Critical care oct 2010

Volume 6, Number 4

October-December 2010

Emerging Antibiotic Resistance in Pseudomonas: A Challenge Role of Clinical Signs in the Diagnosis of Late-onset Neonatal Sepsis and Formulation of Clinical Score Insufficient β-lactam Concentrations in the Early Phase of Sepsis and Septic Shock Klebsiella oxytoca Bacteremia Causing Septic Shock in Recipients of Hematopoietic Stem Cell Transplant: Two Case Reports Extensive Anterior Chest Wall Cellulitis with Central Venous Catheter-related Blood Stream Infection Management of Patient with Splenic Trauma More...

Asian Journal of

Critical Care Volume 6, No 4, October-December 2010

An IJCP Group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor

Contents Contents From the Desk of Group Editor-in-chief

5

KK Aggarwal

Anand Gopal Bhatnagar Editorial Anchor

Critical Care Editorial Board Dr MM Pandit Rao Prof. Anesthesia, BJ Medical College, Pune Dr Vijay Langer Head, Dept. of Anesthesia, Moolchand Medcity, New Delhi Dr Rajesh Chauhan Sr. Anesthetist, Escorts Heart Institute, New Delhi Dr A Kale Prof. Anesthesia, AIIMS, New Delhi Dr Manju Mani Director-Critical Care, Delhi Heart and Lung Institute New Delhi Dr Tarlika Doctor Associate Professor Anesthesia, BJ Medical College, Ahmedabad Dr Sunita Jain, New Delhi

IJCP Editorial Board Dr Alka Kriplani Asian Journal of Obs & Gynae Practice Dr VP Sood Asian Journal of Ear, Nose and Throat Dr Praveen Chandra Asian Journal of Clinical Cardiology Dr Swati Y Bhave Asian Journal of Paediatric Practice Dr Vijay Viswanathan The Asian Journal of Diabetology Dr KMK Masthan Indian Journal of Multidisciplinary Dentistry Dr M Paul Anand, Dr SK Parashar Cardiology Dr CR Anand Moses , Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty Diabetology

clinical Study

Emerging Antibiotic Resistance in Pseudomonas: A Challenge

6

Deepak Arora, Neerja Jindal, Rajiv Kumar, Romit

Role of Clinical Signs in the Diagnosis of Late-onset Neonatal Sepsis and Formulation of Clinical Score

10

Subhranshu Sekhar Kar, Rajani Dube, Samarendra Mahapatra, Sitanshu Sekhar Kar

research article

Insufficient β-lactam Concentrations in the Early Phase of Sepsis and Septic Shock 15 Fabio Silvio Taccone, Pierre-François Laterre, Thierry Dugernier, Herbert Spapen, Isabelle Delattre, Xavier Wittebole, Daniel De Backer, Brice Layeux, Pierr Wallemacq, Jean-Louis Vincent, Frédérique Jacobs

Dr Ajay Kumar Gastroenterology Dr Koushik Lahiri Dermatology Dr Georgi Abraham Nephrology Dr Sidharth Kumar Das Rheumatology Dr V Nagarajan Neurology Dr Thankam Verma, Dr Kamala Selvaraj Obs and Gyne

Advisory Body Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010 Heart Care Foundation of India

case report

Klebsiella oxytoca Bacteremia Causing Septic Shock in Recipients of Hematopoietic Stem Cell Transplant: Two Case Reports

26

Khalid A Al-Anazi, Asma M Al-Jasser, Hazza A Al-Zahrani, Naem Chaudhri, Fahad I Al-Mohareb

Asian Journal of

Review Article

Critical Care Volume 6, No 4, October-December 2010

Contents

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at Daryacha, 39, Hauz Khas Village New Delhi - 110 016 E-mail: editorial@ijcp.com

case report

Extensive Anterior Chest Wall Cellulitis with Central Venous Catheter-related Blood Stream Infection

Printed at Entire Printers Nampally, Hyderabad Š Copyright 2010 IJCP Publications Pvt. Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Pvt. Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Editorial Policies

Dinesh Singh, Anuj Verma, Sourya Acharya, Shital Kriplani, SN Mahajan

clinical algorithm

Management of Patient with Splenic Trauma

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

30

33

emedinews section

From eMedinewS

34

Lighter reading

Lighter Side of Reading

35

Note: Asian Journal of Critical Care does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

Editorial & Business Offices

Delhi

Mumbai

Kolkata

Bangalore

Chennai

Hyderabad

Dr Veena Aggarwal 9811036687 Daryacha, 39 Hauz Khas Village N.D. - 110 016 Cont.: 26965874/75 editorial@ijcp.com drveena@ijcp.com drveenaijcp@gmail.com Subscription Dinesh: 9891272006 subscribe@ijcp.com Ritu: 09831363901 ritu@ijcp.com

Dr Veena Aggarwal 9811036687

Sr. BM Ritu Saigal 9831363901 Flat 5E Merlin Estate Geetanjali 25/8 Diamond Harbour Road Kolkata - 700 008 Cont.: 24452066 ritu@ijcp.com

Sr. BM H Chandrashekar 9845232974 Arora Business Centre, 111/1 & 111/2 Dickenson Road (Near Manipal Centre) Bangalore - 560 042 Cont.: 25586337 chandra@ijcp.com

Sr. BM Chitra Mohan 9841213823 40A, Ganapathypuram Main Road Radhanagar Chromepet Chennai - 600 044 Cont.: 22650144 chitra@ijcp.com

Sr. BM Venugopal 9849083558 H. No. 16-2-751/A/70 First Floor Karan Bagh Gaddiannaram Dil Sukh Nagar Hyderabad - 500 059 Cont.: 65454254 venu@ijcp.com

Building No. D-10 Flat No 43, 4th Floor Asmita Co-operative Housing Society Marvey Road Near Charkop Naka Malad (W) Mumbai - 400 095 drveenaijcp@gmail.com

Sr.: Senior; BM: Business Manager

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

From the desk of Group editor-in-chief

Dr KK Aggarwal Padma Shri and Dr BC Roy National Awardee Sr Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group Editor-in-chief, eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com https//twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook) 







Obstructive sleep apnea (OSA) is associated with coronary artery disease (CAD) and heart failure in men. In a prospective cohort study, 1,927 men and 2,495 women without baseline CAD or heart failure were followed for a median of 8.7 years after baseline polysomnography.1 Among men ≤70 years of age, OSA was associated with an increased risk of myocardial infarction (MI), revascularization or death due to CAD. Among all men, OSA was associated with an increased risk of heart failure. OSA was not associated with coronary heart disease or heart failure in women.

OSA increases the risk for stroke. The largest prospective cohort study followed 5,422 individuals without a history of stroke for a median of 8.7 years.2 Men whose apnea-hypopnea index (AHI) was in the highest quartile were more likely to have an ischemic stroke than men whose AHI was in the lowest quartile. A similar effect was not found among women in the study.

Nocturnal bilevel positive airway pressure improve long-term survival in patients with obesity hypoventilation syndrome. In a series that followed 130 patients receiving BPAP for obesity hypoventilation syndrome, the 1-, 2-, 3- and 5-year survival rates were better than those of historical controls.3 Sleep deprivation is associated with adverse cardiovascular outcomes. In a cross-sectional study of 30,397 adults, the prevalence of MI, angina or stroke was higher among individuals who slept ≤5 hours/night than among those who slept seven hours per night.4

References 1. Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122(4):352-60.

2. Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O’Connor GT, Resnick HE, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010;182(2):269-77.

3. Priou P, Hamel JF, Person C, Meslier N, Racineux JL, Urban T, et al. Long-term outcome of noninvasive positive pressure ventilation for obesity hypoventilation syndrome. Chest 2010;138(1):84-90.

4. Sabanayagam C, Shankar A. Sleep duration and cardiovascular disease: results from the National Health Interview Survey.

Sleep 2010;33(8):1037-42.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

Clinical study clinical practice

Emerging Antibiotic Resistance in Pseudomonas: A Challenge Deepak Arora*, Neerja Jindal**, Rajiv Kumar†, Romit‡

Abstract The present study was undertaken to assess the antibiotic susceptibility patterns of Pseudomonas aeruginosa at a Tertiary Care Hospital in Punjab, India. Due to significant changes in microbial genetic ecology, as a result of indiscriminate use of antimicrobials, the spread of antimicrobial resistance is now a global problem.

Key words: Antibiotic susceptibility patterns, Pseudomonas, antimicrobial resistance, PAF Agar

O

wing to its physiologic versatility; Pseudomonas aeruginosa is considered one of the difficultto-treat pathogens in practice.1,2 It continues to be the major pathogen in patients with immunosuppression, cystic fibrosis and malignancy.3 In a survey conducted by the Center for Disease Control in the United States from 1976 to 1980, its frequency of occurrence as a nosocomial pathogen has increased.3 With the widespread use of antibiotics and the increase in number of immunosuppressed hosts, P. aeruginosa has become a leading cause of gram-negative bacterial infections, es­pecially in immunosuppressed patients who need prolonged hospitalization.4-6 It was also noted that P. aeruginosa bacteremia is associated with higher mortality than other gram-negative bacteremia.7 The underlying immunosuppression as well as the resis­ tance of P. aeruginosa to several antibiotics could be a contribu­tory factor. To overcome the latter, se­veral studies indicate that a combination of antibiotics is the preferable therapy for severe P. aeruginosa infections.8 Antimicrobial agents, treatment of pseudomonal pneumonia is often challenging.9,10 The diversity of clinics and the regional variations in antibiotic protocols result in the different resistance profiles.11,12 Patients hospitalized are at particular risk of acquiring *Assistant Professor, Dept. of Microbiology Adesh Medical College, Bathinda **Professor and Head, Dept. of Microbiology Guru Gobind Singh Medical College, Faridkot † Lecturer, Dept. of Microbiology, Adesh Medical College, Bathinda ‡ Assistant Professor, Dept. of Orthopedics Guru Gobind Singh Medical College, Faridkot Address for correspondence Dr Deepak Arora Assistant Professor Dept. of Microbiology, Adesh Medical College, Bathinda E-mail: drdeepakarora78@gmail.com

nosocomial infections due to serious underlying disease, compromised membrane and skin barriers following the use of invasive devices, and extended length of hospital stay, among other factors. Exposure to various antimicrobial agents may further complicate such hospitalization and create conditions conducive to resistance selection among host bacterial flora or nosocomially-transmitted pathogens. Studies have demonstrated that rates of antimicrobial resistance are greater in bacteria isolated from ICUs compared with other hospital wards and outpatient clinics.13 P. aeruginosa frequently displays resistance to multiple antimicrobial agents.14 Serious infection due to strains of P. aeruginosa that exhibit resistance to all common antipseudomonal antimicrobials is an increasingly serious problem.15 In this study done at Adesh Medical College, Bathinda we aimed to establish the prevalence of P. aeruginosa in our hospital and to compare their antibiotic susceptibility patterns.

Material and Methods The study was conducted over a period of one year (March 2009 to March 2010) at Bathinda. Samples were obtained from patients who were hospitalized for more than 1-week duration. The various specimens obtained were urine, tracheal aspirate, blood and exudate from any lesion which was present (e.g., burn wound, nonhealing ulcer, postoperative wounds). A total of 500 samples were obtained. From different sources out of which 193 were P. aeruginosa.

These specimens were inoculated onto the primary isolation media-like blood agar, MacConkey, eosinmethylene blue and other selective differential media.

Colorless colonies, characteristic of pseudomonas, were Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

clinical study transferred to triple sugar iron (TSI) Agar slants for presumptive identification. P. aeruginosa, a glucose nonfermenting gram-negative rod produced an alkaline red slant and alkaline red or no change in the butt indicator after 24 hours of incubation. A grape-like odor of the growing colonies was also recognized. An isolate presumptively identified in TSI as a glucose nonfermenter was confirmed by inoculating to oxidative fermentative glucose medium, which yielded positive results. The isolates, if inoculated to PAF Agar slants, produced the characteristic greenish pigment.

A total of 193 samples of pseudomonas were obtained from various sources P. aeruginosa ATCC 27853 was used as the control strain. i.e., cefotaxime, ceftriaxone, ceftazidime, amikacin, gentamicin, ciprofloxacin, piperacillin and imipenem. The Kirby-Bauer method using the disk diffusion technique was the procedure of choice for antibiotic sensitivity testing. A sensitive result is defined as a zone of inhibition that meets the interpretive standards recommended by the American Society for Testing and Materials as shown below for inoculation Mueller-Hinton Agar was done using the standard method.

Results Each isolate was evaluated for susceptibility to different antibiotics i.e., cefotaxime, ceftriaxone, ceftazidime, amikacin, gentamicin ciprofloxacin, piperacillin and imipenem. Out of 193 isolates, 136 (70%) were from male patients and 60 (30%) were from female patients.

Maximum resistance was seen to third-generation cephalosporins: 116 (60%) to cefotaxime, 141 (75%) to ceftriaxone, 121 (63%) to ceftazidime. Amikacin showed resistance in 81 (41.5%) and gentamicin in 153 (79%) of the isolates. Ciprofloxacin resistance was seen in 143 (73.2%) isolates while piperacillin resistance was seen in 85 (44%) of the isolates.

Minimum resistance was seen to imipenem five (3.7%).

One hundred ninety-three strains of P. aeruginosa were obtained (Table 1). The rate of iso­lation of P. aeruginosa was 20%. Exudates followed by urine ac­counted for the maximum isolate. The common sources of specimens are shown in Table 2 with the urine and wound discharges on top of the list.

Discussion P. aeruginosa is a major cause of nosocomial infection.

Despite advances in sanitation facilities and the Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

introduction of a wide variety of antimicrobial agents with antipseudomonal activities, life-threatening infections caused by P. aeruginosa continue to be hospital infections. A critical factor in the survival of P. aeruginosa in an unfavorable environment is its ability to transform from a mobile ‘swarmer’ cell to a glycocalyx enclosed microcolony which serves to protect the organisms against the active phagocytes, surfactants, enzymes and high levels of specific antibodies.

Nowadays, the prevalence of P. aeruginosa and the new resistant strains continue in both community-acquired pathogens and hospital originated infections.16 Ceftriaxone and ceftazidime are the commonest third-generation antibiotics in hospital protocols.

