotrophomonas maltophilia

2 (2.6)

17 (6.3)

1 (11.1)

20 (3.7)

Other

8 (3.0)

2 (22.2)

10 (1.8)

Gram-positive

14 (41.2)

36 (47.4)

63 (23.2)

38 (24.8)

151 (27.8)

Enterococcus faecalis

1 (2.9)

3 (3.9)

14 (5.2)

3 (2.0)

21 (3.9)

E. faecium

6 (7.9)

9 (3.3)

3 (2.0)

18 (3.3)

S. aureus

8 (23.5)

18 (23.7)

20 (7.4)

17 (11.1)

63 (11.6)

S. epidermidis

3 (8.8)

5 (6.6)

10 (3.7)

6 (3.9)

24 (4.4)

Other

2 (5.9)

4 (5.3)

10 (3.7)

9 (5.9)

25 (4.6)

4 (5.3)

15 (5.5)

5 (3.3)

24 (4.4)

Fungi Candida albicans

2 (2.6)

11 (4.1)

3 (2.0)

16 (2.9)

Other

2 (2.6)

4 (1.5)

2 (1.3)

8 (1.5)

34 (100.0)

76 (100.0)

271 (100.0)

9 (100.0)

153 (100.0)

543 (100.0)

Total

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100

Susceptible, %

Gentamicin Amikacin

Ciprofloxacin Ertapenem Meropenem Imipenem

Colistin ESBL producer (% resistant)

20 0

Emergency General medical Intensive care n=8 n=11 n=10

Study limitations

Surgery n=26

Fig. 4. Antibiotic susceptibility of E. coli causing healthcare-acquired BSIs among adults (â&#x2030;Ľ13 years) at GSH, 1 October 2011 - 30 September 2012, according to ward groups. 100

Gentamicin Susceptible, %

Amikacin Ciprofloxacin Ertapenem

Meropenem Imipenem

Colistin

Emergency n=8

General medical Intensive care n=10 n=33

Surgery n=26

ESBL producer (% resistant)

Fig. 5. Antibiotic susceptibility of K. pneumoniae causing healthcare-acquired BSIs among adults (â&#x2030;Ľ13 years) at GSH, 1 October 2011 - 30 September 2012, according to ward groups. 100

Ceftazidine

Cefepime 80 Susceptible, %

Meropenem Imipenem

Gentamicin 40

Amikacin Tobramycin

Ciprofloxacin 0

General medical n=4

Intensive care n=65

Surgery n=14

Colistin

Fig. 6. Antibiotic susceptibility of A. baumannii complex causing healthcare-acquired BSIs among adults (â&#x2030;Ľ13 years) at GSH, 1 October 2011 - 30 September 2012, according to ward groups.

and their susceptibility patterns do not differ significantly by ward, apart from the greater

proportion and more resistant Acinetobacter isolates associated with ICUs. This finding

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may be limited by the small numbers of isolates per ward. Surveillance of antibiotic resistance, locally as well as regionally and globally, is important. Consistent application of standard definitions will assist in this ongoing endeavour. As has been pointed out previously,[10] laboratory-based surveillance depends on the culture submission practices of clinicians. Data should be maintained and extractable with an emphasis on facilitating regular analysis and reporting. Reporting should be based on standards that can be widely accepted and applied.

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The chief limitation of this study was our inability to retrospectively assess the accuracy of the contaminant classification. These may be genuine contaminants, but could also include isolates for which clinical information was lacking or represent instances of error or omission by the reporting microbiologist. The majority of the group designated as contaminants were coagulase-negative staphyloccci or corynebacteria, which are recognised skin flora. However, some fungi and mycobacteria were not classified; these are likely to be mostly community acquired. Small numbers of Enterobacteriaceae (n=34) and S. aureus (n=24) were probably incorrectly excluded from the analysis of pathogens; however, the number of these relative to the numbers included was low (290 and 93 included, respectively). Improvements to the reporting system, such as inclusion of additional reporting items to differentiate unclassified isolates, as well as monthly review of data, could minimise these deficiencies. Another important limitation concerns the reporting of all ESBL producers as resistant to all cephalosporins. Potentially, a proportion of these isolates would be susceptible to cephalosporins, particularly cefepime. However, evidence suggests that carriage of multiple ESBL genes is common in SA,[21] and at the time of writing this matter is still under discussion by national microbiology groups. As the study spanned 2011 and 2012, the CLSI interpretive criteria that were applied differed over time. However, the changes were relatively few in number, and did not affect the major findings in relevant antibiotic susceptibilities in this study or alter the empirical treatment recommendations. This report does not allow us to discuss trends in resistance patterns over time, as the analysis was conducted crosssectionally. Additionally, the data do not allow us to comment on incidence of

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infection, either healthcare or community acquired. Changes in culture submission practices over time may have an impact on these reported susceptibility results. As with other studies of this nature, if clinicians are more likely to submit cultures for infections that are not responding to initial empirical treatment, the overall resistance rate will be inflated. We are not aware of any hospitalbased outbreaks occurring during the study period that would have biased our results.

Conclusion

The distinction between community- and healthcare-acquired acquisition of infection is relevant and important to empirical treatment options of BSIs. The findings presented here suggest that healthcare-acquired bloodstream pathogens carry significant resistance phenotypes. As hospital antibiotic use places substantial selection pressure on circulating organisms, efforts must continue to be directed towards improving the appropriateness of antibiotic use. This includes selection of an effective antimicrobial agent, as well as prescribing the optimal dose and duration, for all clinically important bacterial infections. Community-acquired BSIs in this region retain considerable susceptibility to the antibiotics commonly used to treat them. Antibiotic stewardship efforts will be supported by the selection of relatively narrow-spectrum antibiotics for community-acquired infections, even in the tertiary setting. Resistance should be monitored closely so that treatment and antibiotic stewardship practice can continue to be informed by local susceptibility patterns. Differentiation of community- and healthcare-acquired BSIs provides additional useful information, and could be readily incorporated into routine laboratory practice by any laboratory that conducts similar clinical liaison, although measures to ensure accuracy of classification should be included. Acknowledgements. The authors wish to acknowledge the National Health Laboratory Service of South Africa for providing the data to conduct this analysis.

References 1. Laupland KB. Defining the epidemiology of bloodstream infections: The ‘gold standard’ of population-based assessment. Epidemiol Infect 2012;141(10):2149-2157. [http://dx.doi.org/10.1017/S0950268812002725] 2. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005;352(1):39-47. [http://dx.doi.org/10.1056/NEJMoa040275] 3. Skogberg K, Lyytikäinen O, Ollgren J, Nuorti JP, Ruutu P. Population-based burden of bloodstream infections in Finland. Clin Microbiol Infect 2012;18(6):E170-E176. [http://dx.doi.org/10.1111/j.1469-0691.2012.03845.x] 4. Diekema DJ, Beekmann SE, Chapin KC, Morel KA, Munson E, Doern GV. Epidemiology and outcome of nosocomial and community-onset bloodstream infection. J Clin Microbiol 2003;41(8):3655-3660. [http://dx.doi.org/10.1128/JCM.41.8.3655-3660.2003] 5. Aiken AM, Mturi N, Njuguna P, et al. Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: A prospective cohort study. Lancet 2011;378(9808):2021-2027. [http:// dx.doi.org/10.1016/S0140-6736(11)61622-X] 6. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: A systematic review and meta-analysis. Lancet Infect Dis 2010;10(6):417-432. [http://dx.doi.org/10.1016/S1473-3099(10)70072-4] 7. Friedman ND, Kaye KS, Stout JE, et al. Health care-associated bloodstream infections in adults: A reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002;137(10):791-797. [http://dx.doi.org/10.7326/0003-4819-137-10-200211190-00007] 8. French GL. Clinical impact and relevance of antibiotic resistance. Advanced Drug Deliv Rev 2005;57(10):1514-1527. [http://dx.doi.org/10.1016/j.addr.2005.04.005] 9. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: Mortality, length of hospital stay, and health care costs. Clin Infect Dis 2006;42(Suppl 2):S82-S89. 10. Bamford C, Bonorchis K, Elliott E, et al. Antimicrobial susceptibility patterns of selected bacteraemic isolates from South African public sector hospitals, 2010. Southern African Journal of Epidemiology and Infection 2011;26(4):243-250. 11. Levy SB, Marshall B. Antibacterial resistance worldwide: Causes, challenges and responses. Nat Med 2004;10(12s):S122-S129. [http://dx.doi.org/10.1038/nm1145] 12. Grundmann H, Klugman KP, Walsh T, et al. A framework for global surveillance of antibiotic resistance. Drug Resist Updat 2011;14(2):79-87. [http://dx.doi.org/10.1016/j.drup.2011.02.007] 13. Bamford C, Goodway J, Hoffmann R. Rapid identification and susceptibility testing of Gram-negative bacilli from blood cultures using the Vitek. Southern African Journal of Epidemiology and Infection 2010;25(3):28-31. 14. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-First Informational Supplement. CLSI document M100-S21. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. 15. Clinical and Laboratory Standards Institute. Performance standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. CLSI document M100-S22. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. 16. Clinical and Laboratory Standards Institute. Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data; Approved Guideline. 3rd ed. CLSI document M139-A3. Wayne, PA: Clinical and Laboratory Standards Institute, 2009. 17. Hall KK, Lyman JA. Updated review of blood culture contamination. Clin Microbiol Rev 2006;19(4):788-802. [http://dx.doi.org/10.1128/CMR.00062-05] 18. Brink A, Feldman C, Duse A, et al. Guideline for the management of nosocomial infections in South Africa. S Afr Med J 2006;96(7):642-652. 19. De Bus L, Coessens G, Boelens J, Claeys G, Decruyenaere J, Depuydt P. Microbial etiology and antimicrobial resistance in healthcare-associated versus community-acquired and hospital-acquired bloodstream infection in a tertiary care hospital. Diagn Microbiol Infect Dis 2013;77(4):341-345. [http://dx.doi.org/10.1016/j.diagmicrobio.2013.08.009] 20. Visser Kift E, Maartens G, Bamford C. Systematic review of the evidence for rational dosing of colistin. S Afr Med J 2014;104(3):183-186. [http://dx.doi.org/10.7196/SAMJ.7011] 21. Perovic O, Singh-Moodley A, Duse A, et al. National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010 - 2012. S Afr Med J 2014;104(8):563568. [http://dx.doi.org/10.7196/SAMJ.7617]

Accepted 18 March 2015.

DOCTORS CALL FOR LAWYERS TO GET OUT OF HOSPITALS The South African Medical Association Trade Union (SAMA TU) would like to join the health minister Dr Aaron Motsoaledi in calling for “lawyers to get out of hospital and go back to court, and for doctors to get out of courts and go back to hospital”. The increasing frequency and value of medical malpractice claims threatens delivery of health services to the nation, especially the poor. We also agree that access to justice for those who have genuinely suffered at the hands of the healthcare system should never be compromised. However, prevention is better than cure and as stakeholders in health we need to improve the access to and quality of our services. We would like to declare our support and dedicated participation in the minister’s current medico-legal summit. We hope this summit will come up with tangible resolutions and an action plan that will put patients first, protect the interests of the nation, and regulate the healthcare system in a just way. The impact of medico-legal cases has dire consequences for everyone; the limited resources are diverted from life-saving activities, while there is a risk of extinction of critical medical specialties such as gynaecologists, neurosurgery, anaesthesiology, neonatology and others. As SAMA TU we will embark on a nationwide programme to educate doctors on medico-legal issues, and put more emphasis on improving the quality and access to healthcare.

SAMA MED-e-MAIL, 10 March 2015

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A prospective observational study of bacteraemia in adults admitted to an urban Mozambican hospital M Preziosi,1 MD; T F Zimba,2 MD; K Lee,3 MD; M Tomas,2 MD; S Kinlin,2 MD; C Nhatave-Paiva,2 MD; R Bene,2 MD; T Paunde,2 MD; H Lopes,2 MD; S Kalkhoff,4 MD; V Prathap,1 MD; K Akrami,5 MD; E V Noormahomed,1,2 MD, PhD; R T Schooley,1 MD; E Aronoff-Spencer,1 MD, PhD University of California, San Diego, USA Universidade Eduardo Mondlane, Maputo, Mozambique 3 Emory University, Atlanta, GA, USA 4 University of Iowa, Iowa City, USA 5 National Institutes of Health, Bethesda, MD, USA 1 2

Corresponding author: M Preziosi (mpreziosi@ucsd.edu)

Background. Bacteraemia is a common cause of fever among patients presenting to hospitals in sub-Saharan Africa. The worldwide rise of antibiotic resistance makes empirical therapy increasingly difficult, especially in resource-limited settings. Objectives. To describe the incidence of bacteraemia in febrile adults presenting to Maputo Central Hospital (MCH), an urban referral hospital in the capital of Mozambique, and characterise the causative organisms and antibiotic susceptibilities. We aimed to describe the antibiotic prescribing habits of local doctors, to identify areas for quality improvement. Methods. Inclusion criteria were: (i) ≥18 years of age; (ii) axillary temperature ≥38°C or ≤35°C; (iii) admission to MCH medical wards in the past 24 hours; and (iv) no receipt of antibiotics as an inpatient. Blood cultures were drawn from enrolled patients and incubated using the BacT/Alert automated system (bioMérieux, France). Antibiotic susceptibilities were tested using the Kirby-Bauer disc diffusion method. Results. Of the 841 patients enrolled, 63 (7.5%) had a bloodstream infection. The most common isolates were Staphylococcus aureus, Escherichia coli, and non-typhoidal Salmonella. Antibiotic resistance was common, with 20/59 (33.9%) of all bacterial isolates showing resistance to ceftriaxone, the broadest-spectrum antibiotic commonly available at MCH. Receipt of insufficiently broad empirical antibiotics was associated with poor in-hospital outcomes (odds ratio 8.05; 95% confidence interval 1.62 - 39.91; p=0.04). Conclusion. This study highlights several opportunities for quality improvement, including educating doctors to have a higher index of suspicion for bacteraemia, improving local antibiotic guidelines, improving communication between laboratory and doctors, and increasing the supply of some key antibiotics. S Afr Med J 2015;105(5):370-374. DOI:10.7196/SAMJ.8780

Bacteraemia is a common cause of fever among patients presenting to hospitals in sub-Saharan Africa (SSA), but it remains underdiagnosed because many facilities lack the proper resources, and it often presents in nonspecific ways.[1] Furthermore, the worldwide rise of antibiotic resistance makes empirical therapy increasingly difficult, especially in resource-limited settings.[2,3] Maputo Central Hospital (MCH) is a 1 200-bed national referral hospital in Maputo, the capital of Mozambique. It is the principal teaching hospital in Mozambique, in collaboration with Universidade Eduardo Mondlane (UEM). MCH has a modern, automated system in place to perform blood cultures and diagnose bacteraemia, yet historically the system was underutilised. We designed a prospective study to determine the incidence of bacteraemia in patients presenting with fever, a common presenting sign in the medical wards of MCH. The majority of patients admitted to the medical wards at MCH are HIV-positive, commonly presenting in late stages of disease, and not on antiretroviral therapy. This is consistent with other reports from Mozambique and the greater region.[4,5] The differential diagnosis for fever is broad in this population and frequently includes bacteraemia,[1,6-8] although it was rarely considered at MCH prior to this study. The greater context of this study is the Medical Education Partnership Initiative between the University of California, San Diego, USA, and UEM, which focuses on strengthening the

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educational and research infrastructure of Mozambique’s three public medical schools. A major priority of this collaboration is to recruit trainees and junior faculty into lifelong careers in medical education and research while providing them with the skills to make these careers sustainable.[9,10] At the outset of the collaboration, doctors working in the internal medicine department at MCH were surveyed in order to identify problems considered to be of highest importance. ‘We are blind’ was a specific phrase repeated by numerous doctors in this survey, in reference not only to their limited diagnostic resources but also to the lack of medical research done locally. Early efforts to address these problems included implementation of a regular schedule of clinical conferences and journal clubs in the residency training programme, accompanied by improved access to internet and medical information in the hospital, in order to establish a culture of scientific enquiry and evidence-based medicine. Focus later shifted to improvement of biomedical informatics, as well as infrastructure for clinical, operational and epidemiological research. Opportunities for Mozambican medical residents to participate in research projects were sought. This study is the first to be carried out in part by residents in the internal medicine training programme at MCH. It also represents the first study of bacteraemia in a hospitalised adult Mozambican population. In addition to describing the incidence of bacteraemia in febrile adults presenting to MCH and creating an antibiogram, we set out

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to describe the antibiotic prescribing habits of local doctors and to identify links with patient outcomes, with a view to identifying highyield areas for future quality improvement projects.

Methods

Ethical statement

Ethical approval was obtained specifically for this study from the University of California, San Diego Institutional Review Board as well as the Mozambican National Committee for Bioethics and Health.

Study team

We assembled a study team of local Mozambican healthcare workers: a nurse who enrolled and phlebotomised patients, five internal medicine residents who recorded patient clinical information and outcomes, a microbiology laboratory technician charged with processing blood cultures, and a senior infectious disease expert. In addition, there were two collaborators from the USA, one on-site and one off-site.

Patient enrolment

From September 2011 through October 2012, and then again from July 2013 through March 2014, the study nurse enrolled patients on weekday mornings from the internal medicine wards. Inclusion criteria were as follows: (i) ≥18 years of age; (ii) axillary temperature ≥38°C or ≤35°C; (iii) admission in the past 24 hours; and (iv) no receipt of antibiotics as an inpatient. Each patient gave written informed consent. If patients were unable to give consent, an attendant (usually a family member) consented for them. We initially attempted to enrol patients from the emergency room, which was frequently overcrowded and understaffed, but abandoned these efforts out of concern for patient safety and a desire to not influence emergency room doctors’ decisions to admit patients. Once enrolled, the nurse drew 20 mL of blood from each patient and aseptically inoculated two BacT/Alert aerobic blood culture bottles (bioMérieux, France).

Data collection

The in-hospital medical team was responsible for all clinical decisions regarding patient management. Each patient was independently followed by one of the Mozambican internal medicine residents on the study team, who recorded laboratory data as well as outcomes ‘improved’, ‘unimproved’ or ‘died’ from patient charts. Members of the study team did not make clinical decisions but did inform the doctors caring for the patient that their patient had been enrolled in a study and facilitated communication of blood culture results from the laboratory. Nonetheless, in some cases patients were discharged before a complete data set had been recorded. Each team member received an Android tablet with a customised Health Information System application (keep.distributedhealth.org) for data entry. Data were synchronised automatically from tablets to a server when internet was available. An offsite US collaborator reviewed data on a weekly basis and debriefed the study team.

Bacterial culture, identification and antibiotic susceptibility testing

Blood cultures were processed using BacT/Alert i AST bottles in a BacT/ALERT 3D machine (bioMérieux). Isolates from positive cultures were identified by standard biochemical tests as set out in Clinical Laboratory Standards Institute (CLSI) guidelines.[11] Cultures were considered contaminated if they grew coagulase-negative Staphylococcus or diptheroids. Antimicrobial susceptibility testing was performed by standard disc diffusion methods to trimethoprim/

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sulfamethoxazole (1.25/23.75 μg), chloramphenicol (30 μg), oxacillin (1 μg), penicillin (10 μg), ampicillin (10 μg), tetracycline (30 μg), gentamicin (10 μg) ceftriaxone (30 μg), ciprofloxacin (5 μg) and imipenem (10 μg). Phenotypic methicillin-resistant Staphylococcus aureus (MRSA) were determined by oxacillin disc and cefoxitin disc and tested for resistance to vancomycin. In Salmonella isolates, antibiotic susceptibilities were also confirmed using the VitekII system (Card AB AST-N156, bioMérieux). Isolates flagged as extended-spectrum β-lactamase (ESBL) or demonstrating resistance to ceftriaxone or ceftazidime by the disc diffusion method were phenotypically confirmed by the combined double-disc method using ceftazidime and cefepime alone and in combination with clavulanic acid. Breakpoints for resistance were according to CLSI guidelines.[11]

Clinical laboratory data

Clinical laboratory data relevant to this study were processed in five different laboratories. For patients who did not have clearly documented HIV status, a rapid test was performed using both the Determine HIV1/2 Rapid Test (Abbot Laboratories, USA) and the Unigold HIV Rapid Test (Trinity Biotech, Ireland). Per hospital protocol, in the case of discordant results both tests were repeated in one month (there is no third test available as a tiebreaker at MCH). CD4 counts were determined using a FACS-Calibur flow cytometer (BD Biosciences, USA). Complete blood counts were determined with an XE-2100 haematology analyser (Sysmex, Japan). Plasmodium falciparum malaria was diagnosed first with a rapid immunochromatographic test for the HRP-2 antigen (First Response, Premiere Medical Corporation, India); if positive, a Giemsa-stained thick and thin smear was analysed in the regular course of clinical duty by a locally trained microscopist paid by the Ministry of Health. In cases where sputum smears were ordered, Ziehl-Neelsen-stained slides were similarly interpreted by a hospital microscopist. Owing to limited resources, we were not able to implement quality control for microscopy-based diagnoses, and our data reflect what was available to Mozambican doctors charged with caring for enrolled patients.

Statistical analysis

Data were exported from the online database to an Excel spread sheet. Descriptive statistics were calculated with Excel and further analysis was done with free online software (vassarstats.net). Categorical data were compared with the χ2 test and Fisher’s exact test where appropriate. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for clinical predictors of bacteraemia, and clinical predictors for poor outcomes (‘unimproved’ or ‘died’) in patients with bacteraemia. In cases where specific clinical variables or outcomes were not available for all patients, only those patients for whom the variables were known were used in the analysis. Two-tailed p-values of <0.05 were considered statistically significant.

Results

Of the 841 patients enrolled, 63 (7.5%) had a bloodstream infection. Of the 765 (91.1%) patients with a documented outcome, 138 (18.0%) died while in the hospital. Thirteen of 56 (23.2%) patients with bacteraemia and a documented outcome died while in the hospital, but bacteraemia was not a significant predictor of in-hospital mortality (OR 1.41; 95% CI 0.74 - 2.70; p=0.37). However, bacteraemia was significantly linked to the combined endpoint of ‘died’ and ‘unimproved’ as a hospital outcome (OR 1.89; 95% CI 1.07 - 3.39; p=0.03). Characteristics of the patient population and associations with

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bacteraemia are set out in Table 1. There were very few factors associated with

bacteraemia with a p-value <0.20, so a multifactorial analysis was not done.

Fifty blood cultures (5.9%) were considered to be contaminants. The most common pathogenic isolates were S. aureus, E. coli and non-typhoidal Salmonella (NTS) (Table 2). Eight of 17 S. aureus isolates (47.0%) were MRSA, consistent with local hospital epidemiology, and these had variable susceptibility to co-trimoxazole, tetracycline, chloramphenicol and ciprofloxacin. All Gram-positive isolates were sensitive to vancomycin. Of 35 Gram-negative isolates, 10 (28.6%) were resistant to ceftriaxone and 6 (17.1%) to ciprofloxacin. All S. typhimurium isolates were resistant to chloramphenicol, ampicillin and co-trimoxazole, and 4 of 10 (40.0%) had an ESBL phenotype. Two Enterobacter spp., one Klebsiella pneumoniae and one E. coli also had an ESBL phenotype (Table 2). All non-Salmonella Gram-negative isolates were sensitive to gentamicin. Patients with bloodstream infection received empirical antibiotics with a spectrum broad enough to cover their infecting organism in 20/59 cases (33.9%). Among patients who had bacteraemia, those who received ineffective empirical antibiotics were more likely to have a poor clinical outcome (OR 8.05; 95% CI 1.62 39.91; p=0.04) (Table 3). Of all patients, 597 (71.0%) were prescribed empirical antibiotics by the admitting teams. A total of 50 different empirical antibiotic regimens were used. Penicillin was the single antibiotic most often prescribed. Combination therapy

Table 1. Characteristics of study population (N=841) and predictors of bloodstream infection* Bloodstream infection Characteristic

Yes, n (%)

No, n

Male (N=425)

35 (8.2)

390

OR (95%CI)

p-value

1.20 (0.72 - 2.00)

0.52

Female (N=416)

29 (7.0)

387

0.84 (0.50 - 1.39)

0.52

SIRS† (N=663)

50 (7.5)

613

0.658 (0.36 - 1.21)

0.23

No SIRS† (N=136)

15 (11.0)

121

1.52 (0.83 - 2.79)

0.23

SBP ≤90 mmHg (N=90)

12 (13.3)

1.84 (0.94 - 3.56)

0.06

SBP >90 mmHg (N=658)

53 (8.1)

635

0.54 (0.28 - 1.06)

0.06

Hb <5 mg/dL (N=98)

18 (18.4)

1.78 (0.98 - 3.23)

0.06

Hb ≥5 mg/dL (N=660)

47 (7.1)

372

0.56 (0.31-1.02)

0.06

HIV+ (N=652)

55 (8.4)

597

1.07 (0.53 - 2.16)

1.0

HIV– (N=126)

10 (7.9)

116

0.94 (0.46 - 1.89)

1.0

CD4 <200 cells/µL (N=382)

25 (6.8)

357

0.93 (0.42 - 2.04)

1.0

CD4 >200 cells/µL‡ (N=128)

9 (7.0)

119

1.08 (0.49-2.38)

1.0

HIV+ on ARVs (N=263)

24 (9.1)

239

0.80 (0.46 - 1.41)

0.48

HIV+ not on ARVs (N=279)

31 (11.1)

248

1.24 (0.71 - 2.18)

0.48

HIV+ on TMP-SMX prophylaxis (N=453)

34 (7.5)

419

0.69 (0.39-1.22)

0.22

HIV+ without TMP-SMX prophylaxis (N=199)

21 (10.5)

178

1.45 (0.82 - 2.57)

0.22

‡

SIRS = systemic inflammatory response syndrome; SBP = systolic blood pressure; Hb = haemoglobin; ARVs = antiretrovirals; TMP-SMX = trimethoprim-sulfamethoxazole. *Owing to missing data, not all n’s in each category add up to total N. † SIRS defined as at least two of the following: axillary temperature ≥38°C, heart rate >90 bpm, respiratory rate >20/min, and white cell count <4 × 109cells/L or >11 × 109cells/L. ‡ Data available for 34 of 55 HIV+ patients with bacteraemia.

Table 2. Incidence of specific pathogens causing bloodstream infections, and corresponding antibiogram Gram-positive organisms, % susceptibility

PCN

AMP

VAN

TCN

SXT

CAM

CIP

CTX

S. aureus

100

S. pneumoniae

100

Enterococcus spp.

100

N/A

S. agalactiae

100

S. pyogenes

100

Overall susceptibility

Gram-negative organisms, % susceptibility

AMP

TCN

CAM

SXT

CIP

GEN

CTX

IPM

S. typhimurium

N/A

100

S. enteritidis

100

N/A

100

E. coli

100

K. pneumoniae

100

Enterobacter spp.

100

Citrobacter freundii

100

Proteus vulgaris

100

Morganella morganii

100

Acinetobacter baumanii

100

Pseudomonas aeruginosa

100

Overall susceptibility

100

PCN = penicillin; AMP = ampicillin; OX: oxacillin; VAN = vancomycin; TCN = tetracycline; SXT = co-trimoxazole; CAM = chloramphenicol; CIP = ciprofloxacin; CTX: ceftriaxone; GEN = gentamicin; IPM = imipenem; N/A = not applicable.

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Table 3. Predictors of poor outcomes in patients with bacteraemia* Outcome Predictor, n (total N=59)*

Unimproved or died, n (%)

Improved, n (%)

OR (95% CI)

p-value

Incorrect empirical antibiotics (N=36)

17 (47.2)

19 (52.8)

8.05 (1.62 - 39.91)

0.004

Correct empirical antibiotics (N=20)

2 (10.0)

18 (90.0)

0.12 (0.03 - 0.62)

0.004

HIV+ (N=45)

11 (24.4)

34 (75.6)

0.75 (0.17 - 3.43)

0.99

HIV– (N=10)

3 (30.0)

7 (70.0)

1.32 (0.29 - 6.02)

0.99

HIV+ on ARVs (N=21)

6 (28.6)

15 (71.4)

0.74 (0.20 - 2.78)

0.74

HIV+ not on ARVs (N=20)

7 (35.0)

13 (65.0)

1.34 (0.36 - 5.04)

0.74

SBP ≤90 mmHg (N=10)

6 (60.0)

4 (40.0)

2.0 (0.46 - 8.70)

0.29

SBP >90 mmHg (N=38)

12 (31.6)

26 (68.4)

0.5 (0.115 - 2.17)

0.29

SIRS (N=40)

10 (25.0)

30 (75.0)

0.67(0.14 - 3.17)

0.68

No SIRS (N=9)

3 (33.3)

6 (66.7)

1.5 (0.32 - 7.14)

0.68

Salmonella bacteraemia (N=10)

2 (20.0)

8 (80.0)

0.43 (0.08 - 2.25)

0.47

Non-Salmonella bacteraemia (N=46)

17 (37.0)

29 (63.0)

2.34 (0.45 - 12.34)

0.47

S. aureus bacteraemia (N=17)

6(35.3)

11 (64.7)

1.09 (0.33 - 3.61)

1.0

Non-S. aureus bacteraemia (N=39)

13 (33.3)

26 (66.7)

0.92 (0.28 - 3.03)

1.0

SBP = systolic blood pressure; SIRS = systemic inflammatory response syndrome. *Cases of fungaemia (n=4) as opposed to bacteraemia were excluded from this analysis. Owing to missing data (5% of outcomes data, <5% of other variables), n for each characteristic does not add up to total N.

Table 4. Spectrum of antibiotic combinations available at MCH against bacteraemia isolates Antibiotic regimen

% covered

Uncovered organisms

CTX alone

MRSA, ESBL GNRs

CTX + GEN

MRSA

CTX + CIP

MRSA* CIP-resistant GNRs

CTX + GEN + CIP

MRSA* CIP-resistant GNRs

VAN+CTX

ESBL GNRs

VAN+GEN

Salmonella

VAN+GEN + CIP

CIP-resistant Salmonella

VAN + IPM

100

None

IPM alone

MRSA

CTX = ceftriaxone; GEN = gentamicin; CIP = ciprofloxacin; VAN = vancomycin; IPM = imipenem. *Several MRSA isolates in this study showed in vitro susceptibility to CIP, although caution is necessary in using CIP to treat S. aureus infections as resistance is known to occur rapidly.

with oral antibiotics was common. Hospital doctors adjusted empirical antibiotics before discharge in 153/597 cases (25.6%). There was no commonly used empirical antibiotic regimen that had >80% coverage against all collected isolates. Overall, 20/59 (33.9%) of all bacterial isolates showed resistance

to ceftriaxone, the broadest-spectrum anti biotic commonly available at MCH. The spectrums of several antibiotic regimens potentially available at MCH are shown in Table 4. It should be noted that vancomycin and imipenem were rarely used by doctors and are not readily available at MCH.

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In only 4/59 cases of bloodstream infection (6.8%) was the diagnosis of bacteraemia or sepsis recorded in the chart at discharge. The most common diagnosis obtained from medical records was tuberculosis, accounting for >25% of all patients. Tuberculosis was usually diagnosed empirically; in only 13.5% of cases was there a positive smear, and cultures were virtually never done. HIV was recorded as the sole diagnosis for 23.1% of enrolled patients. Eleven patients with bacteraemia were diagnosed as having tuberculosis.

Discussion

As has been reported at other hospitals in SSA, bacteraemia is a common cause of fever at MCH, accounting for nearly 8% of all cases of fever in patients newly admitted to the internal medicine wards. That it was not a significant risk factor for in-hospital mortality largely reflects the severity of illness and consequent high mortality rate of patients admitted to MCH. Furthermore, we were not able to follow up patients after discharge, so the 30-day mortality rate for patients with bacteraemia was probably higher. The predominance of S. aureus was not surprising, although most studies in the region report NTS to be more common than E. coli as a cause of invasive disease.[1] NTS was the most common isolate from febrile patients during the first period (September 2011 - October 2012), but dropped off significantly in the second period (July 2013 - March 2014), being surpassed by E. coli and S. aureus. The vector and routes of transmission for NTS in SSA are largely unknown; it is possible that some environmental factor during the time we were collecting specimens affected the NTS incidence. Several factors may account for the low number of Streptococcus pneumoniae, expected to be higher based on other regional reports.[1] Although no patients enrolled in this study were documented to have received antibiotics at MCH before having their blood cultures drawn, as MCH is a referral centre, many patients may have received antibiotics at peripheral hospitals before transfer. Antibiotic use is widespread in the community, as in other developing countries,[12] and it may simply be that most patients with invasive S. pneumoniae are treated before presenting at MCH. These factors may have decreased the overall rate of bacteraemia in this study, or selected for a sample with a higher resistance rate than that of the community. Antibiotic resistance was common in the bloodstream pathogens we isolated. Nearly half of the S. aureus isolates were MRSA

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and resistant to all first-line antibiotics commonly used at MCH. More than 25% of all Gram-negative organisms had an ESBL phenotype. S. typhimurium, resistant to ampicillin, chloramphenicol and co-trimoxazole, is commonly reported in the region.[13,14] All S. typhimurium isolates described here showed this multidrugresistant phenotype, and 4 of 9 isolates had an ESBL phenotype in addition. This is the first report of invasive ESBL S. typhimurium in Mozambique. Unfortunately, even given this small sample size it appears that there is no simple empirical antibiotic regimen consisting of readily available antibiotics at MCH that will cover all the most common pathogens causing bacteraemia. Penicillinbased regimens that are commonly used at MCH are inadequate. Ceftriaxone is used commonly, and was active against 71% of Gramnegative rods (GNRs) reported here, but is ineffective against MRSA, which accounts for a significant portion of bacteraemia at MCH. Vancomycin was effective against 100% of Gram-positives collected in this study, but it is relatively expensive and in short supply at MCH, and therefore not recommended for widespread empirical use. However, these results underscore the value of vancomycin, and suggest that clearer local guidelines and an antibiotic stewardship programme at MCH could help to ensure its judicious use and save lives. Of the other readily available antibiotics, chloramphenicol has the best coverage of the MRSA reported here, but cannot be recommended for empirical use based on these data. The addition of ciprofloxacin to empirical regimens will expand the spectrum to cover most of the ESBL pathogens described here, and will also cover >50% of the MRSA, although S. aureus has been shown to acquire resistance to ciprofloxacin rapidly.[15] Gentamicin was effective against all nonSalmonella GNRs, but empirical regimens in patients with suspected bacteraemia at MCH (particularly those with AIDS) must cover NTS, given local epidemiology. All GNRs isolated in the course of this study were susceptible to imipenem, which was not consistently available at MCH during the time of this study. These results support the argument for a well-monitored supply of carbapenem antibiotics. According to these data, if neither vancomycin nor imipenem (or other carbapenem antibiotics) are available, the empirical three-drug regimen offering the broadest spectrum at MCH is ceftriaxone + gentamicin + ciprofloxacin (81% coverage, Table 3), although this regimen was used infrequently during the time of this study. There was wide variation in empirical antibiotic regimens prescribed to febrile patients in the medical wards at MCH, and inappropriate empirical choices were linked with bad outcomes. Empirical regimens were infrequently changed during the course of hospitalisation, reflecting an underutilisation of microbiology services at MCH, as well as problems with transmission of information between the laboratory and the wards. Given the rate of antibiotic resistance reported here, it is essential for physicians to maintain a high index of suspicion for bacteraemia, and for them to order blood cultures appropriately in febrile patients. The laboratory must also be able to provide information regarding positive blood cultures and antibiotic susceptibilities promptly, in order to guide subsequent antibiotic adjustment. It was frequently noted during the course of the study that patient follow-up and data completeness were hampered by paper records that were often incomplete, illegible or lost. These problems also affect reporting laboratory information and almost certainly affect clinical care and patient outcomes. Although our study team did not take part in the clinical care of patients, they made every effort to inform doctors when their patients had

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bacteraemia. A variety of factors such as poorly tracked patient transfers and chart movements, difficulty in contacting doctors charged with care for specific patients, and understaffing in the labs and on the wards meant that this was not always successful. As more hospitals in the developing world move from paper charts to electronic medical records, there is hope that these problems can be minimised and patient outcomes improved.

Conclusion

Patients admitted to MCH with bacteraemia have poor outcomes. This study highlights several opportunities for quality improvement, including educating physicians to have a higher index of suspicion for bacteraemia in patients with fever, improving local guidelines for empirical antibiotic therapy and improving communication between the microbiology laboratory and the clinicians, as well as increasing the supply of some key antibiotics such as vancomycin and imipenem. Funding. This research was supported in part by the University of California Center for AIDS Research, a National Institutes of Healthfunded programme (P30 AI036214) supported by the following NIH Institutes and Centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS and NIDDK, and in part by the Fogarty International Center by 1R24TW008908-01: The Eduardo Mondlane Medical Education Partnership. Additionally, the project described was partially supported by the National Institutes of Health, Grant KL2RR031978. References 1. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: A systematic review and meta-analysis. Lancet Infect Dis 2010;10(6):417-432. [10.1016/S1473-3099(10)70072-4] 2. Iroha IR, Esimone CO, Neumann S, et al. First description of Escherichia coli producing CTX-M15-extended spectrum beta lactamase (ESBL) in out-patients from south eastern Nigeria. Ann Clin Microbiol Antimicrob 2012;11:19. [http://dx.doi.org/10.1186/1476-0711-11-19] 3. Schaumburg F, Alabi A, Kokou C, et al. High burden of extended-spectrum beta-lactamase-producing Enterobacteriaceae in Gabon. J Antimicrob Chemother 2013;68(9):2140-2143. [http://dx.doi. org/10.1093/jac/dkt164] 4. Drain PK, Losina E, Parker G, et al. Risk factors for late-stage HIV disease presentation at initial HIV diagnosis in Durban, South Africa. PLoS One 2013;8:e55305. [http://dx.doi.org/10.1371/journal. pone.0055305] 5. Micek MA, Gimbel-Sherr K, Baptista AJ, et al. Loss to follow-up of adults in public HIV care systems in central Mozambique: Identifying obstacles to treatment. J Acquir Immune Defic Syndr 2009;52(3):397405. [http://dx.doi.org/10.1097/QAI.0b013e3181ab73e2] 6. Bedell RA, Anderson ST, van Lettow M, et al. High prevalence of tuberculosis and serious bloodstream infections in ambulatory individuals presenting for antiretroviral therapy in Malawi. PLoS One 2012;7:e39347. [http://dx.doi.org/10.1371/journal.pone.0039347] 7. Mandomando I, Sigauque B, Morais L, et al. Antimicrobial drug resistance trends of bacteremia isolates in a rural hospital in southern Mozambique. Am J Trop Med Hyg 2010;83(1):152-157. [http:// dx.doi.org/10.4269/ajtmh.2010.09-0578] 8. Moon TD, Silva WP, Buene M, et al. Bacteremia as a cause of fever in ambulatory, HIV-infected Mozambican adults: Results and policy implications from a prospective observational study. PLoS One 2013;8:e83591. [http://dx.doi.org/10.1371/journal.pone.0083591] 9. Glass RI, Razak MH, Said M. The importance of research in the MEPI Program: Perspectives from the National Institutes of Health. Acad Med 2014;89(8 Suppl):S9-S10. [http://dx.doi.org/10.1097/ ACM.0000000000000351] 10. Noormahomed EV, Mocumbi AO, Preziosi M, et al. Strengthening research capacity through the medical education partnership initiative: The Mozambique experience. Hum Resour Health 2013;11:62. [http://dx.doi.org/10.1186/1478-4491-11-62] 11. Cockerill FR, Wikler MA, Alder, J, et al. CLSI Performance Standards for Antimicrobial Susceptibility Testing: Twenty-second Informational Supplement. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. 12. Van Boeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: An analysis of national pharmaceutical sales data. Lancet Infect Dis 2014;14(8):742-750. [http://dx.doi.org/10.1016/ S1473-3099(14)70780-7] 13. Okoro CK, Kingsley RA, Connor TR, et al. Intracontinental spread of human invasive Salmonella typhimurium pathovariants in sub-Saharan Africa. Nat Genet 2012;44(11):1215-1221. [http://dx.doi. org/10.1038/ng.2423] 14. Kingsley RA, Msefula CL, Thomson NR, et al. Epidemic multiple drug resistant Salmonella typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome Res 2009;19(12):2279-2287. [http://dx.doi.org/10.1101/gr.091017.109] 15. McGowan JEJ. Abrupt changes in antibiotic resistance. J Hosp Infect 1991;18(Suppl A):202-210.

Accepted 18 March 2015.

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Kaposi’s sarcoma, a South African perspective: Demographic and pathological features R D Mohanlal, MB ChB, FCPath (SA) Anat, MMed Anat Path; S Pather, MB BCh, FCPath (SA) Anat, MMed Anat Path Department of Anatomical Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa Corresponding author: R Mohanlal (reena.mohanlal@nhls.ac.za)

Background. The incidence of Kaposi’s sarcoma (KS) has increased dramatically since the onset of the AIDS epidemic. Of the estimated 66 200 cases of KS worldwide, 58 800 are considered to have occurred in sub-Saharan Africa. Objectives. To describe the epidemiology and pathological characteristics of KS at Chris Hani Baragwanath Academic Hospital (CHBAH), Johannesburg, South Africa. Methods. A retrospective cross-sectional study design was used. Nine hundred and thirty-eight histopathology reports of KS diagnosed in 901 patients at CHBAH between 2005 and 2009 were reviewed. Age, gender, topographic site, CD4 count, HIV status, KS histological stage, findings of human herpesvirus 8 latency-associated nuclear antigen 1 immunohistochemistry and concomitant pathological findings were recorded. Results. The male/female ratio was 1.2:1, the mean age 37 years and the median CD4 count 128 cells/µL. Lower limb skin biopsies accounted for 49.6% of cases. Paediatric, visceral and endemic KS accounted for only limited proportions (1.4%, 1.4% and 1.3% of biopsies, respectively). There were concomitant pathological findings in 4.6% of biopsy specimens, infections and inflammatory dermatoses being the most frequent. Conclusion. The findings of this study highlight the need for allocation of diagnostic and treatment resources for KS. Documentation of the various demographic aspects of KS will prove to be of historical, clinical and histopathological interest as the long-term outcomes of antiretroviral therapy begin to emerge. S Afr Med J 2015;105(5):375-378. DOI:10.7196/SAMJ.8773

Kaposi’s sarcoma (KS) was first described by Moritz Kaposi in 1872. Four forms exist – classic KS, African/ endemic KS, AIDS-related KS and transplant-related KS.[1] Of the estimated 66 200 cases of KS worldwide in 2002, 58 800 were considered to have occurred in sub-Saharan Africa (SSA).[2] Although regarded as a neoplasm, KS is not a typical cancer. It is typically multifocal, it may regress with immune restoration, and the lesional cells are dependent on exogenous growth signals in vitro.[1] Human herpesvirus 8 (HHV8) has been linked to KS. KS occurs most frequently in mucocutaneous sites. However, lymph nodes, visceral organs and unusual sites such as bone may also be involved.[3] Patients may present with minimal or disseminated disease. Clinically, early skin and mucosal lesions may be difficult to recognise as they appear as faint, red-brown to violet macules. The established lesions of KS present as violaceous papules, plaques or nodules. Patients who have bronchopulmonary KS usually present with respiratory symptoms such as cough and breathlessness, while patients with gastrointestinal tract (GIT) KS may present with abdominal pain, nausea, weight loss, GIT bleeding, intestinal obstruction and/or diarrhoea.[4]

KS is confirmed by histopathological examination of biopsy specimens and with relevant ancillary investigations such as HHV8 latency-associated nuclear antigen 1 (LNA-1) immunohistochemistry (IHC). The typical histopathological features encompass a spindle cell proliferation with formation of slit-like vascular spaces, extravasated red bood cells (Fig. 1), haemosiderin pigment, plasma cells and hyaline globules. Three histological stages, patch, plaque and nodular, are recognised based on the clinical appearance and increasing degree of spindle cell proliferation. Furthermore, special morphological variants of KS have been described, e.g. lymphangiomatous,

lymphangiectatic, telangiectatic and keloidal variants among others.[5] Despite the huge burden of disease in resource-limited settings, application of appropriate treatment options is possible and effective. Treatment options for AIDS-related KS include antiretroviral therapy (ART), local treatment, cytotoxic chemotherapy and targeted agents.[6] The disease burden of KS in SSA is enormous. It is diagnosed on a daily basis at Chris Hani Baragwanath Academic Hospital (CHBAH), Johannesburg, South Africa (SA), yet published data from this hospital are lacking. The purpose of this study is to address some of the deficiencies in the literature as it pertains to patients at CHBAH, the largest hospital in the southern hemisphere.

Methods

Fig. 1. Plaque-stage KS (H&E × 200) showing spindle cell proliferation (left arrow) with slit-like vascular spaces (right arrow) and extravasated red blood cells (down arrow).

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An observational retrospective crosssectional study design was used. All cases of KS diagnosed at the Histopathology Laboratory, Division of Anatomical Patho logy, National Health Laboratory Service, CHBAH, from 1 January 2005 to 31 December 2009 were included by performing a SNOMED search of the DISA database using the code M-91403. Data were extracted from the histopathology and virology laboratory reports and

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entered onto a datasheet. The recorded variables included age, gender, HIV status (seropositive or seronegative), CD4 count (recorded when tested within 1 month of the confirmatory biopsy), topographic region biopsied, histological stage of KS (patch, plaque or nodular), HHV8 LNA-1 IHC and concomitant pathological features identified in the same biopsy specimen. Cases of paediatric KS were extrapolated from the main dataset. For the purposes of the study, ‘paediatric’ was defined as children <14 years of age as per the admission regulations at CHBAH. Nodal KS cases were reviewed by a single pathologist (RDM). All information collected was extrapolated onto an Excel spreadsheet and STATISTICA 12 was used for descriptive statistics. Ethical approval was obtained from the Human Research Ethics Committee of the University of the Witwatersrand, Johannesburg (clear ance certificate number: M130533). There was no direct contact with patients, and only linked codes were used during statistical analysis.

Results

In total, 938 biopsies from 901 patients were recorded. The male/female ratio was 1.2:1 (488 males and 412 females). Gender was unknown/unspecified in one patient. Seven hundred and thirty-one patients (81.1% of the total number) were HIVseropositive and 9 were HIV-seronegative as confirmed by HIV enzyme-linked immunosorbent assay (ELISA). HIV status was unknown in 161 (17.9%) cases. There were 396 HIV-seropositive males and 334 HIV-seropositive females (male/female ratio 1.2:1). The mean (standard deviation (SD)) age at biopsy diagnosis of KS for the entire cohort was 36.8 (10.2) years, and 36.4 (9.7) years in the confirmed HIV-seropositive subgroup. The mean age for confirmed HIVseropositive males and females was 38.1 (9.3) and 34.5 (9.7) years, respectively. Age was unspecified, and therefore not recorded, in 12 patients. The median CD4 count recorded within 1 month of confirmed KS was 127.5 (quartile range (QR) 184.5) cells/µL and the mean (SD) was 155.74 (143.58) cells/µL (n=540). Three hundred and eighty-two patients had CD4 counts <200 cells/µL, 127 had counts between 200 and 400 cells/µL, and 27 had counts between 400 and 600 cells/ µL. HIV-seropositive males had a median CD4 count of 130 (QR 127.7) cells/ µL and HIV-seropositive females had a median CD4 count of 120.5 (QR 181.0) cells/µL.

Topographic sites were clinically unspecified in 264 biopsies. The majority of biopsies (where site was specified) were from the skin (81.5%). One case involved the breast and showed spindle cells infiltrating among terminal duct lobular units. HHV8 IHC performed on this case was positive. Thirteen cases of visceral KS were identified, predominantly within the GIT (Table 1). HHV8 LNA-1 IHC stains were applied to 289 biopsies, 93.8% of which were positive. Thirteen cases of paediatric KS were identified from 7 males and 6 females (male/female ratio 1.2:1). The mean (SD) Table 1. Distribution of topographic sites involved by KS n Visceral Oesophagus

Stomach

Small bowel

Colon

Anus

Lung

Total

Oral cavity Tonsil

Tongue

Palate

Oral cavity NOS

Gingiva

Alveolar

Lip

Total

Pharynx/larynx

Lymph node

Skin Abdomen/trunk/back

Lower limbs

334

Upper limbs

125

Head and neck

Chest/breast

Genital area

Total

549

Eye Eyelid

Conjunctiva

Eye NOS

Total

Breast

NOS = not otherwise specified.

