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Pharmacology

Health occupations Letters 17 February 2020 Free

Antibiotic use in animals and humans in Australia

To the Editor: The recent perspective on antibiotic use in animals and humans in Australia1 provides an overview based on sales of antibiotics for livestock during the period 2005–2010. Unfortunately, these are the most recent data available, an important limitation that the authors highlight. Here, I provide details of significant initiatives implemented within the Australian livestock industries since 2010. Indeed, a perspective article published in the MJA in 20122 described the low level of antimicrobial resistance in bacterial isolates from food animals and food products together with work on updating prescribing guidelines and developments in infection control. A comprehensive summary of antimicrobial stewardship (AMS) activities in the pork, poultry, red meat and dairy industries published in 20183 describes the five Rs approach to AMS: taking responsibility for every decision to use antibiotics, reviewing current and ongoing antibiotic use, and reduction, refinement and replacement of antibiotics. A critical element of AMS in livestock practice is focused on removing the need for antibiotics by ensuring that there are biosecurity measures (bio‐exclusion, biocontainment, and individual animal resilience) operating to minimise the presence of pathogens and increase the immunocompetence of animals. Vaccination is a key component of AMS and new vaccine development is an ongoing area of research, with many examples of disease reduction and decreased antibiotic use following the introduction of vaccines.4 The use of antibiotics in livestock in Australia was assessed in the recent global review of antimicrobial resistance,5 and among the 29 countries included in the review, Australia ranked fifth, well below Denmark, a country considered the benchmark for antibiotic use. In addition to the quantity of use, significant attention is paid in Australia to the quality of use of antibiotics, as highlighted in a recent prescribing guideline.6 The absence of current data on antibiotic use remains an important limitation that must be reversed. Nevertheless, there are a multitude of AMS activities being actively implemented which will ensure, as reported in the 2018 article,2 that “Australia's food supply is one of the safest and cleanest in the world”.

Stephen W Page

Pharmacology Letters 17 February 2020 Free

Deprescribing needs to be considered in the pharmacists’ prescribing role

To the Editor: Pharmacist prescribing rights in Australia have recently sparked debate between medical practitioners and pharmacists.1 While discussion on the potential role of pharmacists to prescribe is important, the debate has focused on the initiation of medications. There is a need to acknowledge that prescribing is a process, which, according to the World Health Organization's six‐step Guide to good prescribing, includes “Step 6: Monitor (and stop?) the treatment”.2 Given inappropriate polypharmacy is increasing in older people,3 collaborative deprescribing (defined as the supervised withdrawal of inappropriate medications) with pharmacists, medical practitioners, and patients should therefore be given equal priority within this debate. Expanding the pharmacists’ role to deprescribe in collaboration with the medical practitioner can be considered as an effective mechanism to enact Step 6. Pharmacists are experts in pharmacotherapy, and consistently use a collaborative approach in providing health care. There is growing evidence internationally of the effectiveness of pharmacist prescribing roles that include medication cessation. In New Zealand and the United Kingdom, recent changes in the legislation have enabled suitably trained pharmacists to prescribe, and various studies have tested the feasibility of pharmacists initiating and deprescribing medications in multiple settings, such as nursing homes and general practice.4,5 The pharmacists’ expanded deprescribing role can be achievable with a team‐based approach in which there is a clear delineation of roles and responsibilities, separating the prescribing from the dispensing pharmacist, as in New Zealand.5,6 In Australia, many health practitioners can prescribe medications. For example, nurse practitioners can initiate and deprescribe within the boundaries of legislation and scope; that is, limited by the scope of practice, requirements from the Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme, and by relevant hospital formulary or prescribing arrangements. This may be a model to adopt for expanding the pharmacists’ collaborative deprescribing role. All the steps that underpin prescribing (initiation to withdrawal) are equally important to ensure patient safety, so they receive appropriate medications that are safe and effective. The proposal of expanding the pharmacists’ prescribing role needs to encompass all aspects of the prescribing process. If initiation and continuation of a medication is emphasised, in the context of pharmacists’ prescribing rights in Australia, we may lose focus on patient care and safety.