Table 1. Antimicrobial Sensitivity Pattern of P. aeruginosa Antibiotic

Sensitive no. (%)

Resistant no. (%)

Cefotaxime

77 (40)

116 (60)

Ceftriaxone

52 (25)

141 (75)

Ceftazidime

70 (37)

121 (63)

112 (58.5)

81 (41.5)

40 (21)

153 (79)

Ciprofloxacin

50 (26.8)

143 (73.2)

Piperacillin

108 (56)

85 (44)

Imipenem

188 (96.3)

5 (3.7)

Amikacin Gentamicin

Table 2. Distribution of Specimens of P. aeruginosa Isolates Sources of specimen

Total number

Percentage (%)

Urine

70

36

Wound discharge

40

20

Ear discharge

10

5

Sputum

8

4

Tracheal aspirate

17

8

Blood

2

1

Kidney swab

2

1

Pleural fluid

4

2

Lung abscess

7

3

CVP catheter tip

5

2

Others

17

8

clinical study Resistance to third-generation cephalosporins are significant in our study (60-75%) similar to the study done by Holloway et al.17 P. aeruginosa detected significant resistant against aminoglycosides.18 Reports of the susceptibility of P. aeruginosa to gentamicin have ranged from as low as 49.8% and 77.7%, in Greece, to as high as 96.6% and 99.2%, respectively, in the United Kingdom.19 In our study, the rate of aminoglycoside resistance was also found to be relatively high (resistance to amikacin; 41.5% and gentamicin; 79%). So, antipseudomonal effect of amikacin is higher then gentamycin. Consistent with these findings, resistance to amikacin of P. aeruginosa was still lower than to gentamicin and this correlates with the study done by Smitha et al20 and Javiya et al.21 So, among the aminoglycosides, amikacin has the highest sensitivity; so, amikacin seems to be a promising therapy for pseudomonas infection. Hence, its use should be restricted to severe nosocomial infections.22 However, this data also suggests that resistance to amikacin is increasing progressively in our country.

In various studies, it was reported that increased resistance rates have been detected against carbapenems, quinolones and third-generation cephalosporins for P. aeruginosa worldwide.23-25 In our study, resistance rate against imipenem was lower (3.7%) similar to a study in Spain (14%).26 The resistance of Pseudomonas to the antibiotics in the quinolone group is not consistent and variablility has been reported in different centers.27,28 In a prospective study, resistance to ciprofloxacin in ICU was reported as 8-31%.29 In our study, resistance rate against ciprofloxacin was 73.2%. Quinolone resistance in our study was high as compared to study done by others as 31.9% in Italy, and 26.8% in Latin America.30 This is because of irrational approach of the clinicians of putting patients on quinolones straightaway without going for antibiotic sensitivity. Overall, we have observed that there is increased antibiotic resistance which may be due to the selective pressure from the use of antimicrobial agents, which is a major determinant for the emergence of resistant strains.18,30,31 Conclusion P. aeruginosa is one of the most important bacterial pathogen seriously contributing to the problem of

hospital infection. Drug resistance to P. aeruginosa is rapidly increasing. Irrational and inappropriate use of antibiotics is responsible for the development of resistance of Pseudomonas species to antibiotic monotherapy. Hence, there is a need to emphasize the rational use of antimicrobials and strictly adhere to the concept of ‘reserve drugs’ to minimize the misuse of available antimicrobials. In addition, regular antimicrobial susceptibility surveillance is essential for area-wise monitoring of the resistance patterns. An effective national and state level antibiotic policy and draft guidelines should be introduced to preserve the effectiveness of antibiotics and for better patient management.

References 1. Costerton JW, Lam J, Lam K, Chan R. The role of the microcolony mode of growth in the pathogenesis of Pseudomonas aeruginosa infections. Rev Infect Dis 1983;5(Suppl 5):867-72.

2. Bennett. Principles and Practice of lnfectious Diseases.

2nd edition, 1985.3.

3. Cross A, Allen JR, Burke J, Ducel G, Harris A, John J, et al. Nosocomial infections due to Pseudomonas aeruginosa: review of recent trends. Rev Infect Dis 1983;5(Suppl 5):S837-45.

4. Schimpff SC, Moody M, Young VM. Relationship of colonization with Pseudomonas aeruginosa to development of Pseudomonas aeruginosa bacteremia in cancer patients. Antimicrob Agents Chemother (Bethesda) 1970;10:240-4.

5. Korvick JA, Marsh JW, Starzl TE, Yu VL. Pseudomonas aeruginosa bacteremia in patients undergoing liver transplantation: an emerging problem. Surgery 1991;109: 62-8.

6. Griffith SJ, Nathan C, Selander RK, Chamberlin W, Gordon S, Kabins S, et al. The epidemiology of Pseudomonas aeruginosa in oncology patients in a general hospital. J Infect Dis 1989;160(6):1030-6.

7. Young LS. The clinical challenge of infections due to Pseudomonas aeruginosa. Rev Infect Dis 1984;63 (Suppl 3):603-7.

8. Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med 1989;87(5):540-6.

9. Jarvis WR, Martone WJ. Predominant pathogens in hospital infections. J Antimicrob Chemother 1992; 29(Suppl A):19-24.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

clinical study 10. Weber DJ, Raasch R, Rutala WA. Nosocomial infections in the ICU: the growing importance of antibiotic-resistant pathogens. Chest 1999;115(Suppl. 3):34S-41S.

21. Poole K. Aminoglycosides resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005;49(2): 479-87.

11. Gilligan PH. Pseudomonas and Burkholderia. In: Manual of Clinical Microbiology. Murray RR, Baron EJ, Pfaler MA, et al. (Eds.), American Society for Microbiology, Washington DC 1995:509-19.

22. Hancock REW. Resistance mechanism in Pseudomonas aeruginosa and other nonfermentative gram-negative bacteria. Clin Infect Dis 1998;27:289-99.

12. Trilla A. Epidemiology of nosocomial infections in adult intensive care units. Intensive Care Med 1994;20(Suppl 3):S1-4.

13. Archibald L, Phillips L, Monnett D, McGowan JE Jr, Tenover F, Gaynes R. Antimicrobial resistance in hospitals and outpatients in the United States: the increasing importance of the intensive care unit. Clin Infect Dis 1997;24(2):211-5.

14. Carmeli Y, Troillet N, Eliopoulos GM, Samore MH. Emergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents. Antimicrob Agents Chemother 1999;43(6):1379-82.

15. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant.

Pseudomonas aeruginosa. Clin Infect Dis 2003;37(11): e154-60.

16. Maniatis AN, Trougakos IP, Katsanis G, Palermas J, Maniatis NA, Legakis NJ. Changing patterns of bacterial nosocomial infections: a nine-year study in a general hospital. Chemotherapy 1997;43(1):69-76.

17. Holloway WJ, Palmer D. Clinical application of new parenteral antibiotic in treatment of severe bacterial infection. Am J Med 1996;100(6A):52S-59S. 18. Alkin HE, Torun M, Alacam R. Aminoglycoside resistance patterns in Turkey, Scand J Infect Dis 1988;20(2); 199-203.

19. Smitha S, Lalitha P, Prajna VN, Srinivasan M. Susceptibility trends of Pseudomonas species from corneal ulcers. Indian J Med Microbiol 2005;23(3):168-71.

20. Javiya VA, Ghatak SB, Patel KR, Patel JA. Antibiotic susceptibility patterns of Pseudomonas aeruginosa at tertiary care hospital in Gujarat, India. Indian J Pharmacol 2008;40(5):230-4.

23. Bouza E, Garcia-Gorrote F, Cercenado E, Marin M, Diaz MS. Pseudomonas aeruginosa: a survey of resistance in 136 hospitals in Spain. The Spanish Pseudomonas aeruginosa Study Group. Antimicrob Agents Chemother 1999;43(4):981-2.

24. Bonfiglio G, Carciotto V, Russo G, Stefani S, Schito GC, Debbia E, et al. Antibiotic resistance in Pseudomonas aeruginosa: an Italian survey. J Antimicrob Chemother 1998;41(2):307-10.

25. Rotimi VO, al-Sweih NA, Feteih J. The prevalence and antibiotic susceptibility pattern of gram-negative bacterial isolates in two ICUs in Saudi Arabia and Kuwait. Diagn Microbiol Infect Dis 1998;30(1):53-9.

26. Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1990-May 1999, issued June 1999. Am J Infect Control 1999;27(6): 520-32.

27. Pfaller MA, Jones RN. MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from the Americas: resistance implications in the treatment of serious infections. J Antimicrob Chemother 2000;46(Suppl T2):25-37.

28. Tassios PT, Gennimata V, Maniatis A, Fock C, Legakis NJ; The Greek Pseudomonas aeruginosa Study Group.

Emergence of multidrug resistance in ubiquitous and dominant Pseudomonas aeruginosa serogroup O:11.

J Clin Microbiol 1998;36(4):897-901.

29. Sofianou D, Tsakris A, Skoura L, Douboyas J. Extended high-level cross-resistance to antipseudomonal antibiotics amongst Pseudomonas aeruginosa isolates in a university hospital. J Antimicrob Chemother 1997;40(5):740-2.

30. Maes P, Vanhoof R. A 56-months prospective surveillance study on the epidemiology of aminoglycoside resistance in a Belgian general hospital. Scand J Infect Dis 1992;24(4):495-501.

31. Quinn JP. Clinical problems posed by multiresistant nonfermenting gram-negative pathogens. Clin Infect Dis 1998;27:117-4.

n

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

n

n

Clinical study clinical practice

Role of Clinical Signs in the Diagnosis of Late-onset Neonatal Sepsis and Formulation of Clinical Score Subhranshu Sekhar Kar*, Rajani Dube**, Samarendra Mahapatra*, Sitanshu Sekhar Kar†

Abstract Neonatal sepsis is the most important cause of morbidity and mortality in developing countries. The low-birth-weight (LBW) and preterm babies are more vulnerable to it. It is diagnosed when generalized systemic features are associated with pure growth of bacteria from one or more sites. However, the signs of sepsis are nonspecific and the outcome of a neonate with sepsis depends on its early identification. So, this study is done to evaluate the role of various clinical signs in diagnosing late-onset sepsis, their statistical analysis and to develop a scoring system based purely on clinical signs for early diagnosis and prompt institution of treatment.

Key words: Sepsis, late-onset, clinical score

I

nfection, as either a primary pathology or a complication of other illness, is a major cause of neonatal mortality and morbidity throughout the world.1,2 In developing countries, sepsis accounts for 30-50% of five million total deaths each year.3,4 It is estimated that almost 20% of all neonates develop infection and approximately 1% die of the serious systematic infection.4 The incidence of neonatal sepsis according to the data from National Neonatal Perinatal Database (NNPD, 2002-03) is 30/1,000 live births.5 The microorganisms most commonly associated with sepsis include group B Streptococcus (GBS), Escherichia coli, coagulase-negative Staphylococcus (CONS), Haemophilus influenzae and Listeria monocytogenes.6,7 As the clinical signs of sepsis are mostly nonspecific, hence the outcome of a neonate with sepsis depends on its early identification.8 Through, there are various scoring systems on perinatal risk factors and hematological parameters, there is paucity of data regarding the scoring purely based on clinical signs for the prediction of neonatal sepsis (late onset) and hence the intention of the study is to develop a scoring system for risk predictability and early management. *Associate Professor, Dept. of Pediatrics **Associate Professor, Dept. of Obstetrics and Gynecology † Assistant Professor, Dept. of Community Medicine Hi-Tech Medical College, Pandara, Bhubaneswar and JIPMER, Puducherry Address for correspondence Dr Subhranshu Sekhar Kar Associate Professor, Dept. of Pediatrics Plot No.: 1, Lane-12, Aryabrata Colony, Jagannath Nagar, Rasulgarh Bhubaneswar - 751 010, Odisha E-mail: drsskar@gmail.com

10

Aim and Objectives To evaluate the role of various clinical signs in the diagnosis of late-onset neonatal sepsis, their statistical analysis and formulation of clinical score.

Material and Methods The present prospective study was undertaken in the NICU (neonatal intensive care unit) and SCNU (special care neonatal unit), Hi-Tech Medical College, Bhubaneswar, during the year 2007-2010.

Selection of Cases The newborns who had clinical signs of sepsis after three days of life were included in this study. Those having major congenital malformations were excluded.

Data Collection

In all cases, a detailed maternal and neonatal history with respect to symptoms, signs, complications and other relevant data were recorded in a pre-prepared proforma. All admitted neonates were monitored for clinical signs till 28 days of life or till discharge from hospital whichever is earlier. Babies showing any of the clinical signs were evaluated for sepsis. Repeat sepsis screen and cultures were done only if there was a fresh clinical sign after 72 hours of first blood culture.

Categories

The neonates were grouped into three categories  Definite sepsis n Presence of clinical signs Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

clinical study Isolation of bacterial infective agent from either blood or cerebrospinal fluid (CSF) Probable sepsis n Presence of clinical signs n Two screening parameters positive n Blood/CSF culture sterile No sepsis n Presence of clinical signs n Sepsis screen and cultures - negative n





Clinical Signs Studied          

     

Sick looking Apnea Refusal to feed Increased prefeed aspirate Lethargy Chest retraction Seizure Grunting Sclerema Abdominal distension increasing abdominal girth by 2 cm Central cyanosis Increased respiratory rate >60/min Hypothermia (axillary temperature <36°C) Fever (axillary temperature >37.5°C) Bradycardia - (Heart rate <100/min) Tachycardia - (Heart rate >160/min)

Sepsis Screening Parameters



CRP mESR TLC ANC Band cell count I/T (Immature to total neutrophil) ratio



Platelets

    

Observations

The study cohort included 160 neonates with 210 symptomatic events (i.e., the occurrence of one or more clinical signs in each event). Out of 160 cases, male-tofemale ratio was - Male (118): Female (42) = 2.8:1 and Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

majority 91% (=146) babies were preterms with mean gestational age ± SD = 31.4 ± 3.4 weeks. One hundred fifty (93%) were low-birth-weight (LBW) babies and 10 (6.2%) weighed >2.5 kg at birth with mean birth weight (mean ± SD) = 1,378 ± 507 g.

