February 2019 Volume 42 Number 1 AN INDEPENDENT REVIEW nps.org.au/australian-prescriber CONTENTS EDITORIAL Does size matter? Addressing 2 pack size and antibiotic duration TM McGuire ARTICLES Optimal antimicrobial duration 5 for common bacterial infections HL Wilson, K Daveson, CB Del Mar Prescribing for 10 transgender patients L Tomlins Nitrofurantoin and fosfomycin for 14 resistant urinary tract infections: old drugs for emerging problems BJ Gardiner, AJ Stewardson, IJ Abbott, AY Peleg Prescribing for adolescents 20 M Kang, K Kim The hot patient: acute 24 drug-induced hyperthermia N Jamshidi, A Dawson LETTERS TO THE EDITOR 4 NEW DRUGS 29 Alirocumab for hypercholesterolaemia Apalutamide for prostate cancer Baricitinib for rheumatoid arthritis Migalastat for Fabry syndrome Rufinamide for seizures Tildrakizumab for psoriasis Emicizumab for haemophilia A VOLUME 42 : NUMBER 1 : FEBRUARY 2019 EDITORIAL Does size matter? Addressing pack size and antibiotic duration Treasure M McGuire In Australia, most antibiotics are prescription- therefore be influenced by not only the dose Assistant director of only so prescribers are the custodians of judicious prescribed but also the inherent characteristics of pharmacy, Mater Health use. They need to balance their concerns about the antibiotic.7 Services, Brisbane antibiotic resistance with their responsibility for Conjoint senior lecturer, Judicious antibiotic use needs to balance prescribing individual patient management. Prescribing with no School of Pharmacy, for too short a period (causing treatment failure, University of Queensland, clinical indication, inappropriate drug choice, and delayed return to health or the development of Brisbane suboptimal dosing and duration can all contribute to complications) with overprescribing which increases 1,2 Associate professor of antimicrobial resistance. Clinical practice guidelines the risk of resistance, non-adherence, adverse effects pharmacology, Faculty are therefore important for improving the quality and and cost. Sub-therapeutic antibiotic concentrations of Health Sciences and cost-effectiveness of infectious disease management. can encourage antibiotic-resistant bacteria.8 Other Medicine, Bond University, However, subtle factors such as the size of antibiotic Gold Coast, Queensland considerations when prescribing include the packs could impact on judicious antibiotic use. characteristics of the infecting organism, the patient’s Antibiotic prescribing in primary care is largely immune status and the bacterial gene pool. Keywords empiric and symptom based. Antibiotics are usually antibiotic resistance, clinical While clinical evidence favours prolonged treatment to started without microbiological testing. Clinical practice guidelines, drug prevent the relapse of conditions such as enterococcal practice guidelines usually focus on antibiotic choice, packaging endocarditis, only short courses are needed for with a recommended dose, frequency and duration, uncomplicated urinary tract infections in women. but have limited advice on resistance patterns.3 Aust Prescr 2019;42:2–3 Evaluation of 13 meta-analyses to optimise antimicrobial Optimising the dose and duration of antibiotic https://doi.org/10.18773/ duration in common bacterial infections determined treatment could simultaneously minimise both the austprescr.2019.005 that the duration of therapy could be shortened in symptomatic period and the selection pressure most of these infections by at least three days without for resistance.4 compromising patient outcomes.9 However, for many Clinical practice guideline recommendations differ infections managed in the community, the optimum globally, particularly for the duration of antibiotic treatment duration is unknown. therapy.5,6 When two UK guidelines for community- To improve the likelihood of success in clinical trials, acquired pneumonia were critically assessed, there a longer duration of antibiotics than the theoretical was a key difference of 2–3 days in the recommended minimum may be used. Only after establishing course of antibiotics for infections of low–moderate efficacy are equivalence trials of shorter durations severity.5 Similarly, there were major differences in conducted. As non-inferiority trials require large the recommended treatment duration for paediatric numbers of patients, cost drives trial design towards infections across seven reputable clinical practice single rather than multiple duration arms. Several guidelines.6 The fact that recommendations about pharmacokinetic and pharmacodynamic models have the duration of therapy are based more on expert been proposed for duration-randomised trials to opinion than strong scientific evidence is not widely overcome cost as a barrier.10 To extend the lifespan