Pharmacology

Current Good Clinical Practice guidelines are bureaucratic and should align with less burdensome examples of international trial policy

Tanya Symons · Steve Webb · John R Zalcberg

To the Editor: We would like to highlight some points arising from the discussion by Hamblin and colleagues regarding euglycaemic diabetic ketoacidosis associated with sodium–glucose cotransporter type 2 (SGLT2) inhibitors.1 First, clinicians should be aware that this condition occurs not only in the perioperative context but also in systemically unwell patients with medical problems. Apart from the periprocedural insult, four categories of precipitating factors are recognised: intercurrent illness; dietary modifications (eg, prolonged fasting, very low calorie diet); medication changes (especially reducing or stopping insulin); and health system factors (eg, use in misdiagnosed type 2 rather than type 1 diabetes, and lack of patient education on the handling of SGLT2 inhibitors perioperatively).2,3,4 Second, diabetic ketoacidosis is more frequently reported with major surgery; for example, cardiothoracic, bariatric and abdominal surgery (postoperative ileus contributing). Third, clinicians should be aware that the current recommendations5 are based on low quality evidence and are potentially subjective. For example, the use of glycated haemoglobin levels < 75 mmol/mol (9%) as one factor to stratify lower patient risk, while intuitive, is not an unequivocal finding in the literature.4 We are in agreement that one should not overreact to capillary ketone levels in the perioperative period; these should be interpreted in conjunction with other acidosis markers (pH, bicarbonate and base excess). We differ regarding the authors’ statement that blood ketone testing is warranted only in unwell or symptomatic patients. In our clinical experience, we have encountered asymptomatic presentations with ketone levels > 2.0 mmol/L and acidosis before colonoscopy, despite the cessation of SGLT2 inhibitors on the day of the scheduled colonoscopy, necessitating deferral and inpatient treatment.6 Bowel preparation, diet modification and changes in diabetes medications are possible contributory factors for a minor procedure such as colonoscopy. Further, not all patients attend a pre‐assessment clinic and on the day of their procedure may be unable to recollect their diabetic medications. For these reasons, as recommended by the Australian Diabetes Society, it is prudent to check capillary ketones (using a single glucose strip) on admission for all patients with type 2 diabetes regardless of symptoms in the periprocedural period.5 Finally, in patients who have not held their SGLT2 inhibitors sufficiently or who have ketosis, the decision to proceed should depend on a nuanced appraisal integrating the complexity of the procedure, precipitating factors, and degree of acidosis.