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age in the paediatric group was 6.5 (3.4) years. HIV status was unknown in 2 paediatric patients, was confirmed to be negative in 1 and was positive in 10. Six CD4 counts were available, with a median of 217.0 (QR 204.0) cells/µL. Lymph nodes (n=5) were the most frequently represented topographic site in this subgroup. Other sites included palate (1), small bowel (1), skin of upper limb (1) and lower limb (2), and foreskin (2). Twelve biopsies of KS from 9 HIV ELISA-seronegative patients (1 child and 8 adults) were seen. There was no history of transplantation in these patients. The male/female ratio was 1.3:1, the mean (SD) age was 55.4 (19.7) years, and the commonest site biopsied was skin of the lower limb. Stages of KS were recorded in the histopathology reports of 708 biopsies. One hundred and nine cases (15.4%) were of patch stage, 380 (53.7%) were of plaque stage and 219 (30.9%) showed nodular-stage KS. Special morphological variants were recorded in 17 cases. Eleven lymphangiomatous (Fig. 2), 1 telangiectatic and 5 lymphangiectatic variants were documented. Special morphological variants were most frequently noted in lower-limb skin biopsy specimens (41.2%). Concomitant pathological features were recorded in 4.6% of all biopsies, with infections constituting 27.9% of the additional pathology noted (Table 2). Seven cases of granulomatous inflammation and KS were seen in the same biopsy specimen. Five were recorded in skin punch biopsies, 1 from a lymph node and an additional case from the breast. Periodic acidSchiff and Ziehl-Neelsen special stains performed on all 7 cases were negative for micro-organisms. Polymerase chain reaction (PCR) for Mycobacterium genus was positive in 1 case of cutaneous KS which had concomitant granulomatous inflammation. Furthermore, acid-fast bacilli were detected in the sputum of an additional patient who had synchronous cutaneous KS and granulomatous inflammation. The features in two skin punch biopsies raised the possibility of concomitant syphilis owing to the presence of a dense lymphoplasmacytic infiltrate. In one case, Warthin-Starry special stain to detect spirochaetes was negative and serological confirmation was advised. Three cases of concomitant candidiasis were recorded in oral cavity biopsies. There were 27 cases of nodal KS, 12 of which showed concomitant pathology. One of these showed granulomatous

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Fig. 2. Lymphangiomatous variant of KS (H&E × 100).

Table 2. Concomitant pathology in biopsy specimens in which KS was diagnosed Type of concomitant pathology

Infections Cytomegalovirus

Candida

Cryptococcus

Possible syphilis

Herpes simplex virus

Granulomatous inflammation due to Mycobacterium

Subtotal

Dermatitis Seborrhoeic dermatitis

Spongiotic dermatitis NOS

Interface dermatitis

Granulomatous inflammation NOS

Subtotal

Panniculitis

Other Human papillomavirus

Verruca

Chalazion

Intussusception

Gastritis

HIV lymphadenitis

Castleman’s disease

Total

NOS = not otherwise specified.

inflammation (as above), 10 showed HIV lymphadenitis and the remaining case showed concomitant Castleman’s disease.

Discussion

Of the tens of thousands of cases of KS diagnosed worldwide, the vast majority are believed to have occurred in SSA.[2] While developed countries are experiencing a decline in the incidence of KS as a result

of timeous ART initiation, KS remains a cause of significant morbidity and mortality in developing countries like SA owing to suboptimal availability of ART.[7] SSA is home to approximately 80% of the world’s HIV-infected female population, and heterosexual transmission of HIV remains the main mode of spread worldwide.[8] In SA, the risk of developing KS is related to the transmission pattern of HIV, which is predominantly heterosexual.[9] The male/ female ratio of patients diagnosed with confirmed HIV-associated KS in this study is in keeping with the trend of KS shifting from a male-predominant disease[10] and is reflective of the high prevalence of HIV among young women, who bear the brunt of HIV in SA. This is in contrast to the initial recognition of KS as a male-predominant disease in homosexual men in the USA in the 1980s. The mean age of patients diagnosed with KS at CHBAH was similar to the findings of Mosam et al.[9] and may change as the longterm effects of the ART roll-out programme begin to emerge. It is predicted that with ART, HIV-seropositive patients will live longer and may therefore present later with KS.[11] The mean and median CD4 counts we have demonstrated are lower than those documented in comparable studies.[9] Interestingly, 28.5% of the 540 patients with known CD4 counts had values in excess of 200 cells/µL. This is in keeping with the suggestion that in Africa severe immunosuppression is not a prerequisite for the development of KS.[12] KS most commonly involves mucocutaneous topographic regions.[3] Our study is supportive of this, as at least 63.5% of all KS biopsies at CHBAH during the study period originated from mucocutaneous sites. The limited number of visceral KS may be attributed to under-sampling, as synchronous, more easily accessible mucocutaneous lesions in these patients may have been biopsied instead. KS involving topographic sites considered unusual by Pantanowitz and Dezube[13] in this study included 2 cases in the larynx, 9 in conjunctiva and 1 in the breast. HIV status was not available in 17.9% of patients. This may be attributed to a number of reasons, including patients refusing consent for HIV testing, HIV testing at a peripheral hospital not linked to the DISA database at CHBAH, failure to recommend HIV testing or failure to specify the patients’ status in the clinical history section of the laboratory requisition form. Pitche et al.,[14] in a study of 20 cases of African/endemic KS, found a male/female ratio of 9:1 in contrast to the lower male/

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female ratio of patients with endemic KS at CHBAH of 1.3:1. Interestingly, HHV8 LNA-1 staining was only applied to 30.8% of biopsies at CHBAH during the study period. This reflects variable individual pathologists’ practice, as in the appropriate clinical context the histopathological diagnosis may be based on the presence of typical morphological features of KS. In SA’s public health sector, immunohistochemistry-related cost factors also play an influential role. In this study, the majority (93.8%) of HHV8 LNA-1 immunohistochemical stains performed on KS biopsies were positive, more than the 64% positivity recorded by Ramos da Silva et al.[15] HHV8 PCR testing may be indicated in those cases displaying clinical and morphological features of KS but negative HHV8 immunohistochemical staining. Paediatric KS (diagnosed in patients aged <14 years) accounted for 1.4% of all biopsies and lymph nodes (n=5) were the most frequent site represented. The findings of Stefan et al.[16] revealed a median age of 6 years, similar to our findings of a median of 7 years. However, their average CD4 count was higher (mean 440 cells/µL v. 209.2 cells/µL in our study), and the most commonly affected site was the skin. Further studies to determine the incidence of paediatric KS may be useful in light of the rigorous prevention of mother-tochild transmission antiretroviral programme, as the impact of reduced vertical transmission of HIV infection may result in a decline in the incidence of KS in children. In this study, patch-stage KS was diagnosed least frequently of the three histological KS stages. Patch-stage KS may be a subtle manifestation clinically. It is probable that patients are more likely to recognise and be concerned about well-established and/ or larger lesions. Moreover, from a clinical viewpoint, larger lesions are likely to be more representative and provide greater diagnostic/confirmatory yield. Plaque- and nodular-stage KS lesions are therefore more frequently targeted for biopsy. Granulomatous inflammation was seen in 7 of our specimens, with 2 cases of confirmed Mycobacterium infection. As highlighted by Ramdial et al.,[17] adequate investigation of granulomatous inflammation for confirmation of concomitant M. tuberculosis is crucial in highlighting possible multidrug resistance and non-compliance. The review article by Grayson[18] addressed concomitant pathology in cutaneous KS. Our CHBAHbased study documents concomitant patho logy occurring in extracutaneous KS biopsy specimens. As concomitant pathology was noted in approxi mately half of all

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KS-containing lymph node biopsy specimens, reporting pathologists should be vigilant. Treatment options for AIDS-related KS include ART, local treatment (radiation, topical agents), cytotoxic chemotherapy and targeted agents. KS lesions regress with initiation of ART. ART inhibits HIV replication, decreases production of HIV-tat and ameliorates the immune response to HHV8.[6] Semeere et al.[7] demonstrated a reduction in the incidence of KS by 72% in ART users compared with non-ART users. These findings were corroborated by Bohlius et al.,[19] who concluded that the most effective treatment modality remains ART, as it significantly decreases morbidity and mortality. ART may be associated with immune reconstitution syndrome (IRIS). KS-IRIS has been well documented. Recently, it has been shown that the incidence of KS-IRIS is higher in Africa than in the UK, with 13.9% of individuals developing KS-IRIS, a rate 2.5 times higher than European cohorts.[20] Chemotherapy which includes anthracyclines is used for treatment of visceral disease and progressive mucocutaneous lesions. Local therapy such as radiotherapy is useful for palliation, management of bulky lesions and cosmesis. In this era of molecular medicine, targeted pathogenesis-based treatments such as antiangiogenic compounds, retinoic acid, hormonal agents and antiherpes agents are also being used in the treatment of KS.[6]

Study limitations

A possible limitation of this study is that there was an element of sampling bias, as CHBAH is a tertiary hospital. Patients treated at this hospital are likely to have a greater burden of disease (i.e. lower CD4 counts and more advanced HIV infection) than those treated at local clinics. Clinical data regarding ART use were not available.

Conclusion

KS is a pathogenetically and morphologically diverse disease. The epidemiology has changed dramatically since AIDS-associated KS was first diagnosed in the 1980s. With the introduction of ART, the demographics may shift once again as the effects of therapy become apparent. In conclusion, this study highlights the clinicopathological aspects and burden of HIV-associated KS at CHBAH and includes limited representation of endemic, paediatric and visceral KS subgroups. The histopathological spectrum of KS, including special morphological variants, and presence of concomitant pathology have also been reported. The findings of this study serve as a foundation on which further comparative research could be based.

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Acknowledgments. Special thanks to Prof. E Libhaber for assistance with statistical analysis, Susan Radebe for slide retrieval and Eric Liebenberg for assistance with photography. We acknowledge the contribution of patients and staff at CHBAH in making this institution an inspirational place to work at. Funding acknowledgement. This research received no financial grants. SP was supported by SATBAT/FIC grant number 3U2RTW007370-05S1. References 1. Ganem D. KSHV infection and the pathogenesis of Kaposi’s sarcoma. Annu Rev Pathol 2006;1:273296. [http://dx.doi.org/10.1146/annurev.pathol.1.110304.100133] 2. Parkin D. The global health burden of infection associated cancers in the year 2002. Int J Cancer 2006;118(12):3030-3044. [http://dx.doi.org/10.1002/ijc.21731] 3. Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med 2013;137(2):289-294. [http://dx.doi. org/10.5858/arpa.2012-0101-RS] 4. Dezube B. Clinical presentation and natural history of AIDS related Kaposi’s sarcoma. Hematol Oncol Clin North Am 1996;10(5):1023-10229. [http://dx.doi.org/10.1016/S0889-8588(05)70382-8] 5. Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol 2008;3:31-39. [http://dx.doi.org/10.1186/1746-1596-3-31] 6. Cattelan A, Trevenzoli M, Aversa S. Recent advances in the treatment of AIDS-related Kaposi’s sarcoma. Am J Clin Dermatol 2002;3(7):451-462. [http://dx.doi.org/10.2165/00128071-200203070-00002] 7. Semeere A, Busakhala N, Martin J. Impact of antiretroviral therapy on the incidence of Kaposi’s sarcoma in resource rich and resource limited settings. Curr Opin Oncol 2012;24(5):522-530. [http:// dx.doi.org/10.1097/CCO.0b013e328355e14b] 8. De Cock K, Jaffe H, Curran J. The evolving epidemic of HIV/AIDS. AIDS 2012; 26(10):1205-1213. [http://dx.doi.org/10.1097/QAD.0b013e328354622a] 9. Mosam A, Hurkchand H, Cassol E, et al. Characteristics of HIV-1-associated Kaposi’s sarcoma among women and men in South Africa. Int J STD AIDS 2008;19(6):400-405. [http://dx.doi.org/10.1258/ijsa.2008.007301 10. Sitas F, Newton R. Kaposi’s sarcoma in South Africa. J Natl Cancer Inst Monogr 2000;2000(28):1-4. [http://dx.doi.org/10.1093/oxfordjournals.jncimonographs.a024250] 11. Daly M, Fogo A, Mcdonald C, Morris-Jones R. Kaposi sarcoma: No longer an AIDS defining illness? A retrospective study of Kaposi sarcoma cases with CD4 counts above 300/mm3 at presentation. Clin Exp Dermatol 2014;39(1):7-12. [http://dx.doi.org/10.1111/ced.12163] 12. Cassol E, Page T, Mosam A, et al. Therapeutic response of HIV-1 subtype C in African patients coinfected with either Mycobacterium tuberculosis or human herpes virus-8. J Infect Dis 2005;191(3):324-332. [http://dx.doi.org/10.1086/427337] 13. Pantanowitz L, Dezube B. Kaposi sarcoma in unusual locations. BMC Cancer 2008;8:190-198. [http:// dx.doi.org/10.1186/1471-2407-8-190] 14. Pitche P, Kombate K, Owono F, Tchangai-Walla K. Kaposi’s sarcoma in a hospital setting in Lome (Togo): A study of 93 cases. Int J Dermatol 2007;46(Suppl 1):42-44. [http://dx.doi.org/10.1111/j.13654632.2007.03464.x] 15. Ramos da Silva S, Bacchi M, Bacchi C, Elgui de Oliviera E. Human bcl-2 expression, cleaved caspase-3 and KSHV LANA-1 in Kaposi sarcoma lesions. Am J Clin Pathol 2007;128(5):794-802. [http://dx.doi. org/10.1309/TFU2FXK3AP0C9R2X] 16. Stefan D, Stones D, Wainwright L, Newton R. Kaposi sarcoma in South African children. Pediatr Blood Cancer 2011;56(3):392-396. [http://dx.doi.org/10.1002/pbc.22903] 17. Ramdial P, Sing Y, Subrayan S, et al. Granulomas in acquired immunodeficiency syndrome-associated cutaneous Kaposi sarcoma: Evidence for a role for Mycobacterium tuberculosis. J Cutan Pathol 2010;37(8):827-834. [http://dx.doi.org/10.1111/j.1600-0560.2010.01544.x] 18. Grayson W. Recognition of dual or multiple pathology in skin biopsies from patients with HIV/AIDS. Patholog Res Int 2011;2011:398-546. [http://dx.doi.org/10.4061/2011/398546] 19. Bohlius J, Valeri R, Maskew M, et al. Kaposi’s sarcoma in HIV infected patients in South Africa: Multicohort study in the antiretroviral therapy era. Int J Cancer 2014;135(11):2644-2652. [http:// dx.doi.org/10.1002/ijc.28894] 20. Letang E, Lewis J, Bower M, et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: Higher incidence and mortality in Africa than in the UK. AIDS 2013;27(10):16031613. [http://dx.doi.org/10.1097/QAD.0b013e328360a5a1]

Accepted 18 March 2015.

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Ocular surface squamous neoplasia among HIV-infected patients in Botswana K T Steele,1,2 MD; A P Steenhoff,1,2,3,4 MB BCh, DCH, FCPaed (SA); G P Bisson,1,2,5,6 MD, MSCE; O Nkomazana,7,8 MD erelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA P Botswana-University of Pennsylvania Partnership, Gaborone, Botswana 3 Division of Infectious Diseases, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA 4 Center for AIDS Research, University of Pennsylvania, Philadelphia, PA, USA 5 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 6 Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PA, USA 7 Faculty of Medicine, University of Botswana, Gaborone, Botswana 8 Princess Marina Hospital, Gaborone, Botswana 1 2

Corresponding author: O Nkomazana (nkomazanao@mopipi.ub.bw)

Background. Ocular surface squamous neoplasia (OSSN) is a group of ocular tumours that has been rising in incidence among HIVinfected individuals in sub-Saharan Africa. Surgical excision is the mainstay of treatment for OSSN in this region. Methods. This retrospective cohort study examined the clinical characteristics and treatment modalities used for 468 patients with OSSN from a large tertiary referral center in Gaborone, Botswana, over a 10-year period from 1998 to 2008. Results. The estimated annual incidence of OSSN in Botswana reached a peak of 7.0 cases per 100 000 persons per year in 2004. The mean age of the patients in the study was 38 years (interquartile range 30 - 44), and 53.9% were women. Of the patients, 48.5% were known to be HIV-infected, 1.5% were HIV-uninfected, and 50.0% had unknown HIV status. Among HIV-infected patients with CD4 counts, the median CD4 count was 192 cells/µL. As initial OSSN treatment, 20.7% of patients received simple surgical excision, 70.9% received surgical excision with adjunctive beta radiation, 0.9% received evisceration, 1.3% received enucleation, and 6.2% underwent surgical removal of unknown type. The overall rate of known recurrence was 7.1%; however, among those with at least 6 months of follow-up, the recurrence rate was 24.2%. Rates of known recurrence after simple surgical excision and surgical excision with adjunctive beta-radiation were 10.3% and 5.4%, respectively. Conclusion. This study confirms the high incidence of OSSN among young individuals in Botswana. Further investigation is warranted to determine the most effective treatment modalities to prevent recurrence of OSSN among patients in sub-Saharan Africa. S Afr Med J 2015;105(5):389-383. DOI:10.7196/SAMJ.8524

Conjunctival intraepithelial neoplasia (CIN), characterised by dysplasia involving a partial to full thickness of the epithelium, and invasive squamous cell carcinoma (SCC) of the conjunctiva belong to a single disease spectrum termed ocular surface squamous neoplasia (OSSN).[1] In Western countries, OSSN was long regarded as a relatively rare, slow-growing tumour primarily affecting elderly men,[2,3] but recent evidence suggests a 12-fold increased risk among patients with advanced HIV disease in the USA.[4,5] In sub-Saharan Africa (SSA), the incidence of OSSN has increased exponentially in recent years, and it is now the most common malignancy of the ocular surface in this region.[6] Moreover, relative to OSSN in Western countries, OSSN in SSA is more aggressive and affects younger individuals, who are typically females in the 3rd and 4th decades of life.[7-9] The rising incidence has been attributed to the HIV epidemic, as the majority of African individuals affected are HIV-infected.[5,10,11] Ultraviolet B radiation[12,13] and human papillomavirus (HPV)[14,15] have also been implicated in the pathogenesis of OSSN in this region. Surgical excision is the mainstay of treatment for OSSN,[16] but recurrence rates following excision remain unacceptably high, ranging from 15% to 52%.[1] In an effort to reduce recurrence rates, primary excision has been combined with various adjunctive therapies, including cryotherapy, chemotherapy and radiotherapy.[17] The present study describes the clinical characteristics, treatment modalities and preliminary outcomes among OSSN patients at a tertiary referral

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hospital in Gaborone, Botswana, a country with a population HIV seroprevalence of 17.1%.[18]

Methods

This retrospective cohort study included consecutive patients with OSSN presenting to Princess Marina Hospital (PMH), a tertiary hospital in Gaborone, Botswana, between 1 February 1998 and 31 March 2008. PMH is the ophthalmology referral centre for the southern half of Botswana, treating almost 50% of all surgical ocular conditions in the country, including OSSN. The standard of care at PMH during the study period was as follows. Patients with a clinical diagnosis of OSSN determined by an ophthalmologist in the eye clinic were scheduled for surgical excision. Surgical excision specimens were sent to the pathology division of the National Health Laboratory of Botswana for diagnosis by a clinical pathologist. All OSSN patients treated during the study period received surgical excision. Adjunctive beta radiation applied during and following surgery was introduced, and became standard of care, in 2002. The source for beta radiation was strontium 90. Beta radiation at a dose of 6 000 centigray (cGy) was applied with an oval disc applicator to the base and margins of the excision site at the time of surgery, and was then given weekly at the same dose for 6 weeks. Patients were treated free of charge. For the present study, patients with a diagnosis of OSSN were identified from existing surgical records as well as from pathology laboratory records. Patient characteristics and surgery-related data were collected, including age, sex, affected eye, date of surgical excision,

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Results

During the 10-year period 1998 - 2007, 468 patients were treated for OSSN by surgical excision at PMH. The estimated annual incidence of OSSN in Botswana increased over the study period from 2.6 (range 1.0 - 5.3) cases per 100 000 persons in 1998 to a peak of 7.0 (range 4.7 - 14.0) per 100 000 in 2004 (Fig. 1). The demographics

10 9 Incidence, /100 000 persons

clinical diagnosis and histological diagnosis. Primary treatment modality was determined either from surgery records in cases where a special surgery was used (e.g. evisceration, enucleation) or based on the date of surgical excision of OSSN. The first cohort included patients who received simple surgical excision for OSSN during the time period 1 February 1998 - 31 December 2001. The second cohort included patients who received excision with adjunctive beta radiation during the time period 1 January 2003 - 31 March 2008. Patients treated during the year 2002 were not included in either cohort, as it could not be determined whether these patients received adjunctive beta radiation or not. Patients were categorised as having CIN/dysplasia or invasive SCC of the conjunctiva based on the histological diagnosis from the pathology laboratory records. Duration of follow-up was based on visits to the ophthalmology clinic determined from the clinic’s records. HIV-related variables, including CD4 count, viral load and highly active antiviral therapy (HAART) status, were collected from Meditech, the computerised medical record system in place at PMH since 2004. Recurrence was defined as a repeat diagnosis of OSSN in the same eye after treatment of OSSN with surgical excision. We continued to monitor for recurrences in the pathology and surgery records through to 31 March 2009, all study patients being followed up for recurrences for a minimum of 12 months. Given that PMH is the ophthalmology referral centre for the southern half of Botswana, the estimated annual incidence of OSSN was calculated using half of the population of Botswana as the at-risk population. Sensitivity analyses were performed varying the proportion of the population treated at PMH from 25% to 75% to determine an upper and lower limit of the annual incidence estimate. The total population of Botswana according to the World Bank was used for these calcu lations.[19] Statistical analyses were performed using STATA version 9.1 (USA). The study was approved by the Health Research and Development Committee of Botswana’s Ministry of Health as well as the institutional review boards at PMH and the University of Pennsylvania.

8 7 6 5 4 3 2 1 0 1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

Year

Fig. 1. Estimated annual incidence of OSSN per 100 000 persons in Botswana, 1998 - 2007.

and baseline clinical characteristics of the study population as well as the treatment modalities used are presented in Table 1. The mean age of the patients in the study was 38 years (interquartile range (IQR) 30 - 44), and the majority (53.9%) were women. The HIV status and median CD4 count of patients in the study are presented in Table 1. Of the 180 (38.5%) HIV-infected patients who had CD4 counts available during the study period, 85 (47.2%) had CD4 counts <200 cells/µL and 152 (84.4%) had CD4 counts <400 cells/µL. Forty-three of the 150 patients (28.7%) with viral loads available had unsuppressed viral loads (>1 000 copies/ mL). Of the 85 patients with CD4 counts <200 cells/µL at any time during the study period (who would have been eligible for free HAART according to Botswana’s HIV guidelines at the time), 17 (20.0%) were on HAART prior to OSSN surgery, 13 (15.3%) were initiated on HAART within 1 year after surgery, 9 (10.6%) were initiated on HAART later in the study period, and 46 (54.1%) had no evidence of HAART initiation during the study period. Five of the 7 (71.4%) confirmed HIVuninfected patients were under the age of 45, and 6 (85.7%) were female. Two of the HIV-uninfected patients were diagnosed with CIN/dysplasia and 1 with SCC, and 4 had no histological diagnosis available. All HIV-uninfected patients were treated with adjunctive beta radiation, and none experienced recurrences during the study period. Of all 468 patients, 33 (7.1%) experienced known recurrences during the study period. Baseline clinical characteristics and initial treatments of patients who experienced recurrences are presented in Table 1 and data pertaining to timing and treatment

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of recurrences in Table 2. The mean age of patients who experienced recurrences was 36 years (IQR 29 - 41), and 20 of the 33 patients (60.6%) who experienced recurrences were women. The median time to recurrence was 6 months (IQR 2 - 17). Only approximately half of the study patients (n=247, 52.7%) had documented ophthalmology clinic follow-up (mean duration of follow-up 13 months, IQR 1 - 21 months) and only 95 patients (20.3%) had at least 6 months of follow-up. Among patients with at least 6 months of follow-up, 23 (24.2%) had one or more recurrences. While 10 of 97 patients (10.3%) treated with surgical excision alone and 18 of 332 (5.4%) treated with adjunctive beta radiation experienced recurrences, the actual recurrence rates in this population are therefore probably higher.

Discussion

This study of OSSN patients in Botswana contributes to the growing literature documenting the rising incidence of OSSN in SSA and its association with the HIV epidemic. The estimated annual incidence of OSSN in Botswana has risen from 0.13 (range 0.09 - 0.27) cases per 100 000 persons in 1993[20] to a peak of 7.6 (range 5.0 15.1) per 100 000 in 2004. This estimated incidence rate, which may be an underrepresentation of the true incidence rate, is high even for SSA, as estimated incidences of OSSN from other countries in the region are 2.2/100 000 persons in Tanzania and 2.1/100 000 in Uganda.[21,22] These differences in OSSN incidence may reflect differences in HIV prevalence; Botswana has an estimated adult HIV prevalence of 23.0%, whereas the estimated adult HIV prevalences in Tanzania

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Table 1. Characteristics of patients treated for OSSN at PMH, February 1998 - March 2008 Characteristic

Total (N=468)

Recurrence (N=33)

No recurrence (N=435)

<20

14 (3.0)

14 (3.2)

20 - 29

86 (18.4)

9 (27.3)

77 (17.7)

30 - 39

177 (37.8)

14 (42.4)

163 (37.5)

40 - 49

104 (22.2)

8 (24.3)

96 (22.0)

50 - 59

34 (7.3)

1 (3.0)

33 (7.6)

60-69

14 (3.0)

1 (3.0)

13 (3.0)

≥70

14 (3.0)

14 (3.2)

Unknown

25 (5.3)

25 (5.8)

Male

185 (39.5)

13 (39.4)

172 (39.6)

Female

252 (53.9)

20 (60.6)

232 (53.3)

Unknown

31 (6.6)

31 (7.1)

Right

186 (39.7)

16 (48.5)

170 (39.1)

Left

172 (36.8)

14 (42.4)

158 (36.3)

Both

4 (0.9)

Unknown

106 (22.6)

3 (9.1)

103 (23.7)

Positive

227 (48.5)

22 (66.7)

205 (47.1)

Negative

7 (1.5)

7 (1.6)

Unknown

234 (50.0)

11 (33.3)

223 (51.3)

192 (122 - 288)

153 (76 - 221)

CD4 count <100 cells/µL, n (%)

42 (9.0)

6 (18.2)

36 (8.3)

CD4 count 101 - 200 cells/µL, n (%)

43 (9.2)

3 (9.1)

40 (9.2)

CD4 201-400 cells/µL, n (%)

67 (14.3)

5 (15.2)

62 (14.3)

CD4 > 400 cells/µL, n (%)

28 (6.0)

3 (9.1)

25 (5.7)

CD4 count unknown

288 (61.5)

16 (48.4)

272 (62.5)

On HAART prior to initial OSSN surgery

39 (17.2)

3 (13.6)

36 (17.6)

Initiated on HAART after initial OSSN surgery

60 (26.4)

9 (40.9)

51 (24.9)

HAART status unknown

128 (56.4)

10 (45.5)

118 (57.5)

162 (34.6)

15 (45.4)

147 (33.8)

SCC of conjunctiva

102 (21.8)

15 (45.4)

87 (20.0)

Well-differentiated SCC of conjunctiva

38 (8.1)

38 (8.7)

Moderately differentiated SCC of conjunctiva

4 (0.9)

Superficial /surface SCC of conjunctiva

18 (3.8)

18 (4.1)

Age group (years), n (%)

Gender, n (%)

Eye affected

HIV status, n (%)

CD4 count within 1 year of OSSN excision (cells/µL), median (IQR)

HAART status, n (%) of confirmed HIV-infected patients

Initial histological diagnosis by pathologist, n (%) SCC of conjunctiva

Dysplasia/CIN

124 (26.5)

5 (15.2)

119 (27.3)

Carcinoma in situ

15 (3.2)

2 (6.1)

13 (3.0)

Severe dysplasia

34 (7.3)

34 (7.8)

Moderate to severe dysplasia

14 (3.0)

14 (3.2)

Moderate dysplasia

34 (7.3)

3 (9.1)

31 (7.1)

Mild to moderate dysplasia

16 (3.4)

16 (3.7)

Mild dysplasia

6 (1.3)

6 (1.4)

Ocular surface squamous neoplasia

5 (1.0)

5 (1.1)

182 (38.9)

13 (39.4)

169 (38.9)

Conjunctival neoplasm not confirmed by biopsy

Continued ...

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Table 1. (continued) Characteristics of patients treated for OSSN at PMH, February 1998 - March 2008 Characteristic

Total (N=468)

Recurrence (N=33)

No recurrence (N=435)

Simple excision

97 (20.7)

10 (30.3)

87 (20.0)

Excision + adjunctive beta radiation

332 (70.9)

18 (54.6)

314 (72.2)

Evisceration

4 (0.9)

1 (3.0)

3 (0.7)

Enucleation/eye removal

6 (1.3)

1 (3.0)

5 (1.1)

Unknown surgery (during year 2002)

29 (6.2)

3 (9.1)

26 (6.0)

Initial OSSN surgery, n (%)

Table 2. Recurrences among OSSN patients (N=33) treated at PMH, 1998 - 2008 Characteristic

n (%)

OSSN recurrences per patient 1

26 (78.8)

5 (15.2)

1 (3.0)

Time to first OSSN recurrence (years) <1

22 (66.7)

1-2

9 (27.3)

2-3

2 (6.0)

Treatment of OSSN recurrence Simple excision

8 (18.2)

Excision + adjunctive beta radiation

30 (68.2)

Evisceration

3 (6.8)

Enucleation/eye removal

3 (6.8)

and Uganda are 5.1% and 7.2%, respectively.[23,24] In accordance with the assertion that the rising incidence of OSSN in African countries is related to the HIV epidemic, studies from this region have reported high rates of HIV seropositivity among OSSN patients, ranging from 71% to 92%.[25-27] In the present study, 97.0% of patients with HIV tests available were HIV seropositive, though HIV status was unknown for 50.0% of patients in the study. Alternatively, the rising incidence of OSSN may be related in part to increased rates of detection of OSSN over time. In keeping with previous studies from Africa,[2,21] the majority of OSSN patients in Botswana were in the 3rd, 4th or 5th decade of life. The mean age of OSSN patients in our Botswana patient population was 38 years, comparable to mean ages of 38.7 years and 37.7 years in studies from Tanzania and Zimbabwe, respectively.[26,28] Interestingly, the present study and several previous studies from SSA found that HIV-uninfected patients who developed OSSN were not significantly older than those infected with HIV, suggesting that other causes independent of HIV infection, such as ultraviolet light or HPV infection, may play a role in the pathogenesis of OSSN among young Africans.[8,26,27] In the present study, OSSN displayed a slight female predominance, which has been reported in several other SSA studies.[21,25] The female predominance of OSSN in this region may reflect the higher HIV prevalence in women relative to men, which is certainly the case in Botswana (19.8% v. 13.9%).[18] In addition to affecting younger, mostly female, individuals in Africa, OSSN has been reported to be a more rapidly growing, aggressive tumour among

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SSA populations.[7] In support of this, 16 patients in the present study had invasive tumours that ultimately required evisceration (n=7) or enucleation (n=9), resulting in loss of the affected eye. Emerging evidence suggests that OSSN may be an AIDSdefining illness among patients in SSA. In the present study, the median CD4 count within 1 year of OSSN surgery was 192 cells/ µL (IQR 122 - 288), and more than half of the OSSN patients had CD4 counts <200 cells/µL, consistent with a diagnosis of AIDS. A recent study from Tanzania reported that 85% of OSSN patients had CD4 counts <200 cells/µL, and the median CD4 count of patients at the time of presentation was 71 cells/µL.[25] Similarly, in Uganda the median CD4 count among HIV-infected OSSN patients was 111 cells/µL (IQR 62 - 221), and 65% of HIV-infected OSSN patients died of AIDS-related complications at a median of 20 months after OSSN diagnosis.[8] Despite the fact that many patients have advanced HIV disease at OSSN diagnosis, evidence suggests that OSSN may be the first clinical manifestation of HIV infection in the majority of patients, and that patients may often be unaware of their HIV status at presentation with OSSN.[27,29] Together, these findings highlight the critical role of eye clinics in conducting HIV testing and referring patients for CD4 monitoring and HAART initiation, if appropriate. Given the high percentage of OSSN patients who are not only HIVinfected but also have advanced HIV disease, this is likely to be a high-yield method of identifying patients who are eligible and would benefit from lifesaving HAART therapy but would otherwise not have been initiated on HAART because they have no other clinical manifestations of HIV infection. Simple surgical excision is the mainstay of treatment for OSSN in Africa,[10] yet few studies have examined the efficacy of simple surgical excision for the prevention of recurrences in African populations. High rates of recurrence (16.6%, 31.2%) have been reported following surgical excision of OSSN in Tanzania and Kenya.[25,30] However, a countrywide study in Uganda reported a recurrence rate of 3.2% among OSSN patients treated with simple surgical excision with a median follow-up of 32 months,[8] suggesting that surgical excision alone may provide adequate prevention of recurrence if proper removal technique is employed. In the present study, we found an overall recurrence rate of 7.1% among OSSN patients in Botswana, but in patients with at least 6 months of follow-up, the rate increased to 24.2%. Our recurrence rate calculations are certainly limited given that follow-up data were not available for about half of the patients. As a result, we may have missed some patients who experienced recurrences because they failed to return to the eye clinic (e.g. because they died, sought treatment in the private sector, moved to another region or chose not to seek Western medical treatment despite clinically significant symptoms). In addition, the lack of data on other confounding variables, such as surgical margins, limits our ability to compare these two interventions statistically. However, the present data indicate that at least 1 in 10 patients who received simple

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surgical excision experienced a recurrence, suggesting that adjunctive therapies may be needed to control recurrences adequately in this HIV-infected African population. Whether adjunctive beta radiation is an effective alternative is unclear from this dataset, but the results suggest that further investigation is needed.

Conclusion

This study of OSSN patients from Botswana affirms the rising incidence of OSSN in association with the HIV epidemic. Further research is warranted to determine whether surgical excision alone is sufficient to prevent recurrences in this population, or whether adjunctive therapy is required. The finding that young HIV-negative women are also affected by OSSN in SSA also warrants further investigation as to whether the epidemiology of OSSN is changing even outside of the HIV epidemic. References 1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39(6):429-450. [http:// dx.doi.org/10.1016/S0039-6257(05)80054-2] 2. Lee GA, Hirst LW. Retrospective study of ocular surface squamous neoplasia. Aust N Z J Ophthalmol 1997;25(4):269-276. [http://dx.doi.org/10.1111/j.1442-9071.1997.tb01514.x] 3. McKelvie PA, Daniell M, McNab A, Loughnan M, Santamaria JD. Squamous cell carcinoma of the conjunctiva: A series of 26 cases. Br J Ophthalmol 2002;86(2):168-173. [http://dx.doi.org/10.1136/ bjo.86.2.168] 4. Guech-Ongey M, Engels ES, Goedert JJ, Biggar RJ, Mbulaiteye SM. Elevated risk for squamous cell carcinoma of the conjunctiva among adults with AIDS in the United States. Int J Cancer 2008;122(11):2590-2593. [http://dx.doi.org/10.1002/ijc.23384] 5. Karcioglu ZA, Wagoner MD. Demographics, etiology, and behavior of conjunctival squamous cell carcinoma in the 21st century. Ophthalmology 2009;116(11):2045-2046. [http://dx.doi.org/10.1016/j. ophtha.2009.09.031] 6. Ateenyi-Agaba C. Conjunctival squamous cell carcinoma associated with HIV infection in Kampala, Uganda. Lancet 1995;345(8951):695-696. [http://dx.doi.org/10.1016/S0140-6736(95)90870-6] 7. Poole TR. Conjunctival squamous cell carcinoma in Tanzania. Br J Ophthalmol 1999;83(2):177-179. [http://dx.doi.org/10.1136/bjo.83.2.177] 8. Waddell KM, Downing RG, Lucas SB, Newton R. Corneo-conjunctival carcinoma in Uganda. Eye 2006;20(8):893-899. [http://dx.doi.org/10.1038/sj.eye.6702043] 9. Pola EC, Masanganise R, Rusakaniko S. The trend of ocular surface squamous neoplasia among ocular surface tumour biopsies submitted for histology from Sekuru Kaguvi Eye Unit, Harare between 1996 and 2000. Cent Afr J Med 2003;49(1-2):1-4. 10. Sasco AJ, Jaquet A, Boidin E, et al. The challenge of AIDS-related malignancies in sub-Saharan Africa. PLoS One 2010;5(1):e8621. [http://dx.doi.org/10.1371/journal.pone.0008621] 11. Nkomazana O, Tshitswana D. Ocular complications of HIV infection in sub-Sahara Africa. Curr HIV/ AIDS Rep 2008;5(3):120-125. [http://dx.doi.org/10.1007/s11904-008-0019-z] 12. Ateenyi-Agaba C, Dai M, Le Calvez F, et al. TP53 mutations in squamous carcinomas of the conjunctiva: Evidence for UV-induced mutagenesis. Mutagenesis 2004;19(5):399-401. [http://dx.doi. org/10.1093/mutage/geh048]

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13. Newton R, Ferlay J, Reeves G, et al. Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye. Lancet 1996;347(9013):1450-1451. [http://dx.doi.org/10.1016/ S0140-6736(96)91685-2] 14. Tornesello ML, Duraturo ML, Waddell KM, et al. Evaluating the role of human papillomaviruses in conjunctival neoplasia. Br J Cancer 2006;94(3):446-449. [http://dx.doi.org/10.1038/sj.bjc.6602921] 15. Simbiri KO, Murakami M, Feldman M, et al. Multiple oncogenic viruses identified in ocular surface squamous neoplasia in HIV-1 patients. Infect Agent Cancer 2010;5:6. [http://dx.doi.org/10.1186/1750-9378-5-6] 16. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997;115(6):808-815. [http://dx.doi.org/10.1001/ archopht.1997.01100150810025] 17. Gichuhi S, Irlam JJ. Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals. Cochrane Database Syst Rev 2007;2:CD005643. [http://dx.doi.org/10.1002/14651858. CD005643.pub3] 18. National AIDS Coordinating Agency, United Nations, The African Comprehensive HIV/AIDS Partnership, Central Statistics Office. Botswana AIDS Impact Survey II: Popular Report. New York: United Nations, 2005. http://www.unbotswana.org.bw/undp/documents/final_popular_report_feb06. pdf (accessed 5 October 2012). 19. World Bank. The World Bank Data: Population, Total. Washington: World Bank, 2012. http://data. worldbank.org/indicator/SP.POP.TOTL (accessed 5 October 2012). 20. Semo B, Bisson G, Nkomazana O. Ocular surface squamous neoplasia in HIV-infected patients in Botswana: An AIDS-defining illness? Presented at the 8th International Conference on Malignancies in AIDS and other Immunodeficiencies, 29-30 April 2004, Bethesda, MD, USA. 21. Furahini G, Lewallen S. Epidemiology and management of ocular surface squamous neoplasia in Tanzania. Ophthalmic Epidemiol 2010;17(3):171-176. [http://dx.doi.org/10.3109/09286581003731544] 22. Parkin DM, Wabinga H, Nambooze S, Wabwire-Mangen F. AIDS-related cancers in Africa: Maturation of the epidemic in Uganda. AIDS 1999(18):2563-2570. [http://dx.doi.org/10.1097/00002030199912240-00010] 23. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic 2013. http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/ documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf (accessed 10 November 2014). 24. Tanzania Commission for AIDS (TACAIDS), Zanzibar AIDS Commission (ZAC), National Bureau of Statistics (NBS), Office of the Chief Government Statistician (OCGS), and ICF International 2013. Tanzania HIV/AIDS and Malaria Indicator Survey 2011-12. Dar es Salaam, Tanzania: TACAIDS, ZAC, BS, OCGS, and ICF International, March 2013. 25. Waddell KM, Lewallen S, Lucas SB, et al. Carcinoma of the conjunctiva and HIV infection in Uganda and Malawi. Br J Ophthalmol 1996;80(6):503-508. [http://dx.doi.org/10.1136/bjo.80.6.503] 26. Porges Y, Groisman GM. Prevalence of HIV with conjunctival squamous cell neoplasia in an African provincial hospital. Cornea 2003;22(1):1-4. [http://dx.doi.org/10.1097/00003226-200301000-00001] 27. Spitzer MS, Batumba NH, Chirambo T, et al. Ocular surface squamous neoplasia as the first apparent manifestation of HIV infection in Malawi. Clinical and Experimental Ophthalmology 2008;36(5):422425. [http://dx.doi.org/10.1111/j.1442-9071.2008.01794.x] 28. Makupa II, Swai B, Makupa WU, White VA, Lewallen S. Clinical factors associated with malignancy and HIV status in patients with ocular surface squamous neoplasia at Kilimanjaro Christian Medical Centre, Tanzania. Br J Ophthalmol 2012;96(4):482-484. [http://dx.doi.org/10.1136/ bjophthalmol-2011-300485] 29. Pradeep TG, Gangasagara SB, Subbaramaiah GB, Suresh MB, Gangashettappa N, Durgappa R. Prevalence of undiagnosed HIV infection in patients with ocular surface squamous neoplasia in a tertiary center in Karnataka, South India. Cornea 2012;31(11):1282-1284. [http://dx.doi.org/10.1097/ ICO.0b013e3182479aed] 30. Chisi SK, Kollmann MK, Karimurio J. Conjunctival squamous cell carcinoma in patients with human immunodeficiency virus infection seen at two hospitals in Kenya. East Afr Med J 2006;83(5):267-270. [http://dx.doi.org/10.4314/eamj.v83i5.9432]

Accepted 18 March 2015.

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Rheumatic fever and rheumatic heart disease among children presenting to two referral hospitals in Harare, Zimbabwe P Gapu,1 MB ChB, MMed; M Bwakura-Dangarembizi,1 MB ChB, MMed, MSc (Clin Epidemiol); G Kandawasvika,1 MB ChB, MMed, MPhil; D Kao,2 MD; C Bannerman,1 MB ChB, MRCP; J Hakim,1 MB ChB, FRCP; J A Matenga,1 MB ChB, MRCP 1 2

College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe University of Colorado, Denver, USA

Corresponding author: P Gapu (paradzaigapu@yahoo.co.uk)

Background. Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain significant causes of morbidity and mortality in resource-limited settings. In Zimbabwe ARF/RHD characteristics have not been systematically documented. Objectives. To document cases of ARF/RHD among children presenting at referral hospitals in Harare, Zimbabwe, determine their clinical and echocardiographic characteristics, and identify opportunities for improving care. Methods. A cross-sectional survey was carried out in which consecutive children aged 1 - 12 years presenting with ARF/RHD according to the 2002/3 World Health Organization modified Jones criteria were enrolled. Results. Out of 2 601 admissions and 1 026 outpatient visits over 10 months, 50 children were recruited, including 31 inpatients with ARF/RHD and 19 outpatients with chronic RHD. Among inpatients, 9 had ARF only, 7 recurrent ARF with RHD, and 15 RHD only. The commonest valve lesions were mitral regurgitation (26/31) and aortic regurgitation (11/31). The commonest reason for admission was cardiac failure (22/31). The proportion of ARF/RHD cases among inpatients aged 1 - 12 years was 11.9/1 000. Of the 22 with RHD, 14 (63.6%) presented de novo and 1 had bacterial endocarditis. Among the outpatients, 15 had cardiac failure while echocardiographic findings included mitral regurgitation (18/19) and aortic regurgitation (5/19). At presentation, 18/26 known cases were on oral penicillin prophylaxis and 7 on injectable penicillin. Of those on secondary prophylaxis, 68.0% reported taking it regularly. Conclusion. ARF/RHD remains a major problem and cause of hospital admissions in Harare, Zimbabwe. Children often present late with established RHD and cardiac failure. With the majority on oral penicillin, secondary prophylaxis was suboptimal in a resource-limited setting unable to offer valve replacement surgery. S Afr Med J 2015;105(5):384-388. DOI:10.7196/SAMJ.9076

Acute rheumatic fever (ARF) continues to be a significant cause of acquired heart disease in resourcelimited settings.[1-3] If recurrent or associated with moderate to severe carditis during the initial episode, ARF may lead to rheumatic heart disease (RHD), resulting in progressive and permanent cardiac valve damage.[4] Primary episodes of ARF occur mainly in children aged 5 - 15 years and are rare in children under 5 years of age.[5] Predisposing factors for ARF and RHD include poor socioeconomic conditions, undernutrition, overcrowding, close person-to-person contact and poorly developed healthcare facilities.[1,6] Owing to improved standards of living, medical care and use of antimicrobial agents, ARF and RHD are no longer a significant problem in most developed countries except for certain ethnic groups such as the indigenous populations of Australia and New Zealand.[7,8] Estimates from 2005 showed that most of the 15 - 19 million people affected by RHD worldwide were living in developing countries, and an estimated 233 000 people were dying annually from RHD. [7] Recent estimates based on community-based echocardiographic screening suggest that the burden could be much higher,[9] with estimates from Mozambique showing a prevalence of RHD of 30.4/1 000 among schoolchildren.[2] This is higher than the estimated RHD prevalence of 5.7/1 000 from earlier studies for sub-Saharan Africa (SSA).[7] In a recent review by Zühlke et al.,[10] hospital-based estimates showed that RHD remains a significant cause of morbidity in Africa, with 6.6 - 34%

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of patients hospitalised with cardiovascular diseases or seen in echocardiographic clinics having RHD. Complications of ARF and RHD include valve insufficiency, heart failure, infective endocarditis and death.[11] Surgical repair or replacement of damaged heart valves remains largely unavailable in the developing world,[12] and non-surgical management of ARF and RHD with palliative treatment of heart failure and secondary prophylaxis to slow progression continue to be the primary forms of treatment available in these resource-limited settings.[1,3,12] SSA has historically been estimated to be the region most affected by RHD,[7] prompting the Pan-African Society of Cardiology to initiate a programme to raise Awareness of the disease, encourage Surveillance of the disease pattern, Advocate for resources and promote Prevention programmes (ASAP), aiming for the control and elimination of ARF/RHD in the region.[13] While sites with register-based RHD control programmes have been set up in some African countries,[14,15] little is known about RHD in Zimbabwe and the country has largely lagged behind in implementing these control programmes. The real burden of ARF and RHD, the clinical and demographic characteristics of these patients, and the adequacy of treatment practices have not been documented systematically. The objectives of the present study were therefore to document cases of ARF and RHD among children presenting at referral hospitals in Harare, to determine their clinical and echocardiographic characteristics, and to identify opportunities for improving care of these patients in Zimbabwe.

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Methods

Permission to conduct the study was obtained from the Harare Central Hospital Medical Ethics Board and the Joint Research Ethics Council of the College of Health Sciences, University of Zimbabwe, and Parirenyatwa Central Hospital. Written informed consent from caregivers and assent from children aged 8 - 12 years were obtained. A descriptive, cross-sectional survey of children 1 - 12 years of age seen at Harare and Parirenyatwa Central hospitals in Harare, Zimbabwe, was carried out between July 2012 and May 2013. At both hospitals, patients seen in the paediatric units are aged ≤12 years, while those younger than 1 year were excluded from the study because of the rarity of group A streptococcal (GAS) sore throat and ARF below this age.[1,5] The children treated at these two institutions are either referred from the surrounding city, district and provincial health facilities or admitted through the emergency department. Children hospitalised in the paediatric medical wards in both hospitals or seen in the paediatric cardiac clinic based at Parirenyatwa Hospital were screened for possible enrolment in the study. They were enrolled if they showed evidence of congestive cardiac failure (CCF), cardiac murmur, arthritis or chorea and if they satisfied the 2002/3 World Health Organization modified Jones criteria for ARF and RHD.[1] Children were considered to have ARF recurrence in the presence of a documented prior history of ARF or established RHD.[16] Hospitalised patients were followed up to discharge or death during the initial presentation. The data collected for each patient included demographics, clinical features, history of sore throat in the preceding 4 weeks, echocardiographic features, and select laboratory results as ordered by the attending paediatrician (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leucocyte count and anti-streptolysin O titre (ASOT)). Reference laboratory values specific to the Zimbabwean population have not been established, so standard laboratory reference values were used. A 12-lead resting electrocardiogram (ECG) and rhythm strip were used to assess for the presence of arrhythmias and a prolonged PR interval according to age-appropriate references.[17] Where available, the patient’s most recent chest X-ray was reviewed and the presence of cardiomegaly noted. A complete two-dimensional paediatric echocardiogram was performed in all the hospitalised eligible patients and in 18 of the outpatients with Doppler and colour flow mapping according to American Society of

Total hospitalised children 2 601

Total clinic visits 1 026

2 499 did not meet inclusion criteria 102 children had carditis and/or arthritis and/or chorea Congenital heart disease n=18, cardiomypathy n=16, cor pulmonale n=12, severe anaemia n=11, tuberculous pericarditis n=8, septic arthritis n=1, juvenile idopathic arthritis n=3, choreoathetoid cerebral palsy n=1, consent denied n=1

31 children had ARF or RHD

19 children had chronic RHD

Total children with ARF and/or RHD n=50

Fig. 1. Flow diagram of patient enrolment.

Echocardiography guidelines.[18] Pulmonary hypertension was defined as an estimated right ventricular systolic pressure >35 mmHg by continuous-wave Doppler.[17] All images were recorded and subsequently reviewed by an independent paediatric cardiologist. Echocardiography was performed using a Sonosite M-turbo USS SN NG020N portable echocardiography machine, with a P21x/5-1 MHz transducer (Sonosite Inc., USA).

Statistical analysis

Data were collected, verified and checked for completeness and missing data retrieved from admission and laboratory records. This was then entered into a REDCap (Research Electronic Data Capture) database hosted at the University of Zimbabwe.[19] The data were first exported to Microsoft Excel (Microsoft Corporation, USA) for quality assessment, then imported into Stata, version 10.1 (StataCorp, USA) for descriptive analysis. Descriptive statistics between patient groups were compared using the χ2 test. A p-value of <0.05 was considered significant.