The frequency of occurrence of apnea was maximum followed by lethargy and tachycardia. However, tachycardia, increased prefeed aspirates, increased respiratory rate and abdominal distension were more common in definite sepsis whereas refusal to feed, sick-looking and hypothermia were more common in probable sepsis. But in the no-sepsis group, refusal to feed, increased prefeed aspirate and tachycardia predominated. In this study, central cyanosis, sclerema, seizures and bradycardia were not present in any group (Table 2 and 3).

It was found that, with respect to the symptomatic events (n = 210), two clinical signs were present in 94 events (44.8%), followed by one sign in 62 events (29.5%), three clinical signs in 34 events (16.2%) and ≥4 signs in 20 (9.5%) events, respectively. And out of 210 symptomatic events in 60 (28.5%) events, blood culture was positive (definite sepsis), in 34 (16%) events, sepsis screen was positive only (probable sepsis) and in 116 (55.5%) events, no sepsis was found.

The sensitivity of clinical signs varied from 3 to 47% and specificity from 51 to 97%. The positive-predictive value (PPV) ranges from 8.3 to 50%. Grunting is the only sign having LR+ of >2.

The clinical signs showing LR+ >1 were considered for clinical score, score 1 was given for signs with LR+ between 1 and 2, and score 2 for signs with LR+ >2.

The combined clinical score of 2 and 3 had PPV of 45 Table 1. Day of Occurrence of Symptomatic Events (n = 210) Onset (days)

Frequency of occurrence (events)

Percentages (%)

4-7

90

42.8

8-14

66

31.4

15-21

30

14.3

22-28

24

11.5

Total

210

100

The mean of onset (days) = 10.7 ± 6.8

11

clinical study Table 2. Presenting Clinical Signs Presenting feature

Frequency of occurrence (Events) (n = 210)

%

Sepsis

No sepsis

Sick looking

38

18.1

20

18

Refusal to feed

24

11.4

6

18

Lethargy

76

36.1

40

36

Apnea

102

48.6

46

56

Increased prefeed aspirates

24

11.4

10

14

Chest retraction

12

5.7

6

6

Grunting

8

3.8

6

2

Abdominal distension

28

13.3

16

Increased respiratory rate

34

16.2

Bradycardia

0

Tachycardia

Events (n = 210)

Sepsis Definite

Probable

8 (40%)

12 (60%)

Refusal to feed (n = 6)

2 (33.3%)

4 (66.7%)

Lethargy (n = 40)

24 (60%)

16 (40%)

28 (60.8%)

18 (39.2%)

8 (80%)

2 (20%)

Chest retraction (n = 6)

4 (66.7%)

2 (33.3%)

Grunting (n = 6)

4 (66.7%)

2 (33.3%)

Abdominal distension (n = 16)

12 (75%)

4 (25%)

12

Increased respiratory rate (n = 16)

12 (75%)

4 (25%)

16

18

Bradycardia (n = 0)

0

0

0

0

0

Tachycardia (n = 20)

18 (90%)

2 (10%)

46

22

20

26

Hypothermia (n = 4)

2 (50%)

2 (50%)

Hypothermia

8

3.8

4

4

Fever (n = 20)

12 (60%)

8 (90%)

Fever

36

17.1

20

16

Seizure (n = 0)

0

0

Seizure

0

0

0

0

Sclerema (n = 0)

0

0

Sclerema

0

0

0

0

Central cyanosis (n = 0)

0

0

Central cyanosis

0

0

0

0

and 40%, respectively. However, a clinical score of 4 gave a maximum PPV of 100% and LR+ of 3. So, this predictive ability is significantly more than any of the clinical signs in isolation.

Discussion Infections are the single largest cause of neonatal deaths globally. Klebsiella pneumoniae and Staphylococcus aureus were the two most common organisms isolated.

Based on the onset, neonatal sepsis is classified into two major categories: Early-onset sepsis which usually presents with respiratory distress and pneumonia within 72 hours of age and late-onset sepsis that usually presents with septicemia and pneumonia after 72 hours of age. Clinical features of sepsis are 12

Table 3. Relationship of Sepsis with Occurrence of Events

Sick looking (n = 20)

Apnea (n = 46) Increased prefeed aspirates (n = 10)

nonspecific in neonates and a high index of suspicion is required for timely diagnosis. Although blood culture is the gold standard for the diagnosis of sepsis, culture reports would be available only after 48-72 hours. In our study, there is a male preponderance which is due to the prevalent custom of taking male babies preferentially to healthcare institutions and also because female babies are immunologically more competent.9,10 Gerdes et al11 reported that male infants are four times vulnerable to sepsis than females. Also majority of this study group are preterms which may be attributed to the occurrence of more number of premature deliveries in our institution hence they are more prone for sepsis.12 It is found that the mean age of onset of symptomatic events is 10.7 Âą 6.8 days. Majority occurred between 4-7 days of life.

This is in accordance with other studies.13 Also apnea, lethargy and tachycardia were the common clinical Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

clinical study signs present in babies at enrolment for evaluation of sepsis which is similar to the study by Fanaroff et al.14 Any illness in neonates is bound to present with a constellation of clinical signs, hence, majority of symptomatic events presented with two clinical signs per event. Sixty (28.5%) events belong to the culture positive group hence classified under definite sepsis category which correlates with the report by Singh et al.15 Gram-negative sepsis predominates in our study (Table 4) with Klebsiella being the most frequent gram-negative isolate and S. aureus the gram-positive one. Kuruvilla et al16 reported similar isolates in his study in 1998. However, the incidence of CONS is low in our set up. It is seen from Table 5, that the sensitivity of clinical signs is low (3-47%). It is because of the variable presentation of clinical signs at one time or other. Also, the PPV is low as these signs may be present in multiple other causes apart from sepsis.14 This study tries to find out a scoring system based on individual clinical signs, hence signs with LR+ >1 are included in the score (Table 6). The diagnostic value of combined clinical score are depicted in Table 7.

A clinical score of 4 and maximum PPV of 100% with a positive LR of 3 meaning, when the clinical score is 4 then there is three times higher chance that

the clinical signs are due to sepsis and there is 100% probability of presence of disease among test positives.

Scores for diagnosis of early-onset sepsis based on clinical, laboratory and perinatal risk factors have been developed by many workers.17,18 But in India, where ready access to laboratory tests is meagre, the score based on clinical signs can significantly contribute to the diagnosis of late-onset septicemia and its early management.

Table 4. Bacteriological Profile in Definite Sepsis Bacteria

No. of events (n = 60)

Percentage

Gram-positive bacteria

26

43.3

Staphylococcus aureus

18

30

Enterococcus faecalis

6

10

Coagulase-negative Staphylococcus (CONS)

2

3.3

Gram-negative bacteria

34

56.7

Klebsiella pneumoniae

12

20

Alcaligenes faecalis

8

13.3

Escherichia coli

6

10

Enterobacter spp.

4

6.7

Acinetobacter

4

6.7

Table 5. Statistical Analysis of Clinical Signs in Definite Sepsis Signs

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

LR+

LR-

Apnea (n = 102)

47

51

28

70

0.95

1.08

Lethargy (n = 76)

40

65

32

73

1.14

0.92

Tachycardia (n = 46)

30

81

39

74

1.57

0.86

Sick looking (n = 38)

13

80

21

70

0.65

1.08

Fever (n = 36)

20

84

33

73

1.25

0.95

Increased respiratory rate (n = 34)

10

81

18

69

0.5

1.1

Abdominal distension (n = 28)

20

89

43

74

1.8

0.89

Refusal to feed (n = 24)

3

85

83

69

0.22

1.13

Increased prefeed aspirate (n = 24)

17

91

41

73

1.6

0.93

Chest retraction (n = 12)

7

95

33

72

1.22

0.99

Grunting (n = 8)

7

97

50

72

2.33

0.96

Hypothermia (n = 8)

3

96

25

71

0.07

0.95

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

13

clinical study 4. Stoll BJ. The global impact of neonatal infection. Clin Perinatal 1997;24(1):1-21.

Table 6. Clinical Score Clinical sign

Score

Lethargy

1

Tachycardia

1

Fever

1

Abdominal distension

1

Increased prefeed aspirate

1

Chest retraction

1

Grunting

2

5. Report of the National Neonatal Perinatal Database (National Neonatology Forum), 2002-2003.

6. Klinger G, Levy I, Sirota L, Boyko V, Reichman B, Lerner-Geva L. Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants. Am J Obstet Gynecol 2009;201(1):38.e1-6.

7. van den Hoogen A, Gerards LJ, Verboon-Maciolek MA, Fleer A, Krediet TG. Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative Agents. Neonatology 2010;97(1): 22-8.

8. Gotoff SP, Behrman RE. Neonatal septicemia. J Pediatr 1970;76(1):142-53.

Table 7. Statistical Analysis of Clinical Score Score Sensitivity Specificity PPV (%) NPV (%)

LR+

2 3 4

2 1.6 3

47 13 3

77 92 99

45 40 100

78 73 72

Key Message  The early diagnosis and timely treatment of neonatal sepsis is rather difficult due to the nonspecific clinical presenting signs.  Also, in India ready access to laboratory tests is meager and cost-prohibitive.  So, on the basis of the clinical score, i.e., a score ≥4 which has 100% PPV, early diagnosis and prompt institution of therapy can be started without waiting for other laboratory parameters.

The clinical score may be very useful in resource poor settings.

References 1. Rennie Janet M, Roberton NRC. TB of Neonatology.

3rd edition, 1999:1109.

2. Khatua SP, Das AK, Chatterjee BD, Khatua S, Ghose B, Saha A. Neonatal septicemia. Indian J Pediatr 1986;53(4):509-14.

3. Bang AT, Bang RA, Bactule SB, Reddy HM, Desmukh MD. Effect of home-based neonatal care and management of sepsis on neonatal mortality: field trial in rural India. Lancet 1999;354:1955-61.

9. Singh M. Care of Newborn. 5th edition 1999:211.

10. Klein JO, Marey SM. Bacterial sepsis and meningitis.

Infectious Disease of the Fetus & Newborn Infant. 3rd edition 1990:601-50.

11. Gerdes JS, Polin RA. Sepsis screen in neonates with evaluation of plasma fibronectin. Pediatr Infect Dis J 1987;6(5):443-4.

12. Gotoff SP. Nelson Textbook of Pediatrics. 2000;16:541.

13. Sepsis and septic shock. Drug Ther Perspect 2001;17(6): 8-13.

14. Fanaroff A, Sheldon B, Wright LL, Verter J, Poland RL, Baur CR, et al. Incidence, presenting features risk factors and significance of late onset sepsis in VLBW infant.

The National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J 1998;17(7):593-8.

15. Singh M, Narang A, Bhakoo ON. Evaluation of sepsis screen in the diagnosis of neonatal sepsis. Indian Pediatr 1987;24(6):39-42.

16. Kuruvilla KA, Pillai S, Jesudason M, Jana AK. Bacterial profile of sepsis in a neonatal unit in South India. Indian Pediatr 1998;35(9):851-7.

17. Takkar VP, Bhakoo ON, Narang A. Scoring system for prediction of early neonatal infections. Indian Pediatr 1974;11(9):597-600.

18. Bergvist G, Eriksson MN, Zetterström R. Sepsis and perinatal risk factors. Acta Pediatr Scand 1979;68(3): 337-9.

n

14

n

n

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

research article clinical practice

Insufficient β-lactam Concentrations in the Early Phase of Sepsis and Septic Shock Fabio Silvio Taccone*, Pierre-François Laterre, Thierry Dugernier, Herbert Spapen, Isabelle Delattre, Xavier Wittebole, Daniel De Backer, Brice Layeux, Pierr Wallemacq, Jean-Louis Vincent, Frédérique Jacobs

Abstract Introduction: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock. Methods: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration. Results: 80 patients were treated with piperacillintazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillintazobactam. Conclusions: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem.

Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

Key words: Sepsis, septic shock, β-lactam, broad-spectrum-antibiotics, PK analysis

S

evere sepsis and septic shock remain a major cause of morbidity and mortality in medical and surgical ICUs.1 Although early and appropriate antibacterial therapy is considered a priority in the management of patients with sepsis,2,3 there is evidence that optimizing antibiotic dosage regimens to achieve therapeutic concentrations in the blood and at the site of infection is equally important.4 Antibiotherapy in critically ill septic patients usually consists of a broad-spectrum β-lactam combined with a glycopeptide and/or an aminoglycoside.5 These drugs cover a large variety of pathogens and can be empirically used for Gram-negative bacterial infections, including those caused by Pseudomonas aeruginosa. The activity of β-lactams is predominantly time-dependent and requires serum and tissue antibiotic concentrations above the minimal inhibitory concentration (MIC)

Citation: Taccone et al., Insufficient b-lactam concentrations in the early phase of severe sepsis and septic shock. Critical Care 2010, 14:R126.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

of the pathogen to achieve adequate bacterial killing.6 This effect is independent of peak levels and there is no significant post-antibiotic effect, except for carbapenems.

Clinical data suggest that maximum killing of bacteria occurs when serum concentrations are maintained above the MIC of the causative pathogens for extended periods;7,8 this may be especially appropriate in patients with compromised host-defences, including critically ill patients.9,10 However, in conventional bolus dosing regimens, serum β-lactam concentrations may fall to low levels between doses,11,12 with potentially negative effects on clinical response and emergence of resistances.

Antibiotic dosage regimens used in ICU patients are often based on pharmacokinetic (PK) data that were obtained in healthy volunteers or less severely ill patients. Moreover, they rarely take into account the dynamic changes of the septic process that can reduce the efficacy of anti-infective treatments and consequently affect patient outcomes.6 During severe sepsis and septic shock, increased volume of distribution 15

research article (Vd) and cardiac output can reduce serum drug concentrations, whereas decreased protein binding and end-organ dysfunction induce higher antibiotic levels.13 Optimizing antibiotic dosage strategy should involve PK parameters, but therapeutic drug monitoring is necessary in septic patients because large interindividual PK variations make it difficult to predict antibiotic levels.14 As previous PK studies on β-lactams in ICU patients have excluded the most severely ill patients or were conducted in the steady-state period of treatment,15-17 the main objective of this study was to determine whether the currently recommended first dose of four broad-spectrum β-lactams (piperacillintazobactam, ceftazidime, cefepime, and meropenem) provide adequate plasma concentrations in critically ill septic patients in the ICU. We also tried to determine whether clinical or hemodynamic parameters could affect the PK profile of these drugs during such severe infections.