Lisa Kouladjian O'Donnell · Mouna J Sawan

Toxicology Letters 3 February 2020 Free

Recognising injuries related to needlestick injury in farmers: the importance of identifying high pressure injections with mineral oil

To the Editor: Currie and colleagues highlight the important topic of animal vaccines as occupational hazards and the need for improved clinician advice to manage patients safely.1 The article title describes “high pressure” injections, yet the oil emulsion vaccine of most concern, against ovine Johne's disease, is delivered via a standard needle injection. All accidental mineral oil injections are of concern (as are all high pressure injections). Appropriate identification and advice can be obtained by contacting a Poisons Information Centre (PIC). This was not discussed by Currie and colleagues, although it was recommended in a reference they cited.2 Unlike some vaccine manufacturers, the publicly funded PIC service provides 24‐hour emergency medical advice (131 126) for the public and health professionals. PICs access the Australian National Poisons Register, which allows rapid identification of the dozens of oil‐containing vaccines. Currently in Australia, oil adjuvant vaccines lack clear labelling to identify the presence of oil on the front packaging. Increased prominence would aid recognition, similar to initiatives for active ingredients within human therapeutic products. Indeed, review of the unscheduled status of most animal vaccines is required as they possess a risk assessment profile at odds with the Scheduling Policy Framework.3 Improved pharmacovigilance of veterinary products (and agrochemicals) is urgently required, particularly regarding the risks posed to human health. Unpublished analysis of data from Australian PIC annual reports identified about 2000 cases annually of human exposures to veterinary pharmaceuticals. We recently reported on human exposures to veterinary pharmaceuticals from New South Wales PIC calls from 2014 to 2016, with 30 exposures to Johne's disease vaccine alone.4 Collectively, PICs have over 20 times the number of reports to the designated authority for post‐market surveillance; the Australian Adverse Experience Reporting Program run by the Australian Pesticides and Veterinary Medicines Authority received 91 reports for human effects from registered veterinary medicines and agricultural chemical products combined in 2015.5 There is an opportunity for PICs to be engaged more efficiently in surveillance, which would allow the collection of additional information through follow‐up calls to understand risk factors, evaluate outcomes and recommend interventions to prevent future injuries. This would facilitate improvements in management of human exposures to veterinary pharmaceuticals to protect occupational health.

Jared A Brown · Nicholas A Buckley · Rose Cairns · Claire E Wylie

Mja2 50448
Women's health Letters 13 January 2020 Free

Influenza and pertussis vaccination of women during pregnancy in Victoria, 2015–2017

To the Editor: As reported by Rowe and colleagues1 in their retrospective analysis of maternal immunisation, uptake of influenza and acellular pertussis vaccines among pregnant women remains unacceptably low. One contributing factor may be inconsistent messaging. Historically, vaccine manufacturers have included precautions about the lack of data on use in pregnancy in their product information sheets. Such precautions have been shown to lead to vaccination hesitancy and refusal among pregnant women.2,3 In contrast, the current edition of the Australian Immunisation Handbook states: “Pregnant women are routinely recommended to receive influenza vaccine … and pertussis‐containing vaccine”.4 In 2018, the Therapeutic Goods Administration asked its Advisory Committee on Vaccines to provide independent expert advice on the available safety data on influenza vaccination in pregnancy with regards to the pregnancy category of influenza vaccines. The Advisory Committee on Vaccines advised that “adoption of Australian Pregnancy Category A should be considered by sponsors for certain inactivated influenza vaccines”.5 Pregnancy Category A signals to doctors and the public that the vaccine has been used by large numbers of expectant mothers with no evidence of harm to their babies. This is in line with the Australian Immunisation Handbook: “Clinical trial data and observational studies show no increased risk of congenital defects or adverse effects in the fetuses of women who received influenza vaccine during pregnancy”.4 Following the publication of the Advisory Committee on Vaccines statement, two of the four adult influenza vaccines and one of the two acellular pertussis vaccines used to vaccinate pregnant women in Australia have changed their pregnancy category to Category A. These changes show that the Australian regulator is receptive to feedback from the medical community on how to improve immunisation rates. Hopefully, the reclassification of the pregnancy category of these vaccines will translate into increased maternal uptake and better outcomes for Australian mothers and babies.