Results

Patient screening and enrolment are summarised in Fig. 1. A total of 2 601 children aged 1 - 12 years were admitted to the paediatric medical units over the study period. One hundred and two children (3.9%) presented with a cardiac murmur, CCF, arthritis or chorea. Of the 2 601 children hospitalised during the study period, 31 had ARF and/or RHD, giving an overall case rate of 11.9/1 000 hospitalised children. Only two of the children were aged <5 years, and both had ARF only. Chronic RHD was

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present in 22 of 85 children hospitalised with cardiovascular-related conditions, giving a case rate of RHD among such children of 25.9%. There were a total of 1 026 outpatient visits by children aged 1 - 12 years, from which 19 children were seen with chronic RHD.

Demographic characteristics

Of the 50 children seen with ARF and/or RHD, 32 (64.0%) were female. The median age was 9.5 years (interquartile range 7.5 10.5 years). All of the children were black Africans. A reported family history of RHD was present in 3/50 children (6.0%). Most of the children seen were from either a rural or farming area of residence (54.0%) or an urban high-density area (30.0%).

Clinical presentation

Table 1 summarises the clinical features of enrolled subjects. Among the 16 children with ARF, 9 (56.3%) presented with an initial episode of ARF, while ARF recurrence with established RHD was present in 7 children (43.8%), of whom 2 had a documented history of prior ARF; both had established RHD. Overall, 15/41 (36.6%) of children with chronic RHD presented de novo with no prior documented history of ARF or RHD. The proportion of patients presenting with RHD in the absence of prior documented ARF was higher among hospitalised children (14/22, 63.6%). The most common clinical feature at hospitalisation was carditis, which was present in 25/31 (80.6%) children, of whom 22/25 (88.0%) had CCF. Acute cardiac failure was present in 20/22 (90.9%) children

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Table 1. Description of the children seen with ARF and/or RHD, including clinical features Hospitalised patients (n=31) All (N=50) n (%)

ARF only (N=9) n (%)

ARF + RHD (N=7) n (%)

RHD only (N=15) n (%)

Outpatients (RHD only) (N=19) n (%)

Prior history

26 (52.0)

2 (28.6)

6 (40.0)

18 (94.7)

De novo RHD

15 (30.0)

5 (71.4)

9 (60.0)

1 (5.3)

Arthritis

4 (44.4)

1 (14.3)

1 (6.7)

Carditis

4 (44.4)

6 (85.7)

15 (100.0)

19 (100.0)

Cardiomegaly on chest X-ray, when available

1/6

6/6

11/11

6/6

Chorea

3 (33.3)

2 (28.6)

Subcutaneous nodules

1 (14.3)

Fever

6 (66.7)

5 (71.4)

4 (26.7)

Polyarthralgia

3 (33.3)

3 (42.9)

3 (20.0)

Elevated acute phase reactants

8 (88.9)

5 (71.4)

5 (33.3)

Elevated ESR

4 (44.4)

4 (57.1)

2 (13.3)

Elevated CRP

4 (44.4)

3 (42.9)

2 (13.3)

Leucocytosis

3 (33.3)

4 (57.1)

4 (26.7)

Elevated ASOT

7 (77.8)

5 (71.4)

1 (6.7)

A recent history of sore throat

5 (55.6)

4 (57.1)

5 (33.3)

Prolonged PR interval for age

2 (22.2)

3 (20.0)

Clinical pulmonary hypertension

25 (50.0%)

2 (28.6)

14 (93.3)

9 (47.4)

Prior history of RHD

Clinical features

Table 2. Description of the echocardiographic features in children presenting with ARF/RHD Hospitalised patients (n=31) All (N=49) n (%)

ARF only (n=9) n (%)

ARF + RHD (n=7) n (%)

RHD only (n=15) n (%)

Outpatients, RHD only (n=18) n (%)

44 (89.8)

4 (44.4)

7 (100)

15 (100)

18 (100)

MR + MS

2 (4.1)

0 (0.0)

1 (14.3)

1 (6.7)

MR + AR

16 (32.7)

0 (0.0)

2 (28.6)

9 (60.0)

5 (27.8)

Left ventricular systolic dysfunction

21 (42.9)

3 (33.3)

4 (57.1)

7 (46.7)

7 (38.9)

Pulmonary hypertension

17 (34.7)

1 (11.1)

1 (14.3)

11 (73.3%)

4 (22.2)

hospitalised with RHD and in 2/9 (22.2%) children hospitalised with ARF only. Among the 16 children with ARF, one major Jones criterion was present in 11 (68.8%) and two major criteria in 5 (31.3%), specifically carditis plus chorea in 3, carditis plus arthritis in 1 and carditis plus subcutaneous nodules in 1. No child had more than two major Jones criteria. Carditis was the most common major Jones criterion, present in 10 children (62.5%), followed by chorea in 5 (31.3%) and arthritis also in 5 (31.3%). Subcutaneous nodules were uncommon and seen in only 1 child (6.3%), while none had erythema marginatum. The most common minor Jones criteria were fever in 11 (68.8%), elevated acute-phase reactants in 13 (81.3%) (being leucocytosis in 7 (43.8%)), elevated ESR in 8 (50.0%) and elevated CRP in 7 (43.8%). Polyarthralgia was present in 6 children (37.5%) and first-degree heart block in 2 (12.5%). Elevated ASOT was present in 12 children (75.0%) with ARF, while there was a history of sore throat within the preceding 4 weeks in 9 (56.3%). Comorbid illnesses were present in 12/31 hospitalised children (38.7%), including pneumonia in 5, tonsillitis in 2, ascites in 2,

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severe anaemia in 1, post-streptococcal glomerulonephritis in 1 and cerebrovascular accident in 1. Among the 19 children seen as outpatients, 15 (78.9%) had chronic cardiac failure and 18 (94.7%) a cardiac murmur.

Echocardiographic findings

Among the hospitalised children, the most common valve lesion was mitral regurgitation (MR), present in 26/31 (83.9%) and in 11/16 (68.8%) of the children with ARF (Table 2). Aortic regurgitation (AR) and mitral regurgitation were present concurrently in 11/22 children (50.0%) with ARF and/or RHD. Mitral stenosis (MS) was present in 2 patients aged 9 and 12 years, and no patient had aortic stenosis or isolated AR. Left ventricular systolic dysfunction was present in 14/31 hospitalised children (45.2%) and pulmonary hypertension in 13 (41.9%). Among outpatients, MR was present in all of the 18 children (100%) who underwent echocardiography at presentation, AR in 5 (27.8%) and pulmonary hypertension in 4 (22.2%).

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Complications of ARF/RHD

Congestive cardiac failure (22/31, 71.0%) and pulmonary hyper足 tension (13/31, 41.9%) on echocardiography were the commonest complications of ARF/RHD in hospitalised children. On 12-lead ECG, no patient was found to have cardiac arrhythmias. One hospitalised child had suffered a cerebrovascular accident secondary to infective endocarditis. Two (6.5%) of the 31 hospitalised children died, one from severe heart failure and the other from infective endocarditis.

Treatment and secondary prophylaxis

Medical therapy for complications was the main form of treat足 ment available for children with ARF/RHD, with no open heart surgical facilities available locally. One child who was hospitalised for evaluation had undergone mitral valve replacement in another country. Of the 26 patients known to have ARF/RHD, 25 (96.2%) were on secondary penicillin prophylaxis at presentation (Table 3). The majority (18/25, 72.0%) of the children were on oral penicillin, while 7/25 (28.0%) were on long-acting intramuscular penicillin prophylaxis. One child, a known case of ARF who was not on antibiotic prophylaxis at presentation, had been hospitalised with recurrent ARF and RHD. Almost a third (8/25, 32.0%) of the known cases self-reported forgetting to take secondary penicillin prophylaxis regularly. There was no significant association between the type of penicillin prophylaxis and a reported history of missing antibiotic prophylaxis (p=0.15). Table 3. Secondary prophylaxis n/N (%) Penicillin prophylaxis at presentation

25/26 (96.2)

Oral penicillin

18/25 (72.0)

Injectable penicillin

7/25 (28.0)

Reported history of missing antibiotic prophylaxis

8/25 (32.0)

Discussion

This study showed that ARF remains common and is a major cause of hospitalisation among children presenting to referral hospitals in Harare. A number of children presented de novo with established RHD and cardiac failure, and secondary antibiotic prophylaxis for children with ARF/RHD was suboptimal. It was significant that 63.6% of the children who were hospitalised with established RHD presented without a prior history of ARF, showing that even patients <12 years of age tended to present late. This was a higher proportion compared with the 8.6% of patients with de novo presentation of RHD seen in the Heart of Soweto study[20] and the 38% in a Fijian study,[16] although those studies included older patients who may have had different healthcare-seeking behaviour compared with younger children. However, in a longitudinal study in Australia, it was noted that the risk of developing RHD following initial diagnosis of ARF decreased with older age and time from diagnosis.[21] The overall case rate of ARF/RHD among hospitalised children aged 1 - 12 years was high at 11.9/1 000, with 25.9% of the children hospitalised with cardiovascular-related conditions having established RHD. In a recent review by Z端hlke et al.,[10] 6.6 - 34% of children hospitalised or seen in echocardiographic clinics in Africa had RHD. While no significant association between gender and ARF has been described in the literature, in this study there were more females than males with ARF/RHD, with 64.0% being female. A positive

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family history of RHD was found in 6.0% of the patients in this small study, which is consistent with previous work that showed a genetic association, with a positive family history being present in 2 - 14% of patients with ARF.[22-25] Clinical and echocardiographic features among children with ARF were comparable to findings from similar settings, with carditis being the commonest major Jones criterion.[24,26] The rate of migratory polyarthritis in this cohort was relatively low at 31.3%. A recent worldwide review described a higher frequency of arthritis, almost equal in frequency to carditis (59.3% v. 59.5%).[25] The frequency of chorea (31.3%) was similar to findings from other hospital-based studies in low-resource settings, where this ranged from 18.8% in India[22] to 27.5% in Brazil.[24] Subcutaneous nodules were rare (6.3%), and no child presented with erythema marginatum. In studies from other low-resource settings these major criteria ranged in frequency from 0% to 5.9%,[22-25] while in Montreal, Canada, a developed country with a predominantly Caucasian population, Carceller et al.[27] found a higher proportion with erythema marginatum of 23.5%. Among the minor Jones criteria, the frequency of fever (68.8%), and polyarthralgia (37.5%) was not significantly different from previous findings by other workers.[16,24-26] Elevated CRP was present in 43.8%, comparable to 42% seen in Sydney, Australia.[26] In contrast, the frequency of elevated ESR (50.0%) was lower than 94% observed in Saudi Arabia.[28] One child in the present study was noted to have concurrent ARF and post-streptococcal glomerulonephritis, an unusual occurrence that is thought to be due to some GAS strains being both nephritogenic and rheumatogenic.[29] Among the children with ARF, mitral regurgitation was the predominant valve lesion on echocardiography. Mitral valve regurgitation has been found to be the most frequent cardiac lesion in patients with ARF with documented frequencies varying from 21.6% in India[22] to 77% in Australia,[26] and has also been associated with recurrent episodes of ARF. All 15 children hospitalised with RHD alone had chronic CCF, a very high proportion compared with Fiji, where CCF was the reason for admission in 51% of children.[16] Only one child (6.7%) was admitted with infective endocarditis in the present study, which is lower than findings reported in the Fiji (10.6%),[16] Canadian (16.3%)[27] and Indian (36.5%)[22] studies. These differences may be explained in part by age; in the present study the oldest patient was 12 years old, whereas the other investigators included older patients. However, despite the relatively young age of children in the present study there was still a high frequency of CCF, which may be due to late presentation with severe forms of the disease. MR was also the predominant valve lesion in children with RHD only, being present in all of the children, followed by AR in 42.4%. This is comparable to previous observations in Fiji, where 91% of the patients had mitral valve involvement,[16] but was higher than in India, where MR was present in 39.5% and AR in 3.9%,[22] probably owing to late presentation in this setting with more advanced disease. MS was rare, as expected given the age limit of 12 years in the patients seen. No arrhythmias were documented, which is not surprising given the young population that was studied in this series. Treatment of patients with complications of RHD was primarily supportive, with no facilities for surgical repair. Only one patient had mitral valve replacement done while her family was living in another country. Open-heart surgery is currently not available in Zimbabwe. Optimising secondary antibiotic prophylaxis is necessary to improve ARF and RHD outcomes, especially in settings where surgical options are not available. In this study secondary antibiotic prophylaxis was mainly with oral penicillin, which is suboptimal,

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consistent with other studies.[22,30] Secondary prophylaxis has been shown to be effective only when there is a high level of compliance, with an increased risk of recurrence and more severe RHD among patients defaulting treatment.[31-33] While the majority (96.2%) of children previously diagnosed with ARF/RHD were on penicillin prophylaxis at presentation, only 68.0% reported taking the prophylaxis regularly. This lack of adherence to penicillin prophylaxis has also been reported in a study from 16 developing countries between 1986 and 1990, when adherence was reported to be 63.2%.[30] Although 68.0% were said to be adherent to secondary prophylaxis, 76.0% of patients in this series were on oral penicillin. Several previous studies have shown parenteral penicillin to be more efficacious than oral penicillin.[34-36]

Study limitations

This was a hospital-based study with the usual limitations. The wards were visited daily to screen all hospitalised children. Hospitalised children tend to reflect only the severe cases, and minor cases may be missed. Community rates of ARF and RHD cannot be directly inferred from this hospital-based data. Other study variables such as regular use of penicillin prophylaxis were based on history only and could have been affected by recall bias. The relatively small sample size also reduced the statistical power of the study.

Conclusions

ARF remains a significant problem and cause of hospital admissions among children presenting at referral hospitals in Harare, Zimbabwe, many of whom present with de novo advanced RHD. Clinical and echocardiographic features of patients with ARF and RHD in Zimbabwe were comparable to findings from other studies done in resource-limited settings. Adherence to secondary penicillin prophylaxis among patients with ARF and RHD in this setting was suboptimal, and many patients were using oral penicillin for secondary prophylaxis instead of the preferred parenteral form. These findings suggest that there is a need to raise awareness among patients, healthcare workers and policy makers on the importance of improving management of ARF and RHD patients, including best treatment practices to enable optimal utilisation of the available resources and consideration of establishing cardiac surgery programmes. Acknowledgements. We thank the children and their caregivers involved in the study, hospital staff at Harare and Parirenyatwa hospitals, statisticians Mr V Chikwasha and Mr P Mapingure, Prof. K Nathoo, Prof. E Havranek, and the CHRIS/NECTAR programme of the University of Zimbabwe College of Health Sciences. Disclosures. The authors have no relevant disclosures. Funding. This publication was made possible by a grant (number R24TW008905-05) from the Office of Global AIDS Coordinator and the US Department of Health and Human Services (National Institutes of Health, Fogarty International Centre). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the US government. References 1. World Health Organization. Rheumatic Fever and Rheumatic Heart Disease. Report of a WHO Expert Consultation, Geneva, 29 October - 1 November 2001. WHO Technical Report Series 923. Geneva: World Health Organization, 2004. http://whqlibdoc.who.int/trs/WHO_TRS_923.pdf (accessed 3 June 2013). 2. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007;357(5):470-476. [http://dx.doi.org/10.1056/ NEJMoa065085]

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3. Sliwa K, Mocumbi A O. Forgotten cardiovascular diseases in Africa. Clin Res Cardiol 2010;99(2):6574. [http://dx.doi.org/10.1007/s00392-009-0094-1] 4. Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheumatic heart disease: Genetics and pathogenesis. Scand J Immunol 2007;66(2-3):199-207. [http://dx.doi.org/10.1111/j.13653083.2007.01974.x] 5. Tani LY, Veasy LG, Minich LL, Shaddy RE. Rheumatic fever in children younger than 5 years: Is the presentation different? Pediatrics 2003;112(5):1065-1068. [http://dx.doi.org/10.1542/peds.112.5.1065] 6. Steer AC, Carapetis JR, Nolan TM, Shann F. Systematic review of rheumatic heart disease prevalence in children in developing countries: The role of environmental factors. J Paediatr Child Health 2002;38(3):229-234. [http://dx.doi.org/10.1046/j.1440-1754.2002.00772.x] 7. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005;5(11):685-694. [http://dx.doi.org/10.1016/S1473-3099(05)70267-X] 8. Carapetis JR. Rheumatic heart disease in developing countries. N Engl J Med 2007;357(5):439-441. [http://dx.doi.org/10.1056/NEJMp078039] 9. Paar JA, Berios NM, Rose JD, et al. Prevalence of rheumatic heart disease in children and young adults in Nicaragua. Am J Cardiol 2010;105(12):1809-1814. [http://dx.doi.org/10.1016/j.amjcard.2010.01.364] 10. Zühlke L, Mirabel M, Marijon E. Congenital heart disease and rheumatic heart disease in Africa: Recent advances and current priorities. Heart 2013;99(21):1554–1561. [http://dx.doi.org/10.1136/ heartjnl-2013-303896] 11. Chin TK, Chin EM, Siddiqui T, et al. Pediatric rheumatic heart disease. http://emedicine.medscape. com/article/891897 (accessed 3 June 2013). 12. Remenyi B, Carapetis JR, Wiber R, Taubert K, Mayosi BM. Position Statement of the World Heart Federation on the Prevention and Control of Rheumatic Heart Disease. Nat Rev Cardiol 2013;10(5):284-292. [http://dx.doi.org/10.1038/nrcardio.2013.34] 13. Mayosi BM, Robertson K, Volmink J, et al. The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006;96(3):246. 14. Engel EM, Zühlke L, Robertson K. Rheumatic fever and rheumatic heart disease: where are we now in South Africa? SA Heart 2009;6(1):20-23. http://journal.saheart.org/index.php?journal=SAHJ&page=a rticle&op=view&path%5B%5D=97 (accessed 1 June 2013). 15. Zühlke LJ. Rheumatic heart disease and the ASAP programme: Fresh insights into an old disease. CME 2011;29(11):460-462. 16. Steer AC, Kado J, Jenney AWJ, et al. Acute rheumatic fever and rheumatic heart disease in Fiji: Prospective surveillance, 2005-2007. Med J Aust 2009;190(3):133-135. 17. Park MK. Pediatric Cardiology for Practitioners. 5th ed. Philadelphia: Mosby Elsevier, 2008. 18. Lai WW, Geva T, Shirali GS, Frommelt PC, et al. Guidelines and standards for performance of a pediatric echocardiogram: A report of the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr 2006;19(12):1413-1430. [http://dx.doi.org/10.1016/j. echo.2006.09.001] 19. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research Electronic Data Capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377-381. [http://dx.doi.org/10.1016/j. jbi.2008.08.010] 20. Sliwa K, Carrington M, Mayosi BM, et al. Incidence and characteristics of newly diagnosed rheumatic heart disease in Urban African adults: Insights from the Heart of Soweto Study. Eur Heart J 2010;31(6):719-727. [http://dx.doi.org/10.1093/eurheartj/ehp530] 21. Lawrence JG, Carapetis JR, Griffiths K, Edwards K, Condon JR. Acute rheumatic fever and rheumatic heart disease: Incidence and progression in the Northern Territory of Australia, 1997 - 2010. Circulation 2013;128(5):492-501. [http://dx.doi.org/10.1161/CIRCULATIONAHA.113.001477] 22. Ravisha MS, Tullu MS, Kamat JR. Rheumatic fever and rheumatic heart disease: Clinical profile of 550 cases in India. Arch Med Res 2003;34(5):382-387. [http://dx.doi.org/10.1016/S0188-4409(03)00072-9] 23. Bitar FF, Hayek P, Obeid M, Ghazerddine W, Mikati M, Dbaibo GS. Rheumatic fever in children: A 15 year experience in a developing country. Pediatr Cardiol 2000;21(2):119-122. [http://dx.doi. org/10.1007/s002469910017] 24. De Carvallo SM, Dalben I, Corrente JE, Magalhaes CS. Rheumatic fever presentation and outcome: A case series report. Rev Bras Reumatol 2012;52(2):236-246. 25. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3(1):67-84. [http://dx.doi.org/10.2147/CLEP.S12977] 26. Smith MT, Lester-Smith D, Zurynski Y, Noonan S, Carapetis JR, Elliot JE. Persistence of acute rheumatic fever in a tertiary children’s hospital. J Paediatr Child Health 2011;47(4):198-203. [http:// dx.doi.org/10.1111/j.1440-1754.2010.01935.x] 27. Carceller A, Tapiero B, Rubin E, Miro J. Acute rheumatic fever: 27 year experience from the Montreal’s pediatric tertiary care centers. An Pediatr (Barc) 2007;67(1):5-10. [http://dx.doi.org/10.1157/13108071] 28. Al Quirash M. The pattern of acute rheumatic fever in children: Experience at the Children’s Hospital, Riyadhi, Saudi Arabia. J Saudi Heart Assoc 2009;21(4):215-220. [http://dx.doi.org/10.1016/j. jsha.2009.10.004] 29. Kula S, Saygili A, Tunaoglu S, Olgunturk R. Acute post streptococcal glomerulonephritis and acute rheumatic fever in the same patient: A case report and a review of the literature. Anadolu Kardiyol Derg 2003;3(3):272-274. 30. World Health Organization. WHO programme for the prevention of rheumatic fever/rheumatic heart disease in 16 developing countries: Report from phase 1 (1986-90). WHO Cardiovascular Diseases Unit and Principal Investigators. Bull World Health Organ 1992;70(2):213-218. 31. World Health Organization. Antibiotic Use for the Prevention and Treatment of Rheumatic Fever and Rheumatic Heart Disease in Children: Report for the Second Meeting of WHO’s Subcommittee of the Expert Committee of the Selection and Use of Essential Medicines. Geneva: WHO, 2008. http://www. who.int/selection_medicines/committees/subcommittee/2/RheumaticFever_review.pdf. (accessed 25 June 2013). 32. Lutalo SK, Mabonga N. Experience on follow-up of registered rheumatic fever patients in the Zimbabwean Midlands. Trop Geogr Med 1986;38(3):277-282. 33. Pelajo CF, Lopez-Bernitez JM, Tores JM, de Oliveira SKF. Adherence to secondary prophylaxis and disease recurrence in 536 Brazilian children with rheumatic fever. Pediatr Rheumatol Online J 2010;8(1):22. [http://dx.doi.org/10.1186/1546-0096-8-22] 34. Manyemba J, Mayosi BM. Intramuscular penicillin is more effective than oral penicillin in secondary prevention of rheumatic fever – a systematic review. S Afr Med J 2003;93(3):212-218. 35. Mayosi BM. The four pillars of rheumatic heart disease control. S Afr Med J 2010;100(8):506. 36. Geber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: A scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics. Circulation 2009;119(11):1541-1551. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.109.191959]

Accepted 4 November 2014.

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Validation of a severity-of-illness score in patients with tuberculosis requiring intensive care unit admission C F N Koegelenberg,1 MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm (SA), PhD; C A Balkema,1 MD; Y Jooste,1 MB ChB; J J Taljaard,2 MB ChB, MMed (Int); E M Irusen,1 MB ChB, FCP (SA), PhD ivision of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg D Academic Hospital, Tygerberg, Cape Town, South Africa 2 Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa 1

Corresponding author: C F N Koegelenberg (coeniefn@sun.ac.za)

Background. There is a paucity of data on the determinants of mortality due to tuberculosis (TB) in the intensive care unit (ICU). Objective. To develop a simple severity-of-illness score for use in patients with TB admitted to an ICU. Methods. A scoring system was generated by retrospectively identifying the four most significant and clinically unrelated predictors of mortality from an existing prospectively collected dataset (January 2012 - May 2013), and combining these with known predictors of poor outcome. Results. Of 83 patients admitted with TB, 38 (45.8%) died in the ICU. The four parameters identified from the retrospective analysis were: (i) HIV co-infection with a CD4 cell count <200/µL; (ii) a raised creatinine level: (iii) a chest radiograph showing diffuse parenchymal infiltrates/miliary pattern; and (iv) absence of TB treatment on admission. These were combined with septic shock and a low arterial partial pressure of oxygen/fractional inspired oxygen (P:F) ratio to generate a six-point severity-of-illness score (one point for each parameter). The scores for survivors were significantly lower than those for non-survivors (mean (standard deviation) 2.27 (1.47) v. 3.58 (1.08); p<0.01). A score of ≥2 was associated with significantly higher mortality than a score of <2 (7.1% v. 46.4%; odds ratio (OR) 15.03; 95% confidence interval (CI) 1.86 - 121.32; p<0.01), whereas a score of ≥3 was associated with a significantly higher mortality than a score of <3 (64.6% v. 20.0%; OR 7.29; 95% CI 2.64 - 20.18; p<0.01). Conclusion. The proposed scoring system identified patients at increased risk of dying from TB in the ICU. Further prospective studies are indicated to validate its use. S Afr Med J 2015;105(5):389-392. DOI:10.7196/SAMJ.9148

The incidence of tuberculosis (TB) remains high in much of the developing world, where infectious diseases including HIV still represent major challenges to healthcare systems.[1,2] Previous studies have shown that approximately 1.5% of adults being treated for active TB in academic hospitals develop respiratory failure requiring admission to an intensive care unit (ICU).[3] The mortality rate of patients with acute respiratory failure due to TB is higher than that of patients with respiratory failure due to other causes, and ranges from 40% to 80%.[2,4-6] There is still a paucity of data on the determinants of mortality from TB in the ICU. Recent evidence suggests that the Acute Physiology and Chronic Health Evaluation II (APACHE II) score is predictive of patient mortality.[2] The APACHE II score needs to be performed after 24 hours of ICU admission, however, and is not validated as a severity-of-illness score in an emergency setting.[7] The aim of this study was to develop and retrospectively validate a simple severity-of-illness score for use in patients with TB requiring ICU admission.

Methods

Study design and population

We used data from a previously published study in which all patients with TB admitted to the medical ICU of Tygerberg Academic Hospital, Cape Town, South Africa (SA), from January 2012 to May 2013 were prospectively enrolled in order to identify potential parameters of poor outcome.[2] A simple severity-of-illness score, based on our published dataset as well as other known poor prognostic factors, was subsequently retrospectively applied to the study population’s admission data in order to assess its validity.

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Tygerberg Academic Hospital, a 1 380-bed facility, is one of two referral centres in Cape Town and renders a tertiary service to a population of about 1.5 million. The study was approved by the Stellenbosch University Health Research Ethics Committee. Patients were considered to have active TB if at least two of the following criteria were met: (i) smear positive for acid-fast bacilli (AFB) or GeneXpert MTB/RIF (Cepheid, SA) on sputum, tracheal aspirate or any other clinical specimen; (ii) culture positive for Mycobacterium tuberculosis (MTb) on sputum, tracheal aspirate or any other clinical specimen; (iii) histopathological identification of TB granuloma on biopsied tissues; (iv) strong clinical suspicion of active TB; (v) strong radiological evidence of active TB; or (vi) pleural fluid with a lymphocyte predominance (>75% lymphocytes and/or lymphocyte/neutrophil ratio >0.75) with an adenosine deaminase level >40 IU/L. A strong clinical suspicion of active TB required at least two of four constitutional symptoms (loss of weight with accompanying fever, night sweats, productive cough, loss of appetite for >2 weeks) as well as known TB contact or a history of previous pulmonary TB. Positive cultures were identified as MTb and tested for susceptibility to rifampicin and isoniazid using the MTBDRplus line probe assay (Hain LifeSciences, Germany).

Clinical data, laboratory, imaging and related investigations

Patient demographics, comorbid diseases (including HIV infection, AIDS, chronic obstructive pulmonary disease (COPD) and diabetes) and relevant medication use were documented. Laboratory investigations collected included white cell count, platelet count, serum haemoglobin, serum albumin, C-reactive

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protein, creatinine, alanine aminotransferase (ALT) and serum glucose. Absolute CD4 counts were measured in all HIV-positive patients. All admission chest radiographs were reviewed by two pulmonologists blinded to the clinical data and classified as follows: (i) cavitation; (ii) miliary or diffuse interstitial infiltrates; (iii) lobar consolidation; (iv) pleural effusion; (v) isolated lymphadenopathy; or (vi) normal. The APACHE II score was calculated for all patients during the first 24 hours of the ICU stay.[7]

Management, course and complications

All patients were managed according to local guidelines and received maximal supportive therapy.[2,8] The standard combination antiTB treatment regimen was used unless significant renal or hepatic impairment or confirmed drug resistance was present.[8] Standard diagnostic criteria for the diagnosis of shock, renal failure, multiorgan dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) were used, as defined by accepted international criteria.[9-11] Patients were categorised as either ICU/hospital survivors or non-survivors.

Statistical aspects and development of the severity-ofillness score

Descriptive statistics and χ2 or Fisher’s exact tests (where indicated) were performed on dichotomous categorical variables, and t-tests on continuous data. A scoring system was generated by identifying the four most significant and clinically unrelated parameters identified from the prospective data collection and combining these with two known predictors of poor outcome: septic shock and a low arterial partial pressure of oxygen/fractional inspired oxygen (P:F) ratio.[9,11] For simplicity, we decided not to generate a weighted scoring system.

Results

Study population characteristics

Over the study period, 83 patients with TB (mean (standard deviation (SD)) age 36.5 (12.9) years, 38 males, 44 HIV-positive) were admitted to the medical ICU. The majority of the patients (n=69, 83.1%) had active pulmonary TB; 14 patients had exclusive evidence of extrapulmonary TB and 23 had both pulmonary and extrapulmonary TB. Extrapulmonary involvement included pleural disease (n=13), disseminated disease (n=11), meningitis (n=7), abdominal TB (n=4)

and disease at other sites (n=2). Thirty-two patients (38.6%) were on TB treatment at the time of admission. The mean duration of ICU admission was 11.9 days (range 1 - 56). The primary reason for admission was acute respiratory failure in two-thirds of patients (n=56). Other reasons included a decreased level of consciousness (n=7), surgery of the gastrointestinal tract (n=3) and concomitant disease not directly related to TB (n=3). Tracheal aspirates (TAs) were obtained from all but three patients; 39.8% were AFB-positive. Mycobacterial cultures obtained from a variety of sites, including TAs, were positive in 48 patients (57.8%). Other sources included pleural fluid, cerebrospinal fluid (CSF), blood, lymph nodes, ascites, urine and placenta. The diagnosis of TB in the absence of direct microbiological proof was based on a high clinical probability combined with radiological evidence (n=14), pleural fluid analysis alone (n=5), CSF analysis (n=7) or histological findings (n=1). Only two patients had isoniazid monoresistance; none had multidrug-resistant TB (MDR-TB). In total, 45 of 83 patients survived ICU admission (ICU mortality 45.8%) and 34 survived to hospital discharge (in-hospital mortality 59.0%). Three patients who were readmitted all survived their respective ICU and hospital admissions.

Predictors of mortality

The clinical, radiological and laboratory data of ICU survivors and non-survivors are summarised in Tables 1 - 3. Of the 31 patients with HIV co-infection and a CD4 count <200 cells/µL, 16 did not survive the ICU (OR 5.87; 95% CI 1.11 - 30.95; p=0.04). Renal failure was present in 31 patients. Of these, 24 did not survive hospital admission (OR 3.70; 95% CI 1.15 - 10.09; p=0.02). Neither ARDS (n=26, 35.6%) nor MODS (n=25, 30.1%) was associated with increased mortality. The ICU course was complicated by the development of ventilator-associated pneumonia in 19 patients (27.7%), which did not adversely influence outcome.

Suggested severity-of-illness score

We combined septic shock and a low P:F ratio with the following four parameters identified as potentially significant in our study cohort: (i) HIV with CD4 count <200 µL; (ii) renal failure; (iii) diffuse parenchymal infiltrates/miliary pattern on the chest radiograph; and (iv) absence of TB treatment on admission. We subsequently

Table 1. Clinical data, ICU survivors v. non-survivors All (N=83)

Survivors (N=45)

Non-survivors (N=38)

OR (95%CI)

p-value

Gender (female), n

0.89 (0.37 - 2.11)

Age (years), mean (SD)

36.5 (12.9)

35.2 (11.6)

37.3 (13.8)

N/A

0.80

APACHE II, mean (SD)

20.7 (8.3)

19.3 (7.7)

22.4 (8.8)

N/A

0.09

Pulmonary TB, n

1.65 (0.58 - 6.10)

0.59

Isolated pulmonary TB, n

1.47 (0.61 - 3.52)

0.52

Extrapulmonary TB, n

0.68 (0.28 - 1.63)

0.26

Isolated extrapulmonary TB, n

0.61 (0.18 - 1.99)

0.56

HIV-positive, n

0.66 (0.28 - 1.57)

0.47

HIV with CD4 <200, n

31/44

15/26

16/18

5.87 (1.11 - 30.95)

0.04

AIDS, n

1.46 (0.57 - 3.61)

0.59

Diabetes mellitus, n

0.94 (0.23-3.79)

COPD, n

2.52 (0.44 - 14.64)

0.41

TB treatment on admission, n

0.37 (0.15 - 0.95)

0.06

N/A = not applicable.

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Table 2. Radiological findings, ICU survivors v. non-survivors Parameter

All (N=83), n

Survivors (N=45), n

Non-survivors (N=38), n

OR (95%CI)

p-value

Cavitation

0.19 (0.04 - 0.95)

0.03

Miliary and diffuse interstitial

14.61 (4.71 - 45.36)

<0.01

Lobar consolidation

0.05 (0.01 - 0.43)

<0.01

Pleural effusion

0.47 (0.13 - 1.67)

0.38

Lymph node enlargement alone

N/A

Normal

N/A

N/A = not applicable.

Table 3. Laboratory data, ICU survivors v. non-survivors Parameter

Reference

Total (N=83) Mean (SD)

ICU survivors (n=45) Mean (SD)

ICU non-survivors (n=38) Mean (SD)

p-value

CD4 count (cells/µL)

600 - 1 500

160.2 (163.6)

198.5 (180.7)

104.8 (119.1)

0.06

P:F ratio

>300

215.2 (113.2)

220.0 (115.5)

209.4 (111.8)

0.67

White cell count (× 10 /L)

4.0 - 11.0

13.5 (7.1)

14.1 (6.7)

12.8 (7.6)

0.41

Platelet count (× 109/L)

150 - 400

282.8 (165.7)

307.6 (175.1)

253.4 (150.9)

0.14

Haemoglobin (g/dL)

12.0 - 15.0*

9.76 (2.41)

9.52 (2.55)

10.04 (2.23)

0.26

Serum albumin (g/L)

35 - 50

25.1 (6.3)

25.1 (7.0)

25.1 (5.5)

0.98

C-reactive protein (mg/L)

175.2 (94.4)

168.8 (93.3)

183.0 (97.0)

0.53

Creatinine (µmol/L)

<90*

137.7 (152.0)

131.6 (139.4)

145.0 (167.4)

0.69

ALT (U/L)

5 - 40

133.8 (305.1)

178.6 (398.8)

84.8 (138.1)

0.21

Serum glucose (mmol/L)

4.4 - 6.1

8.80 (4.76)

8.32 (4.55)

9.35 (5.00)

0.33

*For females.

proposed the following scoring system, designated ‘SCCOR-TB’, with one point for each of the parameters: (i) septic shock; (ii) HIV with CD4 <200/µL; (iii) creatinine >140 µmol/L (male) or >120 µmol/L (female); (iv) P:F O2 ratio <200; (v) chest radiograph showing diffuse parenchymal infiltrates/miliary pattern; and (vi) absence of TB treatment on admission. The scoring system was subsequently retrospectively applied to the study population’s admission data.

Mortality rates according to the suggested severity-of-illness score

Severity-of-illness scores (Table 4) were significantly lower in survivors than in non-survivors (mean (SD) 2.27 (1.47) v. 3.58 (1.08); p<0.01). Moreover, a score of ≥2 was associated with a significantly higher mortality than a score of <2 (7.1% v. 46.4%; OR 15.03; 95% CI 1.86 - 121.32; p<0.01). Likewise, a score of ≥3 was associated with a significantly higher mortality than a score of <3 (64.6% v. 20.0%; OR 7.29; 95% CI 2.64 - 20.18; p<0.01).

Discussion

We found the mortality rate among patients admitted to the ICU with TB to be extremely high: approximately 46% did not survive the ICU admission, and 59% died in hospital. Although only a few clinical parameters, special investigations or other ancillary tests predicted outcome, we were able to retrospectively validate a simple sixpoint scoring system based on septic shock, HIV with CD4 counts, creatinine values, P:F ratios, chest radiography and TB treatment on admission. Severity-of-illness scores were significantly lower in survivors than non-survivors. Almost 1/2 patients with a score of ≥2 did not survive (v. <1/10 with a score of <2; p<0.01), whereas 2/3 patients with a score of ≥3 died (v. 1/5 with a score of <3; p<0.01).

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Table 4. Mortality rates according to the suggested severity-ofillness score SCCOR-TB

Total (N=83), n

Survivors (N=45), n

Non-survivors (N=38), n

Mortality, %

≤1

7.1

28.6

44.4

≥4

76.7

7.1

≥2

46.4

20.0

≥3

64.6

Our mean APACHE II score of 20.7 predicted a mortality rate of 30 - 40%,[7] suggesting that this globally used score underestimates mortality in this population. Moreover, it is only calculated after 24 hours of admission, making it an impractical initial severity-of-illness score for use in patients with TB requiring ICU admission. Simple severity-of-illness scores have been shown to be accurate in predicting a poor outcome in other severe illnesses, e.g. the Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN), which was recently validated at our institution.[12] Our data suggest that SCCOR-TB cutoffs of both ≥2 and ≥3 were associated with significant increments in mortality, which could potentially guide clinicians in identifying patients at a significantly increased risk of dying from TB in the ICU.

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We specifically aimed to identify parameters that could be readily assessed at practically all levels of medical care, and used both the prospective data set in addition to known poor prognostic factors (e.g. septic shock) to develop the score.[9] Although the ORs of the various parameters differed, we opted to test our proposed scoring system with equally weighted parameters, in line with recent trends for simplicity.[13] In an attempt not to ‘double-penalise’ HIV-positive patients and use clinically related parameters, we opted to include the parameter HIV with a CD4 count <200/µL (OR 5.87), rather than AIDS (OR 1.46) or any other AIDS-defining diseases. Active TB itself has a significant impact on CD4 cell homeostasis,[14] and our data suggest that non-survivors tend to have a lower count (105 v. 199; p=0.06). We confirmed the well-known association between the lack of radiological evidence of cavitation and increased mortality.[15] More over, we found that the presence of miliary and diffuse interstitial infiltrates was significantly associated with mortality (OR 14.6; p<0.01). The latter parameter was therefore included in the proposed scoring system. Delay in the initiation of anti-TB treatment is known to increase mortality.[16] We found that survivors were more likely to be on TB treatment on admission than non-survivors (p=0.06), and therefore also included this in our scoring system. Our study has several potential limitations. We avoided suggesting a complex weighted scoring system (which would arguably have yielded a statistically more accurate system), as we aimed to develop a simple severity-of-illness score that can potentially be used at practically any level of care in SA. There was not a single case of MDR-TB in our cohort, and drug susceptibility was therefore not included in the scoring system. Furthermore, a selection bias towards healthier patients being referred and admitted to the ICU may have been present, given the limited ICU resources in our setting.[2] We included a small proportion of cases (14/83) in which diagnoses were never microbiologically confirmed (diagnosed on clinical and radiological criteria). Although this is not an infrequent practice in studies from high endemic areas,[17] it may have introduced some bias. In conclusion, we were able to validate a simple scoring system based on six parameters: septic shock, HIV with CD4 counts, creatinine values, P:F ratios, chest radiography and TB treatment

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on admission. The proposed scoring system can potentially identify patients at an increased risk of dying from TB in the ICU. Further prospective studies are indicated to validate its use. Funding. None. References 1. World Health Organization. Global Tuberculosis Report 2013. Geneva: World Health Organization, 2013. http://www.who.int/tb/publications/global_report/en/ (accessed 10 November 2014). 2. Balkema C, Irusen E, Taljaard J, Koegelenberg C. Tuberculosis in the intensive care unit: A prospective observational study. Int J Tuberc Lung Dis 2014;18(7):824-830. [http://dx.doi.org/10.5588/ ijtld.13.0044] 3. Levy H, Kallenbach J, Feldman C, Thorburn J, Abramowitz J. Acute respiratory failure in active tuberculosis. Crit Care Med 1987;15(3):221-225. [http://dx.doi.org/10.1097/00003246-19870300000008] 4. Lee PL, Jerng J, Chang Y, et al. Patient mortality of active pulmonary tuberculosis requiring mechanical ventilation. Eur Respir J 2003;22(1):141-147. [http://dx.doi.org/10.1183/09031936.03. 00038703] 5. Penner C, Roberts D, Kunimoto D, Manfreda J, Long R. Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. Am J Respir Crit Care Med 1995;151(3):867-872. [http:// dx.doi.org/10.1164/ajrccm.151.3.7881684] 6. Zahar J, Azoulay E, Klement E, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med 2001;27(3):513520. [http://dx.doi.org/10.1007/s001340000849] 7. Knaus W, Draper E, Wagner D, Zimmerman J. APACHE II: A severity of disease classification system. Crit Care Med 1985;13(10):818-829. [http://dx.doi.org/10.1097/00003246-198510000-00009] 8. Koegelenberg CFN, Nortje A, Lalla U, et al. The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care. S Afr Med J 2013;103(6):394-398. [http://dx.doi.org/10.7196/samj.6344] 9. Bone R, Balk R, Cerra F, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101(6):1644-1655. [http:// dx.doi.org/10.1378/chest.101.6.1644] 10. Bellomo R, Ronco C, Kellum J, Mehta R, Palevsky P. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8(4):R204-R212. [http://dx.doi.org/10.1186/cc2872] 11. ARDS Definition Task Force, Ranieri V, Rubenfeld G, Thompson BT, et al. Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012;307(23):2526-2533. [http://dx.doi.org/10.1001/ jama.2012.5669] 12. Kannenberg SM, Koegelenberg CF, Jordaan HF, von Groote-Bidlingmaier F, Visser WI. Toxic epidermal necrolysis and Stevens-Johnson syndrome in South Africa?: A 3-year prospective study. Q J Med 2012;105(9):839-846. [http://dx.doi.org/10.1093/qjmed/hcs078] 13. Douma R, Mos I, Erkens P, et al. Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: A prospective cohort study. Ann Intern Med 2011;154(11):709-718. [http://dx.doi.org/10.7326/0003-4819-154-11-201106070-00002] 14. Skogmar S, Schön T, Balcha T, et al. CD4 cell levels during treatment for tuberculosis (TB) in Ethiopian adults and clinical markers associated with CD4 lymphocytopenia. PLoS One 2013;8(12):e83270. [http://dx.doi.org/10.1371/journal.pone.0083270] 15. Barnes P, Leedom J, Chan L, et al. Predictors of short-term prognosis in patients with pulmonary tuberculosis. J Infect Dis 1988;158(2):366-371. [http://dx.doi.org/10.1093/infdis/158.2.366] 16. Zahar J, Azoulay E, Klement E, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med 2001;27(3):513520. [http://dx.doi.org/10.1007/s001340000849] [PMID: 11355119] 17. Theron G, Peter J, Meldau R, et al. Accuracy and impact of Xpert MTB/RIF for the diagnosis of smearnegative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid. Thorax 2013;68(11):10431051. [http://dx.doi.org/10.1136/thoraxjnl-2013-203485]

Accepted 18 March 2015.

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Outcomes of TB/HIV co-infected patients presenting with antituberculosis drug-induced liver injury S Naidoo,1 MB ChB; D Evans,2 DBiomed; E Jong,3 MD, PhD; K Mellet,3 MB ChB, Dip HIV Man; R Berhanu,4 MD, DTM&H, Dip HIV Man elen Joseph Hospital, Johannesburg, South Africa H Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Clinical HIV Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 4 Right to Care, Helen Joseph Hospital, Johannesburg, South Africa 1 2

Corresponding author: S Naidoo (sashelin@gmail.com) Background. South Africa has a significant burden of tuberculosis (TB). Anti-TB drug-induced liver injury (TB DILI) is one of the most serious adverse events that can arise from TB treatment (TBT). There are limited data on TB DILI among HIV-infected patients and those on antiretroviral therapy (ART). Objective. To describe characteristics of HIV-infected patients presenting with TB DILI and the proportion reintroduced on standard or modified TBT after DILI. Methods. This was a retrospective study of TB/HIV co-infected patients with DILI between 1 July 2009 and 30 September 2012. The primary focus of interest was HIV-infected patients with TB DILI on ART (ART/TB DILI) v. not on ART (TB DILI). Results. A total of 94 patients were included, 41 with TB DILI and 53 with ART/TB DILI. Compared with patients with TB DILI, patients with ART/TB DILI were more likely to present with symptomatic DILI (71.2% v. 51.2%; p=0.03) and had a lower median alanine aminotransferase level at diagnosis (89 IU/L v. 118 IU/L; p=0.008), a lower rate of ALT decline (–23 IU/L v. –76 IU/L; p=0.047) and longer duration of TBT at DILI diagnosis (53 days v. 11 days; p<0.001). In 71.8% of patients, standard TBT was reintroduced. More patients with ART/TB DILI than TB DILI required modified TBT (37.2% v.17.1%; p=0.05; crude odds ratio 2.17; 95% confidence interval 0.95 - 4.96). The rate of death/loss to follow-up was higher in the ART/TB DILI group (18.9% v. 14.5%). Conclusion. A significant number of TB/HIV co-infected patients were not able to tolerate standard TBT. Furthermore, ART appears to complicate TBT, with relatively fewer patients reintroduced on standard TBT. S Afr Med J 2015;105(5):393-396. DOI:10.7196/SAMJ.8217

Tuberculosis (TB) and HIV are inextricably linked; not only are HIV-infected people up to 30 times more likely to develop active TB in their lifetimes, but they also have a higher risk of dying from TB than those who are not infected with HIV.[1-3] This dual-disease phenomenon has significant implications for South Africa (SA), which has the highest number of TB/HIV co-infected patients in the world.[1-3] Anti-TB drug-induced liver injury (TB DILI) is one of the most serious adverse consequences of TB treatment (TBT), with a significant impact on TBT outcomes. A proportion of patients who experience TB DILI will require modification of the highly effective standard regimen, which relegates them to suboptimal regimens and exposes them to poor treatment outcomes with increased morbidity and mortality.[4-6] Furthermore, TB DILI impacts negatively on health resources as it increases costs and utilisation of health services.[7] Examples of this include increased nurse and physician visits, and the more intensive testing and monitoring that become necessary. The consequences of TB DILI are experienced most prominently by the developing world, including SA, where resources are limited and the TB disease burden is high. The effect of antiretroviral therapy (ART) on TB DILI is not clear. A study conducted in both hospitalised patients and outpatients in Jimma, Ethiopia, found that the effect of ART is not significantly associated with outcome or adverse effects in TB/HIV co-infected patients.[8] However, a study conducted in hospitalised patients in Cape Town, SA, demonstrated a higher in-hospital and 3-month mortality of 35% in the ART/TB DILI group compared with 27% in patients with TB DILI alone. This was significantly higher than the

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8% mortality at 6 months among the general population of patients with TB/HIV co-infection treated at the hospital.[9] The aim of this article is to describe patient characteristics of an SA adult HIV-infected population presenting with TB DILI, determine the factors that impact on the reintroduction of a standard or modified TBT regimen, and compare TB DILI with ART/TB DILI.

Methods

Study site and population

This study was a retrospective folder review of adult HIV-infected TB DILI patients presenting to a hospital-based TB clinic in Johannesburg, SA, between 1 July 2009 and 30 September 2012. Included were all adult (age ≥18 years) HIV-infected TB DILI patients receiving standard first-line TBT for confirmed or probable active TB. Standard first-line TBT is a fixed-dose combination of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (ETH) during the intensive phase of treatment, and RIF and INH during the continuation phase of treatment. The diagnosis of TB was considered confirmed when acid-fast bacilli could be demonstrated by microscopy, when Mycobacterium tuberculosis (MTB) was detected by a molecular amplification technique (Cepheid GeneXpert MTB/RIF, USA; Genotype MTBDR Hain Lifescience, GmbH, Germany), or when a tissue biopsy sample demonstrated histopathological changes in keeping with TB. In the absence of such confirmation, the diagnosis was considered probable when clinical and/or radiological signs of TB infection were associated with a definitive response to treatment after initiating TBT. Patients were excluded if they had resistance to RIF or INH on lineprobe assay or phenotypic drug susceptibility testing, if neither clinic nor

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hospital medical files were available for review, or if they presented at the TB clinic outside the study period. A diagnosis of TB DILI was defined as: (i) alanine aminotransferase (ALT) level more than three times the upper limit of normal (ULN), associated with symptoms of acute hepatic injury (abdominal pain, nausea, vomiting, anorexia or jaundice); (ii) ALT level more than five times the ULN in the absence of any symptoms; or (iii) total bilirubin (TBR) more than two times the ULN. The ULN for ALT and TBR as per the SA National Health Laboratory Service reference range was 40 IU/L and 21 IU/L, respectively.