Emily J Meyer · Venkatesan Thiruvenkatarajan · David Jesudason

Medicine in the pre‐antibiotic era offers lessons still relevant today, particularly regarding the prudent use of valuable medications The handwritten line on an archived envelope stored in a safe in The Children's Hospital at Westmead undercroft — “The first child in Australia to have ‘Penicillin’ therapy” (Box 1) — understates the remarkable story of how an experimental drug was requested, approved and delivered in secrecy during the Second World War for one child. The “Penicillin Papers”, rediscovered in 2018 by the Heritage Committee of The Children's Hospital at Westmead, highlight important questions of ongoing relevance. The story of the fortuitous discovery of penicillin by Alexander Fleming in 1928 has entered popular consciousness. What is less well known is how penicillin, which dramatically changed the course of medicine, came to be given to patients. The patient: a small boy in wartime Sydney On 17 June 1943, Peter, almost 7 years old, was admitted to the Royal Alexandra Hospital for Children with fever and increasing drowsiness. During the following 24 hours he reported headache, and a lumbar puncture found turbid cerebrospinal fluid (CSF) with an “uncountable number of leucocytes”, and Streptococcus pneumoniae “type 18” was cultured, a serotype that frequently caused meningitis.1 Sulfonamide drugs were manufactured in Australia in the 1940s, but between 1942 and 1945 stocks were strictly controlled, being reserved almost exclusively for military campaigns in New Guinea.2 Peter, diagnosed with pneumococcal meningitis, was treated with intravenous sulfapyridine for four days, and his fever resolved (Box 2); daily lumbar punctures showed CSF clearing. Treatment switched to oral sulfapyridine, but his fever and vomiting returned. Further intravenous sulfapyridine for one day was followed by extremely painful subcutaneous sulfadiazine infusions for 18 days, then by oral sulfathiazole for four days. Sulfadiazine was obtained from the 118th General Hospital of the United States Army, based in Herne Bay (now Riverwood) and staffed by health professionals from the Johns Hopkins University Hospital in Baltimore. Access to the restricted sulfa drugs was granted by Major McPherson Brown (1906–1989), a professor at the Johns Hopkins, suggesting early involvement of the US Army. By 10 July, however, Peter's CSF was again culture‐positive for S. pneumoniae and the outlook was “grave”. In 1943, penicillin was a highly experimental drug; clinical trials in US troops in Sicily were underway, and only two scientific articles on its clinical use had been published.3,4 In the US, the unenviable task of rationing the small supply for civilian use fell to Chester Keefer, professor of medicine at Boston University Hospital and chairman of the National Research Council Committee on Chemotherapy. Keefer personally vetted each penicillin request, restricting its use to cases in which all other treatments had failed.5 To better understand its potential and limitations, he collected detailed information on all patients given penicillin. Fortunately for Peter, his father was Lieutenant Commander Leo Harrison, a Navy surgeon working as a base medical officer in Sydney in 1943. It is likely that his father's connections with US Army doctors helped secure access to the treatment that ultimately saved his life. On the morning of Saturday, 10 July, Sir Alan Newton, chairman of the Medical Equipment Control Committee, cabled Washington to request urgent supply of penicillin for Peter. At 4:30 pm, one million units (600 mg) were despatched from Washington to San Francisco, together with documents stipulating that the penicillin was for research purposes only, and on the understanding that clinical notes would be provided to the National Research Council following treatment. The penicillin was transported by Liberator bomber from San Francisco to Hawaii, and from there via Brisbane to Sydney, arriving at the Royal Alexandra Hospital at midnight on Thursday, 15 July. The first dose was administered to Peter intramuscularly at 12:18 am on 16 July. Over ten days he received 15 000 units (9 mg) penicillin intramuscularly every four hours, and 10 000 units (6 mg) intrathecally. Today, 5 million units intravenous benzylpenicillin per day would be recommended for a boy of Peter's weight (almost 22 kg). Although Peter's condition improved dramatically, waking from “a stupor” to eat a full breakfast within 48 hours, the dose and treatment duration were inadequate. By 21 July, Peter was again febrile and CSF cultures were positive. Regretting that type‐specific pneumococcal antiserum had not also been requested, Newton had sent a second cable to Washington on 16 July. Rabbit anti‐pneumococcal (type 18) serum arrived and 100 000 units were administered intramuscularly each day from 23 July to 1 August, and oral sulfadiazine from 26 July to 8 August. On 18 September 1943, Peter was discharged home “cured”. Seventy‐five years later, he and his family (Box 3) were interviewed by ABC News reporter Tracy Bowden,6 after his case had been re‐discovered by The Children's Hospital at Westmead Heritage Committee. Research secrecy There are three references in the medical literature regarding this incredible case. The first was a report published in the Medical Journal of Australia in June 1944 by the treating physicians Donald Vickery and Lindsay Dey.7 The second, a short mention by Newton in a speech to the British Medical Association, was published in July 1944;2 the third, a letter by Dey's son in the MJA in August 1981,8 described his father's recounting of events that “would have made an excellent basis for a film”. The initial publication7 was delayed by the condition that details of the case be released only to the US National Research Council, effectively a non‐disclosure agreement. Discussions about research secrecy are as old as science itself.9 Proponents of openness argue that it promotes innovation and enhances productivity and efficiency of research. Openness is essential for testing hypotheses and fostering collaboration. Sharing information with the public fulfils moral obligations to provide evidence for shaping policy and to be accountable for the use of public funds. Conversely, research secrecy is often justified as protecting credit and intellectual property, shielding scientists and human research participants from stigmatisation or harassment, and minimising threats to national or international security. The financial interests of biotechnology and pharmaceutical companies further complicate the discussion. In 1943, arguments for secrecy about experimental penicillin treatments were compounded by the need to protect the limited supplies of the drug. It is pertinent here that the reverse of the envelope containing the Penicillin Papers was marked “Silence saves soldiers” (Box 1). Under the direction of Keefer, the Committee on Chemotherapy charged “accredited investigators” with assessing thousands of requests for penicillin.5 A strict allocation policy was adopted to ensure that decisions were made on clinical grounds. Only patients with severe infections caused by sulfonamide‐resistant, penicillin‐susceptible streptococci, gonococci and staphylococci, should receive penicillin, and only then if a cure could be expected. Access, compassionate and otherwise Equitable allocation of limited medical resources is a problem that often confronts clinicians and public authorities, particularly in resource‐constrained environments and during wartime, natural disasters,10 or epidemics.11 In 1943, Vickery and Dey did all they could to obtain the experimental drug penicillin for their patient. Wartime priorities in Australia did not include active control of therapeutic substances, although the National Health and Medical Research Council dealt with some medication access questions.12 In the US, the Food and Drug Administration (FDA) first addressed access to investigational drugs for therapeutic purposes in January 1963,13 three months after President Kennedy had approved the amendment of the Food, Drug, and Cosmetic Act that strengthened the FDA mandate to approve medications.14 The process of “expanded access”, the preferred FDA term for compassionate use — that is, of an unlicensed drug or device outside clinical trials — was formalised in 1987 in response to requests for access to investigational anti‐retroviral agents.13 In Australia, the Therapeutic Goods Administration (TGA) was established in 1989 as the national regulatory body; its Special Access Scheme, introduced in response to the 1991 Baume report,15 is the mechanism by which doctors can secure access to unlicensed drugs for selected patients. The 1962 American drug law amendments, passed in the wake of the thalidomide catastrophe, had the potential to make children “therapeutic orphans”, as many drugs have been tested only in adults.16 Paediatricians today regularly use medications off‐label, but the use of unlicensed drugs is less common and usually restricted to neonatal intensive care.17 Fortunately, the importance of including children in clinical trials is increasingly recognised internationally by research institutions and funding and regulatory agencies.18 Further, the FDA was empowered to provide financial incentives for including children in clinical trials and licensing applications by the 2007 Best Pharmaceuticals for Children and Pediatric Research Equity Acts.19 Lessons for the post‐antibiotic era from the pre‐antibiotic era Sulfonamides, the first effective antimicrobial agents, were available from the mid‐1930s, but drug resistance was widespread by the 1940s. One initial control on penicillin use was the requirement for demonstrated penicillin susceptibility and sulfonamide resistance: an early form of antimicrobial stewardship. As we approach the post‐antibiotic era because of rapidly increasing antimicrobial resistance, institutional, national and international antimicrobial stewardship programs are being implemented to protect the limited therapeutic options available for many infections. Multimodal programs incorporate pharmacokinetic and pharmacodynamic principles to avoid treatment failure through undertreatment, as experienced by Peter in 1943.20 In the future, strengthening these antimicrobial stewardship programs by integrating molecular technologies and high throughput screening methods will be critical. We also need to rediscover non‐antibiotic approaches to treating infections, including serotherapy21 and bacteriophage therapy.22 Both were widely and successfully employed in the early 20th century, and Peter's ultimate recovery in August 1943 appeared to require type‐specific anti‐pneumococcal serum treatment. However, our reliance on antibiotics over the past century has led to clinical and research neglect of alternative treatment modalities, although interest has revived in recent years, particularly in bacteriophage therapy.22 Greater investment in alternative treatment options is needed, as well as investigation of novel therapeutic and infection prevention strategies. Box 1 – The “Penicillin Papers”, retrieved from a safe in the basement of The Children's Hospital at Westmead in 2018, include letters and telegrams about the acquisition of penicillin from the United States and its use for treating Peter Harrison Source: The Penicillin Papers; courtesy of The Children's Hospital at Westmead. Box 2 – Details from transcribed observation charts for the first patient in Australia to be treated with penicillin, 1943 Source: The Penicillin Papers; courtesy of The Children's Hospital at Westmead. Box 3 – Peter Harrison (right), the first person in Australia to be treated with penicillin, pictured with his family in 2018, together with Bethany Robinson (second from right), the University of Sydney student who rediscovered the “Penicillin Papers”

