Epic Pharmacy Circuit Newsletter April 2019

April 2019

clinical initiatives, research and current updates in treatment

ANT I B IOTICS

AURA (Antimicrobial Use and Resistance in Australia) A summary of the second Australian report on Antimicrobial Use and Resistance in Human Health Daniel Prasopsang, Epic Pharmacy Hollywood The AURA report provides data and analysis, primarily from 2015, from the AURA surveillance system regarding antimicrobial use, the appropriateness of antimicrobial prescribing, developing concerns for antimicrobial resistance (AMR), and a comparison of Australia’s current standing with other countries.

The AURA surveillance system is a part of the Australian Government’s first strategy on AMR, National Antimicrobial Resistance Strategy 2015 to 2019. It provides information and support to clinicians and policy/program developers to strengthen Australian antimicrobial stewardship strategies.

Key findings include: Antimicrobial use in hospitals ¬¬ Antimicrobial use peaked in 2010, and has continually decreased between 2010 and 2015. ¬¬ Data from the 2015 Hospital National Antimicrobial Prescribing Survey (NAPS) found 40.5% of patients in hospital received at least one antimicrobial. ◦◦ 23.3% of this prescribing did not comply with guidelines and 21.9% was considered inappropriate. ◦◦ Reasons for inappropriate hospital use included:

¬¬Antimicrobial not required (19.6%) ¬¬Incorrect choice/ spectrum too broad (25.2%) ¬¬Duration of treatment (17.7%) ¬¬Incorrect dose (19.5%) ◦◦ The most common indication for antimicrobial use was surgical prophylaxis ¬¬40.5% of antimicrobial therapy for surgical prophylaxis was deemed to be inappropriate. ◦◦ Reasons for inappropriate surgical prophylaxis use included: ¬¬Antimicrobials not required (22%) ¬¬Incorrect dose (27.6%) ¬¬Incorrect duration (29.9%) ¬¬ There has been continued improvement in minimising the amount of surgical prophylaxis prescriptions extending beyond 24hrs (41.8% in 2013 to 27.4% in 2015).

◦◦ However the optimal target is 5% or less ¬¬ The four therapeutic classes of antimicrobials most likely to contribute to AMR in hospitals are aminoglycosides, third/ fourth generation cephalosporins, fluoroquinolones and macrolides. ◦◦ Since 2011, most hospital peer groups demonstrated a decline in use of these four classes.

Antimicrobial use in the community ¬¬ In 2015, almost half of the Australian population (about 10.7 million people) had at least one antimicrobial dispensed under the Pharmaceutical Benefits Scheme (this does not include privately dispensed items). ¬¬ Australian rates of antimicrobial use in the community are substantially higher than in comparable countries (see Figure 1).

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Figure 1

Comparison of community antimicrobial use in Australia and other similar countries, DDD/1,000 inhabitants per day.

Australia (2015) England (2015) Canada (2014) Denmark (2015) Norway (2015) Sweden (2015) Netherlands (2015)

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Defined daily doses per 1,000 inhabitants per day Sources: PBS (Australia); CIPARS (Canada); DANMAP (Denmark); ESPAUR (England); NethMAP (Netherlands); SWEDRES (SWEDRES (Sweden)

Comparison of community antimicrobial use in Australia and other similar countries, by number of prescriptions dispensed.

Australia (2015) Scotland (2015) England (2015) Canada (2014) Sweden (2015)

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Prescriptions dispensed per 1,000 inhabitants Sources: PBS (Australia); CIPARS (Canada); ESPAUR (England); SAPG (Scotland); SWEDRES (Sweden)

¬¬ A large proportion of antimicrobials prescribed were not recommended

by Australian Guidelines (Therapeutic Guidelines). ◦◦ Of patients who presented to a general practitioner for colds and other upper respiratory tract infections, 60% had an antimicrobial prescribed where no indication was recorded. ¬¬ Rates of resistance in the community remain relatively stable and are low by world standards.

Antimicrobial use in residential aged care facilities The first investigation into antimicrobial use and appropriateness in residential aged care facilities was conducted in 2015 (the pilot Aged Care National Antimicrobial Prescribing Survey (acNAPS)).

Findings include: ¬¬ Whilst only 4.5% of residents showed signs and symptoms of infections, 11.3% of residents were prescribed an antimicrobial. ¬¬ 31.4% of prescriptions for antimicrobial treatment had been prescribed for longer than six months, and of these, only 51% included a documented indication and only 2% had a review or stop date recorded.