Study procedure

Information obtained from the patients’ medical records included date of birth, gender, site of TB, basis of diagnosis, phase of treatment, symptoms, comorbid conditions, hepatotoxin ingestion (including prescription medication, traditional or herbal remedies, and alcohol), HIV status, CD4 count, ART details, serial liver function tests (LFTs), viral hepatitis studies, abdominal ultrasound findings and TB drug reintroduction details. Pattern of liver injury was based on the predominant pattern of liver enzyme elevation. An LFT that demonstrated a predominant elevation of TBR (v. ALT) was considered cholestatic, primarily elevated ALT (v. TBR) was considered transaminitis, and nondiscernible cases were considered mixed.

Study definitions

The exposure was defined as HIV-infected patients on ART presenting with TB DILI (ART/TB DILI) v. not on ART (TB DILI). The main outcome of the study was the proportion of patients reintroduced to a standard or modified treatment regimen after a DILI diagnosis. A standard treatment regimen was defined as the successful reintroduction of a regimen containing RIF and INH, whereas a modified treatment regimen was defined as a case where worsening clinical or biochemical parameters precluded the reintroduction of both RIF and INH. Secondary outcomes included retention in care and rate of decline in LFT (TBR, ALT, gamma-glutamyl transferase, albumin) after TB DILI diagnosis. Loss to follow-up was defined as more than 180 days since the last clinic visit.

Statistical analysis

Patient demographics and clinical charac teristics of the cohort were summarised using descriptive statistics. Groups (TB DILI v. ART/ TB DILI) were compared using Student’s t-test for parametric or normally distributed data, the Kruskal-Wallis test for non-parametric

data or data that are not normally distributed for continuous variables, and the χ2 test for proportions. The association between potential risk factors and reintroduction on a modified treatment regimen was performed using logistic regression to estimate the odds ratio (OR) with 95% confidence intervals (CIs). Data were collected and imported into SAS version 9.3 (SAS Institute Inc., USA) for analysis.

Ethics

The study was approved by the Human Research Ethics Committee of the University of the Witwatersrand, Johannesburg (Certi ficate number: M120750).

Results

A total of 94 patients with TB DILI were identified from TB clinic records. Table 1 shows the baseline characteristics of the study

Table 1. Characteristics of patients with TB DILI and ART/TB DILI All (N=94)

TB DILI (n=41)

ART/TB-DILI (n=53)

Age (years), median (IQR)

40 (33.7 - 44.9)

39 (32.9 - 44.7)

39 (34.5 - 44.7)

Gender male, n (%)

45 (47.9)

20 (48.8)

25 (47.2)

Site of TB, n (%) Pulmonary

18 (19.1)

6 (14.6)

12 (22.6)

Extrapulmonary

76 (80.9)

35 (85.4)

41 (77.4)

CD4 (cells/µL), median (IQR) <50, n (%)

77 (31 - 160)

79 (35 - 107)

76 (31 - 187)

38 (40.4)

16 (39.0)

22 (41.5)

51 - 100, n (%)

22 (23.4)

13 (31.7)

9 (17.0)

101 - 250, n (%)

24 (25.5)

10 (24.4)

14 (26.4)

>250, n (%)

10 (10.6)

2 (4.9)

8 (15.1)

83 (88.3)

40 (97.6)

43 (81.1)

Phase of TBT at DILI diagnosis, n (%) Intensive phase Continuation phase

8 (8.5)

1 (2.4)

7 (13.2)

Unknown

3 (3.2)

0 (0)

3 (5.7)

Symptomatic DILI, n (%)

59 (62.8)

21 (51.2)

38 (71.2)

Duration of TBT at DILI diagnosis (days), median (IQR)

31.0 (8.0 - 62.0)

11.0 (4.5 - 30.5)

53.0 (28.0 - 70.0)

Duration between stopping TBT and starting re-challenge (days), median (IQR)

2.0 (0.0 - 7.0)

1.0 (0.0 - 3.0)

5.0 (0.0 - 7.0)

Pattern of liver injury, n (%) Cholestatic

39 (41.5)

17 (41.5)

22 (41.5)

Transaminitis

18 (19.1)

7 (17.0)

11 (20.8)

Mixed Duration of ART at DILI diagnosis (days), median (IQR)

37 (39.4)

17 (41.5)

20 (37.7)

33.0 (20.0 - 81.0)

31.5 (25.0 - 62.0)

49.4 (27.5 - 245.5)

ART regimen, n (%) NRTI/NNRTI-based regimen

47/53 (88.68)

PI-containing regimen

4/53 (7.55)

Unknown

2/53 (3.77)

TBR (IU/L), median (IQR)

50.0 (24.0 - 89.0)

46.0 (14.5 - 93.5)

57.0 (26.0 - 84.0)

ALT (IU/L), median (IQR)

101.5 (58.0 - 202.0)

118.0 (74.5 - 241.0)

89 (55.0 - 202.0)

Albumin (g/L), median (IQR)

18.0 (15.0 - 22.0)

18.0 (15.0 - 21.5)

18.5 (16.0 - 24.0)

New treatment regimen, n (%) Standard

56/78 (71.8)

29/35 (82.9)

27/43 (62.8)

Modified

22/78 (28.2)

6/35 (17.1)

16/43 (37.2)

NNRTI = non-nucleoside reverse-transcriptase inhibitors; NRTI = nucleoside reverse-transcriptase inhibitors; PI = protease inhibitor.

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population. The average patient age was 40 years (interquartile range (IQR) 33.7 - 44.9). The study included 45 males (47.9%) and 49 females (52.1%). Eighty-three cases of TB (88.3%) were considered to be confirmed diagnoses, and of these patients 80.9% had extrapulmonary TB. The median CD4 count at DILI diagnosis was 77 cells/µL (IQR 31 - 160). In 83 cases (88.3%) patients presented with TB DILI while on the intensive phase of treatment. On average patients experienced symptoms for 6.5 days (IQR 3.0 - 10.0) before seeking medical attention. However, only 59 patients (62.8%) had symptoms of TB DILI. The most common symptoms were jaundice, vomiting, abdominal pain and anorexia. Abdominal ultrasound was performed on 76 patients (80.8%), of whom the majority had one or more features suggesting abdominal TB. Patients had received TB treatment for an average of 31.0 days (IQR 8.0 62.0) at the time of DILI diagnosis. The interval between stopping TBT and initiating a new treatment regimen was 2 days (IQR 0.0 - 7.0). Exposure to various hepatotoxic drugs (excluding ART) and alcohol was found in 31 (40.8%) and 13 (18.8%) cases, respectively. None of the patients was serologically positive for hepatitis A virus, whereas 9 (12.3%) and 3 (4.1%) tested positive for hepatitis B surface antigen and anti-hepatitis C antibodies, respectively. The pattern of liver injury most frequently encountered was cholestatic (41.5%), followed by mixed (39.4%) and transaminitis (19.1%). In total, 53 patients (56.4%) were receiving ART, for a median duration of 33.3 days (IQR 20 - 81) before the DILI diagnosis. The most common ART regimen was tenofovir (TDF), lamivudine (3TC) plus efavirenz (EFV) (69.8%). Patients with ART/TB DILI were similar to those with TB DILI in terms of age, gender, CD4 count at DILI diagnosis, site of TB and pattern of liver injury. More patients with ART/TB DILI than TB DILI presented with symptomatic DILI (71.2% v. 51.2%; p=0.03). Patients with ART/TB DILI had a lower median ALT at DILI diagnosis, with a smaller proportion more than two times the ULN compared with those with TB DILI (89 IU/L v. 118 IU/L; p=0.008 and 56.6% v. 73.2%; p=0.018). Furthermore, there was a significant difference between the groups for ALT decline between baseline and 4 weeks (–76 U/L v. –23 IU/L; p=0.047), with greater changes observed in the TB DILI group. Patients with ART/TB DILI had been on TBT for longer than those with TB DILI (53 days v. 11 days; p<0.001). The time between stopping TBT and reintroduction of new drugs was also longer in patients with ART/TB DILI (5.0 days v. 1.0 days; p=0.007). More patients with ART/ TB DILI than with TB DILI were reintroduced onto modified TBT (37.2% v. 17.1%; p=0.05, and crude OR 2.17; 95% CI 0.95 - 4.96).

Patients who were not reintroduced onto either standard or modified treatment regimens because they were lost from care (17.0%) were typically older (median age 41.3 years v. 38.9 years), had lower CD4 counts (<50 cells/µL; 50% v. 38.5%), had pulmonary TB (31.3% v. 16.7%) and had symptomatic DILI (81.3% v. 59.0%), compared with those who were reintroduced. The rate of death/loss to follow-

up was higher (10/53; 18.9%) among those with ART/TB DILI than among those with TB DILI (6/41, 14.5%; p=0.588) (Table 2). Overall, it took 17.0 days (IQR 14.0 - 72.0) from interrupting TBT to reaching a definitive treatment regimen (standard or modified). In 56 patients (71.8%) a standard treatment regimen could be reintroduced, while 22 patients (28.2%) required a modified treatment regimen in order

Table 2. Characteristics of patients who achieved standard or modified treatment regimen v. those who were lost from care Achieved standard or modified treatment regimen (n=78)

Characteristics

Lost from care (n=16)

p-value

Gender male, n (%)

38 (48.7)

7 (43.8)

0.717

Age (years), median (IQR)

38.9 (33.7 - 44.6)

41.3 (38.8 - 51.9)

0.061

ALT at DILI diagnosis, median (IQR)

109 (59 - 218)

87 (57 - 132)

0.469

TBR at DILI diagnosis, median (IQR)

48 (21 - 92)

57 (39 - 81)

0.366

Symptomatic DILI, n (%)

46 (59.0)

13 (81.3)

0.105

CD4 count (cells/µL), median (IQR)

82 (31 - 162)

49 (27 - 152)

0.302

ART/TB DILI, n (%)

43/78 (55.1)

10/16 (62.5)

0.588

TB DILI, n (%)

35/78 (44.9)

6/16 (37.5)

DILI during intensive phase of TBT, n (%)

68 (87.2)

15 (93.8)

0.672

DILI after start of TBT (days), median (IQR)

32 (7 - 62)

29 (11 - 61)

0.992 0.178

Site of TB, n (%) Pulmonary

13 (16.7)

5 (31.3)

Extrapulmonary

65 (83.3)

11 (68.8)

Concomitant medications, n (%)

24 (30.8)

6 (37.5)

0.727

Pattern of liver injury – mixed, n (%)

14 (18.0)

4 (25.0)

0.804

Table 3. Factors associated with reintroduction onto modified TBT Proportion with outcome, n (%)

Crude OR (95% CI)

Adjusted OR (95% CI)

TB DILI

6/22 (27.3)

ART/TB DILI

16/22 (72.3)

2.17 (0.95 - 4.96)

1.52 (0.76 - 3.09)

Male

9/22 (40.9)

Female

13/22 (59.1)

1.37 (0.66 - 2.83)

0.88 (0.52 - 1.51)

≤50

18/22 (81.8)

>50

4/22 (18.2)

1.94 (0.87 - 4.32)

1.65 (0.62 - 4.42)

6/22 (27.3)

Yes

16/22 (72.7)

1.57 (0.70 - 3.51)

1.03 (0.54 - 1.95)

>100

9/22 (40.9)

<100

13/22 (59.1)

0.85 (0.42 - 1.75)

0.98 (0.57 - 1.69)

Pulmonary

6/22 (27.3)

Extrapulmonary

16/22 (72.7)

0.53 (0.26 - 1.10)

0.77 (0.39 - 1.53)

Characteristics DILI diagnosis

Gender

Age (years)

Symptomatic DILI

CD4 count (cells/µL)

Site of TB

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to continue TB therapy. We report the association between ART/TB DILI v. TB DILI (OR 1.52; 95% CI 0.76 - 3.09) with being reintroduced on a modified treatment regimen, adjusted by age, gender, symptomatic DILI, CD4 count at DILI diagnosis and site of TB. The ORs for symptomatic DILI and age >50 years were 1.03 (95% CI 0.54 - 1.95) and 1.65 (95% CI 0.62 - 4.42), respectively, while female gender (0.88; 95% CI 0.52 - 1.51) and extrapulmonary TB (0.77; 95% CI 0.39 - 1.53) appeared protective (Table 3). Patients reintroduced on a modified treatment regimen had a lower baseline median ALT (89.0 IU/L, IQR 55.0 - 202.0) than those introduced on a standard treatment regimen (118 IU/L, IQR 74.5 241.0; p=0.030). The rate of decline of ALT and TBR 4 weeks after DILI diagnosis was slower in patients reintroduced on a modified treatment regimen (16.0% v. 46.0%; p=0.03) than in those reintroduced on a standard regimen (72.0% v. 63.0%; p=0.04).

Discussion

In this retrospective study we describe patient characteristics and final treatment regimen of 94 TB/HIV co-infected patients presenting with TB DILI at a hospital-based TB clinic. Previous studies have suggested that age >35 years, hypoalbuminaemia and female gender are risk factors for TB DILI.[10] This study suggests that age >35 years and hypoalbuminaemia are possible risk factors. In 71.8% of TB DILI cases, a standard TBT regimen containing RIF and INH could be reintroduced. According to our study, higher ALT and shorter duration of symptoms at TB DILI diagnosis were associated with successful reintroduction of a standard TBT regimen. The association between higher ALT and successful reintroduction of a standard treatment regimen is unexpected; it may represent true hepatoxicity to PZA, which is reversible with drug cessation, or it may represent transient elevations of liver enzymes or unrelated liver injury as opposed to true TB DILI. Conversely, factors associated with a modified treatment regimen include ART, male gender, symptomatic DILI and age >50 years â&#x20AC;&#x201C; although these did not achieve statistical significance. In this study, more than half of the TB DILI patients were exposed to ART. Differentiating between TB DILI, ART-induced DILI and immune reconstitution inflammatory syndrome (IRIS) is challenging.[10-12] When comparing TB DILI patients on ART v. not on ART, we observed some interesting differences. Patients on ART tended to have a significantly longer duration of TBT at DILI diagnosis, lower ALT at DILI diagnosis, longer treatment interruption until rechallenge of TBT, smaller serial changes in ALT, and higher odds of receiving a modified TBT regimen. The differential diagnosis for these patients includes TB DILI, ART DILI, TB IRIS, viral hepatitis, other hepatotoxins, sepsis and chronic liver conditions. A definitive diagnosis for the deranged liver function is difficult to make because it requires a liver biopsy, which is not routinely performed. According to this study, healthcare workers seem to be more cautious with reintroducing TBT, especially PZA, in this ART patient group. Rechallenge with PZA was previously not recommended, but a recent trial has shown that most patients tolerate it.[13] Unfortunately we did not capture data on interruption or modification of ART. However, the majority of patients (69.8%) in this study were receiving a regimen (TDF/3TC/EFV) considered to pose low risk for the development of hepatotoxicity.[14]

Study limitations

The quality of data captured was dependent on information entered into the medical record. There were some instances where documentation was incomplete, most notably for exposure to other potentially hepatotoxic substances. A small sample size that reached the modified treatment regimen (n=22) may have limited our ability to estimate outcomes in this group accurately, so we interpret these results with caution and recommend a larger sample size and longer follow-up. We have limited data on LFTs before starting TBT, as these are not routinely done in SA. Furthermore, patients who died or were

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lost to follow-up were excluded from the analysis because they could not be reintroduced onto a standard or modified regimen. This may have introduced selection bias. However, there were no differences in the baseline characteristics of patients who died or defaulted as opposed to those who reached the study-defined endpoint (Table 2).

Conclusions

Owing to the lack of evidence to compare the efficacy of various reintroduction guidelines, the management of TB DILI remains a controversial topic that lacks a prevailing global consensus.[13] Most guidelines are based on expert opinion.[10-12] In 2013, the South African HIV Clinicians Society published a consensus statement on the management of TB DILI in HIV-infected individuals.[15] The consensus statement provides healthcare workers with practical guidance on reintroducing TBT and ART. There is an important need for future studies to further investigate the underlying mechanism of TB DILI. The ability to differentiate true TB DILI from other hepatic insults will allow for more accurate diagnosis and appropriate management. IRIS, HIV-related opportunistic infections, and other hepatotoxins (e.g. alcohol and prescription and traditional medicines) are common in our setting and may masquerade as TB DILI. Patient education and counselling are simple yet important steps that can be taken to reduce the impact of TB DILI. We have demonstrated that a significant proportion of patients will require modified TBT. These patients are likely to be males aged >50 years who are on ART and present with symptomatic DILI. There also appears to be an association between ART and more severe DILI. Funding. DE and RBâ&#x20AC;&#x2122;s funding was provided by the US Agency for International Development (USAID) under the terms of agreement USAID674-A-12-00029. This study was made possible by the generous support of the American people through Cooperative Agreement AID 674-A-12-00029 from USAID. The contents of the article are the responsibility of the authors and do not necessarily reflect the views of USAID, the National Institutes of Health or the US government. Right to Care provided some funding for technical and logistic support and for the provision of treatment for patients in this study. References 1. World Health Organization. Tuberculosis fact sheet No. 104, March 2012. www.who.int/mediacentre/ factsheets/fs104/en/ (accessed 27 April 2012). 2. World Health Organization. Tuberculosis global facts 2011/2012. www.who.int/entity/tb/ publications/2011/factsheet_tb_2011.pdf (accessed 27 April 2012). 3. Baddeley A, Dias HM, Falzon D, et al. Global Tuberculosis Control: WHO Report 2011. Geneva: World Health Organization, 2011. 4. Schaberg T. The dark side of antituberculosis therapy: Adverse events involving liver function. Eur Respir J 1995;8(8):1247-1249. [http://dx.doi.org/10.1183/09031936.95.08081247] 5. Tostmann A, Boeree MJ, Aarnoutse RE, et al. Antituberculosis drug-induced hepatotoxicity: Concise up-todate review. J Gastroenterol Hepatol 2008;23(2):192-202. [http://dx.doi.org/10.1111/j.1440-1746.2007.05207.x] 6. Shang P, Xia Y, Liu F, et al. Incidence, clinical features and impact on anti-tuberculosis treatment of anti-tuberculosis drug induced liver injury (ATLI) in China. PLoS One 2011;6(7):e21836. [http:// dx.doi.org/10.1371/journal.pone.0021836] 7. Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167(11):14721477. [http://dx.doi.org/10.1164/rccm.200206-626OC] 8. Hassen AA, Belachew T, Yami A, et al. Anti-tuberculosis drug induced hepatotoxicity among TB/ HIV co-infected patients at Jimma University hospital, Ethiopia: Nested case-control study. PLoS One 2013;8(5):e64622. [http://dx.doi.org/10.1371/journal.pone.0064622] 9. Schutz C, Ismail Z, Proxenos CJ, et al. Burden of antituberculosis and antiretroviral drug-induced liver injury at a secondary hospital in South Africa. S Afr Med J 2012;102(6):506-511. 10. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An Official ATS Statement: Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174(8):935-952. [http://dx.doi.org/10.1164/rccm.200510-1666ST] 11. European Respiratory Society. Tuberculosis management in Europe. Recommendations of a task force of the European Respiratory Society (ERS), the World Health Organization (WHO), and the International Union against Tuberculosis and Lung Disease (IUATLD) Europe Region. Eur Respir J 1999;14(4);978-992. [http://dx.doi.org/10.1183/09031936.99.14497899] 12. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: Recommendations of the Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1998;53(7):536-548. [http://dx.doi.org/10.1136/thx.53.7.536] 13. Sharma SK, Singla R, Sarda P, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis 2010;50(6):833-839. [http://dx.doi.org/10.1086/650576] 14. Nunez M. Hepatotoxicity of antiretrovirals: Incidence, mechanisms and management. J Hepatol 2006;44(1 Suppl):S132-S139. [http://dx.doi.org/10.1016/j.jhep.2005.11.027] 15. Jong E, Conradie F, Berhanu R, et al. Consensus statement: Management of drug-induced liver injury in HIVpositive patients treated for TB. S Afr J HIV Med 2013;14(3):113-119. [http://dx.doi.org/10.7196/sajhivmed.976]

Accepted 18 March 2015.

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The poor children of the poor: Coping with diabetes control in a resource-poor setting F P R de Villiers, PhD, FACP, FCPaed, MMed (Paed) Department of Paediatrics and Child Health, MEDUNSA Campus, Sefako Makgatho Health Sciences University, Pretoria Corresponding author: F P R de Villiers (alfafrancois@yahoo.co.uk)

Background. Coping with diabetes control is difficult for newly diagnosed and experienced patients alike. Children with diabetes face severe challenges, as they may not yet have attained the necessary cognitive, fine motor or psychosocial skills required for performance of the tasks required from the diabetic patient. Most therefore require some adult assistance. Objectives. To establish whether paediatric diabetic patients are adequately supported by their families in terms of giving insulin injections and doing home blood glucose monitoring (HBGM), and whether insulin and the necessary equipment are appropriately stored in their homes. Methods. Patients attending a paediatric diabetes clinic were interviewed. The data collected included demographic variables, type of insulin, measurement of insulin doses, administration of insulin, and blood glucose monitoring tests. Results. Twenty-five subjects were interviewed: 18 measured the insulin themselves, five mothers and one aunt did so, and in one case the mother and patient did so together. The four children aged ≤10 years had their insulin measured by their mothers, but one had to administer the injection himself. Eight of the nine children aged 11 - 15 years measured and administered the insulin themselves; in four cases the doses were checked by an adult. The mothers of four children did the fingerpricks, and eight children were helped with measuring the results. Only two children aged 11 - 15 years had their doses checked by an adult. Conclusion. Adult assistance with regard to both insulin injections and HBGM is rarely forthcoming. The children seem not to be sufficiently supported by their families. S Afr Med J 2015;105(5):397-399. DOI:10.7196/SAMJ.8496

Coping with diabetes control is difficult for newly diagnosed and experienced patients alike. The child is often critically ill at diagnosis, and the child and the family are faced with a lifelong condition, as well as loss of the child as he/she used to be. All suddenly face complex technical challenges.[1] Later, the constant repetition of testing and insulin administration, unremitting dietary vigilance and careful adjustment of every aspect of living with the disease potentially become wearisome.[1,2] Many children over the age of 10 years administer their own insulin injections,[3] although some authorities believe that the parents should take complete control up to the age of puberty, i.e. about 13 or 14 years.[4] However, children vary in their development and with regard to the age at which self-treatment is appropriate.[3] Parents should not expect that children will continue self-injection without parental interest and guidance, and will sometimes find themselves having to take over the injections again.[3] It must be noted that some patients store insulin inappropriately, measure it incorrectly, and neglect home blood glucose monitoring (HBGM). Multiple re-use of disposable insulin syringes for six injections is common, the practice being supported by a study in which syringes were re-used an average of 6.3 times without infections.[5] In Bangladesh, syringes were used 31.3 times on average (maximum 120 times).[6] In contrast to the vast literature on the biology of diabetes mellitus, little is written on the practical aspects of diabetes care. We undertook a study in our clinic at the Dr George Mukhari Academic Hospital, Pretoria, South Africa, to establish whether insulin and the other necessary equipment are appropriately stored in the homes of diabetic patients, and whether paediatric diabetic patients are adequately supported by their families.

397

Methods

Patients attending the paediatric diabetes clinic were interviewed by a mother-tongue Tswana speaker in English or Tswana, depending on the patient’s preference. Interviews were conducted on the clinic day before the patient’s consultation, in a private room, and took about 15 minutes. Questions included demographic variables, the type of insulin and injection system and where these were kept, the measurement of insulin doses, insulin injections and blood glucose monitoring tests. Permission for the study was granted by the MEDUNSA Research Ethics Committee, MEDUNSA campus, University of Limpopo (now Sefako Makgatho Health Sciences University), and informed consent was obtained from all subjects. Patients could withdraw at any time without its affecting their therapy or relationship with the clinic staff, and all information was confidential.

Results

Twenty-five subjects were interviewed: nine boys and 16 girls, aged 7 - 18 years. The majority (19) were teenagers, four were aged ≤10 years and two were between 11 and 12 years old. The duration of diabetes ranged from 1 month to 9 years, with a median of 4 years. Two patients had had diabetes for 1 - 3 months, four for 1 - 2 years, 12 for 2 - 5 years, and seven for >5 but <10 years. Glycosylated haemoglobin (HbA1c) values (Table 1) in the study subjects were generally unsatisfactory: only two were in the normal range, five were slightly elevated, eight fell in the range 9 - 11.9%, and five were >12% (in five cases no value could be found). There was a tendency for better controlled HbA1c to correspond with a shorter duration of diabetes (not statistically significant; p=0.151). Twothirds of the patients with a duration of diabetes of <2 years had an HbA1c level <9%, while only 21% of those with a longer duration of diabetes had similar HbA1c values.

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The majority of the patients (20, 80%) were on twice-daily injections with a premixed insulin formulation (Actraphane); this included all the preteens. Four patients administered three injections per day: Actraphane before breakfast, soluble insulin (Actrapid) before supper, and isophane insulin (Protaphane) at 21h00, and only one was on a basal-bolus regimen (isophane insulin at 21h00 hours, with soluble insulin boluses before each meal). All the households had a refrigerator, and none stored insulin in the freezer compartment. At night 88% of the subjects kept the insulin in the refrigerator, while more than half (56%) did so during the day (Table 2). Nine of the subjects (36%) usually carried their insulin with them during the day, while 12 (48%) never did so (Table 3). Eight of those who usually carried the insulin with them replaced it in the fridge on returning home. Three of the patients who were on three injections a day did not take insulin to school; only one on triple injections and the one on basal-bolus therapy did so. Eighteen of the 25 patients measured the insulin themselves, while five mothers did so. In one case the duties were shared between the mother and the child, and in the last, an aunt measured the insulin. The four children who were aged 10 years or younger were assisted by their mothers, but one of these had to administer the injection himself. Eight of the nine children aged between 11 and 15 years measured and administered the insulin themselves; in four cases the doses were checked by an adult. Altogether, 18 children measured the insulin themselves and 20 administered the injection themselves; in all cases the doses were never checked. In only seven cases were the doses ever checked by another (Table 4). Regarding HBGM (Table 5), 14 subjects did fingerpricks them selves. The mother did this in four cases, and one child assisted his mother. About a quarter of the sample (six patients) did not perform HBGM at all. Measuring and recording the results followed approximately the same pattern: only five of the 19 patients were assisted by an adult in the fingerpricks, eight with measuring the results, and four with the recording of their results. Blood glucose control, as measured by HbA1c values, was compared between the children who had some assistance (in injection, HBGM or both) against those who had no help. There was no statistically significant difference between the two groups. The measurement of insulin was demonstrated to the interviewer by 11 of

Table 1. HbA1c values correlated with duration of diabetes* HbA1c (%) Duration

<7, n

7 - 8.9, n

9 - 11.9, n

>12, n

Total, n

1 - 3 months

1 - 1.9 years

2 - 5.9 years

6 - 10 years

Total

*No HbA1c values available for 5 patients.

Table 2. Where the patients kept their diabetic equipment Needles n subjects (%)

Syringes n subjects (%)

Other diabetic equipment n subjects (%)

Bedroom

11 (44)

4 (16)

9 (26)

Kitchen

2 (8)

1 (4)

2 (8)

Refrigerator

14 (56)

Dining room

1 (4)

Cupboard

5 (20)

1 (8)

4 (16)

Wardrobe

3 (12)

2 (4)

3 (12)

Drawer

1 (4)

Box

1 (4)

Cooler bag

1 (4)

N/A

4 (16)

Total

25 (100)

N/A = no regular place of storage.

Table 3. Insulin storage Overnight n subjects (%)

Daytime n subjects (%)

Refrigerator

21 (84)

14 (56)

Box

1 (4)

2 (8)

Kitchen

1 (4)

Other

2 (8)

1 (4)

Carry* plus fridge

6 (24)

Cooler bag plus fridge

1 (4)

Total

25 (100)

*Take to school or leisure activity.

the mothers, and in all cases technique was appropriate.

Discussion

Our clinic serves a periurban, lower socioeconomic, black African population. It is assumed, given the absence of reliable prevalence data, that type 1 diabetes is uncommon in black South Africans. In Tanzania, the annual incidence of type 1 diabetes in children was 1.5/100 000.[7] Accordingly, the relatively small number of patients with type 1 diabetes in our clinic is not surprising.

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Our patients’ high HbA1c values reflect the lack of resources afforded diabetes mellitus at our hospital. The only diabetes educator in the hospital has more duties elsewhere than in the endocrinology service. It has been challenging to obtain analogue insulins, and we have not been allowed to use insulin pumps. Blood glucose testing strips are all too frequently out of stock. These challenges affect the choice of insulin therapy for our patients. Giving premixed insulins twice a day is clearly not appropriate for the majority of patients, most of whom should be on

RESEARCH

Table 4. Measurement and administration of insulin Who measures insulin? n subjects (%)

Who checks insulin? n subjects (%)

Who administers insulin? n subjects (%)

Mother

5 (20)

4 (16)

2 (8)

Mother (sometimes)

1 (4)

Self

18 (72)

20 (80)

Self and mother

1 (4)

3 (12)

Aunt

1 (4)

Sister

1 (4)

Schoolteacher

1 (4)

No one

18* (72)

Total

25 (100)

25* (100)

25 (100)

Table 5. Home blood glucose testing

Acknowledgements. Thanks are due to Dr K E Lengane, who conducted the interviews in English and in Tswana, and to Gillian K de Villiers who performed data entry and analysis. References

Finger prick n subjects (%)

Measure results n subjects (%)

Check result n subjects (%)

Record results n subjects (%)

Mother

4 (16)

3 (12)

Mother (sometimes)

1 (4)

Self

14 (56)

11 (44)

15 (60)

Self and mother

1 (4)

1.5 (6)*

Other family member

2.5 (10)*

1 (4)

No one

6 (24)

21 (84)

6 (24)

Total

25 (100)

*In one case the patient was supervised either by the mother or another family member.

that any remaining insulin be discarded after 4 weeks.[3] Assuming that patients who were on a twice-daily insulin regimen would not need to carry insulin with them, as they can have the first injection before breakfast and the second before supper, it was not clear why seven saw the need to take their insulin to school. In contrast, only two of the five patients who received three or four injections a day carried their insulin with them, perhaps because they returned home at lunchtime for their additional injection. While measurement of the insulin dose is only moderately reliable when a vial and insulin syringe is used, with the Penset the correct amount can be dialled, so mistakes are usually only found early on (or in patients who are partially sighted). Indeed the technique was correct in all our cases, whether using syringes or the Penset. Most of the children had to measure their own insulin without help. This is clearly inappropriate, even in adolescence, and contrasts with a study in the UK where parents needed to reassure themselves by

399

Conclusion

The children in our study were rarely assisted by adults with either their insulin injections or HBGM, and are not sufficiently supported by their families.

*This includes the 5 mothers who always measured the insulin.

multiple daily injections. Many more blood glucose testing strips should be supplied to enable HBGM at least three times a day. Insulin pump therapy may make management more convenient and avoid the many needle pricks, but according to Skogsberg et al.,[8] while there is improved patient satisfaction there is no difference in metabolic control with pump therapy v. multiple daily injections. Several metaanalyses show a statistical difference in favour of pump therapy, but only amounting to a minimal improvement of 0.2 - 0.3% in HbA1c values.[9-12] Similarly, continuous subcutaneous glucose sensing devices exist to improve blood glucose control, but again by a clinically unimportant amount.[13] It is gratifying that every one of our patients had access to a refrigerator. However, despite this some failed to store their insulin in the refrigerator, in an area where day temperatures are usually above 30°C in summer. Insulin should be stored in a refrigerator at 4 - 8°C, and never frozen, or alternatively stored at an ambient temperature of 15 - 25°C, which requires

constant checking, to the extent that some children felt that their parents were too controlling.[1] With the modern spring-loaded lancet devices, fingerprick testing is quite easy. In five cases the children were helped with fingerpricks, in eight with measuring their blood glucose results, and in four with both checking and recording their results.

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1. Marshall M, Carter B, Rose K, Brotherton A. Living with type I diabetes: Perceptions of children and their parents. J Clin Nurs 2009;18(12):1703-1710. [http://dx.doi.org/10.1111/j.13652701.2008.02737.x] 2. Harris ST, Pokorny ME. Living with diabetes: What patients are saying. Care Manag J 2012;13(2):46-50. [http://dx.doi. org/10.1891/1521-0987.13.2.46] 3. Bangstad H-J, Danne T, Deeb L, Jarosz PC, Urakami T, Hanas R. ISPAD Clinical Practice Consensus Guidelines 2009: Insulin treatment in children and adolescents with diabetes. Pediatr Diabetes 2009;10(Suppl 12):82-99. [http://dx.doi.org/10.1111/ j.1399-5448.2009.00578.x] 4. Chase PH, Maahs D. Responsibilities of children at different ages. In: Chase HP, Maahs D. Understanding Diabetes. 12th ed. 2012. Denver, CO: Pink Panther Books, University of Colorado, 2012:ch. 18. 5. Aziz S. Recurrent use of disposable syringe-needle units in diabetic children. Diabetes Care 1984;7(2):118-120. [http:// dx.doi.org/10.2337/diacare.7.2.118] 6. Islam MS, Ali SM. Multiple re-use of disposable insulin syringes in hospital. Bangladesh Medical Research Council Bulletin 1990;16(2):58-61. 7. Swai AB, Lutale JL, McLarty DG. Prospective study of incidence of juvenile diabetes mellitus over 10 years in Dar es Salaam, Tanzania. BMJ 1993;306(6892):1570-1572. [http://dx.doi. org/10.1136/bmj.306.6892.1570] 8. Skogsberg L, Fors H, Hanas R, Chaplin JE, Lindman E, Skogsberg J. Improved treatment satisfaction but no difference in metabolic control when using continuous subcutaneous insulin infusion vs. multiple daily injections in children at onset of type I diabetes mellitus. Pediatr Diabetes 2008;9(5):472-479. [http://dx.doi.org/10.1111/j.1399-5448.2008.00390.x] 9. Jeitler K, Horvath K, Berghold A, et al. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in patients with diabetes mellitus: Systematic review and meta-analysis. Diabetologia 2008;51(6):941-951. [http:// dx.doi.org/10.1007/s00125-008-0974-3] 10. Monami M, Lamanna C, Marchionni N, Mannucci E. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in type 1 diabetes: A meta-analysis. Acta Diabetol 2010;47(Suppl 1):S77-S81. [http://dx.doi.org/10.1007/ s00592-009-0132-5] 11. Pankowska E, B1azik M, Dziechciarz P, Szypowska A, Szajewska H. Continuous subcutaneous insulin infusion vs. multiple daily injections in children with type 1 diabetes: A systematic review and meta-analysis of randomized control trials. Pediatr Diabetes 2009:10(1):52-58. [http://dx.doi.org/10.1111/j.13995448.2008.00440.x] 12. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in type 1 diabetes: Meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008;25(7):765-774. [http://dx.doi. org/10.1111/j.1464-5491.2008.02486.x] 13. Langendam M, Luijf YM, Hooft L, DeVries JH, Mudde AH, Scholten RJPM. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev 2012, Issue 1. Art. No.: CD008101. [http://dx.doi.org/10.1002/14651858. CD008101.pub2]

Accepted 18 March 2015.

RESEARCH

The success of various management techniques used in South African children with type 1 diabetes mellitus K L Kalweit,1,2 BSc (Medical Sciences), BSc Hons (Bioinformatics); N Briers,3 BSc, BSc Hons (Physiology), PhD (Anatomy); S A S Olorunju,4 BSc (Statistics), MSc (Mathematical Statistics), PhD (Applied Quantitative Genetics) S chool of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa Youth With Diabetes, Johannesburg, South Africa 3 Department of Anatomy, Faculty of Health Sciences, University of Pretoria, South Africa 4 Biostatistics Unit, South African Medical Research Council, Pretoria, South Africa 1 2

Corresponding author: K Kalweit (k.kalweit@live.com)

Background. Despite the availability of international guidelines for the treatment of type 1 diabetes mellitus (T1DM) in children, important aspects of treatment are not accessible to all young patients in South Africa (SA). Objective. To investigate factors in diabetes management strategies that are associated with poor glycaemic control and decreased quality of life (QoL) in SA children with T1DM. Methods. Eighty children (mean (standard deviation) age 12.9 (2.7) years) with T1DM were asked to answer standardised questionnaires on demographics, management techniques used and perceptions of diabetes. The height and weight of each child was recorded and glycosylated haemoglobin (HbA1c) measured. Informed consent and assent for each participant was obtained before enrolment. Results. A total of 51.4% of the participants had poor metabolic control, with an HbA1c level >10.0% (86 mmol/mol). Factors in clinical practice found to have a significant association with decreased HbA1c and/or QoL were healthcare system (p<0.001), insulin administration (p=0.001), correction dose (p=0.002), carbohydrate counting (p<0.001) and number of severe hyperglycaemic events (p=0.048). Regular exercise did not show any association with HbA1c classification or QoL. Children from single-parent households were prone to unsuccessful diabetes management regardless of treatment techniques used (p=0.002). Conclusions. The use of premixed insulin without access to rapid-acting insulin, absence of correction doses for hyperglycaemia and lack of carbohydrate counting showed significant association with poor diabetes management. Some recommendations regarding the adoption of more effective diabetes management strategies in the public healthcare system are suggested. S Afr Med J 2015;105(5):400-404. DOI:10.7196/SAMJ.9334

The current prevalence of diabetes in South Africa (SA) is 8.27%, with an incidence rate of 0.8/100 000 for children aged 0 - 14 years.[1] The choice of treatment regimen for children living with type 1 diabetes mellitus (T1DM) should accommodate the child’s age, daily routines, targets of metabolic control, and individual and family preferences. However, different strategies for T1DM management that may assist with these specific needs are not equally accessible in SA. SA has a private and a public (funded) healthcare sector. Children cared for in the private setting have access to a wider range of insulin brands and more testing strips per month than their counterparts in the public system. Private patients also see diabetes educators and dieticians, although the frequency of such visits depends on their medical insurance scheme. Continuous subcutaneous insulin infusion (CSII) pumps are available in SA, but are available only to children on upper-tier insurance schemes owing to the high cost of the machine and its consumables. Insulin is issued by the state to those not covered by medical insurance.[2] However, because test strips for glucometers are not on national tender, availability depends on the individual budget of each public healthcare facility. Diabetes educators are not routinely available in this sector, but ad hoc education is given by nurses and doctors. The availability of dieticians depends on the individual facility. Action plans in the public sector are moving

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towards an integrated chronic care approach where diabetes management services will be combined with hypertension, epilepsy, asthma and other chronic diseases owing to the high rates of comorbidity in the SA population (Prof. Melvyn Freeman, personal communication). There are distinct differences between the resources and tools available to patients treated in public as opposed to private healthcare, but it is not clear whether these differences have a significant impact on the management of diabetes. It would be very beneficial to assess whether certain treatment strategies are more effective than others in improving glycaemic control and quality of life (QoL) in children with T1DM in the SA setting.

Objective

To investigate the effectiveness of different management techniques currently being used by SA children with T1DM. Measurements of glycosylated haemoglobin (HbA1c) and QoL were used to determine the level of treatment success with regard to type of insulin administered, use of correction doses, carbohydrate counting and inclusion of regular exercise.

Methods Sample

The sample consisted of 80 children diagnosed with T1DM who attended diabetes weekend camps. Five camps were randomly

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Data collection

Participants were asked to answer the Novo Nordisk Quality of Life for Youth Questionnaire, the Joslin Problem Areas in Diabetes (PAID) questionnaire, and a newly designed study questionnaire on demographics, management and perceptions of diabetes. The latter questionnaire was validated before implementation by means of a pilot study. The height and weight of each child was recorded and HbA1c measured using the A1CNow+ Multi-test system (Bayer HealthCare, USA).

Data analysis

Because the A1CNow+ system has an upper limit of detection at 13.0% (118 mmol/ mol), HbA1c was converted to HbA1c classification according to the American Diabetes Association guidelines.[3] Table 1 shows that targets are slightly more stringent for adolescents. Special consideration was given to vulnerability to hypoglycaemia in younger children because of their spontaneous physical activity and their difficulty in recognising symptoms of hypoglycaemia. Statistical analyses were performed using Stata version 12 (Stata Corporation, USA), with a two-sided significance cut-off level of ≤0.05. Group comparisons for categorical variables were performed using Fisher’s exact test. The Spearman rank correlation coefficient was used to evaluate the relationship between continuous variables. Student’s t-test or the Kruskal-Wallis test was used to determine differences between continuous variables according to the data distribution profile.

Results

A summary of the demographic charac teristics of the sample, diabetes treatment strategies used and any association of these variables with HbA1c classification or QoL is shown in Table 2. Of the participants,

Table 1. HbA1c levels classified according to American Diabetes Association guidelines[3] HbA1c, % (mmol/mol) HbA1c classification

Children aged 7 - 12 years

Children aged 13 - 18 years

Good

≤8.0 (64)

≤7.5 (59)

Fair

8.0 - 10.0 (64 - 86)

7.5 - 10.0 (59 - 86)

Poor

≥10.0 (86)

100%

80% Percentage of sample

selected from different regions of SA. A diabetes nurse evaluated whether children met the inclusion criteria, which included being SA citizens, >12 months since the diagnosis of diabetes (in order to limit the effect of residual pancreatic function), and age 7 - 18 years at the time of data collection. All the children who were eligible for the study were contacted to ensure an equal opportunity to participate. Only children who signed assent and whose parents gave informed consent were enrolled. A cross-sectional study design was approved by the Research Ethics Committee of the University of Pretoria.

60%

40%

20%

0% Married

Divorced

Never married

Parental marital status

Deceased parent

Fair/Good HbA1c Poor HbA1c

Fig. 1. Proportion of children with poor HbA1c classification compared with those with fair or good classification according to different parental marital status.

51.4% had poor metabolic control, with an HbA1c level >10.0% (86 mmol/mol). A significant association was found between HbA1c classi f ication and healthcare system (p<0.001), parental marital status (p=0.002), insulin administration (p=0.001), correction dose (p=0.002), carbohydrate counting (p<0.001) and number of severe hyperglycaemic events (p=0.048). Fig. 1 shows the proportion of children with poor HbA1c in relation to parental marital status. A high score on the Novo Nordisk QoL questionnaire, on which possible scores range from 0 to 100, indicates a high negative impact of T1DM on QoL and a low score little or no impact. The average score obtained for the sample was 28.7. The total impact of diabetes on QoL as experienced by the children was therefore not significant. However, poorer metabolic control was associated with decreased QoL, specifically in the categories of parental issues, worries about diabetes and self-rated health perception, pointing to the social consequences of poor metabolic control. According to the PAID questionnaire, an extremely low score (0 - 10) combined with poor glycaemic control may be indicative of denial. The average score for the sample

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was calculated as 21.2, showing no major issues overall. A significant association was found between QoL and HbA1c classification (p<0.001), healthcare system (p<0.001), social designation (p=0.009), parental marital status (p=0.005), carbohydrate counting (p=0.004) and number of severe hyperglycaemic events (p=0.021). Ten children (90.9%) using premixed insulin were classified as having poor HbA1c control, with a significant proportion (p<0.001) treated in the public healthcare system. In contrast, 24 children (54.6%) using multiple daily injections (MDIs) had a poor HbA1c. Insulin pumps were used only in the private healthcare sector, with 3 (17.7%) having poor glycaemic control. Eleven participants (84.6%) who used no correction dose for hyperglycaemia were classified as having poor HbA1c. Thirty-five per cent were unable to give correction doses because they had been prescribed premixed insulin without separate rapid-acting insulin, while the rest used MDIs. There was a significant association between correction technique used and healthcare system (p<0.001), with absence of correction more common in the public sector and correction equation more

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Table 2. Demographic characteristics of the sample, diabetes treatment regimens used and their association with HbA1c and QoL outcomes p-value Variable

T1DM children (N=80)

HbA1c

QoL

Age (years), mean (SD)

12.9 (2.7)

Female, %

56.3

BMI, median (IQR)

18.9 (15.7 - 21.4)

Diabetes duration (years), median (IQR)

4.0 (2 - 6.3)

Public healthcare system (%)

48.7

<0.001

<0.001*

0.002

0.005*

0.001

0.002

<0.001

0.004*

Severe hypoglycaemic events (n), median (IQR) 0 (0 - 1)

Severe hyperglycaemic events (n), median (IQR) 1 (0 - 4)

0.048

0.021†

HbA1c classification (%) Good

24.3

Fair

24.3

Poor

51.4

Parental marital status (%) Married

50.6

Divorced

8.9

Never married

25.3

Widowed

15.2

Insulin administration (%) Premixed

13.8

Syringes

2.5

MDIs

62.5

Pump

21.2

Correction dose technique (%) No correction

17.5

Set dose

10.0

Sliding scale

35.0

Correction equation

27.5

Unknown

10.0

Carbohydrate counting (%)

33.8

Regular exercise (%) No physical activity

21.5

1 - 2 days per week for ≥30 min per day

48.1

3 - 4 days per week for ≥30 min per day

22.8

≥5 days per week for ≥30 min per day

7.6

SD = standard deviation; BMI = body mass index ((kg/m ); IQR = interquartile range; NS = non-significant at α≤0.05. * Both PAID and Novo Nordisk Quality of Life for Youth Questionnaire found to be significant, with average p-value shown. † PAID questionnaire found to be significant. 2

frequently used in the private sector. A notable proportion of 36 children (89.6%) who were not using carbohydrate counting were above the recommended targets set by the American Diabetes Association, and again a significant difference was seen between healthcare systems (p<0.001).

Discussion

This study observed several factors in clinical practice that were associated with

poor metabolic control and/or decreased QoL for a child with T1DM, thereby limiting the success of diabetes management. These factors included use of public healthcare, use of premixed insulin (without a correction pen), lack of correction doses, absence of carbohydrate counting, increased number of severe hyperglycaemic events and singleparent households. Patients treated in the public healthcare system demonstrated a significant

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association with the use of premixed insulin (p<0.001), no correction dose for hyperglycaemia (p<0.001) and lack of carbohydrate counting (p<0.001) compared with patients treated in private healthcare settings. Several obstacles specific to public healthcare may be responsible for these associations. The availability of testing strips in governmentfunded facilities is not standard and moreover is severely limited. Correction doses and carbohydrate counting cannot be properly used if the child cannot test his or her blood glucose at least four times a day.[3] Currently children receive between 50 to 100 test strips per month, but this very much depends on the facility’s budget and stock of test strips (Mrs Corine Verwey, personal communication). Given that an insufficient number of test strips are available, testing intensively for a few consecutive days a month may provide more useful information than twice-daily measurements and permit healthcare professionals to make informed decisions about blood glucose patterns and insulin dose adjustments.[4] Previous research investigating the obstacles that public healthcare professionals face in managing diabetes patients listed staff shortages, budgetary constraints and the lack of culturally appropriate and simple educational material.[5] Studies also found that an excessive patient load limited doctors’ ability to provide education to patients during routine consultations, and that lack of post-basic training and a deficiency of diabetes knowledge on the part of nurses may have contributed to the poorer health outcomes of children treated at government diabetes clinics,[5] contrasting with the availability of diabetes nurse educators in private facilities. Almost all the children using premixed insulin were classified as having poor HbA1c. Premixed insulin is often prescribed to children with low treatment compliance because fewer injections are needed, which may explain the very poor success seen with this insulin administration technique. However, if this is true it presents a contradiction. Children using this type of insulin require consistent carbohydrate intake to balance insulin action profile and prevent hypoglycaemia during periods of peak insulin action, especially overnight. [6] If patients are non-compliant in taking insulin, dietary compliance cannot be expected to be high. Another reason why a patient may be prescribed premixed insulin is its relatively low cost; however, children should also have access to rapid-acting

RESEARCH

insulin to control hyperglycaemia and treat ketones, thus negating any cost benefit. Physicians at both private and government institutions have the ability to prescribe an MDI regimen. Previous research has shown no correlation between an increased number of daily injections and adverse QoL,[7] and we also found no association between insulin administration and QoL. Changing to a more intensive MDI regimen would therefore facilitate improved glycaemic control without impacting negatively on QoL. Standard formulae have been created to calculate the number of additional units of insulin requiring administration to correct hyperglycaemia,[8] but such methods are not discussed in international guidelines for the treatment of children with T1DM.[3,4] It is therefore not surprising that correction doses are not standardised in SA. Patients using premixed insulin without access to rapid-acting insulin have no way to correct hyperglycaemia, ensuring the failure of this insulin administration strategy and placing the child at high risk for diabetic ketoacidosis and complications of poor glycaemic control. Children who were not taking correction doses while on an MDI regimen demonstrate a lack of resource utility. They were not educated in correct hyperglycaemia management despite the availability of rapid-acting insulin that could be used to improve metabolic control. As previously mentioned, the use of correction doses is highly dependent on the availability of testing strips, and this may have influenced correction options given to the child. Should children have stable access to test strips, a tool to educate patients on correction doses is the plastic insulin dosage guide designed by Kaufman et al.[9] This plastic card enables patients to easily determine the number of insulin units needed to correct hyperglycaemia based on current blood glucose readings. The tool can be adjusted as the childâ&#x20AC;&#x2122;s insulin sensitivity changes, thereby including the advantages of both sliding scale and correction equation methods while accommodating children with low literacy and numeracy skills. Carbohydrate counting was seen as the most important influence on QoL. Once a child understands how food affects their blood glucose, they are empowered to make healthy dietary decisions without feeling deprived. However, carbohydrate counting requires intensive dietary education and blood glucose monitoring, which may not be available. Lack of sufficient numeracy and literacy skills, as well as food-security issues, are further barriers to this diabetes management strategy. A more suitable method in resource-limited settings may be the use of a consistent eating plan with the flexibility to swap food items with the same carbohydrate content.[4] This strategy could facilitate a gain in QoL while achieving improved glycaemic control without the need for additional testing strips, although comprehensive dietary education would still be necessary. The number of severe hyperglycaemic events was seen to be significantly associated with HbA1c classification and QoL (p=0.048). This seems intuitive, since increasing frequency of hyperglycaemia will elevate HbA1c. It is possible that children who experienced more frequent diabetic ketoacidosis or hospitalisation with hyperglycaemia believe that their diabetes is unmanageable, thus decreasing their QoL. There was no difference in hypoglyacaemic episodes according to site (p=0.9295) or insulin regimen (p=0.5111). This study did not find any association between regular exercise and HbA1c classification or QoL. It was noted that little or no guidance for exercise was given to T1DM children in either public or private healthcare settings. The low proportion of T1DM children participating in sport in this study implies that exercise

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is not undertaken for clinical reasons but rather for social reasons or school requirements, suggesting that exercise is not likely to be maintained after school. Previous studies have failed to show improved glycaemic control with regular exercise, and the majority of the guidelines for T1DM management during exercise are based on personal experience.[10] Despite this, exercise for patients with T1DM is considered highly beneficial, resulting in improvement in increased glucose utilisation, insulin sensitivity and weight management and a reduction in cardiovascular risk factors.[11] It was found that children from single-parent households had decreased glycaemic control and QoL, regardless of healthcare system or management options used. The significant association found between HbA1c and parental marital status (p=0.002) supports previous research indicating that family support is crucial in diabetes management for children.[12] Research has shown that family members who provide high levels of support for diabetes care have children who adhere better to their diabetes regimens.[13] Parents who anticipate imperfect blood glucose levels and use effective communication were shown to raise T1DM children without major problems. Doctors should be aware of this risk factor in their patients. A limitation of this study was the unexpectedly low proportion of T1DM children using public healthcare (48.7%), in contrast to 71.1% of the general SA population making use of government facilities.[14] It is not known whether this difference is due to sampling error or representative of children living with T1DM. Selection bias may have occurred, since the sample consisted only of children who attended diabetes camps; however, these camps were free of charge to children of low socioeconomic status, and advertised to both private and public healthcare patients well in advance. Owing to lack of data on the number of children living with T1DM in SA, it was difficult to calculate the power of this study. It is currently estimated that between 5 000 and 10Â 000 children are living with T1DM in SA (Dr David Segal, personal communication). Despite these caveats, data concerning the success of various management techniques are valid and may be used to highlight clinical practices that are linked to unsatisfactory diabetes management. We believe that our results can be generalised to a large majority of SA children with T1DM, as our study included a wide range in age, duration of diabetes and ethnicity in both the public and private healthcare sectors. We recommend that the SA National Department of Health consider implementing national policies for the treatment of T1DM in order to standardise diabetes management between healthcare systems. Such guidelines should be developed by practising healthcare professionals and academics in the field. The guidelines should be actively disseminated with the inclusion of in-service training for primary healthcare professionals in order to maximise the adoption of the new clinical standards.[5] We also recommend that future international guidelines on the management of diabetes in children and adolescents address insulin dosing methods to correct hyperglycaemia. Greater involvement with schools is also recommended.