Materials and Methods Study Design, Patients, Antibiotic Treatment and Data Collection

This was a prospective, multicenter, observational study performed in four Departments of Intensive Care in Belgium (at the St-Luc Hospital, Erasme Hospital, and UZ-VUB in Brussels and St Pierre Hospital in Ottignies). The study protocol was approved by the university ethics committees of the different hospitals.

Before enrolment, written consent was obtained from the patient or their nearest relative.

All patients admitted to one of the four ICUs between January 2005 and July 2006 were considered for inclusion. Inclusion criteria were a diagnosis of severe sepsis or septic shock,18 either at admission or during the ICU stay, and treatment with a broad-spectrum β-lactam antibiotic (ceftazidime, cefepime, piperacillintazobactam, or meropenem). Patients meeting one of the following criteria were excluded: age less than 18 years or more than 85 years; pregnancy or lactation; previous administration of any of the investigated antibiotics; chronic renal failure requiring dialysis; or allergy to any of the investigated antibiotics. The study period was limited to the first 24 hours of antibiotherapy.

Administration of the four β-lactams was made according to local guidelines. These drugs are generally 16

used in the participating centers to treat hospital- or ICU-acquired infections or in the case of communityacquired infection when a more-resistant pathogen may be involved (recent hospitalization or antibiotic therapy, previous colonization by more resistant strain). Piperacillin-tazobactam was preferred as firstline therapy in cases of proven or suspected intraabdominal infections. Ceftazidime and cefepime was used as first-line therapy in other cases. Meropenem was used as second-line therapy (i.e. failure of piperacillin-tazobactam or cephalosporins) or in case of suspected or previous colonization by extended spectrum b-lactamase Gram-negative bacteria.

In all study patients, demographics, pre-existing chronic diseases, admission diagnosis and biological data were collected in institutional databases. The severity of illness of each patient was characterized using the Acute Physiology and Chronic Health Evaluation (APACHE) II19 and sequential organ failure assessment (SOFA)20 scores determined on the first day of antibiotic treatment. Creatinine clearance (CrCl) was calculated using a standard formula.21 Treatment of patients with catecholamines, mechanical ventilation, hemofiltration or hemodialysis was recorded, as was length of ICU and hospital stay, overall mortality, and cause of death.

Hemodynamic data were collected at baseline, and 8 and 24 hours after the start of the protocol.

Analytic Method for β-lactams

All the patients included in the study received a first dose of 2 g ceftazidime or cefepime, 4 g/0.5 g piperacillin-tazobactam, or 1 g meropenem. The usual daily doses of these antibiotics and dose adjustments for renal function are presented in Additional file 1.

All the patients also received amikacin and the two antibiotics were administered simultaneously over 30 minutes using an infusion pump. Blood samples of 5 mL were collected without anticoagulant immediately before the infusion (0 hour) and 1, 1.5, 4.5, and 6 or 8 hours (depending on the frequency of administration of the β-lactam) thereafter; these blood-draw time points were chosen as they belong to the elimination phase of all four antibiotics. The exact sampling time was recorded by the nursing or medical staff. Blood samples were centrifuged at 4000 g for 10 minutes after blood clotting. To allow for possible drug instability at room temperature, serum samples were stored at -80°C until analysis.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

research article All antibiotic quantitative analyses were performed in a centralized reference laboratory (St-Luc Hospital).

Importantly, as the PK of piperacillin and tazobactam are highly correlated,22 we only measured piperacillin levels. Serum β-lactam concentrations were determined by high-performance liquid chromatography with diode array detection. The intravenous antibiotic formulations were reconstituted according to the manufacturers’ recommendations and diluted in water in order to reach stock solution aliquots of 1 mg/mL, stored at -20°C. Before each assay, a fresh calibration curve was prepared from the stock solution and blank serum at the following concentrations: 0.75, 1, 2, 5, 10, 25, and 50 μg/mL for piperacillin-tazobactam; 5, 10, 25, 50, and 100 μg/mL for ceftazidime; 0.1, 0.25, 0.5, 1, 5, 10, 25, and 50 μg/mL for cefepime or meropenem. The calibration and liquid-liquid extraction procedures as well as chromatographic conditions have been described previously.23 The validation of the four analytical methods was performed over a three-day period with five calibration curves per day (i.e., 15 serum samples per concentration level). All methods were validated according to the published acceptance criteria for specificity, linearity, accuracy, precision (intra-day [repeatability], interday [intermediate precision]) and sensitivity (limit of detection (LOD) and limit of quantification [LOQ]).

Specificity was determined by the ability to identify the β-lactam from its characteristic retention time and ultraviolet spectrum, and the fine resolution of its chromatographic peak. The linearity of the calibration curve was demonstrated by a significant linear regression analysis, with a determination coefficient (r2) more than 0.99. Accuracy was expressed as the percent deviation of the mean observed concentration from the theoretical value, which should not exceed 15%, except at the LOQ (20%). Precision was acceptable if the intra- and inter-day coefficients of variation (CV) were 20% or less at the LOQ and 15% or less at all other concentrations. LOQ was defined as the lowest concentration of the calibration curve, which could be reliably differentiated from background noise with a signal-to-noise ratio of at least 10:1 and quantified with acceptable accuracy (80 to 120%) and precision (CV ≤ 20%); LOD was defined as the lowest concentration that could be detected and reliably differentiated from background noise with a signal-to-noise ratio of at least 3:1.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

The carry-over effect was tested by injecting regular blank samples and ultrapure water into the highperformance liquid chromatography system after high concentration calibrators. Under the described chromatographic conditions, piperacillin-tazobactam, ceftazidime, cefepime, and meropenem were identified by sharp and well-resolved peaks. The linearity was statistically confirmed over the concentration range tested for each β-lactam and was associated with an r2 of more than 0.999. The four analytical methods were accurate and precise. LOD and LOQ were 0.50 and 0.75 μg/mL, respectively, for piperacillintazobactam, 2.00 and 5.00 μg/mL for ceftazidime, and 0.07 and 0.10 μg/mL for cefepime and meropenem.

Appropriate dilution was performed for clinical samples with concentrations above the upper analytic range (corresponding to the calibration curve).

PK Analysis

The PK of the four antibiotics was individually assessed using WinNonlin Professional version 5.0.1. software (Pharsight Corporation, Mountain View, CA, USA). A one-compartment model with first-order elimination was selected to fit the data. Investigated PK parameters included maximal serum concentration (Cmax, calculated by extrapolation of the elimination phase at the end of the infusion) Vd, total clearance (CL), elimination half-live (t1/2) and area under the serum concentration-time curve (AUC). Vd and CL were normalized to the body weight.

PK End-Points

The threshold of MIC required for maximal β-lactam activity is still controversial. In this study, the adequacy of β-lactam therapy was assessed by calculating the time spent greater than four times the target MIC (T > 4 × MIC). For each drug, the optimal T > 4 × MIC was considered as: above 50% for piperacillintazobactam, above 70% for ceftazidime and cefepime, and above 40% for meropenem in Gram-negative bacterial infections.24 As the dosage interval of β-lactams is prolonged in renal impairment [see Additional file 1] we calculated the time before the subsequent administration according to the adjustment of the drug regimen to CrCl for each patient. As there is a large variance in MIC values for different bacteria, we considered the MICs for problematic pathogens, such as P. aeruginosa, commonly isolated in ICU 17

research article patients, as the empiric target threshold.25 Sensitivity thresholds of MIC for this pathogen, as defined by European Committee on Antimicrobial Susceptibility Testing (EUCAST), are: 8 μg/mL or less (ceftazidime, cefepime), 16 μg/mL or less (piperacillin-tazobactam), and 2 μg/mL or less (meropenem) [see Additional file 1].26 We, therefore, classified each patient as having an ‘adequate’ or ‘inadequate’ PK profile according to the percentage of time during which serum drug concentrations remained more than four times the clinical breakpoint for P. aeruginosa (% T > 4 × MIC): 32 μg/mL or more (ceftazidime, cefepime), 64 μg/mL or more (piperacillin-tazobactam), and 8 μg/mL or more (meropenem). Finally, by simulation using the PK parameters of our population, we calculated the probability of achieving target T > 4 × MIC values for other MICs that can be found in ICU-isolated Gramnegative bacteria.

Table 1. Characteristics, Hemodynamic and Biological Data on Admission and Fluid Balance during the First 24 Hours (n = 80) Age (years)

63 ± 13

Male/female

51/29

Body mass index

24.8 ± 4.8

Statistical Analysis

APACHE II on admission

22 (18-28)

Statistical analyses were performed using the SPSS 13.0 for Windows NT software package (SPSS Inc. 2004, Chicago, IL, USA). Descriptive statistics were computed for all study variables. A KolmogorovSmirnov test was used, and histograms and normalquantile plots were examined to verify the normality of distribution of continuous variables. Discrete variables were expressed as counts (percentage) and continuous variables as means ± standard deviation or median (25th to 75th percentiles). Demographics and clinical differences between study groups were assessed using a chi-squared, Fisher’s exact test, Student’s t-test, or Mann-Whitney U test, as appropriate. The Pearson’s (r) correlation coefficient was used to determine linear correlation as appropriate. Association between variables was tested by simple regression analysis and coefficient of determination (R2) in case of non-linear correlation. A P < 0.05 was considered as statistically significant.

SOFA on admission Medical/surgical

8 (5-10) 55/25

COPD

15 (19%)

Diabetes

21 (26%)

Heart disease

30 (38%)

Chronic renal insufficiency

7 (9%)

Liver cirrhosis

12 (15%)

Immunosuppressive drugs

26 (33%)

Malignancy

26 (33%)

Community/hospital infections

25/55

Severe sepsis/septic shock

22/58

Mechanical ventilation

57 (71%)

Acute renal failure

22 (27%)

ICU stay (days)

12 (5-25)

Results

Overall ICU mortality

30 (38%)

Patient Characteristics

Fluid balance (mL/24 h)

2559 ± 2010

Mean IN (mL/24 h)

4449 ± 1877

Mean OUT (mL/24 h)

1890 ± 1538

We enrolled 80 patients (mean age 63 years, 64% male; Table 1) in the current study. Fifty-five (69%) of the patients were medical admissions and 55 had a hospital or ICU-acquired infection; 58 (72%) had septic shock. The median APACHE II score was 22 and the median SOFA score on admission was 8. Fifty 18

seven patients (71%) were treated with mechanical ventilation; 22 patients (27%) had acute renal failure.

Overall ICU mortality was 38%, mostly due to sepsis.

Most infections were respiratory or abdominal and were microbiologically documented in 56 patients (70%). Blood cultures were positive in 32 patients (40%). Forty (50%) cases of sepsis were secondary to Gram-negative bacilli, with 36 infections due to difficult-to-treat pathogens (P. aeruginosa [n = 18]; Enterobacter species [n = 11]; Citrobacter freundii,

Data are expressed as counts (percentage), median (interquartile range) or mean ± standard deviation.

APACHE, Acute Physiology and Chronic Health Evaluation; COPD, Chronic obstructive pulmonary disease; SOFA, Sequential Organ Failure Assessment.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

research article Table 2. Pharmacokinetic Parameters of the β-lactams Vd (L/kg)

Cmax (μg/mL)

AUC (mg.h/mL)

CL (mL/min.kg)

t1/2 (hours)

Piperacillin-tazobactam (n = 27)

0.38 (0.29-0.43)

123 (72-179)

469 (196-896)

2.02 (1.33-4.26)

2.58 (1.51-3.84)

Meropenem (n = 16)

0.43 (0.31-0.77)

35 (29-46)

132 (91-179)

1.87 (1.23-2.63)

2.05 (1.66-3.36)

Ceftazidime (n = 18)

0.48 (0.36-0.71)

63 (48-78)

522 (392-634)

0.89 (0.63-1.34)

5.84 (4.13-7.39)

Cefepime (n = 19)

0.36 (0.33-0.44)

68 (51-86)

310 (234-422)

1.26 (1.07-1.95)

3.37 (2.26-5.34)

Data are expressed as median [range].

AUC: Area under the curve CL: Total clearance; Cmax: Peak concentration; t1/2: Elimination half-time; Vd: volume of distribution.

Table 3. Adequate Concentrations of the Four Drugs, with Regard to Renal Dysfunction Meropenem (n = 16)

Ceftazidime (n = 18)

Cefepime (n = 19)

Piperacillin-tazobactam (n = 27)

T > 4 × MIC (%)

57 (25-100)

45 (8-100)

34 (10-100)

33 (0-100)

Adequate PK, n (%)

12 (75)

5 (28)

3 (16)

12 (44)

CrCl <50 mL/min (%)

5/6 (83)

3/9 (33)

2/12 (17)

10/14 (71)

CrCl >50 mL/min (%)

7/10 (70)

2/9 (22)

1/7 (14)

2/13 (15) *

Data are expressed as counts (percentage) or median (range).

CrCl: Creatinine clearance; MIC: Minimal inhibitory concentration; PK: Pharmacokinetic. *P = 0.03 (vs. CrCl < 50 mL/min).

Hafnia alvei and Morganella morganii [n = 2 for each]; Serratia marcescens [n = 1]).

Pharmacokinetic Data

Of the 80 patients, 16 were treated with meropenem, 18 with ceftazidime, 19 with cefepime, and 27 with piperacillin-tazobactam. The mean PK parameters for the four drugs are shown in Table 2. There was marked inter-individual variation in all PK parameters; Vd was increased for all four drugs when compared with healthy volunteers, with consequently a lower Cmax [see Additional file 1]. The median total CL was also reduced when compared with the median CL in healthy volunteers. The median percentage of T > 4 × MIC was 57% for meropenem, 45% for ceftazidime, 34% for cefepime, and 33% for piperacillin-tazobactam (Table 3). Thirteen patients had plasma concentrations less than four times the target MIC after only 90 minutes (ceftazidime = 1; cefepime = 1; piperacillintazobactam = 11). The number of patients who attained the target percentage T > 4 × MIC was 12 of 16 for meropenem (75%), 5 of 18 for ceftazidime (28%), 3 of 19 (16%) for cefepime, and 12 of 27 (44%) for piperacillin-tazobactam.