Heidi Shukralla · Michael Coory

Mja2 50429
Endocrinology Letters 13 January 2020 Free

Euglycaemic ketoacidosis from an SGLT2 inhibitor exacerbated by a ketogenic diet

To the Editor: A 64‐year‐old woman presented to our emergency department with progressively reduced consciousness over 3 days. This was preceded by 2 days of vomiting and diarrhoea. She had been systemically well before this, with no acute medical issues. She had type 2 diabetes and had been commenced on combination 10 mg empagliflozin and 5 mg linagliptin a year ago after having experienced diarrhoea with metformin. Her most recent glycated haemoglobin level was 58 mmol/mol (reference interval [RI], 20–42 mmol/mol). She had also been trialling the Atkins diet for about 2 months before presentation. Her initial blood tests demonstrated high anion gap metabolic acidosis, an initial blood sugar level of 10.3 mmol/L (RI, 3.2–5.4 mmol/L] and a serum ketone level of 4.7 mmol/L (RI, < 0.6 mmol/L). She was diagnosed as having euglycaemic ketoacidosis secondary to using a sodium–glucose cotransporter type 2 (SGLT2) inhibitor (empagliflozin) and precipitated by her diarrhoeal illness and her Atkins diet. After a dextrose and insulin infusion, the anion gap normalised within 4 hours of presentation. She became progressively more alert within 24 hours of presentation. She was discharged 2 days after presentation with directions never to recommence empagliflozin. This case highlights the risks of combining ketogenic diets such as the Atkins diet with SGLT2 inhibitors, as outlined by Grammatiki and colleagues.1 SGLT2 inhibitors have a diuretic effect as they block the reabsorption of sodium as well as glucose.2 Hypovolaemia stimulates release of counter‐regulatory hormones such as glucagon, cortisol and adrenaline, which further increase insulin resistance, lipolysis and ketogenesis. Our patient's diarrhoeal illness preceding presentation likely exacerbated this hypovolaemia and therefore ketogenesis. High protein, low carbohydrate ketogenic diets such as Atkins in isolation usually only result in a mild, temporary ketosis.3 In the setting of an SGLT2 inhibitor and infective illness, however, it increased our patient's susceptibility to ketosis.

Shampa Sinha · Daniel Gavaghan · Steven Yew

Cardiovascular diseases Letters 16 September 2019 Free

Intensive lipid‐lowering therapy in the 12 months after an acute coronary syndrome in Australia: an observational analysis