Conclusion

This study identified diabetes management strategies that are linked to poor glycaemic control and decreased QoL, which include use of premixed insulin without access to rapid-acting insulin, absence of correction doses for hyperglycaemia, and lack of carbohydrate counting. Treatment strategies at public healthcare facilities were

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found to be significantly less effective than methods used in the private sector. T1DM children from single-parent households were prone to unsuccessful diabetes management regardless of the treatment techniques used. Recommendations regarding the adoption of more effective diabetes management strategies within the public healthcare system are proposed. Conflict of interest. KLK is employed by the non-profit organisation Youth With Diabetes, which gave access to the patients and donated HbA1c testing equipment; however, she played no role in initial patient recruitment. NB and SASO have no conflict of interest to declare. Acknowledgements. The authors wish to thank Youth With Diabetes for access to patients and donation of the HbA1C testing systems. Appreciation also goes to Sr Hester Davel for her assistance in conducting the patient questionnaires. References 1. International Diabetes Federation. Diabetes Atlas. 6th ed. Brussels: IDF, 2013. http://www.idf.org/ atlasmap/atlasmap (accessed 12 January 2014).

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2. Endocrine system, diabetes mellitus. In: Pudifin D, ed. Standard Treatment Guidelines and Essential Drugs List Primary Health Care. Pretoria: Department of Health, 2008:144. 3. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2013;36(Suppl 1):S11-S66. [http://dx.doi.org/10.2337/dc13-S011] 4. Rewers M, Pihoker C, Donaghue K, et al. Assessment and monitoring of glycaemic control. In: Colagiuri S, ed. Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence. Brussels: International Diabetes Federation, 2011:50-98. 5. Daniels A, Biesma R, Otten J, et al. Ambivalence of primary health care professionals towards the South African guidelines for hypertension and diabetes. S Afr Med J 2000;90(12):1206-1211. 6. Wolever TM, Hamad S, Chiasson J, et al. Day-to-day consistency in amount and source of carbohydrate intake associated with improved blood glucose control in type 1 diabetes. J Am Coll Nutr 1999;18(3):242-247. 7. Hoey H, Aanstoot HJ, Chiarelli F, et al. Good metabolic control is associated with better quality of life in 2,101 adolescents with type 1 diabetes. Diabetes Care 2001;24(11):1923-1928. [http://dx.doi. org/10.2337/diacare.24.11.1923] 8. Davidson PC, Hebblewhite HR, Steed RD, et al. Analysis of guidelines for basal-bolus insulin dosing: Basal insulin, correction factor, and carbohydrate-to-insulin ratio. Endocr Pract 2008;14(9):1095-1101. [http://dx.doi.org/10.4158/EP.14.9.1095] 9. Kaufman FR, Halvorson M, Carpenter S. Use of a plastic insulin dosage guide to correct blood glucose levels out of the target range and for carbohydrate counting in subjects with type 1 diabetes. Diabetes Care 1999;22(8):1252-1257. [http://dx.doi.org/10.2337/diacare.22.8.1252] 10. Australian Pediatric Endocrine Group. APEG Handbook on Childhood and Adolescent Diabetes. Parramatta, Australia: Child Health Promotion Unit, Royal Alexandra Hospital for Children, 1996. 11. American Diabetes Association. Physical activity/exercise and diabetes. Diabetes Care 2004;27(Suppl 1):S58-S62. [http://dx.doi.org/10.2337/diacare.27.2007.S58] 12. Cameron F, Skinner T, De Beaufort C, et al. Are family factors universally related to metabolic outcomes in adolescents with type 1 diabetes? Diabet Med 2008;25(4):463-468. [http://dx.doi.org/10.1111/j.14645491.2008.02399.x.]

Accepted 22 January 2015.

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Self-monitoring of blood glucose measurements and glycaemic control in a managed care paediatric type 1 diabetes practice B Davey, BA Hons (Biokinetics); D G Segal, MB BCh, FAAP, FACE Wits University Donald Gordon Medical Centre, Johannesburg, South Africa Corresponding author: D Segal (david@endo.co.za)

Background. Intensive diabetes management requires intensive insulin treatment and self-monitoring of blood glucose (SMBG) measurements to obtain immediate information on the status of the blood glucose level and to obtain data for pattern analysis on which meal planning, insulin and lifestyle adjustments can be made. The value and optimal frequency of SMBGs are often questioned. Objectives. To document the relationship between SMBG frequency and glycaemic control in a managed care paediatric type 1 diabetes practice. Methods. A retrospective analysis was performed on 141 managed care paediatric and adolescent patients over a 1-year period from 1 February 2010 to 30 January 2011. The patients were stratified according to their insulin regimen. The frequency of SMBG was analysed and glycaemic control measured by glycated haemoglobin (HbA1c). Results. A highly significant decrease (p<0.0001) in HbA1c was found when moving from two injections per day to three- and fiveinjection regimens. The average HbA1c and its variability reduced as the diabetes regimen became more intensive. A highly significant decrease (p<0.001) in HbA1c levels was detected as the frequency of SMBG increased, with an average decrease of 0.19% in HbA1c per unit increase in the number of SMBG measurements performed per day. The modal frequency of five SMBG measurements per day was required to achieve the American Diabetes Association and International Society for Pediatric and Adolescent Diabetes guideline recommended target HbA1c of <7.5% for a paediatric population. Conclusion. A beneficial relationship exists between frequency of SMBG and lower HbA1c in paediatric patients with type 1 diabetes. S Afr Med J 2015;105(5):405-407. DOI:10.7196/SAMJ.7686

The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes treatment designed to achieve near-normoglycaemia sub stantially reduced the risk of progression and delayed the development of complications in patients with type 1 diabetes when compared with a conventional treatment approach.[1] The Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a follow-on trial from the DCCT and ‘clinical experience’, highlighted the difficulty of achieving and maintaining near-normoglycaemia in practice.[2] The challenge for healthcare professionals is to devise strategies that help patients to achieve and maintain glycaemic targets safely. Self-monitoring of blood glucose (SMBG) measurements and glycated haemoglobin (HbA1c) have become integral components of intensive diabetes management.[3,4] It is accepted that SMBG can improve compliance with recommendations on diet and exercise and assist with modification of insulin regimens, but some still question its value.[5] There has been recent debate on the utility of SMBG in Washing ton State, USA, where the state attempted to limit the number of test strips supplied to do SMBG testing to one test per day in children.[5] However, after consideration it was decided that patients under 18 years of age with type 1 diabetes would be allowed funding for unlimited self-monitoring of blood sugars. This highlights the need for studies on the effectiveness of SMBG in a paediatric population with type 1 diabetes. Evidence supporting SMBG would need to find a negative correlation between HbA1c and testing frequency. We analysed the relationship between insulin regimen, frequency of SMBG and glycaemic control measured by HbA1c in 141 paediatric and adolescent patients on our diabetes managed care programme.[6]

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Methods

Rationale for selection of the study population

The advantage of using this managed care practice was the ability to quantify frequency of SMBG and blood glucose control accurately. Blood glucose test strip dispensing in the practice was tightly linked to the actual frequency of SMBG obtained from individual patients’ meter downloads at each visit, and the number of test strips dispensed per year was accurately recorded for each patient. A similar process was followed for insulin use, so that a very accurate estimate of daily insulin use could be obtained. Glycaemic control was measured by means of 3-monthly HbA1c level over the 1-year study period. Care was delivered by the same team over the observation period, the study population remained stable with no turnover of patients in the group, and all supplies were obtained from a single source. A total of 141 patients aged 2 - 18 years with type 1 diabetes were included in the retrospective analysis from 1 February 2010 to 30 January 2011. To exclude the effect of the ‘honeymoon period’, only patients who had been diagnosed for >1 year were included. Patients were stratified according to the number of injections they received per day in their treatment regimen. Patients receiving premixed insulin twice daily were classified as being on a two injections per day regimen; if a lunchtime injection of bolus insulin was added they were classified as being on three injections per day. The remainder of the patients were receiving basal insulin at breakfast and dinner or bedtime and bolus insulin at major meals, and were classified as being on five injections per day. No patients were receiving four injections per day. Patients on continuous subcutaneous insulin infusion (CSII) therapy were classified separately. The number of SMBG measurements per day was analysed, as well as total daily dose of insulin and injection regimen. The mean of each patient’s HbA1c

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over the study period was calculated from the average of their 3-monthly tests. All tests were performed on the same DCA Vantage Analyzer (Siemens Medical Solutions Diagnostics, USA).

Chemistry 58 mmol/mol)[15] had a modal testing frequency of five tests per day, ranging from one to nine SMBG tests per day.

Results

The goal of SMBG is to obtain useful information with which to maintain and manage overall glucose status, with an ultimate goal

A total of 141 patients (74 male) were studied. The mean age was 11.7 years (range 2 - 18), the mean duration of diabetes was 4.7 years (range 1 - 12), and the mean amount of insulin used was 0.95 U/kg/d (range 0.3 - 1.47). Nine patients were receiving two injections per day (6.3%), 19 three injections per day (13.5%), 49 five or more injections per day (34.8%), and 64 CSII (45.4%).

of achieving ‘normoglycaemia’ and preventing the long-term complications associated with poor glycaemic control. There are two main reasons for obtaining blood glucose data. The first is to obtain immediate information on the status of the blood glucose level, so that hypoglycaemia and hyperglycaemia can be minimised through timely and meaningful interventions. The second is

Discussion

p<0.0001 10.5

p<0.0001 NS

10.1 8.3

Injection regimen

There was a highly significant decrease (p<0.0001) in HbA1c levels when comparing patients receiving two, three and five injections per day, but the difference in HbA1c levels between five injections per day and CSII was not significant (Fig. 1). The HbA1c standard deviations also differed significantly (p<0.0001) across the four groups, displaying the same pattern as the averages (Table 1). The HbA1c decreased as the number of injections per day increased.

8.2

5.2

4.3 2.3

1.6

2 inj.

3 inj.

5+ inj.

CSII

Fig. 1. HbA1c and testing frequency per injection regimen. (NS = not significant.) 13

Frequency of testing per day

HbA1c, %

There was a highly significant decrease (p<0.001) in HbA1c levels as the frequency of testing increased, with an estimated average decrease of 0.34% per unit increase in the number of SMBG measurements per day (Fig. 2). Using analysis of covariance to correct for the simultaneous effect of the injection regimen, the average decrease in HbA1c was 0.19% per unit increase in SMBG measurements per day (p<0.001). Those on the two injections per day regimen performed on average 1.6 SMBG measurements per day, those on the threeinjection regimen 2.3 per day, those on five injections 4.3 per day, and those on CSII 5.2 per day. In our cohort, patients achieving an American Diabetes Association and International Society for Pediatric and Adolescent Diabetes target HbA1c level of <7.5% (International Federation of Clinical

SMBG, n/d

HbA1c, %

10 R2=0.3411 9

6 0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

SMBG, n/d

Fig. 2. Scatter plot comparing number of SMBG measurements v. HbA1c for all patients.

Table 1. HbA1c according to insulin regimen Insulin regimen 2 injections/day

3 injections/day

5 injections/day

CSII

Patients, n

HbA1c level (%), mean (SD)

10.59 (2.00)

10.02 (1.45)

8.24 (1.03)

8.09 (0.79)

SMBG measurements per day (n), mean (range)

1.6 (0.53 - 4.2)

2.3 (0.5 - 4.8)

4.3 (0.8 - 9.3)

5.2 (1.8 - 9.2)

SD = standard deviation.

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to obtain data for pattern analysis according to which meals can be planned, insulin dosages calculated and lifestyle adjustments made. Certain fundamental behaviours are associated with better glycaemic control,[7] such as the frequency of SMBG measurement,[8] frequency of insulin injections,[1] absence of insulin omission,[9] adherence to meal planning[10] and patient-initiated dose adjust ments.[11,12] These behaviours are the responsibility of each patient and caregiver, with non-adherence resulting in poor diabetic control. SMBG is a painful, costly and onerous task that has become part and parcel of modern-day diabetes management. Numerous testing regimens exist, with little evidence to suggest superiority of one over another. To be beneficial, SMBG needs to be a ‘value add’ to the patient and the medical team. Often patients are not empowered to analyse their SMBG data or to adjust their insulin dosages. This disempowerment may lead to apathy, depression, and conflict within the family. Such patients see minimal benefit from testing, leading to a decline in actual testing frequency, and perhaps even data corruption and embellishment, so that an accurate picture of their glycaemic control becomes impossible to obtain.[13] To the healthcare professional, accurate SMBG data are a valuable aid to the clinical assessment on the basis of which treatment adjustments can be recommended. Other studies support a correlation between frequency of testing and HbA1c reduction.[8,14] Our study supports these findings, showing a 0.19% improvement in HbA1c per unit increase in the number of SMBG measurements performed per day after correcting for the injection regimen. One of the limitations of this study is the interdependence of testing frequency and injection regimen. Both the injection regimen and testing frequency influenced the HbA1c. However, analysis of covariance continued to show that testing frequency had a highly significant negative effect on the HbA1c in this study (p=0.0002). Patients receiving fixed dosages of premixed insulin (i.e two- or three-injection regimen) often perform fewer SMBG measurements. There are two possible explanations for this: patients who volunteer for less intensive regimens such as fixed-dosage premixed insulin also opt to perform fewer SMBG tests per day; and fewer SMBG measurements are required in the day-to-day management of glucose control on this two- or three-injection regimen than on a more intensive regimen of five injections per day. On more intensive regimens, in particular on CSII therapy, patients are preselected according to their ability to perform multiple SMBG measurements a day, and are required to do so to verify the integrity of the pump function in terms of insulin delivery. The only group in which the testing frequency is less influenced by the injection regimen is the five injections per day group. Sub-analysis of this group using regression analysis still found a significant negative correlation between frequency of SMBG measurement and HbA1c (p=0.001). SMBG provides data in the form of an output variable that is a summation of a number of input variables such as insulin dose, insulin type, carbohydrate load and exercise. An increase in testing frequency allows for multiple hypotheses to be tested. The cycle of

407

testing and modification of the input variables strives through each iteration to achieve predictable and desirable glycaemic outcomes. Finding the perfect testing frequency and intensity is a subject of ongoing research. Overall, the study revealed a positive inverse relationship between frequency of SMBG measurements per day and HbA1c after correcting for the insulin regimen.

Conclusion

SMBG is essential for monitoring daily glycaemic control and for detecting and acutely managing hyper- and hypoglycaemic episodes. It also provides data for pattern analysis that can be used to reinforce positive behaviours and reduce negative ones. SMBG analysis assists in meal planning and dosage adjustment, and in so doing minimises glycaemic variability and allows patients to obtain recommended HbA1c targets. A clear beneficial relationship exists between the frequency of SMBG measurements performed per day and a lower HbA1c in paediatric patients with type 1 diabetes. While a tailored approach is required for each patient, restricted access to SMBG test strips should not be allowed to handicap a patient’s diabetes control efforts. References 1. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977-986. [http://dx.doi.org/10.1056/NEJM199309303291401] 2. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration. Arch Intern Med 2009;169(14):1307-1316. [http://dx.doi.org/10.1001/ archinternmed.2009.193] 3. Hansen MV, Pedersen-Bjergaard U, Hellers SR, et al. Frequency and motives of blood glucose self-monitoring in type 1 diabetes. Diabetes Res Clin Pract 2009;85(2):183-188. [http://dx.doi. org/10.1016/j.diabres.2009.04.022] 4. Karter AJ, Ackerson LM, Darbinian JA, et al. Self-monitoring of blood glucose levels and glycemic control: The Northern California Kaiser Permanente Diabetes Registry. Am J Med 2001;111(1):1-9. [http://dx.doi.org/10.1016/S0002-9343(01)00742-2] 5. Washington State Health Care Authority. HTA program, glucose monitoring, self-monitoring in patients under 18 years of age. Health Technol Assess 2011;1-53. http://www.hta.hca.wa.gov/ documents/glucose_monitoring_draft.pdf (accessed 25 May 2011). 6. Distiller LA, Brown MA, Joffe BI, Kramer BD. Striving for the impossible dream: A community-based multi-practice collaborative model of diabetes management. Diabet Med 2010;27(2):197-202. [http:// dx.doi.org/10.1111/j.1464-5491.2009.02907.x] 7. Miller VA, Drotar D. Decision-making competence and adherence to treatment in adolescents with diabetes. J Pediatr Psychol 2007;32(2):178-188. [http://dx.doi.org/10.1093/jpepsy/jsj122] 8. Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R; DPV-Wiss-Initiative. Frequency of SBGM correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes 2011;12(1):11-17. [http://dx.doi.org/10.1111/j.1399-5448.2010.00650.x] 9. Peyrot M, Rubin RR, Kruger DF, Travis LB. Correlates of insulin injection omission. Diabetes Care 2010;33(2):240-245. [http://dx.doi.org/10.2337/dc09-1348] 10. Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care 2002;25(3):608-613. [http://dx.doi. org/10.2337/diacare.25.3.608] 11. Heller S, DAFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: Dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ 2002;325:746. [http://dx.doi.org/10.1136/bmj.325.7367.746] 12. Anderson RM, Funnell MM, Butler PM, Arnold MS, Fitzgerald JT, Feste CC. Patient empowerment: Results of a randomized controlled trial. Diabetes Care 1995;18(7):943-949. [http://dx.doi.org/10.2337/ diacare.18.7.943] 13. Gonder-Frederick LA, Julian DM, Cox DJ, Clarke WL, Carter WR. Self-measurement of blood glucose: Accuracy of self-reported data and adherence to recommended regimen. Diabetes Care 1988;11(7):579-585. [http://dx.doi.org/10.2337/diacare.11.7.579] 14. Schütt M, Kern W, Krause U, et al.; DPV Initiative. Is the frequency of self-monitoring of blood glucose related to long-term metabolic control? Multicenter analysis including 24,500 patients from 191 centers in Germany and Austria. Exp Clin Endocrinol Diabetes 2006;114(7):384-388. [http://dx.doi. org/10.1055/s-2006-924152] 15. IDF-ISPAD Diabetes in Childhood and Adolescence Guidelines. 2011. http://www.ispad.org/sites/ default/files/resources/files/idf-ispad (accessed 25 May 2011).

Accepted 18 March 2015.

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Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP K R Antel,1 MB ChB, FCP (SA), MMed (Med); E Panieri,2 MB ChB, FSC (SA); N Novitzky,3 DipMed, FCP (SA), PhD (Med) epartment of Internal Medicine, Faculty of Health Sciences, University of Cape Town, South Africa D Department of Surgery, Faculty of Health Sciences, University of Cape Town, South Africa 3 Department of Haematology, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: K Antel (katherineantel@gmail.com)

Background. New agents are being used as second-line treatment for immune thrombocytopenia (ITP) and have brought into question the relevance of splenectomy for steroid-resistant ITP. Methods. We retrospectively analysed 73 patients who underwent splenectomy for ITP at our institution over an 11-year period. The median follow-up period was 25 months; patients with follow-up of <1 month were excluded. The outcomes of splenectomy were compared in HIV-positive v. HIV-negative patients. Results. The rate of complete response was 83%, and response was sustained for at least 1 year or until latest follow-up in 80% of patients. Twelve patients were HIV-positive. Splenectomy was laparoscopic in 43 patients (62%) with an overall 16% complication rate. The 90-day mortality rate was 1.38%. There was no statistically significant difference in response or complication rate in the HIV-positive patients. There was a statistically significant (p=0.017) poorer response to splenectomy in the patients with steroid-resistant ITP. Conclusion. Splenectomy is effective and safe irrespective of HIV status and remains an appropriate second-line treatment for ITP. Further research is needed to corroborate our finding of lower response in patients who are steroid-resistant, as this might be a subgroup of patients who may benefit from thrombopoietin agonists as second-line therapy. S Afr Med J 2015;105(4):408-412. DOI:10.7196/SAMJ.8987

Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by immunological destruction of platelets (primarily due to the production of platelet-reactive autoantibodies), along with an inability to compensate by increasing production of platelets as a result of immune-mediated megakaryocyte damage and dysfunction.[1] In ITP a platelet count of >30 × 109/L is generally the goal of treatment, but the decision to treat should be based on the patient’s risk of bleeding, side-effects of medication and patient preference.[2] First-line treatment for ITP is with oral glucocorticoids. Splenectomy has traditionally been employed as second-line treatment, but newer drugs such as rituximab and thrombopoeitin (TPO) agonists have brought the role of surgery into question. Thrombocytopenia is a common problem in HIV owing to cross-reactivity of antibodies to HIV with glycoprotein GPIIb and/ or GPIIIa on the platelet surface or talin within the platelet cyto skeleton.[3,4] Treatment of HIV-associated ITP is with antiretroviral therapy (ART). The use of glucocorticoids is common but is based purely on expert opinion, since there are no trials of glucocorticoids in HIV-associated ITP. Zidovudine was the first antiretroviral to show response in treating HIV-related thrombocytopenia. However, owing to the risk of generating resistance with monotherapy, combination antiretroviral therapy (cART) is preferred (not necessarily including zidovudine) and has been shown to be as effective.[5] Splenectomy for ITP in HIV has been reported mainly in the preART era and its role in HIV-associated ITP in the current era of ART needs to be studied further.[6] Splenectomy has been reported to have a complete response (CR) rate of 85%, but up to 25% of patients relapse during a

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5-year period.[7-9] The most concerning late complication of splenectomy is overwhelming post-splenectomy infection, the risk of which is estimated to be 0.23 - 0.42% per year, with a lifetime risk of 5%.[10] Rituximab is a monoclonal antibody directed against epitopes in B lymphocytes and has been studied in treatment-resistant ITP, but has shown poorer outcomes compared with splenectomy, with a 4.4-fold lower probability of CR at 1 year and a response rate of only 20% at 5 years.[11,12] In a systematic review of 306 ITP patients treated with rituximab, 3.7% experienced severe or life-threatening events and 2.9% (9 patients) died.[13] More recently, recognising that platelet underproduction and megakaryocyte dysfunction play a substantial role in the patho physiology of ITP, TPO receptor agonists such as romiplostim and eltrombopag have become available. They are costly, and as they have little influence on the immune destructive process they need to be taken indefinitely. These TPO agonists have nevertheless been associated with responses (platelet count >50 × 109/L at 6 - 8 weeks) in up to 92% of patients, continuing as long as treatment is maintained.[14] TPO agonists are well tolerated, with a 5-year followup study for romiplostim reporting an 8% rate for serious adverse events and 5% mortality.[14] Rituximab and TPO agonists have not yet been studied systematically in HIV-associated ITP. Considering these non-invasive treatment options, the role of splenectomy continues to be debated. We therefore undertook to investigate response rates to splenectomy in patients with ITP, some of whom were HIV-positive and who had been pretreated with steroids in an era when cART was available. To our knowledge this is the first study reporting outcomes after splenectomy in Africa, in a context of high infectivity with HIV.

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Methods

Patient selection

Seventy-three consecutive patients who had undergone splenectomy for ITP during the period 1 January 2001 - 31 December 2011 were retrospectively identified using surgical and histological records. Patients with primary ITP as well as patients with secondary ITP due to HIV, hepatitis and connective tissue disease were included, but patients with lymphoproliferative disease were excluded. Patients who had platelet counts lower than response (<30 × 109/L) on high-dose steroids or who relapsed after steroid treatment and weaning were referred for splenectomy.[2] All patients met the diagnostic criteria reported by the American Society of Hematology Practice Guidelines.[2] This record review was approved by the ethics committee of the University of Cape Town. The medical records of these patients were analysed for their clinical and laboratory data with regard to diagnosis and initial management, comorbidities, response to treatment, recurrence of thrombocytopenia, salvage therapy, operative type of splenectomy, follow-up platelet counts and complications following splenectomy. After splenectomy the platelet counts at 1 month, 6 months, 1 year or at latest followup (up to September 2013) were recorded to assess response. All platelet counts were checked and if there was any platelet count in the follow-up period <100 × 109/L this was specifically noted. The correlations between HIV status, hepatitis B positivity, antinuclear antibody (ANA) positivity (signalling connective tissue disease), gender, age and the likelihood of a CR after splenectomy were analysed.

Definitions

Response to medical treatment

Steroid resistance. Platelet count of >30 × 109/L never recorded despite treatment with prednisone at a minimum dose of 1 mg/kg for at least 6 weeks. Steroid dependence. Platelet count dropping to <30 × 109/L within 6 months from weaning off steroids.

Response to splenectomy

We used the definitions of response as previously described in the literature, with the addition of ‘sustained response’ as defined.[7] CR. Achievement and maintenance of a platelet count >100 × 109/L for all measurements 30 days or longer after splenectomy and with no additional treatment for ITP, except for the tapering of glucocorticoids.

Partial response. A platelet count of >30 × 109/L for all measurements 30 days or longer after splenectomy, with or without other treatment, excluding patients who qualify for CR. All patients who relapsed after initially achieving a normal platelet count were therefore considered to have a partial response. No response. The platelet count never increased to >30 × 109/L for any measurement 30 days or longer after splenectomy. Sustained response. A platelet count of >100 × 109/L for all measurements for at least 1 year or until last follow-up if followup lasted longer than 1 year.

Definition of hepatitis B-positive and ANA-positive

Patients were regarded as having chronic hepatitis B if the surface antigen was positive or if there was a recorded viral load on polymerase chain reaction on the National Health Laboratory Service system. Over the time period of the study, ANA was reported as positive if it was above the laboratory reference range.

Statistics

Microsoft Excel 2010 (Microsoft Corporation, USA) was used for database and data input. Statistical analyses were performed using STATA statistical software, version 12.0 (STATA Corporation, USA). Descriptive characteristics of the patients were analysed, and means (standard deviations) were used for normally distributed data and medians plus interquartile ranges (IQRs) for non-normally distributed data. Survival analysis was based on the Kaplan-Meier estimate and the logrank test was used for survival comparisons. To assess the association between variables and CR, the prevalence ratio (PR) was calculated (since the prevalence of the ‘CR’ was >10% and in this situation odds ratios (ORs) overestimate the magnitude of risk) and the p-value was calculated by logistic regression. Continuous and categorical variables were compared using the χ2 test, and when the expected frequencies in any cell of the contingency tables were <5 Fisher’s exact test was used. All p-values were considered significant at p<0.05. To compare means, if the data were normally distributed (tested by doing a Shapiro-Wilk test), a t-test was performed; if the data were non-normally distributed, a Wilcoxon-Mann-Whitney test was performed.

Results

Patient characteristics (Table 1)

The median age at splenectomy was 33 years (IQR 22 - 44). There was a female preponder-

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Table 1. Patient characteristics at diagnosis (N=73) Variables Age (yrs), median (range)

33 (16 - 70)

Gender, n (%) Male

17 (23)

Female

56 (77)

HIV status, n (%) Positive

12 (16)

Negative

46 (63)

Unknown

15 (21)

Hepatitis B status, n (%) Positive

5 (7)

Negative

31 (42)

Unknown

37 (51)

ANA, n (%) Positive

19 (26)

Negative

20 (27)

Unknown

34 (47)

Comorbidities, n (%) Diabetes

8 (11)

SLE

9 (12)

10 (14)

SLE = systemic lupus erythematosus; TB = tuberculosis.

ance with a ratio of 3:1; 56 patients (77%) were female. Twelve patients were HIV-positive (16%); in 15 the HIV status was unknown. Of the 36 patients for whom the hepatitis B status was known, 5 were positive (14%). Two patients were pregnant, and one patient underwent splenectomy while pregnant.

Medical treatment prior to splenectomy

Of the patients for whom details regarding treatment prior to splenectomy were available (n=66), 54 (82%) were steroid dependent and 12 (18%) were steroid resistant. All patients had received glucocorticoids at a dose of at least 1 mg/kg/d, and in 27 patients the dose had been 2 mg/kg/d. Prior to splenectomy, azathioprine was prescribed to 23 patients (33%) (Table 2).

HIV-positive population

Of the HIV-positive patients, 7 were female and 5 male and the median age was 36 years (IQR 27 - 40). The median CD4 count at diagnosis of ITP was 253 cells/µL (IQR 163 458); 7 (58%) patients had counts <300 cells/ µL, 2 had counts >700 cells/µL, and 1 patient had a count of 458 cells/µL. The CD4 count was unknown in 2 patients. cART was given to 11 patients prior to splenectomy (for ITP regardless of CD4

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Table 2. Treatments given and response type to glucocorticoids (N=66) n (%) Response to oral steroids Steroid dependent

54 (82)

Steroid resistant

12 (18)

Treatment Prednisone

66 (100)

Azathioprine

23 (33)

Polygam

6 (9)

IVI dexamethasone

5 (7)

Plasmapheresis

5 (7)

Cyclophosphamide

2 (3)

Dapsone

1 (1)

Danazol

1 (1)

IVI = intravenous infusion.

count) for a median duration of 12 months (range 2 - 60). All patients on cART were on a regimen comprising two nucleoside reverse transcriptase inhibitors (a combination of two of zidovudine, lamivudine and stavudine) and a non-nucleoside reverse transcriptase inhibitor (either nevirapine or efavirenz). Three patients were being treated with cART prior to developing ITP and the other 9 patients developed ITP and were subsequently put onto cART (n=7) or AZT monotherapy (n=2).

Operative information

Of the 69 patients for whom operative details were available, 26 patients (38%) had their splenectomy by open laparotomy and 43 (62%) by laparoscopy, with an increasing number of laparoscopic procedures performed in the later years. The median platelet count at splenectomy was 187 × 109/L (IQR 125 - 172). Patients were actively treated preoperatively with platelet transfusions (n=4), intravenous dexamethasone (n=4) and intravenous immunoglobulin (n=4) to raise the platelet count in the short term. The median time from presentation to splenectomy at our institution was 4.7 months (IQR 2.6 - 13) (HIV-negative and positive). In the HIV-positive population it was 3.2 months (IQR 2.1 - 5.9) (p=0.138). This short time to splenectomy is explained by the fact that many patients were referred after initially being managed at a secondarylevel hospital. The time from initial diagnosis could not be established in 15 patients. Median time to discharge was on the 3rd postoperative day (IQR 2 - 4 days); for HIVpositive patients it was day 3 (IQR 2 - 3 days; p=0.5). The intraoperative complication

Table 3. Operative information Type of splenectomy (N=69), n (%) Open laparotomy

26 (38)

Laparoscopic

43 (62)

Intraoperative complications (N=60*), n Mortality

dhesions (converted to open A splenectomy)

leeding (converted to open B splenectomy)

onversion to open C splenectomy, reason not found

Postoperative complications (N=60*), n Death

Intra-abdominal sepsis

Wound infection

Thrombosis

Drip site sepsis

Subacute small-bowel obstruction

*Data missing for 9 patients.

rate for splenectomy was 10% and included conversion to open splenectomy for bleeding (n=2), and intra-abdominal adhesions (n=3). There was no intraoperative mortality. There were 11 postoperative complications in 10 patients (16% all-cause complication rate). The most common postoperative complication was infection (Table 3). Two patients developed postoperative thrombosis: one patient presen ted 8 days after surgery with a pulmonary embolism, and the other developed thrombus in the mesenteric vein. Both patients had normal platelet counts at presentation with thrombosis. Operative bleeding in two patients was associated with surgical difficulties (damage to abdominal vessels) and was not spontaneous or secondary to usual surgical technique; in both, there were no further complications after conversion to open splenectomy. There was no statistically significant difference in postoperative complications according to method of splenectomy. The complication rate in the HIV-positive patients was non-significantly higher than in the HIV-negative patients (18% and 16%, respectively; p=0.59). There was one postoperative death at 10 weeks post surgery, giving a 90-day mortality rate of 1.38%. This patient was HIV-positive, had an uncomplicated splenectomy and was discharged on day 2 post operation. She

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presented again 10 weeks later in septic shock (with an unidentified organism) and required inotropic support and dialysis. Her platelet count remained <30 × 109/L and she died within 24 hours of admission. Of note, this patient had received the 23-valent pneumococcal vaccine as an inpatient the day before her surgery.

Response to splenectomy

Patients were followed up for a median period of 25 months from splenectomy (IQR 12 - 69). Among the patients for whom platelet counts were known for at least a month and could be included in the analysis (n=65), the CR rate was 83% (n=54); 11% (n=7) had a partial response and 6% (n=4) no response. Details for up to 1 year were known for a total of 55 patients, revealing that the sustained response rate was 80% (n=44). At 1 year there was no statistically significant difference between HIV-positive and negative patients’ platelet counts (p=0.69). The group of patients for whom HIV status was unknown had a 90% CR that was non-statistically different from those with known HIV status (p=0.46). Eleven patients did not have a CR. Of these, 7 had a partial response (the median platelet count at 1 year was 113 × 109/L, but response was defined as partial owing to fluctuation) and 4 had no response to splenectomy. All 11 patients were retreated with steroids, and 4 were treated with azathioprine. Of the 7 patients with a partial response, 6 later achieved platelet counts of >100 × 109/L and were weaned off all therapies.

Predictors of response

For an association between variables and CR, a PR was calculated (Table 4). Only one variable showed a statistically significant poorer response to splenectomy. This was steroid-resistant ITP (PR 0.62; p=0.003).

Morbidity and mortality

Seven patients (5 males and 2 females) died in the follow-up period. The total patient follow-up time was 3 710 months, with a mortality rate of 1.89/1 000 patient months (confidence interval (CI) 0.90 - 3.96). Six patients with recorded deaths were HIVnegative and one was HIV-positive. There was no statistically significant difference in mortality rate in the groups by gender (p=0.37) or HIV status (for the HIV-positive group 1.7 deaths/1 000 patient months and for the HIV-negative group 2.4 deaths/1 000 patient months; p=0.96). There was a statistically significant difference in mortality rate (p=0.001) between

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Table 4. Variables and rate of CR with calculated PRs and ORs N

CR n (%)

CI (for OR)

p-value

Male

12 (75)

0.88

0.5

0.11 - 2.76

0.44

Female

42 (85) 0.89

0.58

0.11 - 4.23

0.38

1.05

0.78

0.06 - 43.7

0.61

0.95

0.5

0.01 - 10.7

0.52

1.06

1.4

0.14 - 70.0

0.62

Variables Gender

HIV status Positive

9 (75)

Negative

36(84)

Positive

4(80)

Negative

22(76)

Positive

17 (89)

Negative

17(94)

Hepatitis B

ANA

Diabetes Yes

7(88)

45(83)

Positive

6(60)

Negative

48(87)

Yes

17(74)

30(90)

Discussion

TB 0.69

0.21

0.03 - 1.36

0.06

0.82

0.22

0.03 - 1.26

0.06

0.62

0.24

0.29 - 0.89

0.017

0.89

0.59

0.09 - 6.9

0.42

Azathioprine

Steroid resistant Yes

6(54)

46(87)

Yes

6 (75)

46(84)

SLE

TB = tuberculosis; SLE = systemic lupus erythematosus.

1.00

Survival

0.75

p=0.001

0.50

0.25

1.00 0.00 0

the group that had achieved CR following splenectomy (2 deaths; 0.87/1 000 patient months) and the group that had not had a CR (5 deaths; 13.6 /1 000 patient months) (Fig. 1). Four deaths may have been directly related to the splenectomy: 3 were secondary to sepsis (being asplenic may have contributed to excess mortality risk from sepsis) and 1 from a cerebrovascular accident which may have been attributable to rebound thrombocytosis (this patient’s platelet count was 1 214 × 109/L at the time of readmission). All four patients were on further immunosuppressive therapy (steroids or azathioprine), which may have contributed to their increased risk of sepsis. One death was related to the underlying disease (thrombocytopenia) and one unrelated and due to prostate cancer (Table 5). There was 100% mortality in the non-responders, with all four patients with no response to splenectomy dying in the follow-up period.

100

150

Analysis time (months) Non-complete response

Complete response

Fig. 1. Kaplan-Meier survival estimates by CR.

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In our analysis, CR was seen in 83% and was sustained in 80%, which is similar to that reported in the literature.[7,8,15] Of those who achieved partial response, with the addition of glucocorticoids and/or azathioprine 86% (n=6) later progressed to CR, which was maintained for the duration of follow-up. This is in keeping with other studies showing that a partial response is also consistent with a favourable long-term outcome.[7] In our experience, the CR rate to splenectomy (platelet count >100 × 109/L) and duration of response appear higher than that reported for rituximab and similar to that of the TPO agonists (with maintenance of treatment).[11,14] There was a 100% (n=4) mortality rate in the patients who showed no response following splenectomy; however, only one death was secondary to bleeding. Continued immunosuppression is likely to have contributed to their overall mortality. In the HIV-positive patients, the CD4 count at diagnosis of ITP demonstrated the typical bimodal distribution showing ITP early in HIV with CD4 counts >700 × 106/L, and in late disease with CD4 counts <300 × 106/L. In our small (n=12) HIV-positive cohort the treatment response was favourable and outcomes were not significantly different from the HIV-negative cohort. These observations need to be confirmed in a larger population, but they are in keeping with the only large-scale study looking at splenectomy in HIV-associated ITP, where the response rate to splenectomy was 92% and a favourable long-term (6-month response) outcome was seen in 82%.[6] The complications, morbidity and mortality asso-

RESEARCH

Table 5. Causes of mortality Gender

Age, years

Months post splenectomy

Cause of death

Male

Pneumococcal sepsis

Male

Prostate cancer*

Female

CVA (rebound thrombocytosis)

Female

2.5

Sepsis (pathogen unknown)

Female

Sepsis (ruptured appendix)*

Female

Intracerebral haemorrhage (platelet count <10 × 109/L)

Female

Unknown*

CVA = cerebrovascular accident. *Patients with no response to splenectomy.

ciated with splenectomy were not statistically different in the HIV-positive compared with HIV-negative cohorts. While the complication rate in our cohort was slightly higher than previously reported, this is difficult to interpret since other publications did not define what they considered to be ‘complications’, while we included minor complications such as drip site sepsis.[2] We speculate that the unfavourable response to splenectomy in patients with steroid-resistant disease is possibly due to greater megakaryocyte dysfunction, in addition to increased peripheral consumption. If proven, this could be an important finding as it may help to identify patients who would benefit from TPO agonists rather than pursuing measures that aim to decrease peripheral consumption.

Conclusion

The conclusions from this study are encouraging and support the view that because

of its effectiveness, splenectomy should remain the second-line treatment for ITP in most patients, including HIV-positive patients. We have also identified a patient population with a statistically significant poorer outcome to splenectomy, and further research is needed to distinguish patients whose ITP is primarily due to peripheral consumption (the majority of patients with ITP), and who would therefore be likely to benefit from immunosuppression (such as glucocorticoids and splenectomy), from those whose ITP reflects megakaryocyte dysfunction predominantly and who would benefit from TPO agonists. This may be the first step towards generating more patientspecific, and mechanism-driven, treatment strategies for the second-line treatment of ITP. References 1. Kashiwagi H, Tomiyama Y. Pathophysiology and management of primary immune thrombocytopenia. Int J Hematol 2013;98(1):2433. [http://dx.doi.org/10.1007/s12185-013-1370-4] 2. Neunert C, Lim W, Crowther M, Solberg L jr, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117(16):41904207. [http://dx.doi.org/10.1182/blood-2010-08-302984]

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3. Bettaieb A, Fromont P, Louache F, et al. Presence of crossreactive antibody between human immunodeficiency virus (HIV) and platelet glycoproteins in HIV-related immune thrombocytopenic purpura. Blood 1992;80(1):162-169. 4. Koefoed K, Ditzel HJ. Identification of talin head domain as an immunodominant epitope of the antiplatelet antibody response in patients with HIV-1-associated thrombocytopenia. Blood 2004;104(13):4054-4062. [http://dx.doi.org/10.1182/ blood-2004-01-0386] 5. Carbonara S, Fiorentino G, Serio G, et al. Response of severe HIV-associated thrombocytopenia to highly active antiretroviral therapy including protease inhibitors. J Infect 2001;42(4):251256. [http://dx.doi.org/10.1053/jinf.2001.0833] 6. Oksenhendler E, Bierling P, Chevret S, et al. Splenectomy is safe and effective in human immunodeficiency virus-related immune thrombocytopenia. Blood 1993;82(1):29-32. 7. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: A systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004;104(9):2623-2634. [http://dx.doi.org/10.1182/ blood-2004-03-1168] 8. Vianelli N, Galli M, de Vivo A, et al. Efficacy and safety of splenectomy in immune thrombocytopenic purpura: Long-term results of 402 cases. Haematologica 2005;90(1):72-77. 9. Mikhael J, Northridge K, Lindquist K, Kessler C, Deuson R, Danese M. Short-term and long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura patients: A systematic review. Am J Hematol 2009;84(11):743748. [http://dx.doi.org/10.1002/ajh.21501] 10. Davidson RN, Wall RA. Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 2001;7(12):657660. [http://dx.doi.org/10.1046/j.1198-743x.2001.00355.x] 11. Moulis G, Sailler L, Sommet A, et al. Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: An adjusted comparison of mortality and morbidity. Am J Hematol 2014;89(1):41-46. [http://dx.doi. org/10.1002/ajh.23580] 12. Medeot M, Zaja F, Vianelli N, et al. Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: Long-term follow-up results. Eur J Haematol 2008;81(3):165-169. [http://dx.doi.org/10.1111/j.1600-0609.2008.01100.x] 13. Arnold D, Dentali, F, Crowther, MA, et al. Systematic review: Efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007;146(1):2533. [http://dx.doi.org/10.7326/0003-4819-146-1-20070102000006] 14. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: Safety and efficacy. Br J Haematol 2013;161(3):411-423. [http://dx.doi.org/10.1111/bjh.12260] 15. Han JJ, Baek SK, Lee JJ, Kim S, Cho KS, Yoon H. Long-term outcomes of a 5-year follow up of patients with immune thrombocytopenic purpura after splenectomy. Korean J Hematol 2010;45(3):197-204. [http://dx.doi.org/10.5045/ kjh.2010.45.3.197]

Accepted 18 March 2015.

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DYNAFIL 50 mg: Each film-coated tablet contains sildenafil citrate equivalent to 50 mg sildenafil. Reg. No.: RSA S4 42/7.1.5/1071. NAM NS2 13/7.1.5/0086. DYNAFIL 100 mg: Each film-coated tablet contains sildenafil citrate equivalent to 100 mg sildenafil. Reg. No.: RSA S4 42/7.1.5/1072. NAM NS2 13/7.1.5/0087. For full prescribing information refer to the package insert approved by the Medicines Control Council, September 2012. * Department of Health Website. http://www.health.gov.za – Accessed 19/02/2015. DLC94/03/2015.