of appreciated by clinicians. antibiotics there needs to be collaboration between It is clear that no ‘one-size-fits-all’ for the length of researchers, clinicians and the pharmaceutical an antibiotic course.4 Infection resolution requires industry to conduct equivalence trials. These are the antimicrobial to reach and remain at the site of needed to determine the optimal minimum antibiotic infection in a sufficient concentration for a sufficient regimen for common infections in Australia. time. Concentration-dependent antibiotics such as aminoglycosides display maximal bactericidal Ambiguity about the optimal duration of treatment activity at high concentrations, even if these for a particular indication contributes to uncertainty concentrations are maintained for a relatively about how many doses to put in a pack. However, short time. In contrast, antibiotics displaying time- pack size heavily influences the duration of use. It will dependent activity, for example beta-lactams, continue to do so while consumers are given advice to require free drug at the infection site to be above ‘complete the antibiotic course’. the minimum inhibitory concentration or breakpoint A 2015 analysis of published data on the most concentration for a longer time. Duration can commonly prescribed antibiotics in Australian primary 2 Full text free online at nps.org.au/australian-prescriber © 2019 NPS MedicineWise VOLUME 42 : NUMBER 1 : FEBRUARY 2019 EDITORIAL care and their most common indications found a Prescribing software could improve adherence to clear mismatch between the recommended treatment clinical practice guidelines by commencing with duration in clinical practice guidelines and the the intended indication instead of the antibiotic. pharmaceutical industry packaging.11 Of 32 common The indication would activate consensus regimens prescribing scenarios, 10 had doses in surplus and 18 supported by evidence (or lack thereof). Prescriptions had a shortfall, leaving only four where the pack size would not be printed until dose, frequency and matched the recommended duration. In only two cases importantly duration were entered, overriding the was a shortfall addressed by a repeat prescription. default pack and calculating the required quantity. Any mismatch between pack size and doses Pharmacists would require corresponding dispensing consumed might contribute to leftover antibiotics in software. They would also need to spend more time the community. If these antibiotics are subsequently to implement safety strategies to prevent the reuse of taken by the patient or someone else, it would broken packs with varying expiry dates. contribute to potentially inappropriate use and, Clinicians and the public should be informed that thereby, resistance. Alternatively, unused antibiotics completing the pack is no longer supported by could be discarded into the environment (landfill or evidence and that resistance is primarily due to waste water) which may facilitate the development or overuse. Patients should be empowered to stop their proliferation of resistant strains of bacteria.12 antibiotic after a specified minimum number of days or when they feel better (whichever comes first) While solutions are not obvious, we must be willing and to return any unused doses for safe disposal to to try strategies to reduce the mismatch between the pharmacy where the medicine was dispensed.13 guidelines and antibiotic packaging. Regulations These and similar strategies warrant discussion to could require the industry to package antibiotics in potentially extend the lifespan of antibiotics without accordance with clinical practice guidelines. While compromising patient care. multiple pack sizes would increase costs, government incentives for the production of small packs could increase dispensing flexibility and minimise waste. Conflict of interest: none declared REFERENCES 1. DeRyke CA, Lee SY, Kuti JL, Nicolau DP. Optimising dosing 7. Adembri C, Novelli A. Pharmacokinetic and strategies of antibacterials utilising pharmacodynamic pharmacodynamic parameters of antimicrobials: potential principles: impact on the development of resistance. for providing dosing regimens that are less vulnerable to Drugs 2006;66:1-14. https://doi.org/10.2165/ resistance. Clin Pharmacokinet 2009;48:517-28. 00003495-200666010-00001 https://doi.org/10.2165/10895960-000000000-00000 2. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect 8. Rybak MJ. Pharmacodynamics: relation to antimicrobial of antibiotic prescribing in primary care on antimicrobial resistance. Am J Infect Control 2006;34(Suppl 1):S38-45. resistance in individual patients: systematic review and https://doi.org/10.1016/j.ajic.2006.05.227 meta-analysis. BMJ 2010;340:c2096. https://doi.org/10.1136/