Ameneh Khatami · Philip N Britton · Glendon Farrow · Megan Phelps · Alyson Kakakios

Objective: To examine whether non‐medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT‐P13, Inflectra) is safe and clinically non‐inferior to continued treatment with originator infliximab. Design: Prospective, open label, multicentre, parallel cohort, non‐inferiority study in seven Australian hospitals over 48 weeks, May 2017 – October 2019. Participants: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid‐free clinical remission for at least 12 weeks. Intervention: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT‐P13); patients in three other hospitals continued to receive originator infliximab (control). Main outcome measures: Clinical disease worsening requiring infliximab dose escalation or change in therapy. Results: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT‐P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was –1.1 percentage points (95% CI, –6.1 to 8.2 percentage points), within our pre‐specified non‐inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups. Conclusion: Switching patients with IBD from originator to biosimilar infliximab is safe and non‐inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.

Craig Haifer · Ashish Srinivasan · Yoon‐Kyo An · Sherman Picardo · Daniel Langenberg · Shankar Menon · Jakob Begun · Simon Ghaly · Lena Thin

The associated risks, particularly that of long term use, are underestimated, and appropriate measures are needed

Stephan A Schug

Objectives: To evaluate whether educating junior doctors and hospital pharmacists about analgesic prescribing improved discharge prescribing of opioids for opioid‐naïve patients after surgical admissions. Design: Cluster randomised controlled trial, undertaken during the first half of 2019. Setting: The Alfred Hospital, a major Melbourne teaching hospital with 13 surgical units. Participants: Opioid‐naïve patients discharged from surgical units after a stay of at least 24 hours. Intervention: Surgical units were randomised to the intervention or control arms. Interns, residents, and clinical pharmacists assigned to intervention arm units attended education sessions, presented by the hospital analgesic stewardship pharmacist, about appropriate analgesic prescribing for patients in hospital surgical units. Main outcome measures: The patients prescribed slow release opioids on discharge from hospital during the baseline (1 February – 30 April 2018) and post‐intervention periods (17 February – 30 April 2019). Results: During the baseline period, 1369 intervention unit and 1014 control unit admissions were included in our analysis; during the evaluation period, 973 intervention unit and 706 control unit episodes were included. After adjusting for age, length of stay, pain score, acute pain service involvement, and use of immediate release opioids prior to admission, patients in the intervention group were prescribed slow release opioids at discharge less frequently than patients in the control group (adjusted odds ratio [aOR], 0.52; 95% CI, 0.35–0.77) and were more frequently discharged without any prescribed opioids following the intervention (aOR, 1.69; 95% CI, 1.24–2.30). Providing de‐escalation plans was more frequent for intervention than control group patients prescribed slow release opioids on discharge post‐intervention (OR, 2.36; 95% CI, 1.25–4.45). Conclusions: Specific education for clinicians and pharmacists about appropriate analgesic prescribing for surgical patients is effective in reducing prescribing of opioids at discharge. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000876291 (prospective).

Ria E Hopkins · Thuy Bui · Alex H Konstantatos · Carolyn Arnold · Dianna J Magliano · Danny Liew · Michael J Dooley

High cumulative doses are often unnecessary and can have major adverse effects

Christine F McDonald · Christopher J Worsnop

Since COVID-19 emerged in December 2019, over 1100 clinical studies have been registered globally, including over 500 RCTs