To the Editor: The efficacy of evidence‐based doses of statins is well established. The poor compliance with high intensity lipid‐lowering pharmacotherapy reported by Brieger and colleagues1 in the CONCORDANCE study has been noted in many studies.2 Compliance is related to several factors, including patients’ perspectives and concerns about quality of life and possible adverse effects3 compared with potential benefits. Adverse effects of statins are extensively documented, are dose‐related, and contribute to suboptimal compliance.2 Outcomes with high intensity lipid‐lowering doses are predominantly extrapolated from trials and epidemiological endpoints. Treatment to specific target cholesterol levels is not supported by any direct trial evidence, acknowledged in the United States lipid guidelines since 2013.4 Further, a Cochrane meta‐analysis has failed to show any reduction in hard clinical endpoints such as myocardial infarction, stroke or mortality when receiving statin treatment in the first 3–6 months after acute coronary syndrome.5 The maximum reduction in total mortality reported on statins, around 15% by 3 years, is seen with about 40 mg of simvastatin, equivalent to about 5 mg of atorvastatin, associated with over a 25% reduction in myocardial infarction6 — impressive for a single coronary preventive intervention. The safety and efficacy of only a 10 mg dose of simvastatin led to its approval for over‐the‐counter sale in the United Kingdom in 2005.7 Being competitive enzyme inhibitors, as approved statin doses are increased, plateauing efficacy is overtaken by increases in a variety of adverse effects and potential harms. For example, high dose compared with conventional dose statin (2.5–10 mg of atorvastatin) has no impact on survival (Box) but increases myopathy by up to 29‐fold and liver dysfunction by up to ninefold.6 Higher intensity statin may achieve a small reduction in coronary events (only statistically significant in the Treating to New Targets [TNT] trial10) but at a price with respect to safety, tolerability, overall survival and compliance, particularly in older patients with multiple comorbidities. Instead of increasing statin dose, a greater reduction in cardiovascular risk may be achieved by combining smoking cessation, antithrombotic therapies, control of blood pressure and diabetes, weight loss and other lifestyle measures, each of which can reduce coronary events by 10–20%. Box – Trials comparing conventional versus high intensity statin dose Trials (years of follow‐up) Number of patients Statin Doses* (mg) Major CHD events† (% of cohort) Mortality† (% of cohort) Total CHD SEARCH8 12 064 Simvastatin 2.5 20% 16% 7% 7 years (mean) Simvastatin 10 20% 16% 7% A to Z9 4497 Simvastatin 2.5 12% 7% 5% 2 years (median) Simvastatin 10 12% 6% 4% TNT10 10 001 Atorvastatin 10 8% 6% 2% 5 years (median) Atorvastatin 80 7% 6% 2% IDEAL11 8888 Simvastatin 2 10% 8% 4% 5 years (median) Atorvastatin 80 9% 8% 4% PROVE‐IT TIMI12 4162 Pravastatin 2 9% 3% 1% 2 years (mean) Atorvastatin 80 8% 2% 1% A to Z = Aggrastat to Zocor; CHD = coronary heart disease; IDEAL = Incremental Decrease in Endpoints through Aggressive Lipid Lowering; PROVE‐IT TIMI = Pravastatin or Atorvastatin in Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction; SD = standard deviation; SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; TNT = Treating to New Targets. * Statin doses expressed as equivalent atorvastatin dose, based on mean low‐density lipoprotein‐lowering in a meta‐analysis (Law et al13). †None of the differences in major CHD events and mortality (total and CHD) were significantly different, except major CHD events in TNT (P = 0.002).

Simon B Dimmitt · Jennifer H Martin

Mja2 50324
Pharmacology Letters 16 September 2019 Free

First reported case of extensively drug‐resistant typhoid in Australia

To the Editor: The period from January to March marks the peak season for travellers returning to Australia, and typhoid is a key illness of concern. Since 2016, an extensively drug‐resistant (XDR) typhoid clade has emerged in Pakistan, showing resistance to all first‐line agents.1,2 Over the past 2 years, seven cases have been reported in returned travellers — mostly children — from Pakistan to England, Germany and the United States.1,3,4 We report here the first case of XDR typhoid identified in Australia. A 20‐month‐old Australian‐born girl presented to the Children's Hospital at Westmead with features of enteric fever 14 days after her return from a 3‐month trip to Karachi. Diarrhoea began in Pakistan 6 weeks before her return, and continued despite the use of oral antibiotics prescribed locally in Pakistan. Ten days of high fevers, irritability, vomiting and reduced oral intake prompted admission to our hospital. She was a previously well child and had received routine vaccines. No additional pre‐travel vaccinations had been recommended. Blood and stool cultures grew extended spectrum β‐lactamase‐producing Salmonella enterica serovar Typhi. The isolate showed microbiological features typical for the XDR clade, with resistance to chloramphenicol, ampicillin, trimethoprim–sulfamethoxazole, fluoroquinolones and third‐generation cephalosporins (Box). The isolate was susceptible to meropenem and had an azithromycin minimum inhibitory concentration of 12 mg/L. The child responded to intravenous meropenem and oral azithromycin and was discharged after an uncomplicated 8‐day admission to complete a further week of azithromycin. Notification to the local public health unit facilitated contact tracing. This case was one of 12 travel‐associated, culture‐positive enteric fever cases managed at our hospital in the first 3 months of 2019. This continues a trend toward a higher incidence of enteric fever, as previously reported at our hospital from 2003 to 2015.5 This case highlights the emerging threat of XDR typhoid and the broader global issue of escalating antimicrobial resistance, to which Australia is not immune, especially given increasing travel connectivity. Typhoid must be considered as a diagnosis for febrile returned travellers from endemic regions, including South and South‐East Asia. Typhoid vaccination is recommended from 2 years of age if travel is planned to these regions. The important role of general practitioners in providing travel‐related vaccine advice and care to returning travellers must not be underestimated. Box – European Committee on Antimicrobial Susceptibility Testing (EUCAST) disc diffusion demonstrating zones of inhibition to cefotaxime (COX), amoxicillin–clavulanate (AMC), cefepime (FEP), meropenem (MEM), ampicillin (AMP), imipenem (IMP), ciprofloxacin (CIP), amikacin (AKN), piperacillin–tazobactam (PTZ), fosfomycin (FOS); trimethoprim–sulfamethoxazole (SXT) and gentamicin (GMN)