Drug regimens were adapted because of renal impairment in 41 patients (6 treated with meropenem, 9 with ceftazidime, 12 with cefepime, and 14 with piperacillin-tazobactam). The CrCl was similar among Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

the four groups (piperacillin-tazobactam 56 [ranges: 13 to 164] mL/min; meropenem 64 [22 to 134] mL/ min; ceftazidime 58 [15 to 145] mL/min; cefepime 40 [13 to 150] mL/min). In patients with renal dysfunction (CrCl <50 mL/min), 5 of 6 (83%) attained the target concentration for meropenem, 3 of 9 (33%) for ceftazidime, 2 of 12 (17%) for cefepime, and 10 of 14 (71%) for piperacillin-tazobactam. For piperacillintazobactam, but not for the other antibiotics, patients with renal dysfunction had a significantly higher probability of having adequate drug concentrations than patients with normal renal function (10 of 14 vs. 2 of 13, P = 0.03). Calculating the probability of target T > 4 × MIC attainment for several MICs, values more than 90% were obtained for ceftazidime and piperacillin-tazobactam with MIC of 2 μg/mL or less and for cefepime and meropenem with MIC of 1 μg/mL or less (Table 4).

Correlation with Clinical Variables

No correlation was found between the T > 4 × MIC and any hemodynamic or clinical variable for any of the four drugs, including age, mechanical ventilation, APACHE II or SOFA score at admission, presence of shock, maximum dose of vasopressor agents or fluid balance. There was a significant correlation between CrCl at admission and CL for all drugs (data not shown).

19

research article Table 4. Probability of Target T >4 × MIC Attainment for Various MICs MIC (μg/mL)

Target concentration (μg/mL)

32

Adequate PK N (%) Meropenem (n = 16)

Ceftazidime (n = 18)

Cefepime (n = 19)

Piperacillin-tazobactam (n = 27)

128

0

0

0

1 (4)

16

64

0

0

1 (5)

12 (44)

8

32

0

5 (28)

3 (16)

15 (56)

4

16

3 (18)

14 (78)

7 (36)

21 (78)

2

8

12 (75)

18 (100)

15 (79)

25 (93)

1

4

15 (94)

18 (100)

17 (90)

27 (100)

0.5

2

16 (100)

18 (100)

19 (100)

27 (100)

Data are expressed as counts (percentage). In bold: MIC corresponding to European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for Pseudomonas aeruginosa.

MIC: Minimal inhibitory concentration; PK: Pharmacokinetics.

Discussion In this study, we show that current standard first doses of piperacillin-tazobactam, cefepime and ceftazidime are insufficient to maintain therapeutic serum concentrations greater than four times the MIC of P. aeruginosa in patients with severe sepsis and septic shock. Only with meropenem did a large percentage of patients achieve the bactericidal target of at least 40% T > 4 × MIC. Nevertheless, the probability of reaching the target concentration was greater than 90% only for MICs of 1 μg/mL or less for cefepime, and MICs of 2 μg/mL or less for ceftazidime and piperacillin-tazobactam, suggesting that, for all these drugs, insufficient drug concentrations are obtained for pathogens with higher MICs. Broad-spectrum β-lactams are active against most organisms recovered from ICU patients. Because of the emergence of multidrug-resistant strains and the lack of new antibiotics effective against Gram-negative bacteria,27 a more effective use of existing therapies is necessary. In vivo animal studies have demonstrated that β-lactams have a slow continuous kill characteristic that is almost entirely related to the time during which concentrations in tissue and serum exceed the MIC (T > MIC) for the infecting organism.28,29 The time above the MIC required for maximal β-lactam activity may differ depending on the drug as well as on the pathogen.24 It has been proposed that, in the absence of post-antibiotic effects, the serum concentration of a β-lactam should exceed the MIC for the respective organism for 100% of the dosing interval30 However, 20

experimental studies have suggested that maximum killing of bacteria occurs when β-lactam concentrations exceed four to five times the MIC of the infecting pathogen for extended periods.31,32 For the treatment of infections in humans, optimal β-lactam concentrations are still controversial. Clinical confirmation of the PK parameters needed for optimal β-lactam efficacy is limited because in several studies drug levels were not measured and the patients included had infections caused mostly by sensitive bacteria.33 In patients treated with cephalosporins, T > MIC of 100% was associated with greater clinical cure and bacteriological eradication than T > MIC less than 100%.9 However, the bactericidal activity of cephalosporins has also been shown to be optimal at drug concentrations of about four times the MIC.7 Even if we preferred 4 × MIC as PK end-point in this study, we did not have enough data to compare the efficacy of these two strategies in the human setting, and a prospective study evaluating the different β-lactams concentrations in the treatment of severe infections is necessary.

Studies on serum concentrations of broad-spectrum β-lactams have already reported that drug levels are insufficient in patients with severe infections.

Cefepime (2 g every 12 hours) concentrations were more than 70% T > 16 μg/mL in less than half the patients with sepsis15 and were adequate only for MICs of 4 μg/mL in all eight patients suffering from postoperative infections.34 Septic patients with normal renal function had serum cefepime and ceftazidime levels less than 32 μg/mL after a few hours in most cases.11,12 Ceftazidime trough concentrations were Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

research article below the median MIC of P. aeruginosa in more than half of the patients in another study.35 In only one study, ceftazidime levels were above the MIC of the isolated pathogens for more than 90% of the time interval; however Pseudomonas was isolated in only 4 of 16 patients.16 Finally, piperacillin concentrations were above therapeutic levels (64 μg/mL) for most of the time interval in patients with sepsis36 or nosocomial pneumonia.37 However, serum drug concentrations of meropenem were adequate in most of the patients. In severe infections associated with septicemia, mostly after cardiac surgery, meropenem had serum concentrations above 8 μg/mL for at least 50% of the time in patients with normal and those with reduced CrCl.38 In patients with ventilator-associated pneumonia, mean T > 4 × MIC for Pseudomonas was reported as 52% in one study39 and 46% in another.17

antimicrobial delivery to the target tissues. In view of these results, in septic patients, broad-spectrum βlactams should be administered more frequently than suggested in non-septic patients, or with doses larger than standard regimens to optimize pathogen exposure to bactericidal concentrations of the drugs. Population modeling simulation showed that continuous or extended β-lactam infusions are required to obtain adequate serum concentrations.45 However, clinical data that have shown a better outcome using this strategy have come just from retrospective studies in ICU populations with pneumonia.49,50 Further studies are needed in ICU patients to assess the influence on morbidity and mortality of a strategy whereby antibiotic therapy is selected based on the optimal PK, especially in patients with sepsis and in infections caused by multiresistant pathogens.

Nevertheless, most of these previous studies excluded severely ill patients with septic shock and those with an estimated CrCl limiting the generalization of their results to other populations of critically ill patients.

The number of patients was also limited and analyses concerned only the steady-state of the disease. Finally, some of these studies used lower than recommended dosage regimens, which are associated with an increased mortality when susceptible pathogens with higher MICs are present.40,41 Our study focused on a more severe population of patients, suffering from severe sepsis and septic shock, with higher mortality and morbidity rates than less severely ill ICU populations.42 Importantly, we used recommended β-lactam regimens that have the greatest likelihood of achieving a bactericidal target in nosocomial pneumonia and bloodstream infections due to Gram-negative bacteria.43,44 Finally, because antimicrobial treatment of sepsis is often initiated empirically, when pathogens and MICs are still unknown, we used as the target MIC the clinical breakpoint defined by EUCAST for P. aeruginosa, an organism that is commonly isolated in ICUs and associated with high mortality rates.25 This strategy could then be extrapolated to other ‘difficult-to-treat’ pathogens with high susceptibility breakpoints. The consequences of these low antimicrobial levels may be more cases of therapeutic failure, higher medical costs and greater emergence of resistance.45 Moreover, low plasma levels can contribute to lower than expected βlactam concentrations in the extracellular,46 bronchial47 or peritoneal fluid48 with potentially reduced

Although a relation between the intensity of the septic process and PK abnormalities can be assumed, we did not find any relation between T > 4 × MIC and any demographic, clinical, hemodynamic or biological variables. This finding may be related to the fact that the PK analyses were performed during the early phase of sepsis. Also, as a first dose of antibiotic is largely influenced by Vd, the increased distribution volume may play a key role in reducing antimicrobial concentrations in this setting whereas drug clearance remains the main determinant for drug concentrations at steadystate.13 CrCl and drug CL showed good correlation, as elimination of the studied drugs is largely dependent on glomerular function.11,38 Nevertheless, despite a regimen adapted to renal function, patients treated with piperacillin-tazobactam had a higher percentage of adequate concentrations when CrCl was below 50 mL/min. This finding may be related to the complex elimination of piperacillin-tazobactam, which includes biliary excretion.13 Indeed, the hepatic metabolism of this drug is variable and difficult to measure and most studies on piperacillin-tazobactam PKs in patients with renal failure have included patients with normal hepatic function.51 It is possible that, as severe sepsis is frequently associated with liver dysfunction, this may have contributed to greater than expected drug accumulation in some patients. Further studies are needed to evaluate the impact of renal and hepatic dysfunction on piperacillin-tazobactam regimens in critically ill patients.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

21

research article Our study has some limitations. First, we evaluated the PK profile of β-lactams only during the first dose, and thus cannot make any statement with regard to subsequent doses. Vd may decrease during therapy when capillary leakage subsides and sepsis resolves;52 in such circumstances, coupled with persistent renal dysfunction, standard β-lactam doses may be sufficient to achieve therapeutic concentrations. Second, as only free drug is the active moiety, it has been recommended that all PK/pharmacodynamic indices should be referenced to the unbound (free) fraction of the drug, especially for some drugs such as piperacillin, which has 20 to 30% protein binding.53 Third, the inadequate PK/pharmacodynamic indices observed in our study should be considered in relation to the empirical MIC target, and may be different with other susceptibility patterns (MIC distributions) of pathogens at individual institutions. Attention should therefore be paid to establish the MIC values of these pathogens in order to adapt dosage regimens. Also, CrCl was estimated using the Cockroft and Gault formula, which shows important limitations in predicting the real CrCl in ICU patients.54 Finally, the four groups were heterogeneous and, therefore, the numbers may be too small to fully reflect the characteristics of the drugs in this setting.

However, an important concern is the highly variable and unpredictable inter-individual PKs for cephalosporins and piperacillin and whether these drugs can be considered an appropriate agent to use as initial empirical therapy for critically ill patients with severe sepsis and septic shock, particularly in those with potentially less susceptible Gram-negative bacterial strains.

22

Key Messages  Recommended doses of piperacillin-tazobactam, cefepime and ceftazidime provided serum drug concentrations during the first 24 hours of treatment that were insufficient to cover P. aeruginosa and other less susceptible bacteria in patients suffering from severe sepsis and septic shock.  Recommended doses of meropenem resulted in adequate concentrations to cover P. aeruginosa and other less susceptible bacteria in 75% of patients.  In patients treated with piperacillin-tazobactam, renal dysfunction is associated with a better adequacy of drug concentrations compared with normal renal function.  Therapeutic drug monitoring is necessary to optimize β-lactam concentrations as no clinical or biological variable can predict β-lactam concentrations in this population.

Additional Material

Additional File 1 Three tables showing usual daily doses of antibiotics and dose adaptation to renal function, Minimum inhibitory concentrations (MICs) for Pseudomonas aeruginosa and Enterobacteriaceae according to European Committee on Antimicrobial Susceptibility Testing (EUCAST); and mean pharmacokinetic parameters in healthy volunteers.

Abbreviations APACHE: acute physiology and chronic health evaluation; AUC: area under the curve; CL: total clearance; Cmax: peak concentration; CrCl: creatinine clearance; CV: coefficient of variation; EUCAST: European Committee on Antimicrobial Susceptibility Testing; LOD: limit of detection; LOQ: limit of quantification; MIC: minimum inhibitory concentration; PK: pharmacokinetics; SOFA: sequential organ failure assessment; t1/2: elimination half-time; Vd: volume of distribution.

Conclusions

Competing Interests

The treatment of infections in the critically ill patient remains a significant challenge for clinicians.

Standard first doses of broad-spectrum β-lactams provided inadequate levels to achieve target serum concentrations for extended periods of time in critically ill patients with sepsis. Improved characterization of the pharmacodynamic properties of these antimicrobials may lead to revisions in recommendations on dosing in severe infections, especially in the early phase of severe sepsis and septic shock.

FST, FJ, JLV, TD and PFL have received honoraria for lectures from Astra Zeneca. JLV is also on the speakers list of GlaxoSmithKline. The other authors declare that they have no competing interests.

Authors’ Contributions FJ and PFL conceived the study protocol. FST, FJ, PFL, TD, XW, BL and HS participated in the design and coordination of the study. ID and PW performed the PK analyses. FST, PFL, DDB, JLV and FJ drafted the present manuscript. All authors read and approved the final manuscript.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

research article Acknowledgements We thank all the nurses and doctors who contributed to this study. The study was supported by grants from AstraZeneca, Wyeth Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, and Bristol-Myers Squibb. These companies had no involvement in the writing of the paper or in the decision to submit for publication.

References 1. Vincent JL, Taccone F, Schmit X: Classification, incidence, and outcomes of sepsis and multiple organ failure. Contrib Nephrol 2007, 156:64-74.

2. Kollef MH, Sherman G, Ward S, Fraser VJ: Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999, 115:462-474.

3. Zaragoza R, Artero A, Camarena JJ, Sancho S, Gonzalez R, Nogueira JM: The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit. Clin Microbiol Infect 2003, 9:412-418.

4. Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J: Piperacillin penetration into tissue of critically ill patients with sepsis--bolus versus continuous administration? Crit Care Med 2009, 37:926-933.

5. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, BrunBuisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36:296-327.

6. Pinder M, Bellomo R, Lipman J: Pharmacological principles of antibiotic prescription in the critically ill.

Anaesth Intensive Care 2002;30:134-144.

7. Tam VH, McKinnon PS, Akins RL, Rybak MJ, Drusano GL: Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother 2002, 50:425-428.