Joshua S Davis · David Ferreira · Justin T Denholm · Steven YC Tong

Elevated serum angiotensin‐converting enzyme (ACE) activity, a biomarker for epithelioid granuloma, has a supportive role in the diagnosis and management of sarcoidosis,1 although in population‐based studies its diagnostic usefulness is modest, with positive and negative predictive values of 25.4% and 89.9% respectively.2 Further, elevated ACE activity is non‐specific; it is also found in people with tuberculous and other infectious granulomata, liver disease, lymphoma, diabetes, or hyperthyroidism, and also as a benign familial condition. However, elevated ACE activity can facilitate some clinical decisions, including the diagnosis of Löfgren syndrome or adults with uveitis.1,3 Serum ACE can be assessed by measuring its enzymatic activity or its protein concentration. Most Australian pathology laboratories measure ACE activity, which is predictably inhibited by ACE inhibitor (ACEI) drugs commonly prescribed for people with high blood pressure,4,5 whereas ACE protein level is not affected by these agents. In this study, we investigated the prevalence of ACEI influencing ACE activity results; for cases of markedly elevated ACE, we also evaluated the clinical performance of the two ACE measures with respect to sarcoidosis. In a preliminary evaluation, all discrepant paired results (high mass with low activity) were for patients using ACEIs at the time of sample collection. Between January 2017 and February 2019, we measured ACE activity and protein concentration in parallel; all test requests were initiated by clinicians as part of routine clinical care. Formal ethics approval was not required for collecting and analysing data to assess the quality of routine care. Further details of the study design and laboratory methods are included in the online Supporting Information. A total of 8882 paired test results were retrieved from the Pathology Queensland database for 4206 women (median age, 53.3 years; interquartile range [IQR], 36.0–65.6 years) and 4014 men (median age, 55.2 years; IQR, 42.2–67.3 years). Two discrete populations were evident in the scatterplot of paired results; for 1346 pairs (15.2%; 95% CI, 14.4–15.9%; green in Box 1), ACE activity was low relative to ACE protein, pathognomonic of ACEI interference. The upper reference limits for the two tests and the regression line for samples not affected by ACEIs nearly intersected, suggesting the general biologic equivalence of the two analytic methods and that the discordant results were not attributable to mismatched reference limits (Box 1). The correlation of values for the unaffected samples was moderate (R2 = 0.71) and the differences between the methods greater than predicted by their variances (Supporting Information, figure), indicating that the assays were not interchangeable. The monthly rate of ACEI interference was fairly consistent throughout the study period, despite comments to requesting physicians about the discrepancy between activity and protein levels included in pathology laboratory reports (Box 2). Of the 50 patients with high ACE protein levels (more than 300 μg/L) and ACE activity below the upper reference limit (70 IU/L), 27 (54%; 95% CI, 40–67%) had sarcoidosis (including 16 with ACE activity below the lower reference limit of 20 IU/L). In contrast, four of 16 people (25%; 95% CI, 10–50%) with high ACE activity (greater than 100 IU/L) and ACE protein within the reference interval had sarcoidosis. From a diagnostic perspective, ACEIs erode the negative predictive value of ACE activity, the most useful characteristic of this biomarker (Box 1; Supporting Information, table). Given that ACEI therapy interferes with ACE activity assessment, we recommend measuring ACE protein in routine practice, with the added benefit of convenience and safety of uninterrupted therapy for people taking ACEIs. The lack of influence of laboratory comments on testing behaviour is disappointing, but perhaps unsurprising given the information overload typical of modern medicine.6 Box 1 – Effect of angiotensin‐converting enzyme inhibitor (ACEI) therapy on serum ACE activity: scatterplot of paired ACE activity and protein assay results Pathology test reference intervals are indicated by the dotted lines. The shaded areas indicate result pairs included in the clinical audit (numbers of patients with sarcoidosis/total number audited). Blue: ACE activity not affected by ACEI therapy; 7536 samples, R2 = 0.71. Green: ACE activity affected by ACEI therapy; 1346 samples, R2 = 0.21. Box 2 – Influence of angiotensin‐converting enzyme (ACE) inhibitor (ACEI) therapy on serum ACE activity, by month

Carel J Pretorius · Jacobus PJ Ungerer

Investment is urgently needed in repurposed drugs which could ease the burden of the COVID-19 pandemic

