Knowledge Type: Clinical Articles

An adverse event can be defined as an unintended occurrence associated with the use of a therapeutic good. This may be related to the use of a medicine, vaccine, or medical device. Adverse events are a leading cause of unplanned hospital admissions and deaths. Some studies suggest that medication-related adverse events contribute to between 10% and 30% of all hospital admissions in older patients.

Improving the understanding of adverse events is an important part of ongoing monitoring activities. The Therapeutic Goods Administration (TGA) regulates therapeutic goods in Australia and collects adverse event reports. Reporting suspected adverse events to the TGA is important as it allows safety issues to be identified early. Reports can be submitted by consumers, healthcare professionals, pharmaceutical companies, and medical device suppliers.

What is the purpose of reporting?

When a therapeutic good is first registered on the Australian Register of Therapeutic Goods, information on its safety and efficacy may be limited to clinical trials. Clinical trials do provide important information on adverse events. However, they cannot detect all possible adverse events for a number of reasons, including:

• The duration of a clinical trial may not be sufficient to detect events that take time to develop
• The trial population may not be large enough to detect very rare events
• The population may not be diverse enough to detect events that are more likely in specific patient groups (e.g. those with certain comorbidities, specific age groups, etc.).

This is why ongoing safety monitoring activities are so important. The TGA collects adverse event reports in the Database of Adverse Event Notifications (DAEN). There is a separate database for medicines and medical devices. Reports can be made for all medicines. This includes prescription and non-prescription medicines and complementary medicines such as herbal preparations and nutritional supplements.

The TGA is particularly interested in reports related to:

• New therapeutic goods (the Black Triangle Scheme helps to identify prescription medicines that are new or being used in a different way. For these medicines, the black triangle symbol appears on the product information (PI) and consumer medicine information (CMI) with a reminder to report adverse events);
• Medicine and/or vaccine interactions;
• Unexpected adverse events (i.e. those that do not appear in the product information or product labelling); and
• Serious adverse events (including those suspected of causing death, hospitalization, absence from productive activity, increased investigational or treatment costs, and birth defects).

The TGA encourages reporting of all suspected adverse events. It is not necessary to be certain that a particular therapeutic good caused the adverse event. Even where causality is uncertain, an individual report is still valuable as it contributes to the overall safety data for that therapeutic good. Each report helps the TGA assess the possible role the therapeutic good played in causing the adverse event and helps expand the known safety profile of the therapeutic good.

How to report:

Adverse event reports for medicines and vaccines can be submitted online. Reports can be quickly submitted without registering. However, registering yourself as a user provides additional features such as pre-populating your contact details and the ability to save drafts and view or amend previously submitted reports.

Alternatively, reports related to a vaccine can be submitted via email, fax, or mail using the National Adverse Events Following Immunisation (AEFI) reporting form. Reporting adverse events for vaccines provided under the National Immunisation Program (NIP) can be done via the local health authority who will then share the information with the TGA.

When submitting an adverse event report to the TGA, it is helpful to provide as much detail as possible. The following information is considered the minimum required:

• Your contact details (so that further information can be sought if required);
• Patient identifier (e.g. initials, date of birth, or age. The patient’s name should not be used);
• Details of the product involved; and
• Details of the suspected adverse event.

Outcomes:

The TGA uses information from adverse event reports to identify potential safety signals. When a safety signal is recognised, a detailed evaluation is conducted to establish the therapeutic good’s possible role in the event.

In Australia, it is mandatory for sponsors to report serious adverse events suspected of being related to their therapeutic good. However, reporting by healthcare professionals and consumers is voluntary. It is thought that less than 5% of adverse reactions are actually reported. Under-reporting has the potential to allow rare adverse events to go undetected for longer.

The following actions may be taken by the TGA in response to a safety signal:

• Publishing a Medicines Safety Update or Safety Alert on the TGA website
  • For example, a safety alert was recently published to highlight the potential for liver injury with Garcinia gummi-gutta (Garcinia cambogia) or hydroxycitric acid (HCA).
• Communicating the new safety information to healthcare professionals. This may include details of how to prevent an adverse event or assess risk factors in patients.
• Updates to the product labelling or PI and CMI documents
  • For example, an updated warning regarding the rare risk of cardiovascular death was added to the PI for azithromycin. In this case, there was insufficient evidence to establish or exclude causality. However, the warning provides further information to prescribers and may prompt clinicians to consider screening high-risk patients.
• Limiting the population the product can be used in
  • For example, oral promethazine products should not be used in children under six years of age due to the increased risk of adverse events in this population
• Suspending or cancelling the registration of the product
  • For example, the TGA cancelled the registration of pholcodine cough medicines in 2023 for safety reasons. An investigation found a link between pholcodine use and anaphylactic reactions to neuromuscular blockers during general anaesthesia. The decision to cancel pholcodine products took into account the severity of the potential reaction, the limited efficacy of the product, and the ready availability of therapeutic alternatives.
• Recalling a product
• Requiring the sponsor to conduct postmarket studies if additional information is required

Conclusion:

Reporting adverse events is essential for the ongoing safety monitoring of therapeutic goods. It helps to identify less common adverse events and populations that may be more susceptible. Healthcare professionals are encouraged to submit adverse event reports to support the ongoing monitoring of therapeutic goods in Australia.