Annaleise Howard‐Jones · Alison M Kesson · Alexander C Outhred · Philip N Britton

Mja2 50316
Pharmacology Letters 2 September 2019 Free

Regulatory and other responses to the pharmaceutical opioid problem

To the Editor: We read with interest the article regarding Australia's approach to managing the challenges of pharmaceutical opioid utilisation.1 The various regulatory, service delivery and educational activities described would appear to provide a comprehensive response to this problem. However, we were surprised to note the absence of any reference to the potential of pharmacogenomics in identifying patients at increased risk of opioid toxicity. Various factors dictate how much opioid reaches the brain, how long it stays there, and how sensitive a patient may be to central nervous system (CNS) depression. Many risk factors for opioid toxicity are familiar to doctors. These include high daily opioid dose, extremes of age (neonates and older patients), comorbid conditions (eg, liver, kidney and respiratory disease), concomitant CNS depressants (sedatives and alcohol), and strong inhibitors or inducers of metabolism. In contrast, pharmacogenomics is unfamiliar to many Australian doctors. A recent position statement from major medical colleges describes a coordinated effort by doctors to develop the role of pharmacogenomics in Australian clinical practice.2 Codeine is converted to the active metabolite morphine by the cytochrome P450 enzyme encoded by the gene CYP2D6. Due to variants in CYP2D6, some patients are poor metabolisers (5–10%), have low CNS exposure to morphine, and are unlikely to benefit from or be harmed by codeine. Conversely, other patients are ultrarapid metabolisers of codeine (up to 10%), resulting in high and prolonged CNS exposure to morphine and an increased risk of CNS depression.3 There is an ongoing debate about the place of pharmacogenomics in managing the prescribing of opioids. There is strong support for testing children and nursing mothers taking codeine due to fatal cases of respiratory failure in ultrarapid metabolisers.4 International clinical guidelines recommend that codeine be avoided in poor metabolisers and ultrarapid metabolisers because of lack of efficacy and risk of CNS depression, respectively.3 Considerable research is underway to determine whether pre‐emptive pharmacogenomic testing can help with the pharmaceutical opioid problem.5 To reduce harm from opioids, we recommend testing for CYP2D6 variants as part of a benefit–risk assessment when prescribing codeine, especially for patients with other risk factors for opioid toxicity.

Thomas Polasek · Melody Caramins · Graeme Suthers

Mja2 50297
Pharmacology Letters 2 September 2019 Free

Diabetic ketoacidosis with sodium–glucose cotransporter type 2 inhibitors: a case series