Jennifer H Martin · Nikola A Bowden

Clinical record A 70‐year‐old man with multiple myeloma was admitted to our hospital in 2018, having been hospitalised 10 months previously in the United Kingdom. Following admission to our facility, routine collection of clinical specimens was performed in the setting of an episode of febrile neutropenia. Candida auris was isolated in a urine specimen collected in the presence of an indwelling urinary catheter, without accompanying pyuria. Screening of ward contacts (n = 73) was subsequently performed by collection of composite axilla and groin skin swabs, together with swabbing of possible clinical sites of infection (eg, wounds, catheter sites). Swabs were plated onto Candida chromogenic agar and incubated aerobically for 48 hours at 35°C. Any colonies not typical for C. albicans or C. tropicalis were identified using matrix‐assisted laser desorption ionisation time‐of‐flight (MALDI‐TOF) mass spectrometry. The routine regimen of daily cleaning and disinfection of rooms with 1000 ppm sodium hypochlorite solution was continued. Enhanced infection control measures, including contact precautions and single‐room isolation were instituted. A multidisciplinary taskforce coordinated screening, laboratory and prevention strategies. Review of laboratory reports for the preceding 12 months confirmed this to be the first documented C. auris isolate at our facility. One ward contact, a 38‐year‐old man with diffuse large B cell lymphoma, was identified as colonised with C. auris. The organism was detected in a urine specimen collected in the presence of a long term indwelling urinary catheter. This patient had been admitted to a health care facility in the United Arab Emirates, before direct transfer to our facility about 3 months earlier. Colonised patients had been located in a common ward for 19 days, each in a single room with dedicated bathroom and patient care equipment. They had also been managed on an outlying ward for brief periods (3 and 2 days, respectively) separated in time by 2 days. Neither patient developed clinical features of urinary tract or disseminated C. auris infection and antifungal therapy was not administered. Isolates were confirmed as C. auris by MALDI‐TOF mass spectrometry (each with score of 1.75). Antifungal susceptibility testing by broth microdilution demonstrated isolates were resistant to fluconazole (minimum inhibitory concentration [MIC] > 256 mg/L) and susceptible to caspofungin (MIC, 0.25 mg/L) and anidulafungin (MIC, 0.12 mg/L for Patient 1 and 0.25 mg/L for Patient 2). To investigate relatedness of isolates, whole genome sequencing and bioinformatics analysis were performed. Phylogeographic analysis demonstrated that both were related globally to those contained in the India–Pakistan clade. The median pairwise single nucleotide polymorphism distance between the two isolates was 167, suggesting that while these isolates were related, it was not possible to confirm whether transmission had occurred. Discussion Candida auris is an emerging, drug‐resistant yeast, responsible for hospital outbreaks internationally.1 First recognised as a new species of Candida in 2009, cases have been reported in over 30 countries, including the United Kingdom and United Arab Emirates.1,2 In outbreak settings, bloodstream, urinary tract and deep tissue infections have been reported, in addition to colonisation. The majority of isolates are fluconazole resistant,3 with variable resistance to amphotericin B and the echinocandin class of antifungal agents. Infection is associated with a crude mortality of 30%.3 Key differences between C. albicans (the most frequently identified Candida species in Australia) and C. auris are summarised in the Box. Risks for C. auris acquisition include admission to a high dependency unit, presence of invasive medical devices, underlying immunocompromise or chronic disease and receipt of antibiotic or antifungal agents.4 One case of C. auris invasive disease has previously been reported in Australia,5 but to our knowledge the two cases identified at our facility represent the first possible transmission of C. auris in Australia. Identification of C. auris is challenging, with potential misidentification by routine biochemical methods. If C. auris is included in the reference profile database, MALDI‐TOF mass spectrometry may be used to confirm diagnosis. DNA sequencing also provides confirmation, together with data regarding origins and potential transmission in health care settings.3 Collection of bilateral axilla and groin skin swabs as a combined screening specimen is recommended for optimal yield.6 European and United States guidelines recommend screening of all room contacts of patients with C. auris.6,7 Screening of additional patients (eg, whole ward) is necessary where more than one case is identified. Targeted surveillance of patients who have recently had at least one overnight stay in an overseas facility is also recommended, especially if from a country reporting C. auris cases.6,7 Our experience highlights the importance of this strategy. Clinicians should be aware of risks for C. auris acquisition, including overseas health care encounters. In high risk settings, and where a case of C. auris infection has been identified, timely screening of patients is required to ensure that appropriate control measures are instituted. Lessons from practice Candida auris is an emerging drug‐resistant yeast, now reported in Australian health care facilities. In contrast to C. albicans, which is commonly isolated in community and health care settings, C. auris is generally only identified in high risk hospitalised populations. Risks for acquisition include intensive care or high dependency unit admission, presence of invasive medical devices, underlying immunocompromise or chronic disease, and receipt of broad spectrum antibiotics or antifungal agents. Strict infection control measures, including contact precautions and isolation, are required to reduce risks of transmission. Screening for colonisation is an important element of infection control strategies, and a composite skin swab of axilla and groin is recommended. Timely detection requires laboratory identification. MALDI‐TOF mass spectrometry may be used for confirmation, and whole genome sequencing may provide additional information on possible transmission events. Health care facilities must ensure processes are implemented for screening of patients who have received health care in overseas hospitals. Box – Comparison of clinical and epidemiological characteristics of Candida albicans and Candida auris Candida albicans Candida auris Colonisation Colonisation of patients in community and health care settings is common; a commensal of skin and gut of immunocompetent and immunocompromised hosts Colonisation of patients associated only with hospital outbreaks or transmission, also identified in environment and equipment in hospital outbreak settings Infection Infection most frequently at mucosal sites (eg, oropharyngeal, vulvovaginal); bloodstream and urinary tract infections less frequent Bloodstream, urinary tract and wound infections reported Risks for infection ICU or HDU admission, invasive medical devices, major abdominal surgery, solid tumours, haematological malignancies, broad spectrum antibiotics ICU or HDU admission, invasive medical devices, underlying immunocompromise or chronic disease (eg, diabetes, chronic lung disease, renal failure, cardiovascular disease, or malignancy), broad spectrum antibiotics or antifungal agents Geographical distribution Ubiquitous, community and health care settings Reported only in health care settings, expanding global distribution Laboratory identification Culture using selective chromogenic media Culture together with MALDI‐TOF or DNA sequencing Antifungal resistance Generally susceptible to fluconazole Resistance to fluconazole is likely* HDU = high dependency unit; ICU = intensive care unit; MALDI‐TOF = matrix‐assisted laser desorption ionisation time‐of‐flight mass spectrometry. *Note: agreed fluconazole minimum inhibitory concentration breakpoints for C. auris have not been established

Leon J Worth · Simon J Harrison · Michael Dickinson · Annaliese Diemen · Jennifer Breen · Susan Harper · Caroline Marshall · Deborah A Williamson · Karin A Thursky · Monica A Slavin

To the Editor: The narrative review of diverticular disease by You and colleagues1 is most welcome. While highlighting the ubiquity of the problem and factors that facilitate the development of the disease and outlining an evidence‐based strategy to assess and manage the condition, it is also important to note patient factors, such as comorbidities treated with certain medications, which may facilitate uncomplicated disease becoming complicated. Further, commencing certain medications in patients with diverticular disease may often have unappreciated risks.2,3,4,5 Patients in the prevalent age group often have comorbidities, many of which may be treated with non‐steroidal anti‐inflammatory drugs, corticosteroids, opioids2 and, occasionally, with immunosuppressive therapy. Of these medications, the risk of perforations is highest with corticosteroids.4,5 Specifically, corticosteroids used in the management of rheumatic disease may increase the risk of diverticular abscess perforation 30‐fold.5 The association between complications of diverticular disease and the administration of various medications, particularly corticosteroids, must be emphasised,2,3,4,5 as both uncomplicated and complicated disease may present with non‐specific symptoms, suggesting a broad differential diagnosis.1 Medications must not be overlooked as an iatrogenic risk for complications for both existing and new users.