GUEST EDITORIAL

Practical solutions to the antibiotic resistance crisis Since 2012, when a rallying cry was sounded in SAMJ[1] to take the increasing threat of antibiotic resistance (ABR) seriously, a growing movement of healthcare and animal care practitioners partnered with Government to develop a national strategy framework to preserve antimicrobials for future generations and enact programmes to bring about change in prescribing. While taking into account the diverse burden of infection in South Africa (SA) (HIV, fungal infections, malaria, tuberculosis, and bacteria other than Mycobacterium tuberculosis), our national framework aligns itself squarely with the World Health Organization-led Global Action Plan (GAP) for antimicrobial resistance [2,3] in focusing on the greatest threat â&#x20AC;&#x201C; ABR in bacterial infections. Annually, approximately 700 000 people die from antibioticresistant infections worldwide; this number will rise to 10 million per year by 2050 if our current overuse and misuse of antibiotics is not curtailed.[4] Moreover, if antibiotics are no longer effective, every medical procedure that relies on antibiotics to prevent or treat infection will be affected, changing the face of modern medicine. This is not a futuristic fantasy; it is already happening in SA hospitals, leading to closure of wards, cancellation of operating lists, and patients being sent home without having been operated on because of colonisation with multidrug- or pandrug-resistant bacteria. Welcome to the post-antibiotic era! How this unfolds depends on how you, the reader, in conjunction with the international community, change your prescribing behaviour. Far from being a call to restrict antibiotics from being used, the strategy must be one of access to assuredquality antibiotics and the tools to prescribe them appropriately, rationally and prudently. The key is to ensure that antibiotics are only used for bacterial infections. One can no longer turn a blind eye to the horrific scale of antibiotic abuse with regards to viral upper respiratory tract infections in community practice, or to antibiotic abuse in non-infectious conditions or non-bacterial infections in hospitalised patients. This edition of CME focuses on the practical measures for appropriate antibiotic prescribing and what needs to be done to prevent infection in the first place, thereby negating their need. These interventions, along with heightened surveillance and reporting of resistance patterns and antibiotic use, form the battle strategy to defend the efficacy of antibiotics. The antibiotic pipeline for new classes of antibiotic has been dry for the past 28 years and with regard to antibiotics against Gram-negative infections it is not projected to yield a new antibiotic for the next 10 - 15 years. It therefore cannot be relied on to save the day. Furthermore, no antibiotic has lasted >16 years without resistance developing to it.[5] Hence, the emphasis is on preserving what we have through antibiotic stewardship (an intervention that ensures appropriate optimal antibiotic prescribing, without harming the patient). Stewardship lends itself to a multidisciplinary team approach, although it applies equally to individuals. Interventions that work at a community[6] and hospital[7] level are evidence based, but defining the right combination(s) depends in part on resources and national strategies. In a review by Mendelson,[8] there is a simple checklist that can be employed for stewardship at the prescriber level, and

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programmatic interventions to enable stewardship at the country level. Research and development to improve diagnostics for bacterial infection is a crucial arm of the intervention. Rollout of existing or development of new, point-of-care (POC) or near-POC rapid diagnostic tests is required to reduce diagnostic uncertainty, which often fuels poor prescribing practice. Tests that link bacterial identification to the resistance profile of the organism would provide the most useful information. Boyles and Wasserman[9] outline a logical approach to the use of diagnostics for bacterial infection, and highlight new advances that are set to provide crucial, timeous information to reduce inappropriate antibiotic use. Unless antibiotics are prescribed optimally, the chance of killing the bacteria or ensuring a stasis effect to enhance immunological clearance is lost. Optimising the antibiotic dose is fundamental to success, and the critically ill patient in an intensive care unit poses the greatest challenge in this regard. Richards et al.[10] explore the different facets of critical illness that effect antibiotic dosing and propose a strategy for increased dosing in this high-risk population. How many prescribers will know about or have access to this guest editorial or CME series? How do we disseminate information around antibiotic stewardship more effectively and make use of social media in particular? Goff and Van den Bergh[11] write about the power of Twitter in accessing, educating and communicating with regard to ABR. One is never too old to learn! Infection prevention and antibiotic stewardship go hand in hand as strategies to reduce resistance. Preventing infection negates the need for antibiotics, and hence diminishes use. Antibiotics have long been used to plug our deficiencies in tackling the primary drivers of infection, i.e. social determinants, such as lack of access to clean water and sanitation. Brink and Richards[12] remind us of the power of vaccination in preventing bacterial infection, emphasising the evidence-based reduction in Streptococcus pneumoniae resistance after the introduction of pneumococcal conjugate vaccine, and the potential benefit of increasing influenza vaccine coverage to reduce prescribing for secondary bacterial infection and misdiagnosed viral-induced fevers. Infection prevention to reduce transmission of bacteria in the workplace is equally important, as Whitelaw[13] exemplifies in his evidence-based article. The lack of ability to perform hand hygiene by a large contingent of the SA healthcare workforce is negligent and confers a direct threat to patient safety. Despite the enormous threat we face, the solutions to ensuring that antibiotics are prescribed appropriately, infections are prevented and antibiotic abuse is curtailed are simple and can be easily and rapidly applied. This CME edition is intended to give you the tools to become antibiotic stewardship and infection prevention champions. Will you take up the challenge? Marc Mendelson Guest editor marc.mendelson@uct.ac.za

May 2015, Vol. 105, No. 5

GUEST EDITORIAL

1. Mendelson M, Whitelaw A, Nicol M, Brink A. Wake up South Africa! The antibiotic ‘horse’ has bolted. S Afr Med J 2012;102(7):607-608. 2. World Health Organization. Draft Global Action Plan for antimicrobial resistance. http://apps.who.int/ gb/ebwha/pdf_files/EB136/B136_20-en.pdf (accessed 13 March 2015). 3. Mendelson M, Matsoso MP. The World Health Organization Global Action Plan for antimicrobial resistance. S Afr Med J 2015;105(5):325. [http://dx.doi.org/10.7196/SAMJ.9644] 4. Review on antimicrobial resistance. December 2014. http://amr-review.org (accessed 2 January 2015). 5. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http:// www.cdc.gov/durgresistnace/threat-report-2013/pdf/ar-threats-2013-508.pdf (accessed 3 March 2015). 6. Arnold SR, Straus SE. Interventions to improve antibiotic prescribing practices in ambulatory care. Cochrane Database Syst Rev 2005;(4):CD003539. http://www.ncbi.nlm.nih.gov/pubmed/16235325 (accessed 7 April 2015). 7. Davey P, Brown E, Charani E, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2013;(4):CD003543. 8. Mendelson M. Role of antibiotic stewardship in extending the age of modern medicine. S Afr Med J 2015;105(5):414-418. [http://dx.doi.org/10.7196/SAMJ.9635]

9. Boyles TH, Wasserman S. Diagnosis of bacterial infection. S Afr Med J 2015;105(5):419. [http://dx.doi. org/10.7196/SAMJ.9647] 10. Richards GA, Joubert IA, Brink AJ. Optimising the administration of antibiotics in critically ill patients. S Afr Med J 2015;105(5):419. [http://dx.doi.org/10.7196/SAMJ.9649] 11. Goff DA, Van den Bergh D. Twitter: A tool to improve healthcare professionals’ awareness of antimicrobial resistance and antimicrobial stewardship. S Afr Med J 2015;105(5):420. [http://dx.doi.org/10.7196/ SAMJ.9648] 12. Brink AJ, Richards GA. Use of vaccines as a key antimicrobial stewardship strategy. S Afr Med J 2015;105(5):421. [http://dx.doi.org/10.7196/SAMJ.9651] 13. Whitelaw AC. Role of infection control in combating antimicrobial resistance. S Afr Med J 2015;105(5):421. [http://dx.doi.org/10.7196/SAMJ.9650]

S Afr Med J 2015;105(5):413. DOI:10.7196/SAMJ.9642

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REVIEW

Role of antibiotic stewardship in extending the age of modern medicine M Mendelson, BSc, PhD (Cantab), MB BS, FRCP, DTM&H Division of Infectious Diseases and HIV Medicine, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: M Mendelson (marc.mendelson@uct.ac.za)

Antibiotic resistance is threatening modern medicine. Overuse and misuse of antibiotics is driving resistance to such an extent that we have entered the post-antibiotic era, where some multidrug- and pandrug-resistant bacterial infections are no longer treatable. If the situation is not reversed, 10 million people will die annually of drug-resistant infections by 2050. More than just a question of mortality, such infections are causing the closure of wards, cancellation of operations, and interference with other common medical procedures that rely on antibiotics for their success. The response to this crisis requires co-ordinated international action with increased surveillance of bacterial resistance, infection prevention, and antibiotic stewardship, i.e. access to affordable, quality-assured antibiotics prescribed appropriately. This review describes antibiotic stewardship at the individual patient and programmatic level, which must be adopted by every prescriber if we are to preserve modern medicine for future generations. S Afr Med J 2015;105(5):414-418. DOI:10.7196/SAMJ.9635

Antibiotic overuse and misuse drives resistance

A common misconception suggests that antibiotic resistance (ABR) is a result of the introduction of antibiotics from the 1940s onwards. ABR is, however, an ancient phenomenon; bacterial resistance genes have been identified in ice samples dating back 30 000 years.[1] Naturally acquired bacterial resistance genes are propagated by the survival advantage they confer on bacteria in response to attack from naturally occurring antibacterial proteins produced by other bacteria and fungi. Resistance mechanisms may also be acquired through horizontal gene transfer of mobile genetic elements on plasmids (circular pieces of extrachromosomal DNA) that carry the resistance gene(s) between bacteria.[2] A bacterium that possesses a way of resisting an antibiotic attack has a survival advantage over bacteria that do not. In the presence of an antibiotic to which that bacterium is resistant, the resistant bacterium will be selected out in favour of bacteria that are sensitive to the antibiotic. Hence, Darwinian natural selection is being played out. The antibiotics first discovered by Fleming did not create ABR – their use has provided a survival advantage to resistant bacteria. It therefore follows that the more antibiotics one uses, the more resistance will develop. This paradox threatens modern medicine, which relies so intimately on antibiotics for its successes. Estimates suggest that antibiotics have resulted in an additional 20 years of life expectancy.[3] The use of antibiotics to prevent surgical site infection enables safe surgical procedures that would otherwise carry significant morbidity and mortality.[4] Antibiotics form an integral part of the management of high-risk patients, such as the critically ill in intensive care units, those who are immunosuppressed as a result of transplantation, chemotherapy or HIV, and those with a broad spectrum of bacterial infection – from sepsis to septic shock. For every hour a person with septic shock is not being treated with an antibiotic to which the bacteria are sensitive, mortality increases by 7.8%.[5] Mortality from antibiotic-resistant compared with antibiotic-sensitive infections is increased, as is morbidity and length of hospital stay.[6] Furthermore, resistance comes with heavy financial costs to healthcare systems;

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second- and third-line antibiotics are more expensive.[7] Therefore, to limit resistance we face a critical balance between the need to use antibiotics as life-saving medicines and the need to ensure their appropriate use. We are currently in a state of crisis. Overuse and misuse of antibiotics over the past 70 years has propelled us into a postantibiotic era. Untreatable, pandrug-resistant bacterial infections are increasingly common,[8,9] and colonisation or infection with multidrug-resistant (MDR) bacteria has changed the risk profile of patients to such an extent that medical and surgical procedures may no longer be considered.[10] We have engendered this global disaster by disregarding the basic tenet of antibiotic prescribing, i.e. ‘access not excess’, and by forgetting that, ecologically, antibiotics are a common pooled resource whose use, and exclusion of use through resistance, affects the global population rather than merely our patients or ourselves. Also, individuals and populations travel, and with them resistant bacteria such as New Delhi metallobetalactamase-1(NDM-1)[11] or Klebsiella pneumoniae carbapenemase (kpc)[12] in Gram-negative bacteria, which has ensured the global spread of MDR bacteria to new, susceptible populations. People in low- and middleincome countries (LMICs), where healthcare systems are already overstretched owing to the high burden of infection, are at an even greater disadvantage than those in high-income countries (HICs).

Global response to antibiotic resistance

An international response is required to answer this crisis. The World Health Organization (WHO), whose previous calls for action went largely unheeded,[13,14] has developed a draft global action plan (GAP) as a result of wide stakeholder consultation that will be presented at the 68th World Health Assembly in Geneva, Switzerland in May 2015 for adoption.[15] GAP mandates member states to produce national strategic plans to combat antimicrobial resistance (AMR), with specific emphasis on antibacterial resistance.[16,17] Simply put, there are three fundamental pillars of any strategy that must be strengthened to combat ABR. Firstly, through strengthened surveillance and reporting, we need to learn what the resistance profile of the bacteria in our local environment (community and healthcare settings) is to enable

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appropriate choice of an antibiotic that will be active against a given infection. Secondly, when a bacterium that requires treatment is identified or an empiric antibiotic(s) is needed before its identification, we must optimise the use of that antibiotic to maximise its action (antibiotic stewardship (ABS)). Lastly, we need to pre vent infection before it occurs by attending to social determinants that drive infectious diseases, such as water supply and sanitation, and increase access to and coverage with vaccines. Rigorous infection control practice in healthcare settings to prevent transmission of resistant bacteria from patient to patient must be adopted, chief among which is rigorous hand hygiene. Infection prevention as it relates to ABR is comprehensively reviewed in this CME series by Brink[18] and Whitelaw.[19] The required response is as pertinent to animal and agricultural sectors as it is to human health. As an estimated 80% of all antibiotic use is in animals[20] and its association with acquisition of resistant bacteria by humans is becoming increasingly clear,[21] we disregard the impact of antibiotic use in the animal sector at our peril. However, for the purposes of this review, I concentrate on the essential elements of ABS as it relates to bacterial infections other than tuberculosis in humans.

Antibiotic stewardship at the individual patient level

At an individual patient level, a single fundamental question needs to be asked before any antibiotic is prescribed: ‘Does this patient have a bacterial infection that requires an antibiotic?’ (Fig. 1.) While particularly pertinent to primary care prescribers and the continued unnecessary use of antibiotics for viral upper respiratory tract infections (URTIs), it applies equally to febrile patients admitted to healthcare institutions at all levels. The identification of intensive care patients in the public and private sectors in South Africa (SA) who were on up to 10 different antibiotics concurrently, testifies to this and the need to realise that collective action is needed.[22] Although simpler for patients with a clear source of infection, the question of whether a patient has a bacterial infection becomes more complex when related to an undifferentiated fever, i.e. one that lacks a clear site of origin. Fear of missing a bacterial infection is a strong motivator for prescribing antibiotics,[23] whereas having access to diagnostic tests, ideally those at point-ofcare (POC) to help differentiate the cause of fever, increases appropriate antibiotic use. [24,25] Access to a POC malaria rapid diagnostic test in Zambia led to a four-fold reduction in inappropriate antimalarial prescribing, and

a five-fold increase in the appropriate use of antibiotics for pneumonia.[25] Furthermore, when diagnostic and resistance information is provided in a single test, not only may a diagnosis be established, but the time to appropriate antibiotic use reduced. The automated real-time nucleic acid amplification system Xpert MTB/RIF, which can confirm the presence of tuberculosis and its sensitivity to rifampicin within 2 hours, is one such example.[26] Similarly, rapid POC or close to POC non-culture-based tests for antibioticresistant bacteria other than Mycobacterium tuberculosis are urgently needed, particularly in LMICs with poor access to assured quality diagnostic services. When the source of infection is clear, but the microbial aetiology is not, biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) may be useful tools for specific infections. Both CRP[27,28] and PCT[29,30] have demonstrated utility in differentiating bacterial from viral acute respiratory infection (ARI) in developed countries, and for PCT its use has been estimated to confer substantial economic

gains (USD1.6 billion (ZAR18.8 billion) savings if used across the US health sector) in HICs.[31] In a high tuberculosis-prevalence country such as SA, the utility of CRP and PCT is less clear for ARI, as both are increased in tuberculosis. Furthermore, in a resourcechallenged healthcare setting, PCT, which currently costs in excess of ZAR300 per test, is costly, particularly when used incorrectly.[32] Once the decision has been made to treat with an antibiotic, it is imperative that, whenever possible, adequate specimens are sent to the laboratory to enable identification of the bacteria causing infection and, critically, its sensitivity profile to antibiotics (the antibiogram) before the antibiotic is administered. The likelihood of adverse effects of broad-spectrum antibiotics, whose use is commonly indicated at the start of treatment, is greater than those of directed, narrow-spectrum antibiotics that can be used once sensitivities are known. An antibiogram is a prerequisite for safe de-escalation from a broad- to narrow-spectrum antibiotic. Without it, the prescriber runs the risk of

Is there evidence of bacterial infection? · Fever · Specific organ dysfunction (e.g. dysuria, meningism, productive cough) · Leucocytosis with neutrophilia and left shift, toxic granulation (± biomarkers suggestive of bacterial infection)

Yes

Unsure

Unstable

Is there a clear site of infection/disease?

Stable

Withhold antibiotic Investigate for potential focus of infection

Yes

No antibiotics Symptomatic treatment and look for another cause

Send targeted specimen

Blood culture

Rapid initiation of empiric antibiotics Tailor antibiotic choice to the most likely organism, e.g.: Urinary tract - Escherichia coli, Klebsiella pneumoniae Meninges - Neisseria meningitidis, Streptococcus pneumoniae Skin - Staphylococcus aureus Respiratory tract - S. pneumoniae

Increased risk of resistance Consult hospital guideline

Healthcare associated

Community acquired

What is the narrowest spectrum antibiotic that will cover the most likely causes?

Fig. 1. Algorithm to determine whether a patient has a bacterial infection.

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using a resistant or partially active antibiotic, which may negatively affect the patient’s treatment. Whenever possible, a specimen from the probable site of infection should be sent to the laboratory. If no focus is evident, one or more correctly taken blood cultures are required (Fig. 1).[33] For blood cultures, the volume of blood inoculated is critical in determining yield. In an unselected cohort of adult patients requiring blood culture in the Emergency Department at Groote Schuur Hospital, Cape Town, all cultures were negative if <2 mL of blood were inoculated. The yield doubled if 10 - 12 mL were inoculated compared with 2 - 8 mL (T Boyles – personal communication). Once appropriate cultures have been sent, considering the checklist presented in Box 1 can optimise prescribing. The empiric choice of an antibiotic is determined by the probable identity of the infecting organism and the likelihood of it carrying a resistance gene. For example, Gram-negative Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) commonly cause urinary tract infections (UTIs); therefore, an antibiotic with a spectrum of activity against Gram-negative bacteria is advised. Resistance to commonly used Gram-negative antibiotics for UTI in community-acquired infections in SA is generally still low, but does vary geographically. Therefore, an antibiotic such as an aminoglycoside or ciprofloxacin would be an acceptable empiric choice. However, in SA, hospital-acquired UTI due to Enterobacteriaceae is characterised by high levels of extendedspectrum beta-lactamase production, rendering many resistant to firstline antibiotics, and forcing the use of second-line, broader-spectrum antibiotics.

The optimal dose of an antibiotic depends on a number of factors, including the pharmacodynamic and pharmacokinetic properties associated with individual antibiotics, the patient’s body weight, renal function, and, less commonly, hepatic function. Dosing of many antibiotics is weight dependent, e.g. vancomycin (Box 2), whose dosing frequency must be guided by therapeutic drug monitoring. A lack of attention to weight-based dosing and renally determined dosing frequency represents a common antibiotic prescribing pitfall. Pharmacokinetics play an especially important role in the critically ill patient in whom the volume of distribution may increase, augmented renal clearance may be present, and hypoalbuminaemia may alter the ratio of bound v. unbound antibiotic. Hence, dose must be carefully considered to optimise the effect of the antibiotic, particularly in those who are critically ill. For many prescribers, determining the duration of an antibiotic course is a matter of what is familiar or easy, and bears little or no relation to trial evidence or national guidelines. Therefore, many antibiotic courses are prescribed for ≥1 week. For example, experience from our ABS programme at Groote Schuur Hospital indicated that the vast majority of patients in the Emergency Department who were prescribed ceftriaxone received a prescription for an antibiotic for 2 weeks, irrespective of the indication (M Mendelson – unpublished observations). Unfortunately, a strong evidence base for antibiotic duration is often lacking, meaning that decisions are based not on randomised controlled trials, but on small observational studies or expert opinion. In SA, the Essential Drugs List (EDL) and Structured Treatment Guidelines (STGs)[34]

Box 1. Checklist for optimal antibiotic prescribing 1. Drug – which is the narrowest spectrum antibiotic that I can use to treat this bacterial infection? 2. Dose – many antibiotics require weight-based dosing and their dosing depends on renal and/or hepatic function 3. Dose frequency – dependent on the half-life of the drug and whether the action of the antibiotic depends on the time above the MIC or the area under the concentration/time curve. Calculation of the dosing frequency may require therapeutic drug monitoring, such as for vancomycin or aminoglycosides 4. Duration – should be dictated by evidence from randomised controlled trials whenever possible. Expert opinion from national and international guidelines should be consulted where evidence is weak 5. Route – most antibiotics have good oral bioavailability, but some infections will require intravenous therapy either for the whole or part of the course 6. D e-escalation – applies to the spectrum of antibiotic use and route of administration. All attempts to convert early from parenteral to oral use should be made MIC = minimum inhibitory concentration.

Box 2. Vancomycin dosing All patients should be weighed and GFR estimated All patients should receive a loading dose of 25 - 30 mg/kg All subsequent doses should be 10 - 15 mg/kg (unless inadequate trough levels achieved) Dosing interval and measurement of trough concentrations depends on eGFR eGFR (mL/min)

Dosing interval (hours)

Measurement of trough concentrations

>80

Before 3rd dose

50 - 79

Before 3rd dose

55 - 49

Before 2nd dose

25 - 34

Before 2nd dose

<25, haemodialysis or chronic ambulatory peritoneal dialysis

When trough level <15 mg/mL

3 days after loading dose

Aim for trough concentration of 10 - 20 mg/mL, except for osteitis or endocarditis, or if MIC >1 mg/mL, when trough should be 15 - 20 mg/mL If trough is too low – increase the dose If trough is too high – increase the dosing interval eGFR = estimated glomerular filtration rate.

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Box 3. Criteria for switching from parenteral to oral antibiotic route[61,62] 1. No indication requiring long-term parenteral antibiotic use: endocarditis, meningitis, central nervous system infection, osteomyelitis, prosthetic material infection, Staphylococcus aureus bacteraemia, undrained or undrainable abscess and neutropenic fever 2. Patient is able to take oral medications and lacks indications of potential malabsorption 3. An alternative oral antibiotic is available 4. Temperature <38°C for ≥24 hours 5. Clinically improving or remaining stable

may guide prescribers. The SA Antibiotic Stewardship Programme (SAASP) guidelines for antibiotic prescribing in adults,[35] which is aligned to the EDL and STGs, provide an algorithmic approach to prescribing and further information on treatment duration. It is now available as the ‘SAASP’ App across platforms. The route of administration of an antibiotic depends on the site of infection, how rapidly high drug levels need to be achieved, and ability of a patient to absorb an oral antibiotic. Some infections, such as bacterial meningitis, osteomyelitis or endocarditis, require high levels of antibiotic to be delivered to the site of infection, and necessitate parenteral antibiotics for all or the majority of the course. De-escalation to an oral antibiotic is a key principle of stewardship, as this obviates the need for vascular access and enables removal of a peripheral or central line. This reduces the risk of central line-associated bloodstream infections (CLABSI) or its peripheral counterpart. Prevention of CLABSI reduces morbidity, length of hospital stay and, ultimately, mortality.[36] Box 3 gives guidance for safe de-escalation from the parenteral to oral route.

Antibiotic stewardship at the programmatic level

At a programmatic level, interventions to reduce antibiotic prescribing and improve microbial outcome tend to be either restrictive (limit how a prescriber prescribes) or persuasive (advise the prescriber or give feedback about how they prescribed). Approximately 80% of antibiotics used in humans are prescribed in primary care.[37,38] The success of interventions at the community level depends in part on the barriers to change in that particular community and differs in countries and across borders. A meta-analysis of 39 studies of interventions to improve antibiotic prescribing in ambulatory patients concluded that multi faceted interventions are most effective at achieving overall reduction in use, while printed educational material or feedback and audit were of little value.[39] Interactive educational sessions outperformed the didactic approach, and collaborative educational meetings between

Fig. 2. South African Antibiotic Stewardship Programme prescription chart. different groups involved in prescribing, i.e. a multidisciplinary community stewardship approach, showed promising reductions in antibiotic prescribing.[40] Combining teaching of primary care clinicians in enhanced consulting skills and the introduction of POC CRP into their practices, had an additive effect on appropriate, safe antibiotic prescribing, which was cost-effective.[28,41] The use of delayed prescriptions effectively reduced antibiotic use without increasing mortality.[42-44] All of these interventions are potentially transferable to LMICs, including SA. Successful interventions to reduce prescribing in hospitalised patients have also been the subject of a Cochrane review.[45] Poor study designs in many investigations limited the number of studies included in the analysis to 20%. There were no direct comparative studies between persuasive and restrictive interventions, but a metaanalysis of interrupted time series studies allowed comparison. Interestingly, restrictive interventions (compulsory order forms, expert approval, removal by restriction and

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review and change) were more effective than persuasive (dissemination of educational material, reminders, audit and feedback, and educational outreach) interventions in the first 6 months; yet, there was no difference in the longer term at 12 and 24 months. Whether combinations of intervention type would have a sustained effect needs to be investigated. It is notable that none of the studies included in the Cochrane review was from Africa. ABS has only recently been formally introduced in SA as a change mechanism, led by SAASP since 2012. One study published to date has adopted two persuasive interventions to augment restrictive practices that were already in place at a central hospital in Cape Town;[32] ABS ward rounds and a dedicated antibiotic prescription chart were included in a trial in two general medical wards for a 12-month period, using the previous intervention-free year as comparator. Weekly multidisciplinary ward rounds involved the prescribing physicians, an infectious diseases specialist, microbiologist, infection control officer, and pharmacist. The charts and case

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reports of each patient on a single ward, alternating weekly, were reviewed. Antibiotic use was reduced by 19.6% without an increase in inpatient mortality or 30-day readmission rate. Although not a primary objective of the study, the intervention resulted in a 35% reduction in antibiotic budget. This type of multidisciplinary team is unlikely to be reproducible across SA and most developing country settings; however, a prescriber and pharmacist can form the nucleus of any such stewardship team. A dedicated antibiotic prescription chart in the study by Boyles et al.[32] was designed to focus the prescriber’s attention on the indication for prescribing antibiotics, whether the infection was community or hospital acquired, and provided strong messaging to trigger appropriate sample(s) to be sent for culture (Fig. 2). Antibiotic prescribing was divided into infection episodes – if a patient developed a second or third bacterial infection in hospital, the prescriber would have to go through the same process again, and the antibiotics used to treat that infection could immediately be identified for review and audit. The use of choice architecture, which describes the way in which decisions can be influenced by how choices are presented,[46] was recently used to improve anti-infective prescribing in a comparative study from a large UK teaching hospital.[47] Through its national strategic plan for AMR,[48] SA has national core standards for antimicrobial stewardship (and for infection prevention control) that will be monitored by the Office of Health Standards and Compliance. These standards include the requirement for stewardship committees and teams in all our hospitals and at district level. A clear roadmap for change is being implemented.

Barriers to antibiotic stewardship

Behaviour modification is a major factor in rectifying poor prescribing practice. Inappropriate prescribing is driven by a complex set of prescriber and patient behaviours. At the most basic level, community prescribing is often influenced by prescribers who perceive that their patients will be dissatisfied should they not receive an antibiotic. This is especially evident in how doctors perceive parental expectations.[49] Patient expectations of receiving an antibiotic, particularly for ARI, is often high, and these have a significant influence on prescribing, even when the prescriber believes that an antibiotic is unnecessary.[50,51] Raising public awareness to the risks posed and drivers of ABR is an important intervention. Yet, not all campaigns have been successful;[52] national campaigns in different European countries have had mixed results, with those in Germany, Spain, Greece and the UK being unsuccessful in leading to important reductions in community antibiotic use or knowledge about appropriate use, as opposed to those in Sweden, Norway, France and Belgium. Successful national campaigns are characterised by a multifaceted nature and repetition over several years. Unfortunately, there seems to be no simple relationship between knowledge and appropriate use; in a face-to-face household survey of 10 981 randomly selected UK adults in 2003, multivariate analysis found that better knowledge in women was associated with being more likely to give an antibiotic to someone else for whom it was not prescribed.[53] This endorses the fact that behaviour change is complex and more than merely about providing information. In terms of creating public behavioural change, despite media campaigns being more successful at disseminating information, medical professionals are more successful in changing patient behaviour.[54] Potential behavioural changes in community prescribers include improving their belief in the consequences of overprescribing and addressing their concerns around the consequences of not prescribing. Encouraging patients to adopt self-care for symptomatic relief of URTIs by consulting pharmacists instead of requesting

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antibiotics from doctors and greater mentoring of patients on their antibiotic use have the potential for creating change in antibiotic use at the community level. To enable good stewardship, prescribers must have access to affordable antibiotics of assured quality. Producing a new antibiotic pipeline is not in itself the answer to the ABR problem, as resistance has developed within 16 years of every antibiotic introduced to date;[55] penicillin resistance was first identified 3 years before the antibiotic was introduced. However, lack of access to antibiotics is a major cause of mortality, mainly in children <5 years of age, of whom more currently die of pneumonia owing to a lack of available treatment than of ABR. Substandard and falsified antimicrobials have undermined prescribing in these countries, as has the lack of affordable medicines, whereas the use of generic medicines has successfully driven down cost.[56] Generics produced locally to rigorous good manufacturing practice standards may enhance access to quality-assured antibiotics and thus save lives.[57-59] A strong medicine regulatory authority is a prerequisite to ensure the success of a generic antimicrobial policy.

Conclusion

The development of ABR cannot be prevented, but the extent to which it impacts on modern medicine can be altered through access to assured-quality, affordable antibiotics used in an appropriate manner. The onus is on every prescriber to become an antibiotic steward, ensuring that an antibiotic is only prescribed for a bacterial infection that requires treatment, and that the use of that antibiotic is optimised at an individual patient level. Programmatically, ABS must be developed as part of a national plan along with enhanced surveillance, reporting and infection prevention initiatives. Behavioural change programmes aimed at supporting prescribers and changing patient expectations are critical interventions, as is the need for increased access to diagnostic services and the development of POC or near-POC rapid diagnostics that couple pathogen and resistance information. If we are to alter the course of history, and prevent a situation where 10 million people die annually from antibiotic-resistant infections by 2050,[60] prescribers and public alike need to join the international community in change to preserve this precious resource. References 1. D’Costa VM, King CE, Kalan L, et al. Antibiotic resistance is ancient. Nature 2011;477(7365):457-461. [http://dx.doi.org/10.1038/nature10388] 2. Barlow M. What antimicrobial resistance has taught us about horizontal gene transfer. Methods Mol Biol 2009;532:397-411. [http://dx.doi.org/10.1007/978-1-60327-853-9_23] 3. United Kingdom Government. Infections and the rise of antimicrobial resistance. Annual Report of the Chief Medical Officer 2011;2. https://www.gov.uk/government/uploads/system/uploads/attachment_ data/file/138331/CMO_Annual_Report_Volume_2_2011.pdf (accessed 2 February 2015). 4. Awad SS. Adherence to surgical care improvement project measures and post-operative surgical site infections. Surg Infect (Larchmt) 2012;13(4):234-237. [http://dx.doi.org/ 10.1089/sur.2012.131] 5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34(6):1589-1596. 6. Kayange M, Kamugisha E, Mwizamholya DL, Jeremiah S, Mshana SE. Predictors of positive blood culture and deaths among neonates with suspected neonatal sepsis in a tertiary hospital, MwanzaTanzania. BMC Pediatr 2010;10:39. [http://dx.doi.org/10.1186/1471-2431-10-39] 7. World Health Organization (WHO). WHO Policy Perspective 2005, adapted from WHO Model Formulary, WHO Clinical Guidelines and Management Sciences for Health’s 2004 International Drug Price Indicator Guide. http://www.who.int/management/anmicrobialresistance.pdf (accessed 2 March 2015). 8. Walsh TR, Toleman MA. The emergence of pan-resistant Gram-negative pathogens merits a rapid global political resonse. J Antimicrob Chemother 2012;67:1-3. [http://dx.doi.org/10.1093/jac/dkr378] 9. Migliori GB, De Iaco G, Besozzi G, Centis R, Cirillo DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill 2007;12(5):E070517.1. 10. Smith R, Coast J. The true cost of antimicrobial resistance. BMJ 2013;346:f1493. [http://dx.doi. org/10.1136/bmj.f1493] 11. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: A molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10(9):597-602. [http://dx.doi.org/10.1016/S1473-3099(10)70143-2] 12. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009;9(4):228-236. [http://dx.doi.org/10.1016/S1473-3099(09)70054-4] 13. World Health Assembly. World Health Assembly Resolution WHA51.17. Emerging and other communicable diseases: Antimicrobial resistance. http://apps.who.int/medicinedocs/documents/s16334e/ s16334e.pdf (accessed 2 February 2015). 14. World Health Assembly. World Health Assembly Resolution WHA58.27. Improving the containment of antimicrobial resistance. http://www.searo.who.int/entity/medicines/topics/wha_58_27.pdf (accessed 2 February 2015).

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15. World Health Organization. Draft Global Action Plan for Antimicrobial Resistance. http://apps.who. int/gb/ebwha/pdf_files/EB136/B136_20-en.pdf (accessed 13 March 2015). 16. Mendelson M, Matsoso MP. A global call for action to combat antimicrobial resistance: Can we get it right this time? S Afr Med J 2014;104(7):478-479. [http://dx.doi.org/10.7196/samj.8534] 17. Mendelson M, Matsoso MP. The World Health Organization Global Action Plan for antimicrobial resistance. S Afr Med J 2015;105(5):325. [http://dx.doi.org/10.7196/SAMJ.9644] 18. Brink AJ, Richards GA. Use of vaccines as a key antimicrobial stewardship strategy. S Afr Med J 2015;105(5):421. [http://dx.doi.org/10.7196/SAMJ.9651] 19. Whitelaw AC. Role of infection control in combating antibiotic resistance. S Afr Med J 2015;105(5):421. [http://dx.doi.org/10.7196/SAMJ.9650] 20. United States Food and Drug Administration. Summary report on antimicrobials sold or distributed for use in food-producing animals. Washington, DC: Department of Health and Human Services, 2009. 21. Rinsky JL, Nadimpalli M, Wing S, et al. Livestock-associated methicillin and multidrug resistant Staphylococcus aureus is present among industrial, not antibiotic-free livestock operation workers in North Carolina. PLoS One 2013;8(7):e67641. [http://dx.doi.org/10.1371/journal.pone.0067641] 22. Paruk F, Richards G, Scribante J, Bhagwanjee S, Mer M, Perrie H. Antibiotic prescription practices and their relationship to outcome in South Africa: Findings of the prevalence of infection in South African intensive care units (PISA) study. S Afr Med J 2012;102(7):613-616. 23. Kotwani A, Wattal C, Katewa S, Joshi PC, Holloway K. Antibiotic use in the community: What factors influence primary care physicians to prescribe antibiotics in Delhi, India. Family Practice 2010:1-7. [http://dx.doi.org/10.1093/fampra/cmq059] 24. Shakely D, Elfving K, Aydin-Schmidt B, et al. The usefulness of rapid diagnostic tests in the new context of low malaria transmission in Zanzibar. PLoS One 2013;8(9):e72912. [http://dx.doi.org/10.1371/ journal.pone.0072912] 25. Yeboah-Antwi K, Pilangana P, MacLeod WB, et al. Community case management of fever due to malaria and pneumonia in children under five in Zambia: A cluster randomized controlled trial. PLoS Medicine 2010;7(9):e1000340. [http://dx.doi.org/10.1371/journal.pmed.1000340] 26. Denkinger C, Kik S, Pai M. Robust, reliable and resilient: Designing molecular tuberculosis tests for microscopy centres in developing countries. Expert Rev Mol Diag 2013;13(8):763-767. 27. Huang Y1, Chen R, Wu T, Wei X, Guo A. Association between point-of-care CRP testing and antibiotic prescribing in respiratory tract infections: A systematic review and meta-analysis of primary care studies. Br J Gen Pract 2013;63(616):e787-94. [http://dx.doi.org/10.3399/bjgp13X674477] 28. Cals JWL, Ament AJHA, Hood K, et al. C-reactive protein point of care testing and physician communication skills training for lower respiratory tract infections in general practice: Economic evaluation of a cluster randomized trial. J Eval Clin Pract 2011;17(6):1059-1069. 29. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch Intern Med 2008;168(18):2000-2007. [http:// dx.doi.org/10.1001/archinte.168.18.2000] 30. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections. The proHOSP randomized controlled trial. JAMA 2009;302(10):1059-1066. 31. Schuetz P, Balk R, Briel M, et al. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: A US health system perspective. Clin Chem Lab Med 2015;53(4):583-592. [http://dx.doi.org/10.1515/cclm-2014-1015] 32. Boyles TH, Whitelaw A, Bamford C, et al. Antibiotic stewardship ward rounds and a dedicated prescription chart reduce antibiotic consumption and pharmacy costs without affecting inpatient mortality or re-admission rates. PLoS One 2013;8(12):e79747. [http://dx.doi.org/10.1371/journal. pone.0079747] 33. Ntusi N, Aubin L, Oliver S, Whitelaw A, Mendelson M. Guideline for the optimal use of blood cultures. S Afr Med J 2010;100(12):839-843. 34. Department of Health. Essential Drugs List and Structured Treatment Guidelines. http://www.health. gov.za (accessed 24 March 2015). 35. South African Antibiotic Stewardship Programme. A Pocket Guide to Antibiotic Prescribing for Adults in South Africa, 2015. http://www.fidssa.co.za/images/SAASP_Antibiotic_Gudidelines_2015. pdf (accessed 2 March 2015). 36. The Joint Commission. Preventing Central Line-Associated Bloodstream Infections: A Global Challenge, a Global Perspective. Oak Brook, IL: Joint Commission Resources, 2012. http://www. PreventingCLABSIs.pdf (accessed 24 March 2015). 37. Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: A cross-national database study. Lancet 2005;365(9459):579-587. 38. Wise R. The relentless rise of resistance? J Antimicrob Chemother 2004;54(2):306-310.

39. Arnold SR, Straus SE. Interventions to improve antibiotic prescribing practices in ambulatory care. Cochrane Database Syst Rev 2005;19(4):CD003539. 40. Welschen I, Kuyvenhoven MM, Hoes AW, Verheij TJ. Effectiveness of a multiple intervention to reduce antibiotic prescribing for respiratory tract symptoms in primary care: Randomised controlled trial. BMJ 2004;329(7463):431. [http://dx.doi.org/10.1136/bmj.38182.591238.EB] 41. Little P, Stuart B, Francis N, et al. Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections: A multinational, cluster, randomised, factorial, controlled trial. Lancet 2013;382(9899):1175-1182. [http://dx.doi.org/10.1016/S0140-6736(13)60994-0] 42. Arroll B, Kenealy T, Kerse N. Do delayed prescriptions reduce the use of antibiotics for the common cold? A singleblind controlled trial. Journal of Family Practice 2002;51:324-328. 43. Dowell J, Pitkethly M, Bain J, Martin S. A randomised controlled trial of delayed antibiotic prescribing as a strategy for managing uncomplicated respiratory tract infection in primary care. Br J Gen Pract 2001;51:200-205. 44. Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavy J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;322:336-342. 45. Davey P, Brown E, Charani E, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2013;(4):CD003543. [http://dx.doi.org/ 10.1002/14651858. CD003543.pub3] 46. Thaler R, Sunstein C. Nudge: Improving Decisions About Health, Wealth and Happiness. New Haven, Conn.: Yale University Press, 2008. 47. King D, Jabbar A, Charani E, et al. Redesigning the ‘choice architecture’ of hospital prescription charts: A mixed methods study incorporating in situ simulation testing. BMJ Open 2014;4:e005473. [http:// dx.doi.org/10.1136/bmjopen-2014 005473] 48. Department of Health. Antimicrobial Resistance National Strategy Framework, 2014-2024. Pretoria: Department of Health, 2014. http://www.health.gov.za (accessed 24 March 2015). 49. Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics 1999;103:711-718. 50. Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patients’ expectations on antibiotic management of acute lower respiratory tract illness in general practice: Questionnaire study. BMJ 1997;315(7117):1211-1214. 51. Hoffman D, Botha J. An assessment of factors influencing the prescribing of antibiotics in acute respiratory illness: A questionnaire study. S A Fam Pract 2003;45(6):20-24. 52. Huttner B, Goossens H, Verheij T, Harbarth S. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet Infect Dis 2010;10(1):17-31. [http://dx.doi.org/10.1016/S1473-3099(09)70305-6] 53. McNulty CAM, Boyle P, Nichols T, Clappison P, Davey P. Don’t wear me out – the public’s knowledge of and attitudes to antibiotic use. J Antimicrob Chemother 2007;59:727-738. [http://dx.doi.org/10.1093/ jac/dkl558] 54. Pinder R, Sallis A, Berry D, Chadborn T. Behaviour change and antibiotic prescribing in healthcare settings. Literature review and behavioural analysis. https://www.gov.uk/government/publications/ antibiotic-prescribing-and-behaviour-change-in-healthcare-settings (accessed 1 March 2015). 55. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http:// www.cdc.gov/durgresistnace/threat-report-2013/pdf/ar-threats-2013-508.pdf (accessed 3 March 2015). 56. Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: A secondary analysis. Lancet 2009;373(9659):240-249. 57. Kaplan WA, Ritz LS, Vitello M, Wirtz VJ. Policies to promote use of generic medicines in low and middle income countries: A review of published literature, 2000-2010. Health Policy 2012;106(3):211224. [http://dx.doi.org/10.1016/j.healthpol.2012.04.015] 58. Kaplan WA, Wirtz VJ, Stephens P. The market dynamics of generic medicines in the private sector of 19 low and middle income countries between 2001 and 2011: A descriptive time series analysis. PLoS One 2013;8(9):e74399. [http://dx.doi.org/10.1371/journal.pone.0074399] 59. Narsai K, Williams A, Mantel-Teeuwisse AK. Impact of regulatory requirements on medicine registration in African countries – perceptions and experiences of pharmaceutical companies in South Africa. South Med Rev 2012;5(1):31-37. 60. O’Neill J, chairman.The Review on Antimicrobial Resistance, December 2014. http://amr-review.org (accessed 2 January 2015). 61. McLaughlin CM, Bodasing N, Boyter AC, Fenelon C, Fox JG, Seaton RA. Pharmacy-implemented guidelines on switching from intravenous to oral antibiotics: An intervention study. QJM 2005;98(10):745-752. 62. Mertz D, Koller M, Haller P, et al. Outcomes of early switching from intravenous to oral antibiotics on medical wards. J Antimicrob Chemother 2009;64(1):188-199. [http://dx.doi.org/10.1093/jac/dkp131]

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ARTICLE

Diagnosis of bacterial infection T H Boyles, MA, BM BCh, MRCP, MD, DTM&H, Cert ID (SA); S Wasserman, MB ChB, MMed, FCP (SA), Cert ID (SA) Division of Infectious Diseases and HIV Medicine, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: T H Boyles (tomboyles@yahoo.com)

Accurate diagnosis of bacterial infection is crucial to avoid unnecessary antibiotic use and to focus appropriate therapy. Bacterial infection is the combination of the presence of bacteria and inflammation or systemic dysfunction; therefore, more than one diagnostic modality is usually required for confirmation. History and examination to determine if a patient fits a clinical case definition is sometimes adequate to confirm or exclude a diagnosis. The second stage is bedside tests – some are used widely, such as urine dipstick tests, but others, such as skin scrapings of petechial rashes, are underutilised. The third stage is laboratory tests – indirect non-culture-based tests, including C-reactive protein and procalcitonin tests, when negative, can be used to prevent the unnecessary use of antibiotics. Direct non-culture-based tests detect antigens or specific antibodies, e.g. group A streptococcal antigen testing can be employed to reduce antibiotic use. Culture-based tests are often considered the reference standard in modern microbiology. Because of slow turnaround times, these tests are frequently used to focus or stop antibiotic therapy after empiric initiation. Nucleic acid amplification tests raise the possibility of detecting organisms with high sensitivity, specificity and reduced turnaround time, and novel diagnostic modalities relying on nanotechnology and mass spectrometry may dramatically alter the practice of microbiology in future. S Afr Med J 2015;105(5):419. DOI:10.7196/SAMJ.9647

The Longitude Prize 2014 is a challenge with a £10 million (~ZAR180 million) prize fund to help solve one of the greatest issues of our time.[1] The chosen issue is antimicrobial resistance (AMR) and the challenge is to create a cost-effective, accurate, rapid and easy-to-use test for bacterial infections. Clearly, this is a very important problem that has yet to be fully solved. Overuse of antibiotics, either because of unnecessary initiation or excessive duration, is a key driver of AMR. The rational use of existing diagnostic tests and development of new technologies to help clinicians confirm or exclude bacterial infection have an important role in improving antibiotic prescribing practices, ultimately improving patient outcomes and reducing AMR. The first ever bacteriological diagnosis was made in 1676, when Anton van Leeuwenhoek observed bacteria using a single-lens microscope and Robert Koch later advanced the science by focusing on pure culture of organisms. Since then, there has been great progress in these techniques and modern laboratories now also include state-of-the-art molecular diagnostics. This article describes the breadth of diagnostics currently available for bacterial infection and introduces some newer technologies that are on the horizon.

Bacterial infection

Bacterial infection is primarily a clinical concept that may require the use of supportive bedside or laboratory tests to confirm or exclude. There are two broad factors that are always necessary to confirm the diagnosis: • inflammation or systemic dysfunction; and • direct or indirect evidence of a compatible bacterial pathogen. Inflammation may be localised or result in a systemic inflammatory response syndrome (SIRS) (Box 1). Sepsis refers to the presence of a SIRS response caused by presumed or confirmed infection. Severe sepsis occurs if there is accompanying organ dysfunction and septic shock in the case of hypotension requiring ionotropic support.

Box 1. Definition of the systemic inflammatory response syndrome (SIRS) SIRS is defined as the presence of any 2 of the following 4 criteria: • Temperature <36 ºC or >38ºC • Pulse >90 beats/min • Respiratory rate >20 breaths/min; or arterial partial pressure of carbon dioxide <4.3 kPa • White blood cell count <4 000 cells/mm³ or >12 000 cells/mm³; or the presence of >10% immature neutrophils (band forms)

However, these definitions have recently been criticised; e.g. in one study of >100 000 patients with confirmed infection and organ failure, 12% did not meet the criteria for SIRS.[2] Signs of inflammation are nonspecific, i.e. not limited to bacterial infection, and may be a consequence of non-bacterial infections, trauma, autoimmune diseases or drug reactions. Examples of symptoms associated with local inflammation include dysuria in urinary tract infection and skin redness in cellulitis, but both of these symptoms could also be due to non-infectious causes. Pancreatitis is the classic example of a SIRS response that mimics sepsis, but does not require antibiotics. At the opposite end of the spectrum, bacterial organisms that are recovered from non-sterile sites or other sites without evidence of local inflammation do not necessarily imply infection. For example, a superficial skin swab may culture Staphylococcus aureus, a highly pathogenic and lethal organism, from up to 30% of otherwise healthy people,[3] but does not require antibiotic therapy. Similarly, the finding of nitrites on a urine disptick in the absence of symptoms or urine leucocytes may suggest asymptomatic bacteriuria or bacterial contamination, but not infection. Certain pathogens, however, are considered to be pathological when detected from any site (Mycobacterium tuberculosis is the most important example). The definition of bacterial infection, and assessing the need for antibiotic therapy, therefore requires clinicians to combine symptoms

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and signs of inflammation with diagnostic tests for direct or indirect evidence of a pathogen as a cause of the inflammation.

Diagnostic tests

The diagnostic process begins with a full clinical evaluation (history and examination), followed by bedside or laboratory-based investigations. Each has advantages and disadvantages, but they are rarely employed in isolation. The typical process begins with clinical tests and uses this information to guide bedside tests, followed by laboratory tests – with the probability of the diagnosis shifting with each piece of added information. Bacterial infection can occur in any part of the body with multiple different organisms and therefore the number of available tests is vast. This review discusses broad categories of tests, with specific examples to illustrate the process.

Clinical diagnostics

In general, single clinical parameters are neither sensitive nor specific for bacterial infection. For example, fever is common in bacterial infection, but also often absent, and may be caused by a multitude of other illnesses, e.g. as part of the SIRS response. Therefore, it is usual to group together features from the history and examination to create useful case definitions. Usually case definitions are designed to have high sensitivity but low specificity so that the condition is ‘ruled out’ in patients not fitting the definition. Further testing is then usually required to ‘rule in’ the diagnosis. An example is the case definition of acute meningitis: <7 days of at least two of the four cardinal features (fever, confusion, headache and neck stiffness). This is useful to exclude patients who are very unlikely to have acute meningitis, but further testing with a lumbar puncture is required to rule in the condition. Not all case definitions have low specificity and are sometimes the sole basis for confirming a diagnosis. For example, the case definition for community-acquired pneumonia, which includes a chest radiograph, is fever and/or breathlessness or tachypnoea and/ or tachycardia as well as new or progressive infiltrate on a chest radiograph. Patients fulfilling this case definition are considered to have pneumonia, and the condition is excluded in patients to whom the case definition does not apply. Further bedside or laboratory testing is not required to confirm the diagnosis, but may be useful for monitoring purposes.

Bedside tests

The urine dipstick test is a good example of a bedside test that can assist with diagnosing bacterial infection. The absence of nitrites or leucocytes makes urinary tract infection very unlikely, although pyuria in particular may have many alternative causes. Another routinely used bedside test is wet prep microscopy for the diagnosis of sexually transmitted infections in women. A bedside Gram stain can be extremely helpful for identifying Gram-negative diplococci in a joint aspirate to confirm gonoccocal arthritis,[4] or similarly for making a rapid diagnosis of meningococcaemia from a skin scraping of a petechial rash.[5] Unfortunately, these office tests are not often performed, even though they require minimal training and are cheap. Radiographs usually provide nonspecific evidence of infection, such as infiltrates on a chest radiograph or focal bony lysis suggesting osteomyelitis. More sophisticated radiological techniques such as computed tomography scanning or magnetic resonance imaging are sometimes required, but even these often lack the specificity to confidently rule in bacterial infection. Under these circumstances, it is usually necessary to use a laboratory and possibly a culture-based test to confirm the diagnosis.