If you would like to learn more about reporting adverse events, the Australian Commission on Safety and Quality in Health Care provides an online learning module.

Pharmacogenomics is an emerging field that looks at how genetic variations influence drug effects in individuals. Genetic variations can lead to differences in drug absorption, distribution, metabolism, and excretion (sometimes referred to as ‘ADME’). Variations in ADME processes can cause significant differences in drug exposure between individuals, translating into differences in efficacy and adverse effects.

In some cases, pharmacogenetic testing may be used to inform prescribing practices and individualise medicine use. The potential benefits include enhanced efficacy of prescribed therapies, reduced adverse drug reactions, and reduced drug wastage. A report commissioned by the Australian Centre for Health Research estimated that pharmacogenetic testing could save the Australian healthcare system over $1 billion annually.

Genes associated with altered drug responses include those that code for drug-metabolising enzymes, drug transporters, and human leukocyte antigen (HLA).

Drug-metabolising enzymes

The cytochrome P450 family of enzymes plays a major role in drug metabolism. Cytochrome P450 3A4 is involved in the metabolism of around 55% of prescription drugs, while CYP2D6 or CYP2C19 are involved in the metabolism of around 25% of prescription medicines. However, these enzymes are highly polymorphic, which can cause significant inter-individual differences in drug effects.

In terms of drug response, genetic variations can result in the following phenotypes:

• Poor metabolisers (i.e. have absent or markedly reduced enzyme);
• Intermediate metabolisers (i.e. have reduced enzyme);
• Extensive metabolisers (also referred to as “normal” metabolisers); and
• Ultra-rapid metabolisers (i.e. have high enzyme activity).

Codeine and CYP2D6

Codeine is an interesting example of how polymorphisms can have serious implications for a patient. For codeine to exert its opioid activity, it must be converted to its active metabolite, morphine. This reaction is catalysed by CYP2D6. Patients who are poor metabolisers will have a poor response to codeine. Conversely, patients who are extensive metabolisers or ultra-rapid metabolisers are at a greater risk of experiencing side effects. This is due to a greater conversion of codeine to morphine, which has a 200-fold greater affinity for the mu-opioid receptor. In these patients, serum morphine levels may be much higher than expected, and opioid toxicity is more likely to occur, even at commonly used doses.

Pharmacokinetic studies have found that the use of codeine in people defined as poor metabolisers leads to a 96% lower morphine exposure compared to normal metabolisers. These individuals also showed no difference in analgesia for codeine compared to placebo. Ultra-rapid metabolisers had a 45% higher exposure to morphine compared to normal metabolisers. These patients may be more likely to experience toxicity, even at low codeine doses.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that codeine be avoided in patients who are CYP2D6 ultrarapid metabolisers to avoid severe toxicity. They also recommend avoiding codeine in patients who are poor metabolisers due to the risk of poor effect. Where an alternative opioid is required, tramadol should be avoided as this agent also requires CYP2D6 for conversion to its more active metabolite.

The prevalence of different CYP2D6 phenotypes varies considerably according to ancestral background. On average, it is estimated that around 1-2% of people are ultra-rapid metabolisers, and around 5-10% of people are poor metabolisers. People of North African, Ethiopian and Arab backgrounds are more likely to be ultra-rapid metabolisers, with a reported prevalence of up to 28%.

Cytochrome P450 and depression

The management of depression can be challenging, with 50% of patients not responding to their initial antidepressant and less than 50% of patients achieving remission within 12 months of starting drug therapy. Part of this issue may be related to cytochrome P450 polymorphisms.

Two main enzymes are involved in the metabolism of antidepressants, CYP2D6 and CYP2C19. One retrospective study investigated the impact of cytochrome P450 polymorphisms on health resource utilisation in patients with anxiety and depression. The authors found that patients prescribed a medication not aligned with their pharmacogenetic test results had 69% more healthcare visits than patients whose therapy was aligned with their pharmacogenetics. These patients also had three times more medical absence days and four times more disability claims.

The potential impact of these findings is significant. One Australian study found that a quarter of people taking antidepressants were taking one that did not align with their CYP2D6 and CYP2C19 genotypes. These patients were also found to be more likely to switch between antidepressants, which is suggestive of poor therapeutic effects or adverse effects.