Mark H Arnold

Risk of SGLT2 inhibitor-associated diabetic ketoacidosis in type 2 diabetes: some answers, but more questions

Peter S Hamblin · Rosemary Wong · Leon A Bach

An 80- year- old man presented with 2 days of fever and a widespread, itchy, nonblanching, erythematous rash involving more than 50% of body

David WJ Griffin · Genevieve E Martin · Catriona McLean · Allen C Cheng · Michelle L Giles

Individualised care plans that take greater account of the behavioural and psychological needs of residents are needed

Gerard J Byrne

Upscheduling has not led to substitution with higher strength analgesics, and has reduced the misuse of codeine- containing preparations

Malcolm D Dobbin

An effective approach can only be achieved by a national strategy for averting opioid-related deaths

Nicholas Lintzeris

Objective: To investigate changes in sales to pharmacies of over‐the‐counter (OTC) and prescription analgesics, cold and flu products, and cough suppressants after the rescheduling of codeine as a prescription only medicine in February 2018. Design: Interrupted time series analysis of sales to pharmacies. Setting: Pharmaceutical sales to community pharmacies in Australia, March 2015 – March 2019. The period January 2017 (month after rescheduling was announced) to January 2018 (month before rescheduling was implemented) was excluded from the time series analysis. Main outcome measures: Monthly pack and tablet sales per 10 000 population of OTC and prescription analgesics, cold and flu products, and cough suppressants. Results: During 2016, 7586 packs and 248 127 tablets of OTC codeine per 10 000 population were sold to pharmacies; in the 14 months after rescheduling, a small level increase in monthly prescription codeine sales was evident (2247 tablets/capsules per 10 000 population; 95% CI, 1231–3264 per 10 000 population). Monthly OTC analgesic sales increased by 258 (95% CI, 151–365) packs per 10 000 population and 37 856 (95% CI, 26 143–49 569) tablet/capsules per 10 000 population. Monthly sales of single ingredient paracetamol (41 415 [95% CI, 31 374–51 456] tablets/capsules per 10 000 population), ibuprofen (1392 [95% CI 916–1868] tablets/capsules per 10 000 population), paracetamol/ibuprofen (1618 tablets [95% CI, 1567–1669] tablets/capsules per 10 000 population), and other paracetamol combinations (233 [95% CI, 112–353] tablets/capsules per 10 000 population) all increased, but not those of prescription analgesic products not containing codeine. Rises for OTC cold/flu products containing the opioid derivative dextromethorphan were small; sales of OTC cough suppressants containing opioid derivatives (dextromethorphan, pholcodine, dihydrocodeine) did not change. Conclusions: The rescheduling of codeine was followed by increased sales to pharmacies of paracetamol, ibuprofen, and paracetamol combination products. While these products carry no risk of dependence, their inappropriate use is also associated with harms that warrant adverse event monitoring.

Andrea L Schaffer · Rose Cairns · Jared A Brown · Natasa Gisev · Nicholas A Buckley · Sallie‐Anne Pearson

Objectives: To characterise the community pharmacy supply of naloxone by supply type — individual prescription, prescriber bag, and non‐dispensed (supplied over the counter or expired) — during 2014–2018; to examine whether the 2016 rescheduling of naloxone as an over‐the‐counter drug influenced non‐dispensed naloxone supply volume. Design, setting: Analysis of monthly naloxone prescriptions (Pharmaceutical Benefits Scheme) and sales data (IQVIA), 2014–2018, for Australia and by state and territory; time series analysis of non‐dispensed naloxone supply to assess effect of rescheduling on naloxone supply. Major outcomes: Total naloxone supply to community pharmacies; prescribed and non‐dispensed naloxone supply. Results: During 2014–2018, 372 351 400 μg units of naloxone were sold to community pharmacies: non‐dispensed naloxone accounted for 205 866.5 units (55.3%), prescriber bags for 155 841 units (41.8%), and individual prescriptions for 10 643.5 units (2.9%). Population‐adjusted national naloxone sales to community pharmacies increased between 2014 and 2018 (per year: incidence rate ratio [IRR], 1.15; 95% CI, 1.09–2.22). This increase was primarily attributable to increased volumes of prescriber bag naloxone (IRR, 1.63; 95% CI, 1.50–1.78) and, to a lesser extent, increased individual prescription supply (IRR, 2.04; 95% CI, 1.85–2.26). Non‐dispensed naloxone supply volume was unchanged at the national level (IRR, 0.93; 95% CI, 0.85–1.01); changes in non‐dispensed supply immediately following rescheduling and subsequently were not statistically significant in time series analyses for most jurisdictions. Conclusions: Total naloxone supply to community pharmacies in Australia increased between 2014 and 2018, but rescheduling that enabled over‐the‐counter access did not significantly influence the volume of non‐dispensed naloxone.

Wai Chung Tse · Paul Sanfilippo · Tina Lam · Paul Dietze · Suzanne Nielsen

Sexual dysfunction is a frequent, potentially distressing, adverse effect of antidepressants and a leading cause of medication non‐adherence. Sexual function should be actively assessed at baseline, at regular intervals during treatment, and after treatment cessation. Trials comparing the risk of sexual dysfunction with individual antidepressants are inadequate, but it is reasonable to conclude that the risk is greatest with selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs), less with tricyclic antidepressants (except clomipramine) and mirtazapine, and least with moclobemide, agomelatine, reboxetine and bupropion. Management of antidepressant‐induced sexual dysfunction requires an individualised approach (eg, considering other causes, dose reduction, addition of medication to treat the adverse effect, switching to a different antidepressant). Post‐SSRI sexual dysfunction has been recently identified as a potential, although rare, adverse effect of SSRIs and SNRIs. Consider the possibility of post‐SSRI sexual dysfunction in patients in whom sexual dysfunction was absent before starting antidepressants but develops during or soon after antidepressant treatment and still persists after remission from depression and discontinuation of the drug.