Laboratory tests

There are a vast number of relevant laboratory tests that can be broadly divided into indirect and direct non-culture-based and culture-based tests, and nucleic acid amplification tests (NAATs). Indirect tests such as peripheral white cell count (WCC) and C-reactive protein (CRP) confirm the presence of inflammation when positive, but lack the specificity to differentiate bacterial from non-bacterial causes. However, high neutrophil count with left-shift and CRP >100 mg/mL suggest bacterial infection.[6] Negative results generally exclude inflammation and therefore bacterial infection. There has been great interest in developing more sophisticated pointof-care (POC) tests that can accurately exclude bacterial infection. A number of useful tests are now available, including CRP, which have been shown in clinical trials to reduce antibiotic prescription for respiratory tract infections.[7] Procalcitonin (PCT) is 10 times more expensive than CRP or WCC tests, but more specific for bacterial infection. There is good evidence that antibiotics can safely be withheld, based on low PCT in acute meningitis, acute exacerbations of chronic obstructive pulmonary disease and upper respiratory tract infections.[8] PCT has no value in differentiating bacterial infection from tuberculosis[9] and has very limited value in sepsis.[10] Serial measurements can be used to decide when to discontinue antibiotics, particularly in the intensive care unit setting,[11] although use for this indication may be limited by cost. Current research is examining the complete host-proteome response to bacterial and viral infection to find signatures that can reliably differentiate the two. A recent study showed that the combination of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, and CRP outperformed any individual proteins and routinely used clinical parameters and their combinations.[12] Direct non-culture-based tests generally depend on identifying an antigen from an organism or a serological reaction to that antigen. These tests vary in their performance characteristics, but in general are specific for a particular bacterial infection in the correct clinical setting. An office-based rapid antigen test is available for the detection of group A Streptoccocus in children with sore throat; a positive test rules in the diagnosis with a high degree of certainty and can be used as a basis to confidently prescribe antibiotics.[13] Similarly, stool antigen tests accurately detect the presence of Helicobacter pylori infection,[14] facilitating the use of eradication therapy without the need for endoscopy. Antigen testing is sometimes preferred over culture for diagnosing bacterial infection due to fastidious or unusual organisms – Legionella pneumonia being a good example. A drawback of many antigen tests is reduced sensitivity compared with culture, and in severe or life-threatening illness this cannot reliably exclude infection. An example is bacterial meningitis, where a positive meningococcal[15] or pneumococcal antigen[16] test on cerebrospinal fluid is excellent at confirming those infections, but a negative test is insufficient for discontinuing empiric therapy. Another drawback of antigen tests is their inability to provide antimicrobial susceptibility data; therefore, even if pneumococcal meningitis is diagnosed on the basis of an antigen test, ceftriaxone will have to be continued until minimum inhibitory concentrations of penicillin can be determined from a cultured isolate. Serological tests are sometimes used to diagnose infections caused by bacteria that are difficult to culture. Certain classic tests are unreliable and should not be used, such as the Widal reaction for typhoid. Problems with serology include cross-reactivity with other antigens, particularly when measuring IgM, which reduces specificity, and false-negatives in early infection, which reduce sensitivity. Examples of serological tests used in clinical practice to

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guide treatment are those for Rickettsia in suspected tick bite fever and amoebic serology in liver abscess. For some infections the diagnosis is only confirmed when comparing serological titres from a sample taken at the time of disease with a convalescent sample taken after the patient has recovered. This information is too late to change patient management, but can be useful epidemiologically. Culture-based tests are the basis of modern microbiology and are usually considered the reference standard with which other diagnostic tests are compared. However, cultures are seldom used in clinical practice to make an initial diagnosis of bacterial infection and rarely influence decisions about whether to initiate empiric antibiotic therapy; these are clinical decisions, influenced by findings on examination and supported by nonspecific bedside and laboratory tests. Culture results, which usually take at least 48 - 72 hours to become available, are then generally used to focus or discontinue antibiotics. Exceptions to this rule are patients who are clinically stable enough for antibiotic therapy to be delayed, and conditions such as pyrexia of unknown origin or suspected subacute bacterial endocarditis, where culturing of organisms is usually required before antibiotics can be initiated. The performance of cultures is influenced by the type and site of infection, e.g. the sensitivity of blood cultures for detecting an organism in uncomplicated cellulitis is extremely poor because of the small risk of bacteraemia in this condition.[17] In septic shock, however, the probability of a positive blood culture is about 65%. Although cultures are usually considered to have a high specificity, inappropriate indications or poor sampling technique may diminish this greatly.[18] Examples of unreliable culture results include superficial skin swabs or urine collected from long-term indwelling catheters. Standard culture techniques generally require 48 - 72 hours to pro vide final results, whereas NAATs have the potential to reduce this window to a few hours. The most widely available is polymerase chain reaction (PCR), which relies on amplification and identification of nuclear material. NAATs provide the greatest advantage in terms of turnaround time when they can be performed directly on clinical specimens, such as a stool sample for Clostridium difficile.[19] Other PCRs require the organism to first be cultured from a clinical specimen, which necessarily increases the time to a result. Detailed information about the infection can be obtained from PCR, e.g. the FilmArray blood culture identification panel tests for 24 organisms and multiple resistance genes.[20] The degree of complexity associated with performing the test also varies, e.g. the GeneXpert system (Cepheid, Sunnyvale, CA, USA) is almost fully automated, requiring samples to be added to sealed cartridges that contain all the reagents for the reaction. More complex systems require highly skilled staff working in high-level laboratories, which increase costs and turnaround time. Peptide nucleic acid fluorescent in situ hybridisation (PNA FISH) (AdvanDx, Woburn, Mass., USA) uses fluorescence-labelled synthetic oligonucleotide probes that bind to species-specific ribosomes and can be detected using a fluorescence microscope. Modern platforms can perform tests on blood cultures as soon as they become positive, giving a result within 30 minutes so that Gram stain and species identification results can be released simultaneously.

New technologies

New technologies that are likely to emerge as important diagnostic tools in future include nanoparticle probe technology and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS). Nanosphere’s Verigene Grampositive (BC-GP) blood culture assay is performed directly on

positive blood cultures using nucleic acid extraction and PCR amplification. Target DNA is then hybridised to oligonucleotides on a microarray with automated qualitative analysis. The test was approved by the US Food and Drug Administration in 2014 and currently has the ability to identify 10 Gram-positive and 8 Gramnegative organisms along with multiple resistance genes. Currently, two MALDI-TOFMS platforms are available in the USA, MALDI Biotyper (Bruker Corporation, Billerica, Mass.) and VitekMS System (bio-Mérieux, Durham, NC). MALDI-TOF performs MS on target molecules following ionisation and disintegration; these patterns are compared with known organism fingerprints. It is capable of analysing thousands of samples from specimens per day, including blood, sputum and urine. Another promising infection testing platform that uses PCR followed by electrospray ionisation MS (PCR/ESI-MS) technology is able to rapidly detect >800 bacteria, including unculturable organisms and three classes of antibiotic resistance markers, directly from clinical specimens. In a recent study of 331 blood samples it was able to detect twice as many organisms as culture.[21]

Conclusion

Clinicians must use a combination of clinical signs, bedside tests and laboratory investigations to diagnose bacterial infection. Knowledge of the types of tests available and how to use them appropriately are important tools in improving patient outcomes and rational antibiotic prescribing. References 1. The Longitude Prize 2014. https://longitudeprize.org/ (accessed 6 February 2015). 2. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 17 March 2015. [Epub ahead of print] 3. Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: Epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997;10(3):505-520. 4. Bardin T. Gonococcal arthritis. Best Pract Res Clin Rheumatol 2003;17(2):201-208. 5. Arend SM, Lavrijsen AP, Kuijken I, van der Plas RN, Kuijper EJ. Prospective controlled study of the diagnostic value of skin biopsy in patients with presumed meningococcal disease. Eur J Clin Microbiol Infect Dis 2006;25(10):643-649. 6. Povoa P. C-reactive protein: A valuable marker of sepsis. Intensive Care Med 2002;28(3):235-243. 7. Huang Y, Chen R, Wu T, Wei X, Guo A. Association between point-of-care CRP testing and antibiotic prescribing in respiratory tract infections: A systematic review and meta-analysis of primary care studies. Br J Gen Pract 2013;63(616):e787-e794. [http://dx.doi.org/10.3399/bjgp13X674477] 8. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: A systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171(15):1322-1331. [http://dx.doi.org/10.1001/archinternmed.2011.318] 9. Huang SL, Lee HC, Yu CW, et al. Value of procalcitonin in differentiating pulmonary tuberculosis from other pulmonary infections: A meta-analysis. Int J Tuberc Lung Dis 2014;18(4):470-477. [http://dx.doi. org/10.5588/ijtld.13.0449] 10. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: A systematic review and meta-analysis. Lancet Infect Dis 2013;13(5):426-435. [http://dx.doi.org/10.1016/S14733099(12)70323-7] 11. Assink-de Jong E, de Lange DW, van Oers JA, Nijsten MW, Twisk JW, Beishuizen A. Stop antibiotics on guidance of procalcitonin study (SAPS): A randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients – calculated sample size: 1816 patients. BMC Infect Dis 2013;13:178. [http://dx.doi.org/10.1186/1471-2334-13-178] 12. Oved K, Cohen A, Boico O, et al. A novel host-proteome signature for distinguishing between acute bacterial and viral infections. PLoS One 2015;10(3):e0120012. [http://dx.doi.org/10.1371/journal.pone.0120012] 13. Bisno AL, Gerber MA, Gwaltney JM, Jr, Kaplan EL, Schwartz RH, Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis 2002;35(2):113-125. 14. Lee YC, Chiu HM, Chiang TH, et al. Accuracy of faecal occult blood test and Helicobacter pylori stool antigen test for detection of upper gastrointestinal lesions. BMJ Open 2013;3(10):e003989. [http://dx.doi.org/10.1136/ bmjopen-2013-003989] 15. Sobanski MA, Barnes RA, Coakley WT. Detection of meningococcal antigen by latex agglutination. Methods Mol Med 2001;67:41-59. 16. Samra Z, Shmuely H, Nahum E, Paghis D, Ben-Ari J. Use of the NOW Streptococcus pneumoniae urinary antigen test in cerebrospinal fluid for rapid diagnosis of pneumococcal meningitis. Diagn Microbiol Infect Dis 2003;45(4):237-240. 17. Perl B, Gottehrer NP, Raveh D, Schlesinger Y, Rudensky B, Yinnon AM. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis 1999;29(6):1483-1488. 18. Aronson MD, Bor DH. Blood cultures. Ann Intern Med 1987;106(2):246-253. 19. Pancholi P, Kelly C, Raczkowski M, Balada-Llasat JM. Detection of toxigenic Clostridium difficile: Comparison of the cell culture neutralization, Xpert C. difficile, Xpert C. difficile/Epi, and Illumigene C. difficile assays. J Clin Microbiol 2012;50(4):1331-1335. [http://dx.doi.org/10.1128/JCM.06597-11] 20. Bauer KA, Perez KK, Forrest GN, Goff DA. Review of rapid diagnostic tests used by antimicrobial stewardship programs. Clin Infect Dis 2014;59(Suppl 3):S134-S145. [http://dx.doi.org/10.1093/cid/ciu547] 21. Bacconi A, Richmond GS, Baroldi MA, et al. Improved sensitivity for molecular detection of bacterial and Candida infections in blood. J Clin Microbiol 2014;52(9):3164-3174. [http://dx.doi.org/10.1128/ JCM.00801-14]

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ARTICLE

Optimising the administration of antibiotics in critically ill patients G A Richards,1 MB BCh, PhD, FCP (SA), FRCP; I A Joubert,2 MB BCh, DA (SA), FCA (SA) (Critical Care); A J Brink,3 MB BCh, MMed (Clin Micro) Division of Critical Care, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa 2 Division of Critical Care, Department of Anaesthesia, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa 3 Department of Clinical Microbiology, Ampath National Laboratory Services, Milpark Hospital, Johannesburg, South Africa 1

Corresponding author: G A Richards (guy.richards@wits.ac.za)

Optimal outcome and a reduction in the potential for resistance require that appropriate pharmacokinetic (PK) targets are achieved. Consequently, we need to target drug concentrations that are significantly higher than those conventionally presumed to be adequate. Drug exposure varies according to the molecular weight, degree of ionisation, protein binding and lipid solubility of each agent. In critically ill patients, hypoalbuminaemia increases the free fraction of hydrophilic drugs, which in turn increases the volume of distribution and clearance (CL), both of which result in reduced drug levels. Similarly, augmented renal clearance (ARC), defined as a creatinine clearance (CLcr) of >130 mL/min/1.73 m2, which occurs frequently in critically ill patients, particularly younger patients with normal or near-normal creatinine levels, may also significantly reduce drug exposure. Studies have demonstrated a greater mortality and lower cure with ARC, particularly with the additive effects of obesity, hypoalbuminaemia and increasing resistance, if conventional dosages are used. These concepts apply to antibiotics targeting Gram-negative and -positive organisms. Knowledge of PK and the resistance profiles of organisms in each environment is necessary to prescribe appropriately. This article discusses these issues and the doses that should be used. S Afr Med J 2015;105(5):419. DOI:10.7196/SAMJ.9649

Optimal outcomes require achieving appropriate pharmacokinetic (PK) targets relative to the minimum inhibitory concentration (MIC) of the organism for a specific antibiotic. Antibiotics may be classified as time dependent, where a specific time above the MIC (T>MIC) is required to ensure optimal efficacy, and as concentration dependent, where the ratio of the area under the curve (AUC) to the MIC, also known as the area under the inhibitory curve (AUIC) or the peak-to-MIC ratio, more accurately reflects efficacy (Fig. 1). The AUIC might also be the most accurate parameter for some time-dependent drugs, particularly those with longer half-lives, such as the glycopeptides and linezolid. The optimal T>MIC for the β-lactams is >50% for penicillins, >60% for the cephalosporins and >40% for the carbapenems. For concentrationdependent agents the AUIC should generally be >120 or the peak-toMIC ratio >8 - 10.[1,2] For example, in a study of free antibiotic levels, 248 patients with infection were examined to establish whether or not a target of 50% or 100% T>MIC was achieved. Those who did not achieve the 50% T>MIC target were significantly less likely to have a positive clinical outcome (odds ratio (OR) 0.68; p=0.009), and a positive clinical outcome was associated with increasing 50% T>MIC and 100% T>MIC ratios (OR 1.02 and 1.56, respectively; p<0.03).[3] Whereas these parameters primarily reflect efficacy, there is also the possibility that not achieving them may increase the potential for resistance, as selective pressure increases when there is a prolonged period below the MIC. Organisms that are more resistant have a lower AUIC and/or shorter T>MIC and an increased likelihood of survival.[4,5] Therefore, we might need to target drug concentrations that are significantly higher than those conventionally presumed to be adequate.[6] The mutant prevention concentration (MPC) is

the concentration above which selective proliferation of mutants is unlikely to occur. Mutants are members of the microbial population with inherently higher MICs than the population average. Antibiotic concentrations that are targeted to the overall MIC would potentially be less than the MPC, thereby providing a competitive advantage to the mutant members of the microbial population.[7] Therefore, it is critical that the dose be optimised; some recommendations advise that concentrations should be >4 times the MIC for specific periods to prevent selection of resistant organisms – an essential component of antibiotic stewardship. Fig. 2 illustrates the concept of MPC and potential pitfalls of MIC-based dosing.[8]

Factors impacting on antibiotic exposure

Drug exposure varies according to molecular weight, degree of ionisation, protein binding and lipid solubility. Lipophilic antibiotics, e.g. the fluoroquinolones, have a large volume of distribution (Vd) owing to significant tissue and intracellular penetration. Hydrophilic agents, however, distribute into the extracellular space only and have a much lower Vd. The latter is influenced by a number of factors, such as serum albumin level, augmented renal clearance (ARC) and fluid losses as occurs with an open abdomen and major surgery with blood loss.[9] Albumin level is of particular relevance for highly protein-bound antibiotics such as teicoplanin (90 - 95% bound), especially in criti cally ill patients in whom hypoalbuminaemia frequently occurs. In this setting, the Vd and clearance (CL) of the unbound/free fraction are increased.[10,11] These PK changes could result in suboptimal drug exposure, which may necessitate dose adjustments to ensure that therapeutic exposures are achieved.[12] In this regard, Mimoz et al.,[13]

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Optimal use of antibiotics: PK/PD 10 Serum antibiotic concentration (µg/mL)

Peak to MIC ratio 8

AUIC >120

for efficacy

T>MIC MIC

2 0 0

Time (hours) Dose

Fig. 1. The pharmacokinetics of antibiotics (MIC = minimum inhibitory concentration; T>MIC = time above the MIC; AUIC = area under the inhibitory curve). 10 9

Log10 cfµ/mL

8 7 6 5 4 3

Total Susceptible Resistant

2 1 0

Time (hours)

Fig. 2. Antimicrobial therapy rapidly reduces the total number of colony-forming units owing to a reduction in the number of susceptible organisms. Resistant organisms are afforded a competitive advantage and progressively constitute a bigger proportion of the microbial population.[8]

utilising a high-dose regimen of teicoplanin (12 mg/kg 12-hourly for 48 hours, followed by 12 mg/kg once daily) in critically ill patients with ventilator-associated pneumonia (VAP) and severe hypoalbuminaemia (median albumin concentration 16.1 g/L), observed variations in the fraction of unbound teicoplanin of 8 - 42%. ARC is defined as a creatinine clearance (CLcr) >130 mL/min/1.73 m2. The prevalence varies from 30% to 85% in critically ill and trauma patients and a normal or nearnormal creatinine level may represent a high glomerular filtration rate (GFR). At-risk populations are those with good

physiological reserve, of a younger age and with lower illness severity scores. In this setting, dose increases are appropriate as the potential for subtherapeutic dosing is high. Increased β-lactam clearance in patients with sepsis, but without organ dysfunction, can lead to subtherapeutic levels for significant periods.[14-17] CLcr should be routinely measured if there is doubt about the GFR and evidence that an 8-hour collection may be just as accurate as a 24-hour one. A recent prospective, singlecentre observational study of patients with VAP treated with doripenem or imipenem demonstrated a greater mortality and lower

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cure with CLcr >150 mL/min. Separate PK/pharmacodynamic (PD) modelling suggested that daily doripenem doses (up to 2 g 8-hourly) might be required for adequate drug exposure, particularly with resistant organisms.[17-19] In 128 surgical and medical patients encompassing 599 antibiotic days, ARC, defined as more than one 24-hour CLcr >130 mL/min/1.73m2, was present in 51.6% of patients and in 12% it occurred throughout the hospital stay. The median CLcr was 144 mL/min/1.73m2 (interquartile range (IQR) 98 - 196), the ARC patients were significantly younger (p<0.001) and treatment failure occurred more frequently: 27.3% v. 12.9%; p=0.04.[17] We investigated ertapenem PK in 8 patients with severe sepsis (all of whom had normal renal function) after the administration of the conventional dose of 1 g daily. These patients had a lower maximum concentration (Cmax), AUIC (0-∞), and higher Vd (26.8 L v. 5.7 L) than healthy volunteers, and in 4 patients time above 2 mg/L (the MIC breakpoint for Enterobacteriaceae) of the unbound fraction was <40% and in 2 it was <20%. These lower levels correlated negatively with low albumin, open abdomen and ARC.[20] In summary, systemic inflammation increases the Vd of hydrophilic agents through capillary leak, large-volume crystalloid resuscitation and low albumin levels. Furthermore, altered organ per fusion and therapeutic use of inotropes and vasopressors increase the potential for ARC. The additive effects of obesity and extracorporeal circuits reduce drug exposure in an environment where MICs are increasing inexorably. The overall effect is to increase the potential for treatment failure and select for resistance.[21]

What should be done to limit the impact of reduced drug exposure?

There are two obvious approaches, firstly to increase the dose and secondly to alter the methods of administration (infusion for time-dependent agents and, where possible, larger single daily doses for concentrationdependent drugs), both preferably guided by therapeutic drug monitoring (TDM).

β-lactams

In the abovementioned study by Claus et al.,[17] doripenem was administered at four times the recommended dose – with good outcome. There have been many similar case studies of the outcomes when treating resistant organisms. In a patient with cystic fibrosis infected with multidrug-resistant Burkholderia cepacia, who was treated with meropenem 2 g

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8-hourly as a 3-hour infusion, concentrations >8 μg/mL were achieved for 52% of the dosing interval, with subsequent improvement.[22] In a study of 348 patients using β-lactam therapy (the Defining Antibiotic Levels in ICU (DALI) study – a PK point prevalence study using empirical therapy in the ‘worst case’ scenario), T>MIC was <50% of the dosing interval in 19.2% and <100% in 41.4% of patients. Intermittent infusion significantly increased the likelihood of reaching the target, whereas increased CLcr was independently associated with not reaching the 100% T>MIC target for free drug.[23] Similarly, using a Monte Carlo simulation, Nicasio et al.[24] determined that 3-hour infusions of cefepime or meropenem, both at 2 g three times daily, would be most likely to achieve optimal bactericidal Pseudomonas aeruginosa exposure. When this was implemented, infection-related mortality decreased by 69% (8.5% v. 21.6%; p=0.029), length of stay was reduced (11.7±1 v. 26.1±18.5; p<0.001), there were fewer superinfections, and many ‘non-susceptible’ P. aeruginosa infections were successfully treated.

Tigecycline

The efficacy of tigecycline (TGC) has often been questioned. Metaanalyses of monotherapy v. comparators such as the meta-analysis by Yahav et al.[25] have been done. The latter included 15 trials (N=7 654) where overall mortality was higher (relative risk (RR) 1.29 (1.02 - 1.64)), regardless of infection type; clinical and microbiological failure were higher (RR 1.16 (1.06 - 1.27) and 1.13 (0.99 - 1.30), respectively); and development of septic shock was significantly more frequent (RR 7.01 (1.27 - 38.66)). However, numerous recent studies using increased doses have shown improved outcomes. Patients with hospital-acquired pneumonia were randomised to a 150 mg bolus and 75 mg 12-hourly or a 200 mg bolus and 100 mg 12-hourly v. imipenem 1 g 8-hourly.[26] Clinical cure with the larger dose (17/20; 85.0%) was numerically superior to that with the lower dose (16/23; 69.6%) and to imipenem (18/24; 75.0%). Despite the increased dose, there were no new safety signals. Their conclusion was that higher AUIC ratios may be necessary to achieve clinical cure in hospital-acquired pneumonia. Similarly, in a retrospective study of patients with VAP, in which the main isolates were carbapenem-resistant Acinetobacter (blaOXA-58 and blaOXA-23) and Klebsiella pneumoniae (blaKPC-3), high-dose TGC was compared with standard dose TGC.[27] Organisms were said to be TGC sensitive if the MIC ≤2 mg/L and resistant if the MIC was ≥8 mg/L. The single independent predictor of clinical cure was highdose TGC (OR 6.25 (1.59 - 24.57); p=0.009).

Fluoroquinolones and aminoglycosides

7 - 9 mg/kg for gentamicin or tobramycin should be administered initially, and thereafter a Cmax/MIC ratio of 8 - 10 should be targeted.[36] Even then, levels might not be adequate; 33% of patients receiving 25 mg/kg total body weight amikacin load had a Cmax of 60 mg/L, with positive fluid balance being the major negative predictive factor. To complicate matters further, Monte Carlo simulation of conventional v. high-dose extended-interval administration found resistance to be higher against pathogens with high MICs if T>MIC was <60%, even if Cmax/MIC was high, and that treatment efficacy may not be guaranteed.[37] Illustrative dosing schedules for Gram-negative agents may be seen in Table 1.

Colistin

Colistin is a last-line drug and if used inappropriately resistance will develop rapidly. The form available in South Africa is a prodrug, colistimethate sodium or colistin methanesulfonate (CMS), which makes a bolus dose necessary to achieve therapeutic effect. It is effective against most Gram-negative bacilli, except Proteus spp., B. cepacia, Providencia spp., Serratia marcescens and Morganella spp.[38] The appropriate dose must exceed an MIC of 2 mg/L rapidly to prevent regrowth of more resistant organisms in heteroresistant populations, in which the PK target achieved would be insufficient for eradication.[39] Consequently, a loading dose of 12 million units (MU) administered intravenously over 1 - 2 hours followed by 9 MU daily (4.5 MU twice daily or 3 MU three times daily) administered 12 hours after the loading dose is required.[38,40,41] Colistin is predominantly cleared by unknown non-renal mechanisms and undergoes extensive renal tubular reabsorption.[42] In renal dysfunction, elimination of CMS is decreased and a greater fraction of the administered dose is converted to colistin; however, a loading dose of 12 MU is still required, but maintenance doses are reduced according to CLcr (Table 2).[40] From murine AUC/MIC colistin data, it is estimated that an AUIC of total colistin of 60 is the average achieved without exceeding the dose recommended in the package insert (10 MU), particularly where CLcr is >70 mL/min.[40] Therefore, in an attempt to Table 1. Illustrative dosing and administration schedules for Gram-negative bacilli: Normal renal function • Meropenem 2 g 8-hourly over 3 hours • Imipenem 1 g 8-hourly over 3 hours • Doripenem 1 g 8-hourly over 4 hours • Ertapenem 1 g twice daily • Cefepime 2 g bolus and 6 g daily over 24 hours*

With regard to the concentration-dependent antibiotics, optimising the AUIC of fluoroquinolones reduced the development of resistance and was more likely to eradicate the pathogen.[28,29] Aminoglycosides are generally used suboptimally. To achieve appropriate targets, a much larger dose based on age and weight must be administered once per day and the MIC should be low.[30] In general, aminoglycosides are administered for short periods as empirical therapy to decrease the likelihood of inappropriate therapy for hospital-acquired infections. Peak and trough levels and the MIC of the organism (where possible) should be documented and subsequent doses titrated accordingly.[31] As with other hydrophilic agents where the Vd is increased and in the presence of ARC, concentrations may be suboptimal. Amikacin 15 mg/kg, for example, did not reach effective concentrations, with MICs of 8 mg/L, and it is possible that inconsistent concentrations may have contributed to the lack of effect in studies that investigated whether β-lactam-aminoglycoside combinations confer additional efficacy compared with β-lactams only.[32-35] Some reviewers have suggested that doses as high as 25 - 30 mg/kg for amikacin and

• Ceftazidime 2 g bolus and 6 g over 24 hours* • Piperacillin-tazobactam 4.5 g bolus and 18 g daily* *Temperature ≤25°C.

Table 2. Dosing of colistin Load with 12 MU • 60 kg: 3 MU 8-hourly/4.5 MU 12-hourly Renal impairment – load with 12 MU, then: • CLCr 20 - 50: 1 - 2 MU 8-hourly • CLCr 10 - 20: 1 MU every 12 - 18 hours CRRT – full dose; intermittent HD 1 MU 12-hourly and 1 MU after dialysis • Never use colistin as monotherapy MU = million units; CRRT = continuous renal replacement therapy; HD = haemodialysis.

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reduce resistance, colistin is not administered as monotherapy and options include the carbapenems (provided the MIC is ≤32 mg/L (for carbapenem-resistant Enterobacteriaceae)), tigecycline (Acinetobacter), fluoroquinolones, rifampicin and others, even if the organism is resis tant to these drugs.[43-45]

The glycopeptides, vancomycin and teicoplanin

These concepts regarding dosing are similar when using agents active against Gram-positive organisms. Vancomycin MICs have gradually been increasing, which appears to impact on outcome. In 158 patients with hospital-, ventilator- or healthcare-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, 72.8% had vancomycin MIC ≥1.5 μg/mL. All-cause mortality at day 28 was 32.3%, but this increased as the MIC increased (p=0.001). Consequently, although controversial, it is recommended that other therapies be considered with MICs of 1 - 2 μg/mL.[46] Studies using higher troughs (15 - 20 mg/L), loading doses or continuous infusions differ with regard to improved clinical or microbiological outcome; however, it is hoped that higher dosing may delay resistance by not selecting those organisms with higher MICs.[47-50] In another study from the DALI group, 42 patients either received continuous infusions (CIs) (57%) or intermittent doses (43%) of vancomycin. The PK targets were a Cmin ≥15 mg/L or an AUIC >400 (assuming the MIC was 1 mg/L). The Cmin was highly variable and achieved in only 57% overall, and in 71% (CI) v. 39% (intermittent) (p=0.038). AUIC was achieved in 88% (CI) v. 50% (intermittent) (p=0.008). Whereas CI appeared to be superior, it was still not adequate in achieving targets, and multivariate analysis did not confirm CI as an independent predictor of either.[51] Similarly, teicoplanin is unlikely to achieve therapeutic targets if administered in recommended doses as per the package insert. We performed a study in patients with normal renal function, in whom the standard dose of 400 mg twice daily × 1 day and 400 mg daily thereafter was compared with 400 mg twice daily.[52] With the latter, a Cmin of 15 mg/L was achieved only on day 3, whereas with the former it was never achieved. In another study of 10 patients with chronic bone sepsis, 800 mg twice daily was administered for 48 hours and then 800 mg daily. Samples were taken 15 minutes pre-, and 30 and 120 minutes post-teicoplanin dose. The CL of the free fraction (ff ) was 33.5 L/hour (38.0 - 34.7) compared with the bound fraction 7.0 L/hour (6.8 - 9.8), and the major determinant of ff was albumin with an OR of 0.120 (0.078 - 0.161; p<0.001), with a lesser effect of total dose. This emphasises that multiple factors impact on serum levels whether or not the patients are critically ill.[53]

Linezolid

Linezolid is a time-dependent antibiotic and efficacy improves as the T>MIC increases. However, it is probably only with CI that this can this be achieved when MICs are higher.[54] Boselli et al.[55] demonstrated that a loading dose followed by CI led to concentrations twice that of a linezolid MIC of 4 mg/L in serum and epithelial lining fluid for 100% of the time in critically ill patients with VAP. Why is this important? A recent prospective observational study of 30 critically ill patients showed that levels were frequently inadequate with standard dosing of 600 mg twice daily. The range of the AUC24 was 50.1 - 453.9 mg*h/L (median 143.3) and that of Cmin 0.13 - 14.49 mg/L (median 2.06). Similarly AUC24 <200 mg*h/L and Cmin <2 mg/L, both of which represent inadequate levels, were observed for 63% and 50% of patients, respectively.[56] As the achievement of PK targets is essential, the dose and method of administration must be optimised, and it seems reasonable to utilise TDM where available; where not, CI might significantly improve AUIC.[57] This is not a review of TDM,

Table 3. Illustrative dosing and administration schedules for Gram-positive organisms Normal renal function • Teicoplanin: 800 mg twice daily × 2 days, then 400 mg twice daily • Vancomycin: 1 - 2 g stat, then infuse 2 g daily (target a trough of 15 - 20 μg/mL) Renal dysfunction • Teicoplanin: 400 mg twice daily × 1, then daily • Vancomycin 2 g stat – maintain levels at 15 - 20 μg/mL The following 3 drugs have the same dose, regardless of renal function • Linezolid: day 1 – bolus 300 mg, then infuse 900 mg over 24 h, thereafter infuse 600 mg 12-hourly • Tigecycline: 100 mg stat, then 50 mg twice daily • Rifampicin: 600 mg twice daily

but numerous other studies have proven its worth and it is probably the way of the future.[58] Illustrative dosing schedules for Grampositive agents may be seen in Table 3.

Conclusion

There is currently a crisis with regard to antibiotic resistance. Every day that we delay ensures that we are further from a solution. We have to use antibiotics in an appropriate manner, reduce inappropriate use by all possible means, and reduce the incidence of infection, particularly in hospital. We are at the end of the antibiotic era – perhaps we can make it last a few more years to allow the introduction of new agents, particularly β-lactam antibiotics combined with β-lactamase inhibitors, or until new strategies can be devised. References 1. Drusano GL. Prevention of resistance: A goal for dose selection for antimicrobial agents. Clin Infect Dis 2003;36(Suppl 1):S42-S50. 2. Craig WA. Antimicrobial resistance issues of the future. Diagn Microbiol Infect Dis 1996;25(4):213-217. 3. Roberts JA, Paul SK, Akova M, et al., DALI Study. DALI: Defining antibiotic levels in intensive care unit patients: Are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 2014;58:1072-1083. [http://dx.doi.org/10.1093/cid/ciu027] 4. Baquero F, Negri MC, Morosini MI, Blázquez J. Antibiotic-selective environments. Clin Infect Dis 1998;27(Suppl 1):S5-S11. 5. Baquero F. Low-level antibacterial resistance: A gateway to clinical resistance. Drug Resist Updat 2001;4(2):93-105. 6. Oloffson S, Cars O. Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis 2007;45(Suppl):S129-S136. 7. Sanders CC, Sanders WE. Type I β-lactamases of gram-negative bacteria: Interactions with β-lactam antibiotics. J Infect Dis 1986;154:792-800. 8. Drusano GL. Antimicrobial pharmacodynamics: Critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004;2:289-300. 9. Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med 2013;39:2070-2082. [http://dx.doi.org/10.1007/s00134-013-3088-4] 10. Ulldemolins M, Roberts JA, Rello J, et al. The effects of hypoalbuminaemia on optimizing antibiotic dosing in critically ill patients. Clin Pharmacokinet 2011;50:1-12. [http://dx.doi.org/10.2165/11539220000000000-00000] 11. Vincent JL, Russell JA, Jacob M, et al. Albumin administration in the acutely ill: What is new and where next? Crit Care 2014;18:231. [http://dx.doi.org/10.1186/cc13991] 12. Roberts JA, Pea F, Lipman J. The clinical relevance of plasma protein binding changes. Clin Pharmacokinet 2013;52:1-8. [http://dx.doi.org/10.1007/s40262-012-0018-5] 13. Mimoz O, Rolland D, Adoun M, et al. Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg per day in patients with ventilator-associated pneumonia. Intensive Care Med 2006;32:775-779. 14. Minville V, Asehnoune K, Ruiz S, et al. Increased creatinine clearance in polytrauma patients with normal serum creatinine: A retrospective observational study. Crit Care 2011;15:R49. [http://dx.doi. org/10.1186/cc10013] 15. Fuster-Lluch O, Gerónimo-Pardo M, Peyró-García R, Lizán-García M. Glomerular hyperfiltration and albuminuria in critically ill patients. Anaesth Intensive Care 2008;36(5):674-680. 16. Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: Identifying at-risk patients. Crit Care 2013;17(1):R35. [http://dx.doi.org/10.1186/cc12544] 17. Claus BO, Hoste EA, Colpaert K, Robays H, Decruyenaere J, De Waele JJ. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. J Crit Care 2013;28(5):695-700. [http://dx.doi.org/10.1016/j.jcrc.2013.03.003] 18. Kollef MH, Chastre J, Clavel M, et al. A randomized trial of 7-day doripenem versus 10-day imipenemcilastatin for ventilator-associated pneumonia. Crit Care 2012;16(6):R218. [http://dx.doi.org/10.1186/ cc11862]

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19. Roberts JA, Lipman J. Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility. Crit Care Med 2013;41:489-495. [http://dx.doi.org/10.1097/CCM.0b013e31826ab4c4] 20. Brink AJ, Richards GA, Schillack V, Kiem S, Schentag J. Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis. Int J Antimicrob Agents 2009;33:432-436. [http:// dx.doi.org/10.1016/j.ijantimicag.2008.10.005] 21. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: Implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 2010; 49(1):1-16. [http://dx.doi.org/10.2165/11318140000000000-00000] 22. Kuti JL, Moss KM, Nicolau DP, Knauft RF. Empiric treatment of multidrug-resistant Burkholderia cepacia lung exacerbation in a patient with cystic fibrosis: Application of pharmacodynamic concepts to meropenem therapy. Pharmacotherapy 2004;24:1641-1645. 23. De Waele JJ, Lipman J, Akova M, et al. Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients. Intensive Care Med 2014;40:1340-1351. [http://dx.doi.org/10.1007/s00134-014-3403-8] 24. Nicasio AM, Eagye KJ, Nicolau DP, et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care 2010;25(1):69-77. [http://dx.doi.org/10.1016/j.jcrc.2009.02.014] 25. Yahav D, Lador A, Paul M, Leibovici L. Efficacy and safety of tigecycline: A systematic review and meta-analysis. J Antimicrob Chemother 2011;66:1963-1971. [http://dx.doi.org/10.1093/jac/dkr242] 26. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother 2013;57:1756-1762. [http://dx.doi.org/10.1128/AAC.01232-12] 27. De Pascale G, Montini L, Pennisi M, et al. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care 2014;18:R90. [http://dx.doi.org/10.1186/cc13858] 28. Thomas JK, Forrest A, Bhavnani SM, et al. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob Agents Chemother 1998;42:521-527. 29. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993;37:1073-1081. 30. Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am 2003;17:503-528. 31. Kumar A, Kethireddy S. Emerging concepts in optimizing antimicrobial therapy of septic shock: Speed is life but a hammer helps too. Crit Care 2013;17(1):104. [http://dx.doi.org/ 10.1186/cc11890] 32. Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2014;7(1):CD003344. [http://dx.doi.org/10.1002/14651858.CD003344.pub3] 33. Bliziotis IA, Petrosillo N, Michalopoulos A, Samonis G, Falagas ME. Impact of definitive therapy with beta-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia. PLoS One 2011;6(10):e26470. [http://dx.doi.org/10.1371/journal.pone.0026470] 34. Taccone FS, Laterre PF, Spapen H, et al. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit Care 2010;14(2):R53. [http://dx.doi.org/10.1186/cc8945] 35. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gramnegative bacteria. Clin Microbiol Rev 2012;25:450-470. [http://dx.doi.org/10.1128/CMR.05041-11] 36. Matthaiou DK, De Waele J, Dimopoulos G. What is new in the use of aminoglycosides in critically ill patients? Intensive Care Med 2014;40(10):1553-1555. [http://dx.doi.org/10.1007/s00134-014-3376-7] 37. Zazo H, Martín-Suárez A, Lanao JM. Evaluating amikacin dosage regimens in intensive care unit patients: A pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation. Int J Antimicrob Agents 2013;42:155-160. [http://dx.doi.org/10.1016/j.ijantimicag.2013.04.021] 38. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by Gram-negative bacteria. Antimicrob Agents Chemother 2009;53(8):3430-3436. [http://dx.doi.org/10.1128/AAC.01361-08] 39. Chun-Hong T, Jian Li, Roger L. Activity of colistin against heteroresistant Acinetobacter baumannii and emergence of resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother 2007;51:3413-3415. [http://dx.doi.org/10.1128/AAC.01571-06]

40. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother 2011;55:3284-3294. [http://dx.doi.org/10.1128/ AAC.01733-10] 41. Kift EV, Maartens G, Bamford C. Systematic review of the evidence for rational dosing of colistin. S Afr Med J 2014;104:183-186. 42. Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration. Antimicrob Agents Chemother 2003;47(5):1766-1770. 43. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval colistin administration in critically ill patients: Is this the right dosing strategy? A preliminary study. Clin Infect Dis 2012;54:1720-1726. [http://dx.doi.org/10.1093/cid/cis28640] 44. Petrosillo N, Giannella M, Lewis R, Viale P. Treatment of carbapenem-resistant Klebsiella pneumoniae: The state of the art. Expert Rev Anti Infect Ther 2013;11:159-177. [http://dx.doi.org/10.1586/eri.12.162] 45. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: Importance of combination therapy. Clin Infect Dis 2012;55:943-950. [http://dx.doi.org/10.1093/cid/cis588] 46. Haque NZ, Zuniga LC, Peyrani P, et al.; Improving Medicine through Pathway Assessment of Critical Therapy of Hospital-Acquired Pneumonia (IMPACT-HAP) Investigators. Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest 2010;138:1356-1362. [http://dx.doi.org/10.1378/chest.09-2453] 47. Brink AJ. Does resistance in severe infections caused by methicillin-resistant Staphylococcus aureus give you the ‘creeps’? Curr Opin Crit Care 2012;18:451-459. [http://dx.doi.org/10.1097/MCC.0b013e3283578968] 48. Van Hal SJ, Paterson DL. Systematic review and meta-analysis of the significance of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. Antimicrob Agents Chemother 2011;55:405410. [http://dx.doi.org/10.1128/AAC.01133-10] 49. Dhand A, Sakoulas G. Reduced vancomycin susceptibility among clinical Staphylococcus aureus isolates (‘the MIC Creep’): Implications for therapy. F1000 Med Rep 2012;4:4. [http://dx.doi.org/10.3410/M4-4] 50. Nannini E, Murray BE, Arias CA. Resistance or decreased susceptibility to glycopeptides, daptomycin, and linezolid in methicillin-resistant Staphylococcus aureus. Curr Opin Pharmacol 2010;10:516-521. [http://dx.doi.org/10.1016/j.coph.2010.06.006] 51. Blot S, Koulenti D, Akova M, et al. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Crit Care 2014;18:R99. [http://dx.doi.org/10.1186/cc13874] 52. Brink AJ, Richards GA, Cummins RR, Lambson J; Gauteng Understanding Teicoplanin Serum levels (GUTS) study group. Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients treated for sepsis. Int J Antimicrob Agents 2008;32:455-458. [http://dx.doi. org/10.1016/j.ijantimicag.2008.05.012] 53. Brink AJ, Richards GA, Lautenbach C, et al. A post-authorisation survey to analyse the perioperative teicoplanin plasma concentrations in adult patients with chronic bone sepsis, who received loading doses of 12 mg/kg 12-hourly for 48 hours followed by 12 mg/kg once daily. Crit Care 2012;16(1):3. [http://dx.doi.org/10.1186/cc10676] 54. Adembri C, Fallani S, Cassetta MI, et al. Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: Intermittent versus continuous infusion. Int J Antimicrob Agents 2008;31:122-129. 55. Boselli E, Breilh D, Caillault-Sergent A, et al. Alveolar diffusion and pharmacokinetics of linezolid administered in continuous infusion to critically ill patients with ventilator-associated pneumonia. Antimicrob Chemother 2012;67:1207-1210. 56. Zoller M, Maier B, Hornuss C, et al. Variability of linezolid concentrations after standard dosing in critically ill patients: A prospective observational study. Crit Care 2014;10;18:R148. [http://dx.doi.org/10.1186/ cc13984] 57. Richards GA, Brink AJ. Therapeutic drug monitoring: Linezolid too? Crit Care 2014;18:525-526. 58. De Waele JJ, Carrette S, Carlier M, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: A randomised controlled trial. Intensive Care Med 2014;40:380-387. [http://dx.doi.org/10.1007/s00134-013-3187-2]

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ARTICLE

Twitter: A tool to improve healthcare professionals’ awareness of antimicrobial resistance and antimicrobial stewardship D A Goff,1 PharmD, FCCP; D van den Bergh,2 BPharm, MSc (Med), EngD Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA Director of Quality Leadership, Netcare Ltd, South Africa

1 2

Corresponding author: D A Goff (debbie.goff@osumc.edu)

The World Health Organization urges international collaboration for the containment of antimicrobial resistance (AMR) or ‘superbugs’. If left unchecked, AMR could result in 4.1 million deaths in Africa by 2050. Furthermore, without effective antibiotics, surgical procedures would become much riskier and in many cases impossible. Antimicrobial stewardship requires a multidisciplinary approach; however, many programmes still struggle to achieve the ‘reach’ required to educate and engage all healthcare providers (HCPs). Twitter use among South Africans has grown by 129% in 12 months, from 2.4 million to 5.5 million. HCPs can use Twitter to network and connect with worldwide experts, obtain real-time news from medical conferences, participate in live Twitter chats conducted by experts or medical organisations, or participate in international journal clubs. Used responsibly and professionally, Twitter can spread the call to action and connect frontline healthcare professionals to help win the battle against AMR. S Afr Med J 2015;105(5):420. DOI:10.7196/SAMJ.9648

A special report published in the New England Journal of Medicine, ‘Health and health care in South Africa – 20 years after Mandela’, describes the urgent need to increase the number of healthcare professionals and reflects on some of the major challenges to improving health in South Africa (SA).[1] HIV and tuberculosis lead the list of challenges. However, antimicrobial resistance (AMR) has emerged as an additional challenge. On 17 May 2014 the World Health Organization (WHO) declared that antibiotic resistance threatens the achievements of modern medicine.[2] WHO recommended several resolutions, including ‘to improve among all relevant care providers, the public sector and other sectors and stakeholders awareness of (i) the threat posed by AMR, (ii) the need for responsible use of antibiotics’. No single strategy will contain the emergence and spread of antibiotic-resistant organisms. (Click on the following link to listen to an interview by the New England Journal of Medicine with Otto Cars, MD, PhD, on ‘The prospects for combating antibiotic resistance’: http://www.nejm.org/ doi/full/10.1056/NEJMp1408040.) The SA Antibiotic Stewardship Programme (SAASP) implemented stewardship programmes to promote appropriate antimicrobial prescribing across public and private health sectors.[3] Effective antimicrobial stewardship (AMS) requires a multidisciplinary approach with local ‘champions’. Despite numerous publications documenting escalating AMR, antibiotic misuse continues world wide. The 2014 United States Centers for Disease Control and Prevention (CDC) Vital Signs Report found that 50% of hospitalised patients receive an antibiotic, one-third of vancomycin prescriptions included an error, and physicians in some hospitals prescribe up to three times as many antibiotics as physicians in similar hospitals.[4] This difference suggests there is room for improvement. A recent commentary in Lancet Infectious Diseases on the topic of appropriate antimicrobial use asked, ‘How do we get the message into the hands of non-infectious diseases orientated surgeons, oncologists, and other high users of antimicrobials who we are failing to reach?’[5]

They suggest that social media, using Twitter, may be one of the answers. The purpose of this article is to describe how Twitter can be used to educate and engage all healthcare providers (HCPs) in AMS.

Methods

A PubMed search between 2006 and 2014 using the phrase ‘Twitter and healthcare providers’ yielded 41 unique articles of which 32% were published during the last 2 years. A Google search in 2014 using the phrase ‘twitter and physicians’ yielded multiple blogs and websites. A personal archive of references on AMR and AMS was accessed. Personal communication with healthcare Twitter ‘experts’ was also used.

What is the impact of antimicrobial resistance?

A 2014 report commissioned by the British Prime Minister modelled that if AMR or ‘superbugs’ are left unchecked, it could result in 4.1 million deaths in Africa and >10 million deaths worldwide by 2050.[6] If we fail to contain AMR, surgery will become far more dangerous in a world that relies on prophylactic antibiotics.

How is social media used in South Africa?

According to the SA Social Media Landscape 2014 research report, Facebook is the largest social network in SA, with 9.4 million active users.[7] Twitter’s use among South Africans saw the highest percentage growth among the major social networks, from 2.4 million to 5.5 million (129% growth) in 12 months. Interestingly, 85% of Twitter users access this tool on their phones. With the accessibility of cheap smartphones (for ~ZAR500), the economic and social impact of access not only on smartphones, but also on instant internet, is a game-changer for SA. In addition, the use of the photosharing and special effects app Instagram has exploded in SA, from below 100 000 in 2011 to 680 000 in 2013.

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Why should healthcare providers consider Twitter for antimicrobial stewardship?

Twitter was founded in 2006 as a free social networking tool. Users may write or read posts known as ‘tweets’, that are limited to 140 characters. Unlike Facebook, Twitter users do not have to mutually connect with each other. Users may choose who they want to follow. HCPs can follow experts in their fields, medical journals, professional organisations or patient advocacy groups. The value of Twitter for AMS is in the potential dissemination of information in terms of the number of people it is able to reach. Fig. 1 shows how a tweet is disseminated throughout one’s network of followers. Many frequent prescribers of antibiotics (surgeons and oncologists) do not read infectious diseases journals, where the majority of AMR and AMS articles are published. Twitter provides a vehicle to connect HCPs with each other. A tweet can spread rapidly and widely to a large network. This was demonstrated during the 2014 Ebola epidemic. There were >10 million tweets in 3 weeks from 170 countries mentioning the word ‘Ebola’.[8] Frontline HCPs and citizens from West Africa were tweeting about Ebola in real-time, providing insight

Debbie tweets to Marc and Adrian

Marc retweets message from Debbie to his followers Dena and Jack

Dena retweets message from Marc to her followers

Adrian does not reweet

Jack does not retweet

Sonya retweets to Penny

Anjeliki retweets to Karri

Penny

Karri

Adrian’s followers do not receive Debbie’s tweet

Jack’s followers do not receive Debbie’s tweet

Fig. 1. Dissemination of a tweet.

Table 1. Selected people, organisations and medical journals to follow on Twitter Name

Twitter name

Description

Debra Goff, PharmD

@idpharmd

Infectious diseases pharmacist; global AMS educator; international advisor to SAASP

Marc Mendelson, MD

@SouthAfricanASP

Co-chair SAASP; President of the Federation of Infectious Diseases Societies of Southern Africa

Laura Piddock, PhD

@LauraPiddock

Professor of Microbiology; Director of Antibiotic Action; British Society for Antimicrobial Therapy Chair in Public Engagement

Didier Pittet, MD

@DidierPittet

Director of Infection Control Programme and WHO external lead

Darryl Vine, MD

@EasyASP

Passionate about antibiotic resistance and metrics

Dena van den Bergh, BPharm, MSc (Med), EngD

@inspired2leadQI

Director of Quality Leadership Netcare; Certified Coach; Systems Innovation and Improvement Advisor; Best Care … Always co-founder

Organisations • Centre for Disease Dynamics and Economic Policy

@CDDEP

• ReAct Action on Antibiotic Resistance

@reactgroup

• Antibiotic Action

@TheUrgentNeed

• Save Antibiotics

@saveantibiotics

• The Alliance for the Prudent Use of Antibiotics

@APUANews

Journals • Lancet Infectious Diseases

@TheLancetInfDis

• PLoS One

@PLOSONE

• Journal of the American Medical Association

@JAMA_current

• New England Journal of Medicine

@NEJM

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into the gravity of the epidemic faster than any other method of communication. The Ebola epidemic identified the importance of having access to real-time on-the-go information during an epidemic. In the USA, the CDC used Twitter to provide Ebola updates in real-time.

How do you get started on Twitter?

Getting started on Twitter is quick and easy. First-time users may go to www.twitter.com to sign up and create a free account. Once the account is registered, the Twitter app may be used on a smartphone. For a detailed description of Twitter terminology and how to get started, click on the following link: http://bcpsqc.ca/blog/knowledge/twitterfor-health-care-professionals/ We recommend uploading your photo and writing a brief biographical sketch that identifies you as a physician, pharmacist, nurse or HCP. The key to unleashing the power of Twitter is finding the right people to follow. Remember, you will receive every tweet from each person you follow, so it is wise to look at what they tweet prior to following them. Table 1 includes a selected list of reputable people and organisations who regularly tweet about AMR, and medical journals to follow on Twitter.

Fig. 2. Irish physicians participate in the Centers for Disease Control #antibioticday chat. Click on the following link to view their summary of the Twitter chat: https://storify.com/FfitzP/antibioticday-2014-dublin-ireland?utm_content=storify-pingback&utm_medium=sfy.co-twitter&utm_ campaign=&utm_source=t.co&awesm=sfy.co_e00jY

How is Twitter used as a learning tool for healthcare providers?