To the Editor: Sodium–glucose cotransporter type 2 (SGLT2) inhibitors — dapagliflozin, empagliflozin and now ertugliflozin — have become established second line options for type 2 diabetes, with favourable potential for weight loss and cardiovascular protection.1 However, it soon became clear post‐marketing that they had potential for several pronounced side effects, including euglycaemic ketoacidosis — an unusual form of diabetic ketoacidosis where blood sugar levels remained relatively normal.2 The Therapeutic Goods Administration (TGA) first sent an alert about euglycaemic ketoacidosis in relation to SGLT2 inhibitors in 2015; subsequent alerts in 2018 from the TGA and the Australian Diabetes Society warned specifically about periprocedural risks.3,4 Austin Health has a well developed culture of adverse drug reaction reporting. A multidisciplinary committee includes representation from pharmacy, clinical pharmacology, dermatology and infectious diseases. During 2018, our adverse drug reaction committee forwarded 302 reports to the TGA, estimated to be around 15% of all reports received from Australian hospitals. Since 2016, our adverse drug reaction committee has received 12 reports of patients with diabetic ketoacidosis related to SGLT2 inhibitors, including eight in 2018. The growth in incidence locally in such a short period is alarming. Most patients (75%) had a blood sugar level of 11 mmol/L or lower at presentation. Our committee reviewed the cases in the Box to evaluate severity and causality. SGLT2 inhibitors were considered a probable cause in ten cases; the reaction was considered severe in nine cases, with one death during admission. We report our cases with the aim of increasing awareness around contributing factors, particularly concurrent illness resulting in poor oral intake. Only two of the 12 cases related to a perioperative setting, and in neither situation was the SGLT2 inhibitor withheld prior to surgery. We remind clinicians that the precipitants for diabetic ketoacidosis extend beyond the perioperative period. We advise caution when patients are experiencing other contributing factors illustrated by our case series, including acute illness, reducing insulin doses, poor oral intake, severe dehydration and low carbohydrate diet. Patients should be counselled about the signs of ketoacidosis and advised to seek medical help if they occur. SGLT2 inhibitors should be withheld if a patient is acutely unwell or undergoing surgery, and should only be restarted when the patient is eating and drinking normally.5 Box – Cases of ketoacidosis related to sodium–glucose cotransporter type 2 inhibitors Case Year Medication Dose Severity Causality Potential contributing factors 1 2016 Empagliflozin 10 mg daily Moderate Probable Low dietary intake in perioperative setting 2 2016 Dapagliflozin 5 mg twice a day Severe Probable Perioperative setting 3 2017 Dapagliflozin 10 mg daily Severe Probable Unwell for 3 days prior to presentation — patient had type 1 diabetes 4 2017 Empagliflozin 10 mg daily Severe Possible Concurrent influenza 5 2018 Empagliflozin 10 mg daily Severe Probable Narcosis leading to poor oral intake 6 2018 Empagliflozin 12.5 mg twice a day Severe Probable Weight loss since commencing — worse in the month prior to admission 7 2018 Empagliflozin 25 mg daily Moderate Probable Concurrent pneumonia 8 2018 Dapagliflozin 10 mg daily Moderate Possible Low carbohydrate diet 9 2018 Empagliflozin 10 mg daily Severe Probable Patient unwell with some vomiting for several days before admission 10 2018 Dapagliflozin 5 mg twice a day Severe Probable 5–7 days of loss of appetite 11 2018 Dapagliflozin 10 mg daily Severe (died during admission) Probable Illness for 10 days before admission Pancreatitis 12 2018 Empagliflozin 25 mg daily Severe Probable 5 days of gastroenteritis before admission Weaning insulin doses

Gina McLachlan · Claire Keith · Albert Frauman

Mja2 50302
Environmental health Letters 19 August 2019 Free

Unintended consequences of a cautious approach to e‐cigarette laws

To the Editor: We agree with Catalano and colleagues1 that nicotine liquid needs to be regulated. However, we feel that their letter overstates the risk from nicotine poisoning. The authors state that the minimum potentially lethal dose of nicotine in humans is 60 mg, but the reference used for this claim actually estimates a far higher minimum lethal dose of 500–1000 mg.2 While it is correct to say that the “ingestion of even a small volume could cause serious harm or even death,” the reality is less worrying. The bioavailability of ingested nicotine is as little as 20% due to hepatic first pass metabolism.3 Furthermore, most cases of significant ingestion result in prompt vomiting.4 A recent review of all cases of nicotine exposure reported to the Australian Poisons Information Centres between 2009 and 2016 found that most cases resulted in only mild gastrointestinal symptoms.5 We agree with the recommendation to mandate safety labelling and childproof packaging to reduce risk. However, regulation needs to go further; legalising and enforcing quality and safety standards would help to ensure a safer product and minimise unwanted contamination, as found in a recent Australian study.6 Vaping has a potential role in reducing smoking‐related disease in Australia. A recent large randomised controlled trial demonstrated that vaping is nearly twice as effective as nicotine replacement therapy.7 Regulation needs to find a balance between reducing the risk to children and non‐smokers while making high quality reduced‐risk products available to smokers who are otherwise unable to quit. Overly restrictive regulations are likely to have a net negative effect on public health.

Colin P Mendelsohn · Alex D Wodak

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