Jody Rothmore

Percutaneous coronary intervention with stent implantation (PCI‐S) has revolutionised the management of patients with coronary artery disease at high risk of myocardial infarction and stroke.1 Dual antiplatelet therapy (aspirin with clopidogrel, prasugrel or ticagrelor) is superior to aspirin alone for preventing atherothrombotic events, including stent thrombosis, in patients undergoing PCI‐S,2 and is recommended by Australian guidelines.3 We analysed de‐identified, linked Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule (MBS) data for a 10% random sample of Medicare beneficiaries provided by the Australian Department of Health, to quantify rates of antiplatelet drug dispensing within 30 days of PCI‐S. We included all patients with MBS claims for PCI‐S (items 38306, 38312, 38318) between 1 January 2013 and 30 September 2014. MBS data on PCI‐S procedures are available only for private patients, who account for about 45% of PCI‐S procedures in Australia.4 The medicines of interest for our analysis were clopidogrel and clopidogrel/aspirin (Anatomical Therapeutic Chemical [ATC] codes B01AC04 and B01AC30), ticagrelor (ATC code B01AC24), and prasugrel (ATC code B01AC22). Aspirin alone was not examined because over‐the‐counter use is not captured in PBS claims data. We assessed the association of several factors with antiplatelet medication dispensing within 30 days of PCI‐S, expressed as odds ratios, by logistic regression modelling. The New South Wales Population and Health Services Research Ethics Committee approved the study (Cancer Institute NSW reference, 2013/11/494). Of 2869 patients who underwent PCI‐S during the study period, 2592 (90%) were dispensed antiplatelet drugs within 30 days of the procedure. Dispensing was more frequent for concessional PBS beneficiaries, patients who had not undergone PCI‐S in the preceding year, patients not dispensed antiplatelet drugs during the preceding six months, and patients dispensed proton pump inhibitors within 30 days of the procedure. Antiplatelet therapy was also more frequent among patients from Victoria or Tasmania, Queensland, and Western Australia than for those from NSW or the Australian Capital Territory (Box). Our findings indicate that 10% of patients undergoing PCI‐S did not receive guideline‐recommended dual antiplatelet therapy within 30 days of their procedure. Cost may have been a barrier, as antiplatelet therapy was less frequent among general than concessional PBS beneficiaries; the maximum out‐of‐pocket cost for any single PBS item in 2013 was $5.90 for concessional beneficiaries, but $36.10 for general beneficiaries, and general beneficiaries may have already experienced significant out‐of‐pocket costs for both health insurance and their procedure. In most states, the Public Hospitals Pharmaceutical Reform Agreement6 ensures that PBS‐subsidised medications can be dispensed to patients when they are discharged from hospital. NSW and the ACT, however, do not participate in this agreement; patients are discharged from public hospitals with unsubsidised medicines sufficient for only 2–7 days, after which they must visit a community doctor for prescribing of PBS‐subsidised medications. This inconvenience may contribute to the lower 30‐day dispensing rate in these jurisdictions. We were unable to evaluate the long term clinical effect of antiplatelet therapy as the analysed datasets do not include information about hospital admissions. The number of PCI‐S procedures in Australia increased from 24 500 MBS claims in 2013 to 29 000 in 2018 (http://medicarestatistics.humanservices.gov.au/statistics/mbs_item.jsp), and the number of patients at risk of early stent thrombosis may also have grown. Why some patients undergoing PCI‐S are not receiving dual antiplatelet therapy directly after their procedure should be further investigated. Box – Characteristics of patients undergoing percutaneous coronary intervention with stent implantation (PCI‐S) in Australia, and their association with dual antiplatelet therapy within 30 days of PCI‐S Number of patients Odds ratio (95% confidence interval) Underwent PCI‐S Antiplatelet therapy within 30 days Univariate models Multivariate model Total number of patients undergoing PCI‐S 2869 2592 (90%) Age (years) 18–54 351 (12%) 307 (87%) 1 1 55–64 711 (25%) 640 (90%) 1.29 (0.87–1.93) 1.26 (0.83–1.91) 65–74 965 (34%) 879 (91%) 1.47 (0.99–2.16) 1.17 (0.76–1.81) 75–84 660 (23%) 605 (92%) 1.58 (1.04–2.40) 1.09 (0.66–1.81) 85 or more 182 (6%) 161 (88%) 1.10 (0.63–1.91) 0.83 (0.66–1.60) Sex Women 670 (23%) 604 (90%) 1 1 Men 2199 (77%) 1988 (90%) 0.97 (0.73–1.30) 0.86 (0.63–1.18) State where PCI‐S was undertaken New South Wales/Australian Capital Territory 1121 (39%) 986 (88%) 1 1 Victoria/Tasmania 752 (26%) 694 (92%) 1.64 (1.19–2.26) 1.56 (1.12–2.17) South Australia/Northern Territory 147 (5%) 129 (88%) 0.98 (0.58–1.66) 0.94 (0.55–1.60) Queensland 549 (19%) 504 (92%) 1.53 (1.08–2.19) 1.47 (1.02–2.13) Western Australia 300 (10%) 279 (93%) 1.82 (1.13–2.94) 2.14 (1.28–3.59) PBS patient category General 1453 (51%) 1293 (89%) 1 1 Concessional 1404 (49%) 1299 (93%) 1.53 (1.18–1.98) 1.63 (1.18–2.26) Previous PCI‐S Preceding 12 months 234 (8%) 199 (85%) 1 1 None 2635 (92%) 2393 (91%) 1.74 (1.19–2.55) 1.41 (0.93–2.13) Previous antiplatelet therapy Preceding 6 months 1135 (40%) 995 (88%) 1 1 None 1734 (60%) 1597 (92%) 1.64 (1.28–2.10) 1.96 (1.45–2.64) Anticoagulant therapy within 30 days of PCI‐S No 84 (3%) 77 (92%) 1 1 Yes 2785 (97%) 2515 (90%) 1.18 (0.54–2.59) 1.04 (0.47–2.33) Proton pump inhibitor therapy within 30 days of PCI‐S No 1002 (35%) 931 (93%) 1 1 Yes 1867 (65%) 1661 (89%) 1.63 (1.23–2.16) 1.42 (1.05–1.92) Comorbid conditions (six months before PCI‐S) None 196 (7%) 169 (86%) 1 1 1 180 (6%) 165 (92%) 1.76 (0.90–3.42) 1.47 (0.72–3.01) 2 259 (9%) 234 (90%) 1.50 (0.84–2.67) 1.34 (0.71–2.56) 3 389 (14%) 356 (92%) 1.72 (1.00–2.96) 1.54 (0.84–2.82) 4 452 (16%) 395 (87%) 1.11 (0.68–1.81) 1.01 (0.57–1.79) 5 or more 1393 (49%) 1273 (91%) 1.70 (1.08–2.65) 1.56 (0.88–2.75) PBS = Pharmaceutical Benefits Scheme. *Patients were classified as concessional beneficiaries if all PBS dispensing was concessional during year preceding and the three months following the PCI‐S procedure. †Based on RxRisk comorbidity indices.5