8. Thalhammer F, Traunmuller F, el MI, Frass M, Hollenstein UM, Locker GJ, Stoiser B, Staudinger T, ThalhammerScherrer R, Burgmann H: Continuous infusion versus intermittent administration of meropenem in critically ill patients. J Antimicrob Chemother 1999, 43:523-527.

9. Nicolau DP, Onyeji CO, Zhong M, Tessier PR, Banevicius MA, Nightingale CH: Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations. Antimicrob Agents Chemother 2000, 44:1291-1295.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

10. McKinnon PS, Paladino JA, Schentag JJ: Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T > MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 2008, 31:345-351.

11. Lipman J, Gomersall CD, Gin T, Joynt GM, Young RJ: Continuous infusion ceftazidime in intensive care: a randomized controlled trial. J Antimicrob Chemother 1999, 43:309-311.

12. Lipman J, Wallis SC, Rickard C: Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing. Antimicrob Agents Chemother 1999, 43: 2559-2561.

13. Roberts JA, Lipman J: Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 2009, 37:840-851.

14. Pea F, Viale P, Furlanut M: Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005, 44:1009-1034.

15. Ambrose PG, Owens RC Jr, Garvey MJ, Jones RN: Pharmacodynamic considerations in the treatment of moderate to severe pseudomonal infections with cefepime. J Antimicrob Chemother 2002, 49:445-453.

16. Benko AS, Cappelletty DM, Kruse JA, Rybak MJ: Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections. Antimicrob Agents Chemother 1996, 40:691-695.

17. Jaruratanasirikul S, Sriwiriyajan S, Punyo J: Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-hour infusion or bolus injection.

Antimicrob Agents Chemother 2005, 49:1337-1339.

18. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31:1250-1256.

19. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system.

Crit Care Med 1985, 13:818-829.

20. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the

23

research article European Society of Intensive Care Medicine. Intensive Care Med 1996, 22:707-710.

21. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976, 16: 31-41.

22. Buck C, Bertram N, Ackermann T, Sauerbruch T, Derendorf H, Paar WD: Pharmacokinetics of piperacillintazobactam: intermittent dosing versus continuous infusion. Int J Antimicrob Agents 2005, 25:62-67.

23. Delattre IK, Musuamba FT, Verbeeck RK, Dugernier T, Spapen H, Laterre PF, Wittebole X, Cumps J, Taccone FS, Vincent JL, Jacobs F, Wallemacq PE: Empirical models for dosage optimization of four beta-lactams in critically ill septic patients based on therapeutic drug monitoring of amikacin. Clin Biochem 2010, 43:589-598.

24. Drusano GL: Antimicrobial pharmacodynamics: critical interactions of â&#x20AC;&#x2DC;bug and drugâ&#x20AC;&#x2122;. Nat Rev Microbiol 2004, 2:289-300.

25. Shorr AF: Review of studies of the impact on Gramnegative bacterial resistance on outcomes in the intensive care unit. Crit Care Med 2009, 37:1463-1469.

26. Clinical breakpoints - bacteria [http://www.eucast.org/ fileadmin/src/media/PDFs/EUCAST_files/Disk_test_ documents/EUCAST_breakpoints_v1.0_20091221.pdf ] 27. Falagas ME, Kopterides P: Old antibiotics for infections in critically ill patients. Curr Opin Crit Care 2007, 13:592-597.

28. Andes D, Craig WA: In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations.

Antimicrob Agents Chemother 1998, 42:2375-2379.

29. Mouton JW, Punt N: Use of the T > MIC to choose between different dosing regimens of beta-lactam antibiotics. J Antimicrob Chemother 2001, 47:500-501.

30. Turnidge JD: The pharmacodynamics of beta-lactams.

Clin Infect Dis 1998, 27:10-22.

31. Williamson R, Tomasz A: Inhibition of cell wall synthesis and acylation of the penicillin binding proteins during prolonged exposure of growing Streptococcus pneumoniae to benzylpenicillin. Eur J Biochem 1985, 151:475-483.

32. Craig WA, Redington J, Ebert SC: Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections.

J Antimicrob Chemother 1991, 27(Suppl C):29-40.

33. Angus BJ, Smith MD, Suputtamongkol Y, Mattie H, Walsh AL, Wuthiekanun V, Chaowagul W, White NJ: Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis. Br J Clin Pharmacol 2000, 50:184-191.

34. Ikawa K, Morikawa N, Hayato S, Ikeda K, Ohge H, Sueda T: Pharmacokinetic and pharmacodynamic

24

profiling of cefepime in plasma and peritoneal fluid of abdominal surgery patients. Int J Antimicrob Agents 2007, 30:270-273.

35. Young RJ, Lipman J, Gin T, Gomersall CD, Joynt GM, Oh TE: Intermittent bolus dosing of ceftazidime in critically ill patients. J Antimicrob Chemother 1997, 40:269-273.

36. Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J: First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents 2010, 35:156-163.

37. Boselli E, Breilh D, Cannesson M, Xuereb F, Rimmele T, Chassard D, Saux MC, Allaouchiche B: Steadystate plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia.

Intensive Care Med 2004, 30:976-979.

38. Kitzes-Cohen R, Farin D, Piva G, Myttenaere-Bursztein SA: Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Int J Antimicrob Agents 2002, 19:105-110.

39. De Stoppelaar F, Stolk L, van Tiel F, Beysens A, van der GS, de Leeuw P: Meropenem pharmacokinetics and pharmacodynamics in patients with ventilator-associated pneumonia. J Antimicrob Chemother 2000, 46:150-151.

40. Bhat SV, Peleg AY, Lodise TP Jr, Shutt KA, Capitano B, Potoski BA, Paterson DL: Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by gram-negative organisms. Antimicrob Agents Chemother 2007, 51:4390-4395.

41. Tam VH, Gamez EA, Weston JS, Gerard LN, Larocco MT, Caeiro JP, Gentry LO, Garey KW: Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis 2008, 46:862-867.

42. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D: Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006, 34:344-353.

43. Sun HK, Kuti JL, Nicolau DP: Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: a report from the OPTAMA Program. Crit Care Med 2005, 33:2222-2227.

44. Maglio D, Kuti JL, Nicolau DP: Simulation of antibiotic pharmacodynamic exposure for the empiric treatment of nosocomial bloodstream infections: a report from the OPTAMA program. Clin Ther 2005, 27:1032-1042.

45. Scaglione F, Paraboni L: Pharmacokinetics/ pharmacodynamics of antibacterials in the Intensive Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

research article Care Unit: setting appropriate dosing regimens. Int J Antimicrob Agents 2008, 32:294-3001.

46. Zeitlinger MA, Erovic BM, Sauermann R, Georgopoulos A, Muller M, Joukhadar C: Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis. J Antimicrob Chemother 2005, 56:703-708.

47. Klekner A, Bagyi K, Bognar L, Gaspar A, Andrasi M, Szabo J: Effectiveness of cephalosporins in the sputum of patients with nosocomial bronchopneumonia. J Clin Microbiol 2006, 44:3418-3421.

48. Wise R, Logan M, Cooper M, Ashby JP, Andrews JM: Meropenem pharmacokinetics and penetration into an inflammatory exudate. Antimicrob Agents Chemother 1990, 34:1515-1517.

49. Lodise TP Jr, Lomaestro B, Drusano GL: Piperacillintazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007, 44:357-363.

50. Lorente L, Jimenez A, Palmero S, Jimenez JJ, Iribarren JL, Santana M, Martin MM, Mora ML: Comparison of clinical cure rates in adults with ventilator-associated

pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther 2007, 29:2433-2639.

51. Thompson MI, Russo ME, Matsen JM, Atkin-Thor E: Piperacillin pharmacokinetics in subjects with chronic renal failure. Antimicrob Agents Chemother 1981, 19:450-453.

52. Triginer C, Izquierdo I, Fernandez R, Rello J, Torrent J, Benito S, Net A: Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med 1990, 16:303-306.

53. Muller M, Haag O, Burgdorff T, Georgopoulos A, Weninger W, Jansen B, Stanek G, Pehamberger H, Agneter E, Eichler HG: Characterization of peripheralcompartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrob Agents Chemother 1996, 40:2703-2709.

54. Martin JH, Fay MF, Udy A, Roberts J, Kirkpatrick C, Ungerer J, Lipman J: Pitfalls of using estimations of glomerular filtration rate in an intensive care population.

Intern Med J 2010 in press.

n

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

n

n

25

case report clinical practice

Klebsiella oxytoca Bacteremia Causing Septic Shock in Recipients of Hematopoietic Stem Cell Transplant: Two Case Reports Khalid A Al-Anazi, Asma M Al-Jasser, Hazza A Al-Zahrani, Naem Chaudhri, Fahad I Al-Mohareb

Abstract Background: Klebsiella oxytoca can cause various infectious complications in healthy as well as in immunocompromised individuals. Case Presentations: Case 1: A 49 year old female with multiple myeloma received an autologous hematopoietic stem cell transplant in October 2005. Eight days following her autograft she developed septic shock caused by Klebsiella oxytoca bacteremia which was successfully treated with intravenous meropenem and gentamicin. Case 2: A 29 year old female with sickle cell anemia and severe aplastic anemia underwent an allogeneic hematopoietic stem cell transplant in July 2005.

Seven months following her unsuccessful allograft, she developed septic shock due to Klebsiella oxytoca bacteremia caused by a urinary tract infection. The septic episode was successfully managed with intravenous meropenem and gentamicin. Both patients were treated at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia. To our knowledge, they are the first reports of Klebsiella oxytoca bacteremias and septic shocks in hematopoietic stem cell transplant recipients.

Conclusion: Klebsiella oxytoca should be considered as a possible cause of severe infections in recipients of various forms of hematopoietic stem cell transplantation. However, these infections may be complicated by bacteremias, septic shocks, systemic dysfunctions and even deaths, if not managed promptly and appropriately.

Key words: Klebsiella oxytoca, bacteremia, stem cell transplant

K

lebsiella species are the second most frequent cause of gram-negative bacteremia.1 Since the early 1980s, Klebsiella oxytoca (K. oxytoca) isolateshave been recognized as clinically significant.2 The isolation of this organism from clinical specimens is an indication for therapy.2 Extended spectrum beta lactamase (ESBL) production by K. oxytoca causes bacterial resistance to B-lactam antibiotics and contributes to therapeutic problems.2,3 The organism is usually resistant to the oxyimino B-lactams such as cefotaxime, ceftazidime and the monobactam aztreonam.2 In patients with Klebsiella bacterermia, monotherapy with an antibiotic that is active in-vitro against Klebsiella eg a beta-lactam or an aminoglycoside is a sufficient treatment for hemodynamically stable patients but in severely ill patients having hypotension, an antibiotic combination therapy with a beta-lactam and an aminoglycoside is usually preferred.1 Case Presentations Case 1

A 49 year old Saudi female was diagnosed to have multiple myeloma (MM), IgG kappa, at King Faisal Citation: Al-Anazi et al. Klebsiella oxytoca bacteremia causing septic shock in recipients of hematopoietic stem cell transplant: Two case reports. Cases Journal 2008, 1:160.

26

Specialist Hospital and Research Centre (KFSH & RC) in Riyadh in April 2005. She presented with: fatigue; bony pains; anemia; hypercalcemia; high total protein, IgG level, beta-2 microglobulin and erythrocytic sedimentation rate; 40% plasma cells in the bone marrow and diffuse lytic lesions. After receiving 4 courses of VAD chemotherapy (vincristine, doxorubicin and dexamethasone), her disease became under control.

In September 2005, she underwent an autologous peripheral blood stem cell collection in preparation for an autologous hematopoietic stem cell transplant (HSCT). On admission to the HSCT unit, the patient was asymptomatic and her physical examination did not reveal any abnormality. Investigations showed: CBC: WBC: 4.4 Ă&#x2014; 109/L (neutrophilis: 2.64), Hb 92 g/L and PLT: 419 Ă&#x2014; 109/L. The renal, hepatic and coagulation profiles were all within normal limits and a repeat bone marrow biopsy showed 4% plasma cells. The patient was conditioned with high dose IV melphalan and she received acyclovir, fluconazole and trimethoprim-sulphamethoxazole (TMP/SMZ) as infection prophylaxis. On 5/10/2005, the patient received her autograft without any complications.

In the early post-HSCT period, she developed: grade II mucositis treated with IV morphine infusion and Clostridium difficile colitis treated with Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

case report metronidazole. On 13/10/2005; the patient became febrile so septic screens were taken and she was empirically commenced IV piperacillin-tazobactam 4.5 grams thrice daily and IV gentamicin 2 mg/kg twice daily. On 14/10/05, she started to have high fever and rigors and her BP dropped to 85/40 mm Hg. However, she had no other complaints and physical examination did not reveal any focus of infection. The septic screens were repeated and the IV tazobactam-piperacillin was replaced by IV meropenem 1 gram thrice daily. Few hours later, the patient started to improve clinically and her BP became stable. The central blood cultures taken on 13/10/05 grew K. oxytoca sensitive to augmentin, cefazolin, ceftriaxone, gentamicin and meropenem. The peripheral blood cultures as well as the urine, the throat and the stool cultures were negative. As the patient maintained her hemodynamic stability, she was continued on meropenem and gentamicin. She engrafted her leukocytes on day +14 and her platelets on day + 12 HSCT. After the recovery of her blood counts and the control of her septic episode, the IV antibiotics were replaced by oral cefuroxime. On 23/10/2005, the patient was having no complaints and her repeated physical examination revealed no abnormality. The blood indices, the renal and hepatic profiles were normal. She was sent home on: cefuroxime 500 mg orally twice daily for 4 days in addition to prophylactic TMP/SMZ, acyclovir and fluconazole till day +30 HSCT. Thereafter the patient had regular follow up at the HSCT outpatient clinic and no major complication was encountered.

Case 2

A 29 year old Saudi female with clinically mild sickle cell disease, requiring infrequent blood transfusions and mild analgesia but no iron chelating agents, was diagnosed to have severe aplastic anemia (SAA) at KFSH&RC in Riyadh in late December 2005. She presented with mucosal bleeding, anemic manifestation, pancytopenia and severely hypocellular bone marrow without blasts or abnormal cells. Screens for fanconi anemia and paroxysmal nocturnal hemoglobinuria were negative. Hepatitis serology and viral screens including parvovirus B-19 were also negative. After failing to respond to a course of antithymocyte globulin, cyclosporine-A and prednisone and finding a healthy and an HLA-identical sibling donor, the patient was planned for an allogeneic HSCT. She was conditioned Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

with cyclophosphamide and fludarabine. She received methotrexate and cyclosporine-A as graft versus host disease (GVHD) prophylaxis and fluconazole, acyclovir and penicillin as infection prophylaxis. She received her allograft on 11/7/2005. Unfortunately she had no engraftment so she remained pancytopenic and she was continued on G-CSF in addition to platelet and packed red cell transfusions. She was given various antimicrobials for the repeated infections encountered.