National Alert System for Critical Antimicrobial Resistances (CARAlert) In 2016, a National Alert System for Critical Antimicrobial Resistance (CARAlert) was created to provide timely national data concerning organisms that are important to human health and resistant to last line antimicrobials. ¬¬ The most frequently reported CARAlert in 2016 were Carbapenemaseproducing Enterobacteriaceae (48%). ¬¬ The IMP-type carbapenemase is now endemic on the Australian eastern seaboard in multiple species of enterobacteriaceae, particularly Enterobacter cloacae. ¬¬ The Queensland clone of Methicillin Resistant Staphylococcus aureus (MRSA) has become the dominant community-associated MRSA (CAMRSA) clone in Australia. CA-MRSA is now a more common cause of bacteraemia than healthcareassociated MRSA. ¬¬ Rates of azithromycin non-susceptible Neisseria gonorrhoeae, although low, are increasing in Australia and were the second most reported CARAlert in 2016. ¬¬ Fluoroquinolone usage has decreased, but resistance rates continued to increase in Escherichia coli from blood cultures and Shigella sonnei.

¬¬ Rates of resistance in Enterobacteriaceae species (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae) were generally lower in the community than in hospitals, however, rates in aged care facilities were often as high, or higher than, in hospitals.

Australian resistance rates compared to European countries ¬¬ Vancomycin Resistant Enterococcus (VRE) has emerged as a major healthcare concern in Australia and is now HIGHER than any European country. When enterococci are resistant to vancomycin, only two or three reserved antimicrobials are viable to treat serious infection. ¬¬ For the species Enterococcus faecium, there is now up to 56.8% of isolates resistant to vancomycin. ¬¬ Rates of resistance to fluoroquinolones and third generation cephalosporins in Escherichia coli and Klebsiella pneumoniae remain low in Australia, however they are now increasing. ¬¬ Australia ranks towards the middle in terms of rates of MRSA ¬¬ There are differing rates of MRSA (as a percentage of all Staphylococcus aureus isolates) between Australian states and territories ranging from 5.9% in Tasmania, to 37.3% in the Northern Territory.

The full report can be found here: https:// www.safetyandquality.gov.au/wpcontent/ uploads/2018/01/AURA-2017-SecondAustralian-report-on-Antimicrobial-Useand-Resistance-in-human-health.pdf Reference 1: Information extracted from: Australian Commission on Safety and Quality in Health Care (ACSQHC).

AURA 2017: second Australian report on antimicrobial use and resistance in human health. Sydney: ACSQHC; 2017.

Bisphosphonates for myeloma bone disease Louise Keamy, Icon Group Pharmacy Practice Unit Introduction to myeloma Multiple myeloma (MM) is an incurable haematological malignancy, with an incidence of 6.08 per 100,000.1 It predominantly affects patients over 60 years of age and can result in significant morbidity, primarily caused by the defining clinical features of MM – hypercalcaemia, renal failure, anaemia, and bone lytic lesions. Bone lytic lesions are present at the time of diagnosis in approximately 70% of patients, and will develop in up to 80% of patients over their disease course.2 Bone metabolism in healthy patients is a process known as bone remodeling, and is a delicate balance between the building and destruction of bone. In myeloma bone disease, the normal physiologic balance is lost, and the scale is tipped towards bone destruction. This results in lytic lesions forming within the bone, resulting in a loss of structural integrity. These bone lesions thus greatly increase the risk of skeletal related events (SREs). These include vertebral crush fractures resulting in spinal cord compression, pathological fractures, or the need for radiotherapy or surgery to bone, and these complications frequently result in pain, reduced mobility, and an overall reduction in quality of life.3 The prognosis of patients with MM has greatly increased over the last 10-15 years due to recent anti-myeloma drug developments, therefore preventing complications such as SREs, to ensure optimal quality of life is very important.

Role of bisphosphonates The current strategy for preventing SREs in myeloma bone disease is to stop further bone destruction. Bisphosphonates are able to do this by binding to areas of exposed bone at sites of active remodeling, thereby blocking osteoclast (the destructive cells) access to the bone and decreasing bone resorption.4 This prevents the lytic lesion from getting any bigger, and improves the structural integrity of the bone.