Benjumin Hsu · Michael O Falster · Andrea L Schaffer · Sallie Pearson · Louisa Jorm · David B Brieger

Objective: To examine the prevalence of psychotropic medicine dispensing before and after older people enter residential care. Design: Retrospective national cohort study; analysis of Registry of Senior Australians (ROSA) data. Setting, participants: All concession card‐holding residents of government‐subsidised residential aged care facilities in Australia who entered residential care for at least three months between 1 April 2008 and 30 June 2015. Main outcome measures: Proportions of residents dispensed antipsychotic, benzodiazepine, or antidepressant medicines during the year preceding and the year after commencing residential care, by quarter. Results: Of 322 120 included aged care residents, 68 483 received at least one antipsychotic (21.3%; 95% CI, 21.1–21.4%), 98 315 at least one benzodiazepine (30.5%; 95% CI, 30.4–30.7%), and 122 224 residents at least one antidepressant (37.9%; 95% CI, 37.8–38.1%) during their first three months of residential care; 31 326 of those dispensed antipsychotics (45.7%), 38 529 of those dispensed benzodiazepines (39.2%), and 25 259 residents dispensed antidepressants (19.8%) had not received them in the year preceding their entry into care. During the first three months of residential care, the prevalence of antipsychotic (prevalence ratio [PR], 3.37; 95% CI, 3.31–3.43) and antidepressant dispensing (PR, 1.05; 95% CI, 1.04–1.07) were each higher for residents with than for those without dementia; benzodiazepine dispensing was similar for both groups (PR, 1.01; 95% CI, 0.99–1.02). Conclusions: Dispensing of psychotropic medicines to older Australians is high before they enter residential care but increases markedly soon after entry into care. Non‐pharmacological behavioural management strategies are important for limiting the prescribing of psychotropic medicines for older people in the community or in residential care.

Stephanie L Harrison · Janet K Sluggett · Catherine Lang · Craig Whitehead · Maria Crotty · Megan Corlis · Steven L Wesselingh · Maria C Inacio

To the Editor: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative condition with no cure. Only two treatments with class I evidence exist — riluzole1 and edaravone2 — both with unclear mechanisms of action and modest survival benefits. In Australia, riluzole remains the only treatment approved by the Therapeutic Goods Administration. The Pharmaceutical Benefits Scheme limits initiation of riluzole to patients with at least 60% of predicted forced vital capacity, although facial weakness may make this an unreliable target. Initial and continuing treatment requires patients to be ambulant; or to have good upper limb function or to be able to swallow; and not to have respiratory failure. A recent retrospective study classified patients into different disease severity stages, ranging from 1 (one region involved) to 5 (death); patients with respiratory and nutritional failure were assigned to stage 4.3 The study identified that patients in stage 4 receiving 100 mg of riluzole daily did not progress to the next clinical stage (ie, death) as rapidly as those in milder stages. This suggests that the modest survival benefit experienced by patients taking riluzole comes about by extending the time spent at this stage. A quarter of patients present with bulbar or respiratory onset,4 making many ineligible for treatment, despite data suggesting they may benefit most.5 Mean survival in these forms of ALS is particularly short, meaning the modest survival benefit offered should be considered, as a majority of patients with advanced ALS do not wish to hasten death.6 A recent study of over 4000 trial participants confirmed benefit in both early and late stages,7 supporting use of riluzole throughout the disease. Few prospective studies on late‐stage treatments exist; patient choice in continuing treatment during advanced stages therefore remains paramount. Prospective studies are needed to establish whether the benefit of riluzole is weighted towards more advanced disease. However, recent studies, along with the recognition of the clinical spectrum of ALS, indicate that the current Pharmaceutical Benefits Scheme criteria are too stringent. As we move towards precision‐based medicine, different profiles of therapeutic response are likely. Regulators will be required to rapidly respond to emerging data to ensure the right patients can access the right medications.

Colin J Mahoney · Matthew C Kiernan