On 15/2/2006, the patient was readmitted with fever, rigors, dysuria, dizziness and fatigue for 2 days.

Physical examination showed: temperature: 39.4째C, BP: 80/40 mmHg and pulse rate 112/minute. She was looking unwell and pale. Her chest was clear. There was bilateral loin tenderness but no palpable abdominal organomegaly. The cardiovascular and neurological examinations were normal. After taking blood cultures and septic screens, the patient was commenced on: IV fluids at 150 cc/hour, IV meropenem: 1 gram thrice daily and IV gentamicin 2 mg/kg twice daily in addition to GCSF and blood product transfusion support. Few hours later, the patient started to improve; the pyrexia and the rigors subsided and the BP started to stabilize.

Thereafter the patient maintained her hemodynamic stability. The central and the peripheral blood cultures as well as the urine cultures taken on 15/2/2006 grew: K. oxytoca sensitive to: augmentin, cefazolin, gentamicin and meropenem but resistant to amoxycillin.

On 16/9/2006, the patient was asymptomatic, afebrile, her BP was normal and her repeated physical assessment showed no more loin tenderness. Six days after the septic shock, the IV gentamicin was stopped but the IV meropenem was continued for a total duration of 2 weeks. Later on, the patient remained pancytopenic but clinically and hemodynamically stable. On 22/2/2006, the patient received a booster dose of peripheral blood stem cells from the same donor, which did not have any positive impact on her bone marrow function. On 5/3/2006, the patient was discharged on: prophylactic ciprofloxacin, fluconazole and acyclovir in addition to pentamidine nebulizer 300 mg once/month. Thereafter, she continued to be pancytopenic and to have regular follow up at the HSCT outpatient clinic.

Discussion

Infections caused by K. oxytoca occur in healthy individuals, newborn babies and immunocompromised hosts such as patients with diabetes mellitus, solid tumors 27

case report and leukemia.4-13 These infections may be encountered in patients having: neurosurgical procedures, prostatectomies, colonoscopies, intravascular catheters, platelet transfusions, urinary tract infections and preexisting viral or antibiotic induced colitis.4-7 K. oxytoca can cause systemic infections such as meningitis, adrenal hemorrhage, hemorrhagic colitis and septic shock.4-8 Outbreaks of K. oxytoca infections have been reported in: newborn babies following colonization of their digestive tracts, oncology patients following contamination of intravenous fluids and in cardiac patients following contamination of invasive blood pressure monitoring devices.11-13 Bacteremia caused by K. oxytoca can be nosocomial or community-acquired.4-6,8-14 It is usually associated with polymicrobial bacteremias and occurs in patients with certain underlying conditions eg hepatobiliary or pancreatic disorders, neoplastic disorders and diabetes mellitus.14,15 The clinical manifestations of K. oxytoca infections are very variable and may include: biliary tract infections, primary bacteremias, intravascular device-associated infections, urinary tract infections, skin and soft tissue infections and peritonitis.14,15 These infections may be complicated by: bacteremia and septic shock, disseminated intravascular coagulation and death.5,14,15 The mortality rates range between 9 and 24%.14,15 Poor prognosis and fatal outcomes are associated with: septic shock, deterioration of mental status, polymicrobial bacteremias and having certain underlying conditions such as solid tumors.14,15 In K. oxytoca infections, surgical intervention, which may occasionally be required, has been shown to have a beneficial protective role.14 Previous antibiotic therapy is strongly associated with resistance to the extendedspectrum cephalosporins.14 In patients with K. oxytoca bacteremia, 86% of the strains have been found to be susceptible to cefazolin and almost all the strains have been found to be susceptible to: ampicillinsulbactam, aminoglycosides, cefmetazole, quinolones and carbapenems.15 ESBLs are extremely broad spectrum B-lactamase enzymes that are found in a variety of enterobacteriaceae.

When producing these enzymes, the organisms become highly effective at inactivating various B-lactam antibiotics. The most common ESBL producing organisms are: E. coli, K. pneumoniae and K. oxytoca.3 ESBL producing bacteriae are frequently resistant to 28

many classes of antibiotics including aminoglycosides and fluoroquinolones thus resulting in infections that are difficult to treat.2,3 Piperacillin-tazobactam and cefepime should not be routinely administered for the treatment of ESBL producers. However, carbapenems are considered the treatment of choice for patients infected with ESBL producing pathogens.3 The first patient presented had MM and she received an autologous HSCT after the control of her disease in an attempt to cure the myeloma. Despite giving IV gentamicin and piperacillin-tazobactam to control her febrile neutropenic episode, she developed the septic shock one day later. There was no clinical focus for the infection although it coincided with an episode of colitis treated with metronidazole. Few hours after shifting to IV meropenem, her septic shock became under control. The second patient had recurrent infections as she remained pancytopenic following the failure of her allogeneic HSCT. The urinary tract infection was the cause of her K. oxytoca bacteremia.

As the patient presented to the HSCT clinic with clinical evidence of septicemia (fever, rigors and hypotension), she was immediately commenced on IV meropenem and gentamicin which controlled her septic shock within few hours. In both patients, the organisms were not ESBL producers and the septic episodes were successfully managed in the HSCT unit without resorting to higher levels of care or even inotropic support.

Conclusion

K. oxytoca can cause serious infections, bacteremias and septic shocks in immunocompromised individuals including recipients of various forms of HSCT. Careful clinical assessment, taking enough investigations and administration of appropriate antimicrobial therapy are essential not only to control these infections but also to prevent further complications.

Abbreviations K. oxytoca: Klebsiella oxytoca; MM: Multiple myeloma; SAA: Severe aplastic anemia; HSCT: Hematopoietic stem cell transplantation.

Competing Interests The authors declare that they have no competing interests.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

case report Authorsâ&#x20AC;&#x2122; Contributions All authors participated, from clinical and laboratory points of view, in the management of the patients presented.

Consent Written consents were obtained from both patients for publication of these case reports.

Acknowledgements We are grateful to all medical, nursing and technical staff, at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, who participated in the management of the patients presented.

References 1. Korvick JA, Bryan CS, Farber B, Beam TR, Schenfeld L, Muder RR, Weinbaum D, Lumish R, Gerding DN, Wagener MM: Prospective observational study of Klebsiella bacteremia in 230 patients: outcome for antibiotic combinations versus monotherapy. Antimicrob Agents Chemother 1992, 36(12):2639-2644.

2. Wu SW, Dornbusch K, Goransson E, Ransjo U, Kornvall G: Characterization of Klebsiella oxytoca septicemia isolates resistant to aztreonam and cefuroxime. J Antimicrob Chemother 1991, 28(3):389-397.

3. Nathisuwan S, Burgess DS, Lewis JS II: Extendedspectrum B-lactamases: epidemiology, detection and treatment. Pharmacotherapy 2001, 21(8):920-928.

4. Tang LM, Chen ST: Klebsiella oxytoca meningitis: frequent association with neurosurgical procedures.

Infection 1995, 23(3):163-167.

5. Hori K, Yasoshima H, Yamada A, Sakurai K, Ohkubo E, Kubota A, Uematsu K, Sasio H, Mizokami Y, Shimoyama T: Adrenal hemorrhage associated with Klebsiella oxytoca bacteremia. Intern Med 1998, 37(11):990-994.

6. Haddad J, Marcato N, Cassan P: Septic shock caused by Klebsiella oxytoca after colonoscopy. Gastroenterol Clin Biol 1994, 18(2):181-182.

7. Kashiwagi Y, Sato S, Nakamura M, Kuboshima S, Numabe H, Kawashima H, Takekuma K, Hoshika A,

Matsumoto T: Klebsiella oxytoca septicemia complicating rota virus-associated acute diarrhea. Pediatr Infect Dis J 2007, 26(2):191-192.

8. Boyeldieu D, Vu-Thien H, Dollfus C, Bounetta M, Ballerini P, Gerota I, Moissenet D, Landman J, Tourniaire B, Leverger G: Klebsiella oxytoca septicemia following platelet transfusion. Pathol Biol (Paris) 1999, 47(5): 405-407.

9. Sardan YC, Zarakolu P, Altun B, Yildirim A, Yildirim G, Hascelik G, Uzuno O: A cluster of nosocomial Klebsiella oxytoca bloodstream infection in a university hospital.

Infect Control Hosp Epidemiol 2004, 25(10):878-882.

10. Hogenauer C, Langer C, Beuber C, Lippe IT, Schicho R, Gorkiewicz G, Krause R, Gerstgrasser N, Krejs GJ, Hinterleitner TA: Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis. N Engl J Med 2006, 355(23):2418-2426.

11. Berthelot P, Grattard F, Patural H, Ros A, JelassiSaoudin H, Pozzetto B, Teyssier G, Lucht F: Nosocomial colonization of premature babies with Klebsiella oxytoca.

Probable role of enteral feeding procedure in transmission and control of the outbreak with the use of gloves. Infect Control Hosp Epidemiol 2001, 22(3):148-151.

12. Ransjo U, Good Z, Jalakas K, Kuhn I, Siggelkow I, Aberg B, Anjou E: An outbreak of Klebsiella oxytoca septicemia associated with the use of invasive pressure monitoring equipment. Acta Anaesthesiol Scand 1992, 36(3):289-291.

13. Watson JT, Jones RC, Siston AM, Fernandez JR, Martin K, Beck E, Sokalski S, Jensen BJ, Arduino MJ, Srinivasan A, Gerber SI: Outbreak of catheter associated Klebsiella oxytoca and Enterobacter cloacae bloodstream infections in an oncology chemotherapy center. Arch Intern Med 2005, 165(22):2639-2643.

14. Kim BN, Ryu J, Kim YS, Woo JH: Retrospective analysis of clinical and microbiological aspects of Klebsiella oxytoca bacteremia over a 10 year period. Eur J Clin Microbial Infect Dis 2002, 21(6):419-426.

15. Lin RD, Hsueh PR, Chang SC, Chen YC, Hsieh WC, Luh KT: Bacteremia due to Klebsiella oxytoca: clinical features of patients and antimicrobial susceptibilities of the isolates. Clin Infect Dis 1997, 24(6):1217-1222.

n

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

n

n

29

case report clinical practice

Extensive Anterior Chest Wall Cellulitis with Central Venous Catheter-related Blood Stream Infection Dinesh Singh*, Anuj Verma*, Sourya Acharya**, Shital Kriplani†, SN Mahajan‡

Abstract Central venous catheterization (CVC) is a time honored and tested technique of quickly accessing the major venous systems.

Catheter-related infections can be a great cause of morbidity, mortality and economic distress to the patient. In this review, we will be discussing and focusing on the infective complications of CVC. Key words: Central venous catheter-related infective complications

Case Report A 58-year-old male diagnosed case of chronic renal failure was referred to our hospital for hemodialysis.

The patient was hemodialyzed through a subclavian vein hemodialysis catheter on four occasions in eight days before coming to our hospital.

On clinical examination in our hospital, patient was drowsy, febrile, pulse was 120/minute and regular.

Blood pressure was 90/60 mmHg. Other general physical examination was unremarkable.

On systemic examination, cardiovascular, respiratory and per abdomen examination were within normal limits. On examination of central nervous system (CNS), patient was drowsy with no evidence of any focal neurological deficit. Plantars were bilateral flexor and there were no flapping tremors.

Local examination of site of subclavian catheter showed anterior chest wall cellulitis with skin excoriation, gangrene and peripheral ecchymosis (Fig. 1).

An urgent Dermatology and a Surgery consult was taken and diagnosis was unanimously kept as anterior chest wall cellulitis with excoriation of skin with gangrene (due to extravasation) and peripheral *Resident **Associate Professor † Assistant Professor ‡ Professor and Head, Dept. of Medicine JN Medical College/DMIMSU, Sawangi (M), Wardha Address for correspondence Dr Dinesh Singh Resident Medicine Room No.: T-11, New PG Hostel, AVBRH Campus JN Medical College, Sawangi (Meghe), Wardha - 442 001, Maharashtra E-mail: singhdinesh1@gmail.com

30

Figure 1. Showing anterior chest wall cellulitis with excoriation of skin with gangrene and peripheral ecchymosis.

ecchymosis. The catheter was immediately removed and the catheter tip was sent for culture along with two blood samples from different peripheral venous lines simultaneously. Another catheter was inserted in femoral vein to continue hemodialysis.

Results of other routine investigations in our hospital were as follows: Hemoglobin 10.9 g/dl, total leukocyte count 33,400/mm3 (P-91% L-7%), urea 186 mg/dl, creatinine 5.5 mg/dl, random blood sugar 119 mg/dl.

Liver function tests were within normal limits.

Chest X-ray was normal ruling out any evidence of pneumothorax/pleural effusion. USG abdomen was done to rule out any intra-abdominal/pelvic source of infection. It was normal except for reduced size of kidneys bilaterally with loss of corticomedullary differentiation.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

case report Empirically patient was started on injection ticarcillin + clavulanic acid and injection. Ceftazidime (doseadjusted according to creatinine clearance). Daily dressing at site of infection was done with hydrogen peroxide and betadine solution.

The catheter tip culture revealed growth of coagulasenegative Staphylococcus, which was resistant to amoxicillin/oxacillin/vancomycin and was sensitive to ticarcillin and meropenem. Blood culture also showed growth of coagulase-negative Staphylococcus which had a similar drug sensitivity/resistance profile to that from central venous catheter (CVC). Urine culture showed no growth.

Diagnosis was kept as CVC-related anterior chest wall cellulitis with gangrene with blood stream infection with chronic renal failure. Patient improved with 14 days of antibiotics and regular hemodialysis. Wound healed and counts were normal after two weeks of treatment and patient was discharged.