Twitter provides a dynamic way to share ideas, collaborate and connect with others, educate and build a global healthcare network. The following four topics demonstrate the application of Twitter for HCPs: • Medical conferences. Surgeons, oncologists, cardiologists and urologists are among attendees at non-infectious diseases specialist conferences, who tweet live from a conference to help to disseminate information in realtime and increase the reach. Tweets from conferences will reach members who are not able to attend. It also helps to multiply the impact of scholarship by retweeting messages. At the 2013 American College of Surgeons conference, 434 tweets from the meeting produced 474 776 impressions or views by followers who retweeted the original tweet.[9] • International journal clubs. Twitter journal clubs provide a unique platform for engagement between HCPs worldwide. Urologists have been one of the first to host an international journal club.[10] The organisers select an article from a peer-reviewed journal. Key opinion leaders or the article’s author leads the Twitter chat. Anyone with an internet connection and a Twitter

Fig. 3a. Full articles may be accessed from tweets by clicking on the blue links.

account can participate or monitor the discussion that occurs via tweets. The tweets are indexed using the journal club hashtag (#urojc). They currently have >2 650 followers, who generate a mean of 130 832 impressions each month, far exceeding the traditional reach of journal clubs held in hospitals. An international journal club on AMR would be valuable, as every new and emerging infectious disease is just a plane ride away. • Twitter chats. A Twitter chat is a ‘live’ event that is moderated by an expert and focuses on a particular topic. A predetermined hashtag (#) is used in each tweet to follow the conversation. For example, as part of the 2014 CDC’s Get Smart About Antibiotics campaign, the CDC hosted an antibiotic resistance-themed global Twitter chat using the hashtag (#antibioticday). Fig. 2 shows physicians from Ireland who

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Fig. 3b. Example of a Twitter profile.

participated in the CDC #antibioticday chat. Twitter chats allow experts to field questions from a global audience of HCPs, consumers, patients, policy makers and journalists. Furthermore, it increases the awareness of AMR to a global audience.

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• Networking. Twitter can help to build professional relationships with people you may never meet outside the virtual world. HCPs share an extremely wide range of tweets with links to articles, photos, and YouTube videos. It is not unheard of for colleagues collaborating on research projects to have met via Twitter. Twitter has enabled experts to communicate their research quickly and efficiently throughout each corner of the world. It provides a voice to HCPs who may not publish in peer-reviewed journals, but have many worthwhile thoughts or recommendations to share. The user may click on the blue links that will take them to a full article (Fig. 3a). A tweet may be saved for future viewing by clicking on the yellow star. This tags the tweet as a ‘favourite’ and also alerts the person who sent the tweet that you ‘favourited’ or liked the tweet. An example of a Twitter profile is given in Fig. 3b.

What are the risks of using Twitter as a healthcare provider?

HCPs must realise that as healthcare professionals their tweets are held to a higher standard. Always tweet responsibly and professionally. Remember, what appears on Twitter stays on Twitter forever. Never tweet information that could identify a patient and breach patient confidentiality. We recommend avoiding giving medical advice, as the 140-character limitation of a tweet may preclude writing a thorough response. Twitter, as all social media, is susceptible to inaccurate and erroneous messages. Always read links before retweeting messages from sources you do not know.

How do I overcome my fear of using Twitter?

Over 152 000 tweets per day are sent from 75 000 physicians, pharmacists, nurses and healthcare consultants.[11]

Click on the following link to see the uptake of Twitter by HCPs in Africa and around the world: http://www.creationpinpoint.com/ worldwide-doctors-on-twitter-explore-the-data/ Do not let the world pass you by. Now is the time to help to make a difference in the fight against AMR. Twitter is a vehicle that can connect the world and help to win the battle against AMR. References 1. Mayosi BM, Benatar SR. Health and health care in South Africa – 20 years after Mandela. N Engl J Med 2014;371(14):1344-1353. [http://dx.doi.org/10.1056/NEJMsr1405012] 2. World Health Organization (WHO). WHO Antimicrobial Resistance: Global Report on Surveillance, April 2014. www.who.int/drugresistance/documents/surveillancereport/en/ (accessed 2 December 2014). 3. Mendelson M, Matsoso M. A global call for action to combat antimicrobial resistance: Can we get it right this time? S Afr Med J 2014;104(7): 478-479. [http://dx.doi.org/10.7196/samj.8534] 4. CDC Vital Signs Report, March 2014. www.cdc.gov/vitalsigns (accessed 30 November 2014). 5. Goff DA, Mendelson M. Is it time for antibiotic prenuptial agreement? Lancet Infect Dis 2014;14:11681169. [http://dx.doi.org/10.1016/S1473-3099(14)70992-2] 6. Review on Antimicrobial Resistance. Antimicrobial resistance tackling a crisis for the health and wealth of nations 2014. http://amr-review.org/sites/default/files/AMR%20Review%20Paper%20 -%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf (accessed 3 December 2014). 7. World Wide Worx. http://www.worldwideworx.com/wp-content/uploads/2013/10/Exec-Summary-SocialMedia-2014.pdf (accessed 30 March 2015). 8. Symplur. http://www.symplur.com/healthcare-hashtags/ebola/ (accessed 24 October 2014). 9. Cochran A, Kao LS, Gusani NJ, et al. Use of Twitter to document the 2013 Academic Surgical Congress. J Surg Res 2014;190:36-40. [http://dx.doi.org/10.1016/j.jss.2014.02.029] 10. Thangasamy IA, Leveridge M, Davies BJ, et al. International Urology Journal Club via Twitter: 12-month experience. Eur Urol 2014;66:112-117. [http://dx.doi.org/10.1016/j.eururo.2014.01.034] 11. Creation Pinpoint. http://www.creationpinpoint.com/how-we-differ/big-hcp-data/ (accessed 4 November 2014).

Additional educational resources Best Care Always. http://www.bestcare.org.za Getting started with Twitter. https://support.twitter.com/articles/215585-getting-started-with-twitter Goff DA, Kullar R, Newland J. Review of Twitter for infectious diseases clinicians: Useful or a waste of time? Clin Infect Dis 4 February 2015. [Epub ahead of print] [http://dx.doi.org/10.1093/cid/civ071] South African Antibiotic Stewardship Programme (SAASP). http://www.fidssa.co.za/A_SAASP

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ARTICLE

Use of vaccines as a key antimicrobial stewardship strategy A J Brink,1 MB ChB, MMed (Clin Micro); G A Richards,2 MB BCh, PhD, FCP (SA), FRCP 1 2

Department of Clinical Microbiology, Ampath National Laboratory Services, Milpark Hospital, Johannesburg, South Africa Division of Critical Care, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa

Corresponding author: A J Brink (brinka@ampath.co.za)

Vaccination may prevent bacterial infections and decrease the potential for transmission. Some effective vaccines may reduce bacterial colonisation and exposure to antimicrobials by minimising the spread of resistant strains; in this regard, a substantial indirect immunity has been demonstrated that protects unvaccinated members of society. One of the best documented examples of the crucial role of vaccination has been an adjunct to an antimicrobial stewardship programme. Pneumococcal conjugate vaccines (PCVs), for example, target the most virulent pneumococcal serotypes, which are linked to invasive disease and associated with antibiotic resistance. In this regard, recent local data highlight the remarkable impact of the sequential introduction of 7- and 13-valent PCV (PCV7/PCV13) on the incidence of penicillin-, ceftriaxone- and multidrug-resistant pneumococcal infections in South Africa in only 4 years. Equally impressive have been vaccines directed towards viruses such as influenza, which also have direct and indirect effects on antibiotic consumption. S Afr Med J 2015;105(5):421. DOI:10.7196/SAMJ.9651

Antimicrobial resistance (AMR) has increased world wide to the extent that it is now regarded as a global public health crisis. As acquired resistance is driven mainly by the exposure of bacteria to commonly prescribed antimicrobial agents, pragmatic responses to this problem should be the promotion of judicious use of antimicrobials and prevention of infections that would require antimicrobial treatment. The efficacy of both bacterial and viral vaccines in the reduction of antimicrobial prescriptions has been well described and as such they are a key strategy in the fight against AMR and a crucial component of a comprehensive antimicrobial stewardship (AMS) programme.

The reduction in carriage of serotypes with a high capacity to colonise may also contribute to a reduction in antibiotic resistance, spread and burden of pneumococcal diseases. Reductions in vaccine serotype and all-type invasive pneumococcal disease have also been reported in age groups not eligible for vaccination, demonstrating the extraordinary impact of indirect protection. Of note, this pheno menon extends to mortality, where a substantial population-level decline in pneumococcal-related mortality of nearly 30% was recently found among the unvaccinated population.[2]

Bacterial vaccines

In South Africa (SA), Von Gottberg et al.[3] recently demonstrated an 89% reduction in the incidence of invasive pneumococcal disease by PCV7 serotypes within 4 years of their introduction among vaccinated children <2 years of age (direct effect), and a 57% reduction among unvaccinated adults 25 - 44 years of age (indirect effect). In a recent matched, case-control study Cohen et al.[4] similarly documented the efficacy of PCV7 using a two plus one schedule (6 and 14 weeks, and 9 months) among HIV-uninfected and -exposed SA children. Within the first 2 years of a PCV13 immunisation programme in Nicaragua, lower rates of hospitalisation and outpatient visits for pneumonia among children of all ages were observed.[5] In Israel, in a prospective, long-term, active surveillance survey, a rapid and sharp 2-step decline in pneumococcal and all-cause AOM incidence (with near-elimination of PCV13 disease) in children aged <2 years was noted following sequential PCV7/PCV13 introduction.[6] In the USA, after the introduction of PCV13, isolation of Streptococcus pneumoniae declined in children with chronic sinusitis, including a substantial reduction of PCV13 serotypes, predominantly serotype 19A.[7] The protective effect of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) for the prevention of AOM caused by S. pneumoniae and non-typeable H. influenzae has been documented at 52.6% (for pneumococcal vaccine serotypes) and 35.3%, respectively.[8] Vaccine efficacy against any episode of ear, nose and throat-referred AOM during per-protocol follow-up was 34% (95% confidence interval 21 - 45).

By targeting bacterial pathogens: • Vaccines directly reduce the need for antibiotics by providing direct protection from bacterial disease, regardless of whether the organism is resistant to specific antimicrobials or not. • Vaccines may inhibit carriage by decreasing acquisition and colonisation by bacteria, specifically those targeted by the vaccine. • Vaccines further reduce overall antibiotic consumption owing to indirect protection. This relates to the prevention of or reduction in transmission of pathogenic bacteria between unvaccinated members of the community. Considering these factors, one of the best documented examples of the crucial role of vaccination as an adjunct to an AMS programme has been the pneumococcal conjugate vaccines (PCVs) – the main focus of this article.

Pneumococcal conjugate vaccines

Accumulated evidence suggests that the 13-valent PCV (PCV13) has reduced much of the residual burden of pneumococcal diseases still present in children after the introduction of PCV7.[1] This includes colonisation, and invasive, mucosal and drug-resistant pneumococcal diseases, and relates to the impact of PCV13 on the ‘pneumococcal mucosal trio’ of nasopharyngeal carriage, subsequent acute otitis media (AOM) and pneumonia.

Impact of pneumococcal conjugate vaccines on pneumococcal disease

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Impact of pneumococcal conjugate vaccines on antibiotic resistance

4.5

Impact of pneumococcal conjugate vaccines on antibiotic use

Need for a concurrent programme promoting appropriate antibiotic use with widespread vaccination

Increasing evidence suggests that a campaign to increase vaccine uptake should include a programme to promote appropriate antibiotic use as this appears to have synergistic effects, which seem to be of particular relevance to PCV. • A reduction in antibiotic consumption in primary care in conjunction with an increase

4.0 Penicillin

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Ceftriaxone

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Several studies were conducted to evaluate the direct impact of PCV in reducing antibiotic prescriptions and respiratory illnesses in children. A 5.4% reduction in antibiotic prescriptions was recorded after the introduction of PCV7 at the Kaiser Permanente clinics in Northern California, as well as a 12.6% decrease in second-line antibiotic prescriptions.[9] Overall, PCV7 prevented 35 antibiotic prescriptions per 100 vaccinated children. Furthermore, risk reductions of 15%, 16% and 17% for upper respiratory tract infections, lower respiratory tract infections, and AOM, respectively, as well as a 17% reduction in antibiotic use, were observed in children who were given PCV9.[10] In a study of privately insured children in the USA, a 41.9% reduction in antibiotic prescriptions for AOM was demonstrated from 1997 to 2004 following implementation of the PCV7 immunisation programme.[11] It has been predicted that universal vaccination of children with PCV13 would reduce AOM by an additional 16.3 million cases in the USA compared with vaccination with PCV7. The PHiD-CV10 vaccine is also effective; using the impact of this vaccine on outpatient antibiotic prescriptions, specifically those recommended by the Finnish national treatment guidelines for AOM as the primary endpoint assessment, an 8% efficacy was found.[12]

PCV13

5.0

Cases per 100 000 person-years

As depicted in Fig. 1, the introduction of PCV7 in SA in 2009, followed by PCV13 in 2011, led not only to a dramatic reduction in penicillin- (82%) and ceftriaxone-resistant (85%) pneumococcal infections, but also to multidrug-resistant (MDR) disease (84%).[3] These remarkable results are supported by the matched case-control study by Cohen et al.,[4] confirming that PCV may have a substantial impact on reducing the prevalence of MDR pneumococcal disease, as has been demonstrated in other settings.

PCV7

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Fig. 1. Rates of disease caused by non-susceptible pneumococcal isolates among all ages (A), and among children <2 years of age (B), by antimicrobial agent and year, SA, 2005 - 2012 (adapted and reproduced with permission from Von Gottberg et al.[3] (PCV7 and PCV13 were introduced in 2009 and 2011, respectively)).

in PCV uptake had a synergistic effect on carriage of resistant pneumococci in the cohort studied.[13] Risks for penicillin nonsusceptible S. pneumoniae carriage were 4.2% for immunised children who had not received antibiotics in the preceding 3 months, 8.6% for immunised patients who had received antibiotics, 10.3% for non-immunised patients who had not received antibiotics, and 16.2% for non-immunised children who had received antibiotics (p<0.001). • Hicks et al.[14] recently demonstrated that after the introduction of PCV7 vacci nation, if antibiotic prescribing remained high (particularly cephalosporins and longacting macrolides/azalides), the proportion of non-susceptible invasive pneumococcal disease due to non-vaccine serotypes also remained high, suggesting that

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local prescribing practices continue to contribute to local resistance patterns. Studies such as these reinforce the need for concomitant, judicious antibiotic utilisation intervention programmes.

Viral vaccines

In addition to antibacterial vaccines, such as those against diphtheria, pertussis and H. influenzae type b, vaccines for viruses can also have direct and indirect effects on antibiotic consumption by reducing: • Viral infections and fever syndromes, where antibiotics are frequently and inappropriately used. • Complications of viral infections (e.g. secondary bacterial infection) requiring antibiotics.

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In Finland, 42% of children suffering from seasonal influenza receive antibiotics inappropriately, but in a study in Ontario, Canada, the increased use of influenza vaccination following recommendations for universal use resulted in a 64% decrease in antimicrobial prescriptions for influenza-associated respiratory disease.[15] Targeting selected patient groups, such as postpartum mothers, is also beneficial. Influenza vaccination reduced acute respiratory illnesses, febrile episodes, influenza-like illnesses and healthcare visits in neonates born to vaccinated mothers by 37.7%, 50.3%, 53.5% and 41.8%, respectively, and also reduced antibiotic prescriptions by 45.4%.[16] Madhi et al.[17] recently documented the impact of influenza vaccination on pregnant women in SA. The data showed that vaccination provided protection in pregnant HIV-uninfected and -infected women and that vaccination was also effective in HIVunexposed infants up to 24 weeks after birth.

Conclusion

By reducing the prevalence of infection through vaccination (bacterial or viral) the number of patients visiting medical facilities are minimised, which in the majority of cases avoids the indiscriminate use of antibiotics. Vaccination, therefore, could limit the development of AMR by decreasing the likelihood that bacteria targeted by certain vaccines would be exposed to antimicrobial agents. In this regard, the results of the Community Acquired Pneumonia Immunization Trial in Adults (CAPITA), an efficacy study of PCV13 in the prevention of a first episode of vaccine serotype-specific pneumococcal CAP in 85 000 adults aged ≥65 years, are eagerly awaited. Innovative vaccines targeting hospital-acquired infections are currently under investigation and are also an exciting prospect for the future. Therefore, public authorities are increasingly acknowledging the role of vaccination in the fight against AMR and consider it a key intervention in national AMS programmes.

References 1. Azzari C, Martinón-Torres F, Schmitt H-J, Dagan R. Evolving role of 13-valent pneumococcal conjugate vaccine in clinical practice. Pediatr Infect Dis J 2014;33:858-864. [http://dx.doi.org/10.1097/ INF.0000000000000328] 2. Harboe ZB, Dalby T, Weinberger DM, et al. Impact of 13-valent pneumococcal conjugate vaccination in invasive pneumococcal disease incidence and mortality. Clin Infect Dis 2014;59:1066-1073. [http:// dx.doi.org/10.1093/cid/ciu524] 3. Von Gottberg A, de Gouveia L, Tempia S, et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N Engl J Med 2014;371:1889-1899. [http://dx.doi.org/10.1056/NEJMoa1401914] 4. Cohen C, von Mollendorf C, de Gouveia L, et al. Effectiveness of seven-valent pneumococcal conjugate vaccine (PCV-7) against invasive pneumococcal disease in HIV-infected and -uninfected children in South Africa: A matched case-control study. Clin Infect Dis 2014;59:808. [http://dx.doi.org/10.1093/cid/ciu431] 5. Becker-Dreps S, Amaya E, Liu L, et al. Changes in childhood pneumonia and infant mortality rates following introduction of the 13-valent pneumocovaccine in Nicaragua. Pediatr Infect Dis J 2014;33:637-642. [http://dx.doi. org/10.1097/INF.0000000000000269] 6. Ben-Shimol S, Givon-Lavi N, Leibovitz E, Dagan R. Near-elimination of otitis media caused by 13-valent pneumococcal conjugate vaccine (PCV) serotypes in southern Israel shortly after sequential introduction of 7-valent/13-valent PCV. Clin Infect Dis 2014;59:1724-1732. [http://dx.doi. org/10.1093/cid/ciu683] 7. Olarte L, Hulten KG, Lamberth L, et al. Impact of the 13-valent pneumococcal conjugate vaccine on chronic sinusitis Streptococcus pneumoniae in children. Pediatr Infect Dis J 2014;33:1033-1036. [http://dx.doi.org/10.1097/INF.0000000000000387] 8. Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: A randomised double-blind efficacy study. Lancet 2006;367:740-748. [http:// dx.doi.org/10.1016/s0140-6736(06)68304-9] 9. Fireman B, Black SB, Shinefield HR, et al. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003;22:10-16. [http://dx.doi.org/10.1097/00006454-200301000-00006] 10. Dagan R, Sikuler-Cohen M, Zamir O, et al. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J 2001;20:951958. [http://dx.doi.org/10.1097/00006454-200110000-00008 ] 11. Zhou F, Shefer A, Kong Y, et al. Trends in acute otitis media-related health care utilization by privately insured young children in the United States, 1997-2004. Pediatrics 2008;121:253-260. [http://dx.doi. org/10.1542/peds.2007-0619] 12. Palmu AA, Jokinen J, Nieminen H, et al. Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: A double-blind, cluster randomised phase 3-4 trial. Lancet Infect Dis 2014;14: 205-212. [http://dx.doi.org/10.1016/s1473-3099(13)70338-4] 13. Cohen R, Levy C, de La Rocque F, et al. Impact of pneumococcal conjugate vaccine and of reduction of antibiotic use on nasopharyngeal carriage of nonsusceptible pneumococci in children with acute otitis media. Pediatr Infect Dis J 2006;25:1001-1007. [http://dx.doi.org/10.1097/01. inf.0000243163.85163.a8] 14. Hicks LA, Chien Y, Taylor TH, et al. Outpatient antibiotic prescribing and nonsusceptible Streptococcus pneumoniae in the United States, 1996-2003. Clin Infect Dis 2011;53:631-639. [http://dx.doi.org/10.1093/cid/cir443] 15. Kwong JC, Maaten S, Upshur REG, et al. The effect of universal influenza immunization on antibiotic prescriptions: An ecological study. Clin Infect Dis 2009;49:750-756. [http://dx.doi.org/10.1086/605087] 16. Maltezou HC, Fotiou A, Antonakopoulos N, et al. Impact of postpartum influenza vaccination of mothers and household contacts in preventing febrile episodes, influenza-like illness, healthcare seeking, and administration of antibiotics in young infants during the 2012-2013 influenza season. Clin Infect Dis 2013;57:1520-1526. [http://dx.doi.org/ 10.1093/cid/cit599] 17. Madhi SA, Cutland CL, Kuwanda L, et al. Influenza vaccination of pregnant women and protection of their infants. N Engl J Med 2014;371:918-931. [http://dx.doi.org/ 10.1056/NEJMoa1401480]

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Role of infection control in combating antibiotic resistance A C Whitelaw, MB BCh, MSc, FCPath (SA) (Micro) Division of Medical Microbiology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University and National Health Laboratory Service, Tygerberg Hospital, Cape Town, South Africa Corresponding author: A C Whitelaw (awhitelaw@sun.ac.za)

Infection control has been identified as one of the key interventions in controlling the threat of antibiotic resistance. Reducing the transmission of multidrug-resistant organisms (MDROs) reduces the need for broad-spectrum antibiotics in particular, while interventions that decrease the risk of infection have an impact on the use of any antibiotic. Hand hygiene remains the cornerstone of decreasing the transmission of MDROs. Alcohol-based hand rubs are a cheap, effective and convenient means of performing hand hygiene. Patients colonised or infected with MDROs should be placed on contact precautions, although implementation remains challenging in resourcelimited environments. Screening for certain MDROs may play a role in curbing transmission of these organisms. If implemented, screening must be part of a comprehensive infection control strategy. In resource-limited settings, the costs and potential benefits of screening programmes need to be carefully weighed up. Care bundles have been shown to reduce the incidence of common healthcare-associated infections, including catheter-associated urinary tract infection, ventilator-associated pneumonia, central line-associated bloodstream infection and surgical site infection. These bundles are relatively inexpensive, and can play an important role in reducing antibiotic use and improving clinical outcomes. S Afr Med J 2015;105(5):421. DOI:10.7196/SAMJ.9650

Antimicrobial resistance (AMR) is now well recognised as a global health threat[1] that impacts on human health and may potentially have a major effect on the global economy.[2] The United States Centers for Disease Control and Prevention (CDC) has identified four core actions to combat this challenge, i.e. surveillance, antibiotic stewardship, improved drugs and diagnostics, and preventing spread.[3] While infection control is a very broad topic, this article focuses on measures to prevent the spread of multidrug-resistant organisms (MDROs) in healthcare settings and interventions to prevent infection.

Transmission of multidrug-resistant organisms

Transmission of any infectious agent (whether multidrug resistant or not) implies the presence of a source of the organism, a susceptible host, and a transfer mechanism. Most infectious agents in the healthcare setting are transmitted from humans (most commonly patients, but also healthcare workers (HCWs) or visitors), although transmission from environmental sources has also been well described.[4,5] The greater the number of patients colonised with a particular MDRO (the â&#x20AC;&#x2DC;colonisation pressureâ&#x20AC;&#x2122;), the greater the chance of transmission.[5] Colonised HCWs have also been implicated in the transmission of infectious agents,[6] but are thought to be a far less common source.[5] Although organisms can be transmitted to any patient in hospital, certain patients are at higher risk of colonisation (and therefore of potential infection), including those with underlying medical conditions, those with compromised defences (such as indwelling devices, burns), and those who have undergone recent surgery. There are three broad mechanisms by which organisms can be transmitted in healthcare settings:[4] contact, droplet transmission and airborne transmission. Droplet transmission refers to organisms spread by large respiratory droplets (e.g. pertussis, diphtheria, certain respiratory viruses), while airborne transmission applies to organisms spread on droplet nuclei that remain suspended for prolonged periods (e.g. Mycobacterium tuberculosis, measles, varicella). Neither

of these are a major route of transmission for MDROs, except for MDR tuberculosis, which is not the focus of this article. Contact spread is the most important means of transmission for the vast majority of MDROs in healthcare settings, and can be either direct or indirect. Direct contact transmission occurs when an infected or colonised person comes into physical contact with a susceptible host. Indirect contact transmission implies the presence of some intermediate vehicle â&#x20AC;&#x201C; either human or an inanimate object. Although transmission by items such as contaminated equipment, shared toys and poorly sterilised equipment is possible, the most important means of transmission is via the hands of HCWs.

Prevention of transmission

As the hands of HCWs are the most important means of transmission of MDROs, the importance of hand hygiene cannot be overstated. A number of studies have shown that improvements in hand hygiene are associated with lower healthcare-associated infection rates, and/or reductions in MDRO transmission and acquisition.[7-10] Nonetheless, compliance with hand hygiene recommendations is often poor, with studies reporting rates as low as 20 - 30%.[11-13] The adequate disinfection of hands is easily accomplished by using an alcoholic hand rub, with or without additional disinfectants, e.g. chlorhexidine. The alcohol is responsible for the immediate killing of transient flora on the hands, while the additional agents may exert a residual effect, limiting reacquisition of organisms for a limited period (although the evidence is mainly based on in vitro simulations, and the additional benefit of preventing transmission has not been studied well). Alcohol hand rubs are superior to both ordinary soap and water and medicated soap and water with regard to the efficacy of removal of micro-organisms. This is based on numerous in vitro simulations and clinical evidence.[14] As an example, a 6-year observation study at a tertiary centre in the USA compared 3 years of medicated soap use with 3 years of alcoholic hand rub use, and showed reductions in acquisition of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (21% and

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• after contact with body fluids • after patient contact • after contact with the patient’s environment.

Measures beyond hand hygiene

Fig. 1. The World Health Organization’s ‘Your 5 Moments for Hand Hygiene’ campaign.[14,16]

41% reductions, respectively).[15] This may be due to the greater efficacy of alcohol and improved compliance with hand hygiene, with hand rubs being more easily accessible. Alcohol hand rubs can be manufactured very easily and cheaply if commercial products are not available. One suggested recipe is as follows:[14] • ethanol 96% v/v, 833.3 mL • hydrogen peroxide (H2O2) 3%, 41.7 mL • glycerol 98%,14.5 mL.

acceptability. Neither of these items plays a role in the actual hand disinfection process. Other important factors to remember with regard to the use of alcohol-based hand rubs are: • If hands are visibly soiled, they should first be cleaned with soap and water – before using hand rubs. • Alcohol is less effective at removing spores; hence, when caring for patients with suspected or confirmed Clostridium difficile infections, medicated soap is preferred.

Make up to 1 000 mL with distilled water or boiled and cooled water and shake gently to mix the contents. H202 is added to help eliminate contam inating spores in the bulk solutions, and glycerol acts as an emollient to improve

The World Health Organization is promo ting the ‘Your 5 Moments for Hand Hygiene’ campaign (Fig. 1),[14,16] which recommends that hand hygiene be practised as follows: • before patient contact • before a clean or aseptic procedure

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Other measures have been advocated to reduce the risk of transmission of MDROs. The CDC[4] recommends that all patients colonised or infected with epidemiologically important pathogens (including MDROs) that are spread by contact be placed on contact precautions. This consists of isolating the patient in a room (or placing the patient with others with the same organism), use of gloves for all patient contact, and use of gowns/aprons during patient contact. Where isolation rooms are limited, patients with MDROs may need to be nursed in open wards. However, even there, every effort should be made to implement the glove and gown components of contact precautions. These recommendations are based on expert opinion and knowledge of the transmission mechanism, but there is limited evidence that contact precautions make a significant difference to transmission of MDROs, over and above good hand hygiene and adherence to basic infection control principles.[5,17-19] Many studies include multiple interventions (improved staffing levels, education campaigns, hand hygiene campaigns) in addition to contact precautions, and it is difficult to identify which has the greatest impact. There have been concerns about the impact of isolation on the mental wellbeing of patients.[20] The additional burden of having patients on contact precautions may lead to a reduction in HCW compliance with these precautions.[21] Even given these concerns, there is evidence that implementation of contact precautions does improve hand hygiene compliance,[19] and it is still recommended for patients with MDROs. However, the importance of adequate staffing to sustain contact precautions and standard infection control practices cannot be overstated.

Screening and decolonisation

There is good evidence that active screening of preoperative patients for MRSA, with decolonisation of carriers, results in reductions in postoperative sepsis caused by MRSA and other pathogens.[22] The same effect has been described where all patients were decolonised with nasal mupirocin and chlorhexidine washes without the added cost of screening.[23] Chlorhexidine washes alone have also been shown to reduce the

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acquisition of MDROs and development of healthcare-associated bacteraemia by 23% and 28%, respectively.[24] This raises the question of whether the application of intranasal mupirocin has benefit over chlorhexidine washes. The effect of chlorhexidine washes or wipes on infections with MDR Gram-negative bacteria specifically has not been as well described, and this, together with the descriptions of emerging chlorhexidine resistance, has led to some concerns about the implementation of routine chlorhexidine washes as a decolonisation strategy.[25] Surveillance cultures for carbapenem-resistant Enterobacteriaceae (CRE) have been advocated in a number of reports and recommendations as part of an overall strategy to combat this specific MDRO.[26,27] Screening has been a part of successful CRE control measures described in a variety of settings.[28,29] However, as before, all these studies have included other interventions and it is very difficult to determine the effect of surveillance cultures alone on CRE control. There is evidence that CRE can be controlled without the use of surveillance cultures,[18] and in resource-limited settings in particular it may be more appropriate to increase overall infection control capacity than to focus on screening. Decolonisation strategies have not been well described for any of the resistant Gram-negative organisms. Some studies have demonstrated emergence of resistance during CRE decolonisation regimens (which usually include colistin),[30-32] and this, allied to limited evidence of its efficacy, strongly suggests that decolonisation for multiresistant Gram-negative bacteria should not be attempted. If active screening for CRE carriage is carried out, the main intervention for carriers consists of isolation/cohorting and enhanced infection control measures. The duration of isolation for CRE (and for many other MDROs) is not well defined. CRE can be carried for ≥12 months,[33] and if patients are identified as CRE carriers, it may be valuable to be able to identify them on readmission to hospital. Screening to document elimination of carriage can be attempted; however, it has been suggested that there should be at least two negative cultures (and possibly a negative polymerase chain reaction test) before a known CRE carrier patient can be regarded as no longer carrying this organism.[34] This is an area where more research is required.

Prevention of infection

While many infection control interventions focus on reducing the transmission of organisms, it is as important to identify measures to reduce the risk of infection. Fewer infections translate into reductions in antibiotic use and better patient outcomes. Many professional bodies and groups have adopted the use of ‘care bundles’, whereby different interventions focused on the same infection are combined and practised as a standard of care. In South Africa, this is being driven by the ‘Best Care … Always’ (BCA) campaign (http://www. bestcare.org.za/home). The four infections addressed by the BCA bundles are catheter-associated urinary tract infection (CA-UTI), ventilator-associated pneumonia (VAP), central line-associated bloodstream infection (CLABSI), and surgical site infection (SSI). Although there are some differences in the components of the bundles drawn up by different groups, and there is room for addition or modification, the components of the BCA bundles are as follows: CA-UTI • Avoid unnecessary catheterisation • Insert catheters using an aseptic technique • Maintain catheters based on recommended guidelines • Review the need for catheterisation daily and remove the catheter as soon as possible.

VAP • Elevation of the head of the bed to 45° (or 30° if 45° not possible) • Subglottic drainage of secretions • Assess readiness for extubation daily • Oral care and cleaning with chlorhexidine • Initiation of enteral feeding within 24 - 48 hours of admission. CLABSI • Maximal barrier precautions when inserting line • Chlorhexidine antisepsis when inserting line • Selection of optimal catheter insertion suite (weighing infection and complication risks) • Hand hygiene when caring for line • Review the need for line daily, and remove as soon as possible. SSI • Appropriate antibiotic prophylaxis (timing, choice, duration) • Appropriate hair removal (clippers or depilatory creams, not shaving) • Postoperative glucose control • Maintain postoperative normothermia. Although some of the abovementioned components may be difficult to implement, the majority are relatively simple, require minimal resources, and when implemented can result in a dramatic reduction in infection. The incidence of SSI after colorectal surgery was 2% in patients who received all six components of a bundle, and 17% in those who received only one component.[35] A multicentre before-andafter study in Korea showed a reduction in VAP rates from 4.08/1 000 ventilator-days to 1.16/1 000 ventilator-days after implementation of a VAP bundle.[36] Reductions in VAP rates after implementing bundles have been associated with reduced ventilation-days and length of stay in the intensive care unit (ICU).[37] Implementation of CLABSI bundles has resulted in reductions in CLABSI rates of up to 56%;[38] despite different studies using different bundles, there is a consistent reduction in the rates of these infections.[38-40] Introduction of bundles for CLABSI, VAP and CA-UTI in ICUs of a Saudi Arabian hospital resulted in reductions in the rates of all three infections (86% for VAP, 63% for CLABSI and 50% for CA-UTI).[41]

Conclusion

Infection control has a major role to play in combating the threat of AMR, and many interventions that have proven benefit are relatively inexpensive. Chief among these is hand hygiene. The challenge remains the appropriate implementation of these interventions, and sustaining them once immediate threats are over. Infection control should no longer be seen as the sole responsibility of the infection control practitioner, but that of every HCW. References 1. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance 2014. http:// www.who.int/drugresistance/documents/surveillancereport/en/ (accessed 8 April 2015). 2. O’Neil J. Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations 2014. http://www.jpiamr.eu/wp-content/uploads/2014/12/AMR-Review-PaperTackling-a-crisis-for-the-health-and-wealth-of-nations_1-2.pdf (accessed 8 April 2015). 3. US Centres for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/ (accessed 8 April 2015). 4. Siegel JD, Rhinehart E, Jackson M, Chiarello L; the Healthcare Infection Control Practices Advisory Committee. Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings, June 2007. http://www.cdc.gov/hicpac/pdf/isolation/Isolation2007.pdf (accessed 8 April 2015). 5. Siegel JD, Rhinehart E, Jackson M, Chiarello L; the Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in healthcare settings, 2006. Am J Infect Control 2007;35:S165-S193. 6. Ben-David D, Mermel LA, Parenteau S. Methicillin-resistant Staphylococcus aureus transmission: The possible importance of unrecognized healthcare worker carriage. Am J Infect Control 2008;36(2):93-97. [http://dx.doi.org/10.1016/j.ajic.2007.05.013]

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7. Kaier K, Hagist C, Frank U, Conrad A, Meyer E. Two time-series analyses of the impact of antibiotic consumption and alcohol-based hand disinfection on the incidences of nosocomial methicillinresistant Staphylococcus aureus infection and Clostridium difficile infection. Infect Control Hosp Epidemiol 2009;30(4):346-353. [http://dx.doi.org/10.1086/596605] 8. Stone SP, Fuller C, Savage J, et al. Evaluation of the national Cleanyourhands campaign to reduce Staphylococcus aureus bacteraemia and Clostridium difficile infection in hospitals in England and Wales by improved hand hygiene: Four year, prospective, ecological, interrupted time series study. BMJ 2012;3(344):e3005. [http://dx.doi.org/10.1136/bmj.e3005] 9. Helder OK, Brug J, van Goudoever JB, Looman CW, Reiss IK, Kornelisse RF. Sequential hand hygiene promotion contributes to a reduced nosocomial bloodstream infection rate among very low-birth weight infants: An interrupted time series over a 10-year period. Am J Infect Control 2014;42(7):718722. [http://dx.doi.org/10.1016/j.ajic.2014.04.005] 10. De Angelis G, Cataldo MA, De Waure C, et al. Infection control and prevention measures to reduce the spread of vancomycin-resistant enterococci in hospitalized patients: A systematic review and metaanalysis. J Antimicrob Chemother 2014;69(5):1185-1192. [http://dx.doi.org/10.1093/jac/dkt525] 11. Marra AR, Edmond MB. New technologies to monitor healthcare worker hand hygiene. Clin Microbiol Infect 2014;20(1):29-33. [http://dx.doi.org/10.1111/1469-0691.12458] 12. Tenna A, Stenehjem EA, Margoles L, Kacha E, Blumberg HM, Kempker RR. Infection control knowledge, attitudes, and practices among healthcare workers in Addis Ababa, Ethiopia. Infect Control Hosp Epidemiol 2013;34(12):1289-1296. [http://dx.doi.org/10.1086/673979] 13. Block L, Habicht R, Oluyadi FO, et al. Variability in hand hygiene practices among internal medicine interns. Am J Infect Control 2013;41(11):1107-1108. [http://dx.doi.org/10.1016/j.ajic.2013.03.303] 14. World Health Organization (WHO). WHO guidelines on hand hygiene in healthcare 2009. http:// whqlibdoc.who.int/publications/2009/9789241597906_eng.pdf (accessed 8 April 2015). 15. Gordin FM, Schultz ME, Huber RA, Gill JA. Reduction in nosocomial transmission of drugresistant bacteria after introduction of an alcohol-based handrub. Infect Control Hosp Epidemiol 2005;26(7):650-653. 16. Sax H, Allegranzi B, Uçkay I, Larson E, Boyce J, Pittet D. ‘My five moments for hand hygiene’: A usercentred design approach to understand, train, monitor and report hand hygiene. Journal of Hospital Infection 2007;67:9-21. 17. Huskins WC, Huckabee CM, O’Grady NP, et al. Intervention to reduce transmission of resistant bacteria in intensive care. N Engl J Med 2011;364:1407-1418. [http://dx.doi.org/10.1056/NEJMoa1000373] 18. Kim NH, Han WD, Song KH, et al. Successful containment of carbapenem-resistant Enterobacteriaceae by strict contact precautions without active surveillance. American Journal of Infection Control 2014;42(12):1270-1273. [http://dx.doi.org/10.1016/j.ajic.2014.09.004] 19. Harris AD, Pineles L, Belton B, et al. Universal glove and gown use and acquisition of antibioticresistant bacteria in the ICU: A randomized trial. J Am Med Assoc 2013;310(15):1571-1580. 20. Bearman G, Stevens MP. Control of drug-resistant pathogens in endemic settings: Contact precautions, controversies, and a proposal for a less restrictive alternative. Curr Infect Dis Rep 2012;14(6):620-626. [http://dx.doi.org/10.1007/s11908-012-0299-8] 21. Dhar S, Marchaim D, Tansek R, et al. Contact precautions: More is not necessarily better. Infect Control Hosp Epidemiol 2014;35(3):213-221. [http://dx.doi.org/10.1086/675294] 22. Van Rijen M, Bonten M, Wenzel R, Kluytmans J. Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers. Cochrane Database Syst Rev 2008;8(4):CD006216. [http://dx.doi. org/10.1002/14651858.CD006216.pub2] 23. Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med 2013;368(24):2255-2265. [http://dx.doi.org/ 10.1056/NEJMoa1207290] 24. Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med 2013;368(6):533-542. [http://dx.doi.org/ 10.1056/NEJMoa1113849]

25. Tacconelli E, Cataldo MA, Dancer SJ, et al. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients. Clin Microbiol Infect 2014;20(Suppl 1):1-55. [http://dx.doi.org/10.1111/1469-0691.12427] 26. Carmeli Y, Akova M, Cornaglia G, et al. Controlling the spread of carbapenemase-producing Gramnegatives: Therapeutic approach and infection control. Clin Microbiol Infect 2010;16(2):102-111. [http://dx.doi.org/10.1111/j.1469-0691.2009.03115.x] 27. Centers for Disease Control and Prevention (CDC). Guidance for control of infections with carbapenemresistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. MMWR Morb Mortal Wkly Rep 2009;58(10):256-260. 28. Poulou A, Voulgari E, Vrioni G, et al. Imported Klebsiella pneumoniae carbapenemase-producing K. pneumoniae clones in a Greek hospital: Impact of infection control measures for restraining their dissemination. J Clin Microbiol 2012;50(8):2618-2623. [http://dx.doi.org/10.1128/JCM.00459-12] 29. Schwaber MJ, Carmeli Y. An ongoing national intervention to contain the spread of carbapenemresistant Enterobacteriaceae. Clin Infect Dis 2014;58(5):697-703. [http://dx.doi.org/10.1093/cid/cit795] 30. Oren I, Sprecher H, Finkelstein R, et al. Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with non-absorbable oral antibiotic treatment: A prospective controlled trial. Am J Infect Control 2013;41(12):1167-1172. [http://dx.doi.org/10.1016/j.ajic.2013.04.018] 31. Lubbert C, Faucheux S, Becker-Rux D, et al. Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: A single-centre experience. International Journal of Antimicrobial Agents 2013;42(6):565-570. [http://dx.doi.org/ 10.1016/j.ijantimicag.2013.08.008] 32. Brink AJ, Coetzee J, Corcoran C, et al. Emergence of OXA-48 and OXA-181 carbapenemases among Enterobacteriaceae in South Africa and evidence of in vivo selection of colistin resistance as a consequence of selective decontamination of the gastrointestinal tract. J Clin Microbiol 2013;51(1):369372. [http://dx.doi.org/10.1128/JCM.02234-12] 33. Zimmerman FS, Assous MV, Bdolah-Abram T, Lachish T, Yinnon AM, Wiener-Well Y. Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge. Am J Infect Control 2013;41(3):190-194. [http://dx.doi.org/10.1016/j.ajic.2012.09.020] 34. Feldman N, Adler A, Molshatzki N, et al. Gastrointestinal colonization by KPC-producing Klebsiella pneumoniae following hospital discharge: Duration of carriage and risk factors for persistent carriage. Clinical Microbiology and Infection 2013;19(4):E190-E196. [http://dx.doi.org/10.1111/1469-0691.12099] 35. Waits SA, Fritze D, Banerjee M, et al. Developing an argument for bundled interventions to reduce surgical site infection in colorectal surgery. Surgery 2014;155(4):602-606. [http://dx.doi.org/10.1016/j. surg.2013.12.004] 36. Eom JS, Lee MS, Chun HK, et al. The impact of a ventilator bundle on preventing ventilator-associated pneumonia: A multicenter study. Am J Infect Control 2014;42(1):34-37. [http://dx.doi.org/10.1016/j.ajic.2013.06.023] 37. Rello J, Afonso E, Lisboa T, et al. A care bundle approach for prevention of ventilator-associated pneumonia. Clin Microbiol Infect 2013;19(4):363-369. [http://dx.doi.org/10.1111/j.1469-0691.2012.03808.x] 38. Jeffries HE, Mason W, Brewer M, et al. Prevention of central venous catheter-associated bloodstream infections in pediatric intensive care units: A performance improvement collaborative. Infect Control Hosp Epidemiol 2009;30(7):645-651. [http://dx.doi.org/10.1086/598341] 39. Miller MR, Niedner MF, Huskins WC, et al. Reducing PICU central line-associated bloodstream infections: 3-year results. Pediatrics 2011;128(5):e1077-e1083. [http://dx.doi.org/10.1542/peds.2010-3675] 40. Schulman J, Stricof R, Stevens TP, et al. Statewide NICU central-line-associated bloodstream infection rates decline after bundles and checklists. Pediatrics 2011;127(3):436-444. [http://dx.doi.org/10.1542/ peds.2010-2873] 41. Al-Tawfiq JA, Amalraj A, Memish ZA. Reduction and surveillance of device-associated infections in adult intensive care units at a Saudi Arabian hospital, 2004-2011. Int J Infect Dis 2013;17(12):e1207-e1211. [http://dx.doi.org/10.1016/j.ijid.2013.06.015]

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CONTINUING MEDICAL EDUCATION

CASE REPORT

A lady with a broken heart: Apical ballooning syndrome C Rush,1 MB ChB; M Ntsekhe,2 MD, PhD, FACC 1 2

Department of Internal Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa D ivision of Cardiology, Department of Internal Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa

Corresponding author: C Rush (rshcol002@gmail.com)

Severe chest pain after an emotional argument resulted in the admission of a healthy 72-year-old woman. She was haemo dynamically compromised, with an electrocardiogram (ECG) demonstrating anterior ST-depression and T-wave inver sions (Fig. 1). Her 6-hour troponin T level was 132 ng/L. Cardiac catheterisation revealed unobstructed coronary arteries and a reduced left ventricular ejection fraction (LVEF) of <35%, with basal hyperkinesia and apical segment ballooning (Figs 2 - 5). She was discharged home after 3 days of supportive therapy. At 3 months

she was asymptomatic, with an equilibrium radionuclide angiography scan revealing a normal heart with an LVEF of 73%. First described in Japan in 1990, apical ballooning syndrome accounts for 1 - 2% of suspected acute myocardial infarctions globally.[1,2] Often preceded by an emotional or physical stressor, the syndrome is characterised by transient left ventricle dysfunction and electrographic changes that mimic acute myocardial infarction with minimal release of myocardial enzymes in the absence of obstructive coronary artery disease. [3] Although 90% of all reported cases have been in postmenopausal women, it does occur

across age and gender boundaries.[4] The exact pathophysiological basis of the disease still has to be demonstrated. Recognition of the syndrome is important because of its favourable natural history and the use of only supportive therapy. References 1. Akashi YJ, Goldstein DS, Barbaro G, Takashi U. Takotsubo cardiomyopathy: A new form of acute, reversible heart failure. Circulation 2008;118:2754-2762. [http://dx.doi.org/10.1161/ CIRCULATIONAHA.108.767012] 2. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome: A mimic of acute myocardial infarction. Am Heart J 2008;155:408417. [http://dx.doi.org/10.1016/j.ahj.2007.11.008] 3. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or Takotsubo cardiomyopathy: A systematic review. Eur Heart J 2006;27:1523-1529. 4. Bybee KA, Prasad A, Barsness G, Wright RS, Rihal CS. Clinical characteristics, outcomes and impaired myocardial circulation in patients with transient left ventricular apical ballooning syndrome: A case series from a US medical center. Am J Cardiol 2004;94:343-346.

S Afr Med J 2015;105(5):422. DOI:10.7196/SAMJ.9603

Fig. 1. Twelve-lead ECG demonstrating ST-segment depression and diffuse T-wave inversion. Fig. 4. Left ventriculogram in diastole.

Fig. 2. Coronary angiogram showing an unobstructed left coronary system.

Fig. 3. Coronary angiogram showing an un obstructed dominant right coronary system.

May 2015, Vol. 105, No. 5

Fig. 5. Left ventriculogram in systole with basal segment hyperkinesia and apical segment ballooning.

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True (A) or false (B): SAMJ The simple bread tag – a menace to society 1. I f inhaled by young children, bread tags may become lodged in the larynx or subglottis; being radiolucent and thin, they may be missed on X-ray and on both flexible nasopharyngoscopy and direct laryngoscopy. Recommendations for the management of upper respiratory tract infections in South Africa (SA) 2. Haemophilus influenzae has replaced Streptococcus pneumoniae (the pneumococcus) as the most frequently isolated pathogen following routine vaccination since 2009 of children with pneumococcal conjugate vaccines. 3. Amoxicillin is the initial drug of choice for both acute otitis media and acute bacterial rhinosinusitis in children, provided there is no allergy to penicillin. 4. Concerning the ‘common cold’, clear nasal secretions frequently become purulent without signifying secondary bacterial disease, and coughing is a normal accompaniment. 5. Several trials have demonstrated non-inferiority of once-daily amoxicillin v. twice-daily amoxicillin or penicillin V for treatment of acute pharyngotonsillitis, and once-daily regimens may improve patient adherence. Community- versus healthcare-acquired bloodstream infections 6. Cloxacillin remains a perfectly suitable option in the treatment of community-acquired Staphylococcus aureus. Ocular surface squamous neoplasia (OSSN) among HIV-infected patients in Botswana 7. OSSN is a group of ocular tumours that is rising in incidence among HIV-infected individuals in sub-Saharan Africa, and may be emerging as an AIDS-defining illness. Diabetes control in a resource-poor setting 8. In children with type 1 diabetes mellitus (T1DM) treated in the public sector and requiring insulin injections and blood glucose monitoring, adult assistance is rarely forthcoming. Self-monitoring of blood glucose frequency and glycaemic control in paediatric diabetes 9. In children with T1DM between the ages of 2 and 18 years, a highly significant decrease (p<0.0001) in HbA1c was found when moving from two injections per day to three- and five-injection

regimens, and as the frequency of monitoring of blood glucose testing increased. Role of splenectomy for idiopathic thrombocytopenic purpura (ITP) 10. The first-line treatment for HIV-associated ITP is splenectomy, thus avoiding further glucocorticoid-induced immunosuppression. CME Role of antibiotic stewardship in extending the age of modern medicine 11. Antibiotic use in agriculture is associated with the acquisition of antibiotic resistance in humans. 12. In blood cultures, the volume of blood inoculated is critical in determining yield. Diagnosis of bacterial infection 13. Nitrites on a urine disptick in the absence of symptoms or urine leucocytes may suggest asymptomatic bacteriuria or bacterial contamination rather than urinary tract infection (cystitis or pyelitis). Optimising the administration of antibiotics in critically ill patients 14. Drug exposure varies according to molecular weight, degree of ionisation, protein binding and lipid solubility. Twitter: A tool to improve healthcare professionals’ awareness of antimicrobial resistance and antimicrobial stewardship 15. If left unchecked, antimicrobial resistance could result in 4.1 million deaths in Africa by 2050. 16. Twitter is seldom accessed using smartphones. Use of vaccines as a key antimicrobial stewardship strategy 17. Pneumococcal conjugate vaccines significantly reduce multidrugresistant pneumococcal infections. Role of infection control in combating antibiotic resistance 18. Hand hygiene remains the cornerstone of reducing transmission of multidrug-resistant organisms. 19. The more patients that are colonised with a particular multidrugresistant organism (the ‘colonisation pressure’), the greater the chance of transmission. 20. Contact spread is the most important means of transmission of the majority of multidrug-resistant organisms in healthcare settings, and can be either direct or indirect.

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