There is some suggestion of bisphosphonate use being linked to an improvement in overall survival, with it being hypothesised that bone remodelling itself has a pro-myeloma effect, and therefore blocking this process may help keep the myeloma disease under control.5 A number of clinical trials showed an overall survival benefit with the use of bisphosphonates, however when the data from all trials on this subject were combined into a Cochrane systematic review, this could not be shown definitively. 6

Administration

Whilst some international MM guidelines recommend bisphosphonates only in patients with radiologic evidence of bone disease, other groups recommend them in all MM patients due to the high risk of development of lytic disease and the possible effects on overall survival.7-9 A recent Australian position paper recommends the commencement of bisphosphonates in all patients with MM, regardless of the presence of bone lytic lesions.10

¬¬ Administer over 4 hours (although other guidelines allow a 2-4 infusion time.7, 8)

Contraindications Whilst it is recommended that bisphosphonates are commenced at the same time as active anti-myeloma therapy, there are some common reasons why this may not occur. There are a number of contraindications which prohibit their use, all of which can potentially be overcome.

These contraindications include: requirement for invasive dental procedures such as extractions, severe renal impairment defined as a creatinine clearance of less than 30 mL/ min, and hypocalcaemia which may occur in vitamin D deficiency.11 For this reason, kidney function, corrected calcium and vitamin D levels should be checked before each administration. Patients may require calcium and vitamin D supplementation whilst receiving bisphosphonates. A dental review and completion of any dental work prior to commencing treatment is recommended for all patients, and then every 6 months whilst receiving bisphosphonates to assess for early signs of osteonecrosis of the jaw.

Very high potency bisphosphonates are given intravenously in MM. Zoledronic acid and pamidronate disodium are the two PBSfunded products available.

Zoledronic acid ¬¬ Give over minimum of 15 minutes ¬¬ Dose reductions are recommended for patients with a creatinine clearance between 30-60mL/min.

Pamidronate

¬¬ If creatinine clearance is between 3060mL/min, no dose reduction is required, but infusion should be over 4 hours as this reduces the chance of renal toxicity.

Patients may occasionally experience flu-like symptoms such as fever and headache in the days after an infusion, which are selfresolving but may also be managed with paracetamol.

Future directions Renal impairment is a hallmark feature of multiple myeloma, and is present in between 20% to 40% of cases at the time of diagnosis.12, 13 Due to this, there is a subset of myeloma patients who are unable to receive bisphosphonates to prevent myeloma bone disease as their kidney function is too poor.

A recent study found denosumab, a RANKL inhibitor, was non-inferior to zoledronic acid in MM.14 This demonstrates that denosumab is an effective alternative to zoledronic acid, and it has the benefit of being acceptable for patients with renal impairment (although these patients were not included in this study). At this time, denosumab is not approved by the PBS for this indication.

References available on request.

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What’s New Glyxambi® (empagliflozin/linagliptin: 10mg/5mg tablets, 25mg/5mg tablets) Lisa Keen, Epic Pharmacy Toowoomba

Glyxambi® is a dual therapy medication containing a dipeptidyl peptidase-4 (DDP-4) inhibitor (linagliptin) and a sodium-glucose co-transporter 2 (SGLT2) inhibitor (empagliflozin), indicated in the treatment of type 2 diabetes as an add on treatment to metformin.1 Empagliflozin plus linagliptin therapy combines two medications with complementary mechanisms of action: empagliflozin increases glucose excretion through the kidneys and linagliptin enhances glucose dependent insulin release and inhibits the secretion of glucagon.2 Historically, sulfonylureas are the preferred add on treatment to metformin as they have been shown to decrease HbA1c, are cost effective and have long term safety and microvascular outcomes data.2,3,4 However, consideration must be given to each individual patient and where weight gain and/or hypoglycaemias are problematic, Glyxambi® may be appropriate.5 Glyxambi® has been shown to produce a modest weight loss, have positive short term (4 years) cardiovascular outcomes for at risk populations.6 Common side effects of Glyxambi® include:

increased risk of genital and urinary tract infections, headache, musculoskeletal pain, mild gastrointestinal disturbance and nasopharyngitis.4,6 The patient must be euvolaemic prior to commencing treatment, as empagliflozin has a diuretic effect. Older patients may be at increased risk of volume depletion.6 There is an increased risk of diabetic ketoacidosis (DKA) with empagliflozin. Recent cases have found severe DKA has developed during the perioperative period in type 2 diabetics on SGLT2 inhibitors with normal or mildly elevated blood glucose levels.7 An additional unusual feature of these cases is that some patients had normal urinary ketone levels despite having elevated blood ketones. Dehydration, acute illness, prolonged fasting, low carbohydrate intake, excessive alcohol intake and surgery increase the risk of DKA.7,8 It is recommended that Glyxambi® be ceased three days prior to surgery and restarted once the patient’s condition has stabilised and oral intake is normal.7,8 An increase in other glucose lowering agents may be required during this time.7,8 References available on request.

If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.

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