Discussion Central venous catheterization (CVC) is a time honored and tested technique of quickly accessing the major venous systems. The overall complications with CVC are 15% (Table 1).1 These complications can be potentially life-threatening and consume significant resources for their treatment. In this review, we will be discussing and focusing on the infective complications of CVC. Infectious Complications with CVC Insertion

Types of catheter-associated infections  Catheter colonization: Growth of organisms from catheter segment by semi-quantitative/quantitative culture.  Catheter-related blood stream infections: Isolation of same organism from blood culture and from semi-quantitative/quantitative culture of catheter segment accompanied 2

Table 1. Type and Frequency of Complications Type of complication

Frequency of complication



by clinical symptoms of blood stream infections without any other source of infection.

Exit site infection: Erythema, induration and or purulence (in absence of concomitant blood stream infection) within 2 cm of exit site of catheter.

Risk factors for CVC-related infections are as below:3,4  Use of multilumen catheters  Hemodialysis  Catheter >4 days  Difficulty in catheter insertion  Prolonged stay in ICU before insertion of catheter  Insertion site contamination  Lack of use of occlusive dressing of wounds at the site of catheter  Use of >3 devices  Use of contaminated fluids/solutions  Catheter hub contamination  Use of antibiotic ointments at the site of catheter  Routine change of catheters over a guidewire  Lack of strict asepsis during insertion of catheter.

According to various RCTs jugular vein catheterization is associated with higher risk of CVC-related infections compared to subclavian vein catheters.1,2 Table 2 describes the various organisms implicated in the etiology of catheter-related infections.5,6 Simple interventions or precautions can reduce the risk or prevent catheter-related infections (Table 3).7,8 Table 2. Organisms Causing Catheter-related Infections5,6 Organism

Frequency

Coagulase-negative Staphylococcus

37%

Staphylococcus aureus

13%

Enterococcus

13%

Escherichia coli

2%

Mechanical

5-19%

Pseudomonas aeruginosa

4%

Infectious

5-26%

Klebsiella

3%

Thrombotic

2-26%

Candida

8%

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

31

case report Table 3. Precautions/Interventions to Prevent Catheter-related Infections7,8 Time of precaution

Type of precaution

During catheter insertion

Sterile barrier techniques*

Catheter care after insertion

Use transparent semipermeable polyurethane dressing**

During catheter handling

Use waterless/alcohol-free antiseptics by healthcare professionals

Use of 2% chlorhexidine gluconate/povidoneiodine solution for site preparation

Use sutureless securement devices

Replace dressing if damp, soiled/loose

Conclusions CVCs are indispensible in clinical practice particularly in ICU. Catheter-related infections can be a great cause of morbidity, mortality and economic distress to the patient.

Certain life-threatening infections and cost of care of these catheters can be reduced to a great extent by a few simple/easy precautions taken by the healthcare professionals. The above mentioned guidelines can go a long way in ensuring optimum use of CVC and with minimum risk of infectious complications.

Change dressing at least once a week

References

Avoid topical antibiotic cream at catheter site***

1. Sznajder JI, Zveibil FR, Bitterman H, Weiner P, Bursztein S. Central vein catheterization. Failure and complication rates by three percutaneous approaches.

Arch Intern Med 1986;146(2):259-61.

Changing/ catheter removal

Replacement of catheters by guidewire exchange technique to be avoided$$

Catheter properties

Teflon/Polyurethane catheters have lesser risk compared to PVC##

Prompt removal of unnecessary catheters

Use of antibiotic impregnated catheters# Use cuffed CVC Use CVC with minimum number of ports Site of catheter insertion

Subclavian vein has lesser risk of infection compared to femoral/internal jugular vein

Others

Do not use hemodialysis catheters for blood drawing or applications other than hemodialysis

*Cap, mask, gowns, sterile drape and gloves. **Helps to secure device, continuous visual inspection of site, permits bathing without saturating the dressing with less frequent changing. ***Potential to promote fungal infections and antimicrobial resistance. # First-generation catheters: Chlorhexidine/Silver sulfadiazinecoated on external lumen. Second-generation catheter: Drugs impregnated on external + internal lumen. Minocycline/rifampcin impregnated catheter. ## Catheters made of polyvinyl chloride or polyethylene are likely less resistant to the adherence of micro-organisms than are catheters made of teflon, silicone elastomer or polyurethane. $$ If patients have tenderness at the insertion site, fever without obvious source, or other manifestations suggesting local or blood stream infection, the dressing should be removed to allow thorough examination of the site.

2. Pearson ML; Hospital Infection Control Practices Advisory Committee. Guideline for prevention of intravascular device-related infections. Infect Control Hosp Epidemiol 1996;17(7):438-73.

3. Maki DG, Mermel LA. Infections due to infusion therapy. In: Hospital Infections. Bennett JV, Brachman PS, (Eds.), Little Brown and Co.: Boston, MA 1998: 689-724.

4. Mermel LA, McCormick RD, Springman SR, Maki DG. The pathogenesis and epidemiology of catheter-related infection with pulmonary artery Swan-Ganz catheters: a prospective study utilizing molecular subtyping.

Am J Med 1991;91(3B):197S-205S. 5. CDC. National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1990-May 1999, issued June 1999. Am J Infect Control 1999;27(6):520-32.

6. Schaberg DR, Culver DH, Gaynes RP. Major trends in the microbial etiology of nosocomial infection. Am J Med 1991;91(3B):72S-75S. 7. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med 2003;348(12):1123-33.

8. Oâ&#x20AC;&#x2122;Grady NP, Alexander M, Dellinger EP, Gerberding JL, Hearol SO, Maki DG, et al; Center for Disease Control Prevention. Guidelines for the prevention of intravascular catheter-related infections. MMWR Recomm Rep 2002;51(RR-10):1-29.

n

32

n

n

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

CLINICAL aLGORITHM clinical practice

Management of Patient with Splenic Trauma

Trauma patient

Unstable

Stable patient

Surgery

Radiological assessment (CT, ultrasound, scintigram)

Splenectomy or Splenic repair

Evidence of additional organ damage

Isolated splenic trauma

Conservative management

Indications for Splenectomy

Indication

Pathology

Bleeding

Trauma: Iatrogenic or spontaneous

As part of surgical resection

During total gastrectomy, distal pancreatectomy

Diagnostic

Splenomegaly of unknown cause Pyrexia of unknown origin (PUO)

Staging

Hodgkinâ&#x20AC;&#x2122;s disease

Therapeutic

Hypersplenism Idiopathic thrombocytopenia purpura Hemolytic anemia, giant spleen with symptoms

Others

Splenic abscess, hydatid disease

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

33

emedinews section clinical practice

From eMedinewS

Insulin Resistance Increases Risk of Heart Disease

conducting yet another study to further substantiate their claim.

Much research points to the fact that diabetes is related to coronary heart disease, but it is unclear what causes this link. Therefore, a group of researchers set out to determine whether heart disease in those with diabetes is caused by increased insulin resistance, changes in metabolic factors, or other symptoms of diabetes. The researchers used a tool called the Archimedes model to estimate the proportion of heart attacks that could be prevented by keeping insulin at healthy levels versus keeping other metabolic functions at healthy levels.

They found that approximately 42% of heart attacks would be prevented if insulin resistance levels were normal. This led researchers to conclude that the link between heart disease and diabetes is primarily insulin resistance.

Novel Agent Cuts Stroke in Hard-to-treat Afibrillation

Risk for Fifth Dose DTaP Vaccine Reaction Higher when Injected in Arm Risk for a local reaction to the fifth dose of the diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) is higher when it is injected in the arm, according to a retrospective cohort study reported in Pediatrics.

Exercise more Effective than Angioplasty Angioplasty is the most common procedure performed in heart disease or heart attack patients. It involves using a stint to widen arteries clogged with plaque or atherosclerosis. Researchers announced at an annual meeting of the European Society for Cardiology that exercise could be more effective than angioplasty to reduce heart disease. German researchers referenced a study where they found that nearly 90% of heart patients who rode stationary bikes regularly were free of heart problems one year after they started their exercise regimen. Among patients who had an angioplasty instead, only 70% were problem-free after a year.

They concluded that exercise may be more effective at warding of heart problems than the procedure, and are

In patients with atrial fibrillation who can’t take vitamin K antagonist therapy, the experimental anticoagulant apixaban is superior to aspirin for preventing stroke or systemic embolism, final results of the AVERROES trial confirmed.

Infertility Update What are the Complementary and Alternative Treatments of Infertility?

Acupuncture

In a German study published in 2002, acupuncture performed 25 minutes before and after in vitro fertilization (IVF) embryo transfer increased IVF pregnancy rates. In a similar study conducted by The University of South Australia in 2006, the acupuncture group’s odds (although not statistically significant) were 1.5 higher than the control group. Although definitive results of the effects of acupuncture on embryo transfer remain a topic of discussion, study authors state that it appears to be a safe adjunct to IVF. —Dr Kaberi Banerjee, Director Precious Baby Foundation

Medifinance Update Company Size

Many funds restrict the types of stocks they buy for the fund based on the size of the company. The size of the company is measured by its market capitalization (market cap - measures the company’s worth by multiplying its stock price by the number of shares outstanding). Generally, small cap funds are more risky than large cap funds as minor changes in a small cap company’s stock price can have a major impact on its market cap. However, if you can take the ups and downs, there can be greater rewards for investors in small cap funds. n

34

n

n

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

lighter reading clinical practice

Lighter Side of Reading

Laugh a While

Quote

Three Vampires Walk into a Bar

Three vampires walk into a bar and sit down at a table.

The waitress comes over and asks the first vampire what he would like. The first vampire responds, “I vould like some blood.” The waitress turns to the second vampire and asks what he would like. The vampire responds, “I vould like some blood.” The waitress turns to the third vampire and asks what he would like. The vampire responds, “I vould like some plasma.”

The waitress looks up and says, “Let me see if I have this order correct. You want two bloods and a blood light?”

—Dr GM Singh

A principle is the expression of perfection, and as “imperfect beings like us cannot practice perfection, we devise every moment limits of its compromise in practice.

”

—Mahatma Gandhi

Dr. Good and Dr. Bad Situation: A patient was diagnosed with HIV-AIDS.

You will die within 10 years

You can live a fairly normal life span

© IJCP Academy

An Inspirational Story Migrating Geese

The next season, when you see the geese migrating, going to a warmer place, to sort the winter…

Pay attention that they fly in a ‘V’ formation. Maybe you will be interested in knowing why they do it this way. By flying in a ‘V’ formation… The whole flock increases the flight efficiency by 71% compared to just one bird flying alone.

Lesson: In the 1980s, a young adult diagnosed with AIDS typically survived less than one year. Today, a similar person can expect to live to age 70 or beyond if he or she is diagnosed with HIV infection early, has access to and receives appropriate therapy, and can tolerate the drugs and their side effects.

Dr KK Aggarwal

Illusion

Knowledge is Amusing 







 

TYPEWRITER is the longest word that can be made using the letters only on one row of the keyboard.

DRAWING ROOM was actually a ‘withdrawing room’ where people withdrew after Dinner. Later the prefix ‘with’ was dropped.

The strongest muscle in the body is the TONGUE. The name of all the continents ends with the same letter that they start with Asia, America, Australia and Europe.

Coca-Cola was originally green.

NEWS refers to information from four directions N, E, W and S.

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

35

research article

Subscription Form (Jan-Dec 2011)

Save

Subscribe to all Journals ` 1000/You Pay ` 13,500/-

Special Discount on Institutional Packages

Yes, I am interested in subscribing to the *Institutional Combo Package for one year (Institutional) Yes, I am interested in subscribing to the following journal(s) for one year (Institutional) JOURNALS

ISSUES/YEAR

INSTITUTIONAL (` Amount) 3,500/-

12

(Individual) INDIVIDUAL (` Amount) 1,650/-

12

1,200/-

550/-

12

3,500/-

1,650/-

4

1,200/-

550/-

4

1,200/-

550/-

4

1,200/-

550/-

4

1,200/-

1,500/-

6

Payment Information:

550/-

750/-

Total `14,500/- for 1 Year

Name: ............................................................................................

Pay Amount: ......................................................................................

Speciality: ......................................................................................

Address: ........................................................................................

Dated (dd/mm/yyyy): ..........................................................................

........................................................................................

Country: ..................................... State: .......................................

Cheque or DD No.: .............................................................................

Pincode: ....................................

Telephone: ............................... Mobile: ......................................

Drawn on Bank: ................................................................................

E-mail: ...........................................................................................

Cheques/DD should be drawn in favor of “M/s IJCP Publications Pvt. Ltd.” Payable at New Delhi.

36

Mail this coupon to : IJCP Publications Pvt. Ltd. We accept payments Head Office: Daryacha, 39, Hauz Khas Village, New Delhi - 110 016 Asian Journal of Critical Care Vol. 6, No. 4,by Cheque/DD only.

October-December 2010 Telefax: 26965874/75, 26865644 Mob.: 9891272006 Do not pay Cash.

Subscription Office: 5E, Merlin Estates, 25/8 Diamond Harbour Road, Kolkata - 700 008 Tele No.: 033-24452066 Mob.: 9831363901, E-mail: subscribe@ijcp.com, Website: www.ijcpgroup.com

Asian Journal of

Critical Care Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Asian Journal of Critical Care strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

–

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

–

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript –

Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

–

Confidence intervals for the measurements should be provided wherever appropriate.

Results –

These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

37

Discussion

Figures

–

–

Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

–

All photomicrographs should indicate the magnification of the print.

–

Special features should be indicated by arrows or letters which contrast with the background.

–

The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

–

Color illustrations will be accepted if they make a contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Books Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Articles in Books Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends –

–

38

These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

The legend must include enough information to permit interpretation of the figure without reference to the text.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________ 5. Special requests _____________________________ 6. Suggestions for reviewers (name and postal address) Indian 1.____________Foreign 1._ _______________

2.____________

2._ _______________

3.____________

3._ _______________

4.____________

4._ _______________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission For Editorial Correspondence

Dr K.K. Aggarwal Group Editor-in-Chief

Asian Journal of Critical Care Daryacha, 39, Hauz Khas Village, New Delhi - 110 016 Tele/Fax: 26965874/75, 26865644 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

Asian Journal of Critical Care Vol. 6, No. 4, October-December 2010