Thiopurine methyltransferase

Thiopurine methyltransferase (TPMT) is an enzyme that is crucial for the metabolism of thiopurines. Individuals with an inherited deficiency of this enzyme are at higher risk of adverse effects when treated with a thiopurine.

Profound deficiency of TPMT is found in around 0.3% of the population. These patients may develop severe myelosuppression when treated with usual doses of thiopurines. Around 11% of the population are carriers for this deficiency and may also have some degree of reduced tolerance to thiopurines. The Australian product information recommends testing patients for TPMT activity before starting mercaptopurine, azathioprine, and tioguanine.

Drug transporters

Organic anion-transporting polypeptides (OATP) are a family of transporters that move a wide range of endogenous and exogenous organic compounds. These transporters have a wide tissue distribution and play a role in drug uptake into various tissues, including hepatic uptake prior to drug elimination.

OATP1B1 and simvastatin

The SLCO1B1 gene provides instructions for making the protein, OATP1B1. The OATP1B1 protein is mainly found in the liver and plays an important role in the hepatic elimination of many compounds, including some drugs.

Inherited polymorphisms in the SLCO1B1 gene that lead to reduced function of OATPB1 have been associated with statin-induced myopathy. This is due to reduced hepatic uptake of the statin, which leads to higher plasma levels. Simvastatin is particularly affected by this polymorphism. The CPIC recommend that patients with decreased or poor metaboliser phenotypes should receive a lower dose of simvastatin or be prescribed an alternative statin.

Human leukocyte antigen

Variations in HLA genotype can be used to predict the likelihood of immune-mediated reactions, some of which can be severe and life-threatening.

For example, it is recommended to test for HLA-B*5701 status prior to initiating abacavir therapy. Patients who test positive have a significantly higher risk of hypersensitivity reactions. These reactions can present with symptoms similar to pneumonia, bronchitis or pharyngitis, influenza-like illness, or gastroenteritis.

Some examples of drugs that may be affected by gene variants are shown in Table 1.

Table 1. Drugs affected by gene variants

Gene	Examples of drugs affected	Result
CYP2D6	Codeine	Poor metabolisers – drug is ineffective Ultra-metabolisers – higher risk of toxicity
	Selective serotonin reuptake inhibitors (SSRIs)	Ultra-metabolisers – poor response Poor metabolisers – may need lower dose
CYP2C19	Clopidogrel	Poor metabolisers – reduced effect. Consider alternative therapy.
DPYD	Capecitabine Fluorouracil	Deficiency of dihydropyrimidine dehydrogenase increases risk of severe toxicity.
SLCO1B1	Simvastatin	Gene variants can significantly increase or decrease risk of myopathy.
HLA	Allopurinol	Variants associated with higher risk of allopurinol-related hypersensitivity syndrome and SJS/TEN
	Carbamazepine	Some variants may predispose to SJS, TEN, DRESS, and AGEP.

Abbreviations: AGEP, Acute Generalized Exanthematous Pustulosis; DRESS, Drug Rash with Eosinophilia and Systemic Symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Phenoconversion

Additional factors may need to be considered when interpreting pharmacogenetic results due to phenoconversion.

Phenoconversion refers to the mismatch between an individual’s genotype and phenotype, i.e. their actual drug metabolising capacity differs from what genetic testing predicts. This could be related to a range of factors, such as drug interactions.

Many medications have significant effects on metabolising enzymes. For example, a patient with a genotype for normal codeine metabolism may be converted to a poor metaboliser if codeine is co-administered with a strong inhibitor of CYP2D6 (e.g. terbinafine).

Some examples of agents known to inhibit and induce major drug metabolising enzymes are shown in Table 2.

Table 2. Medications associated with phenoconversion

Enzyme	Inhibitors	Inducers
CYP2C9	Amiodarone Fluconazole Fluoxetine Fluvoxamine Voriconazole	Carbamazepine Rifampicin St John’s wort
CYP2C19	Fluoxetine Fluvoxamine Omeprazole Paroxetine Topiramate	Apalutamide Rifampicin Ritonavir St John’s wort
CYP2D6	Amiodarone Bupropion Cinacalcet Duloxetine Fluoxetine Methadone Paroxetine Terbinafine
CYP3A4	Aprepitant Ceritinib Clarithromycin Cobicistat Idelalisib Posaconazole Ritonavir Voriconazole	Apalutamide Carbamazepine Encorafenib Lumacaftor Phenytoin Rifampicin St John’s wort
UGT1A1	Erlotinib Nilotinib Sorafenib Pazopanib	Carbamazepine Phenytoin Rifampicin
TPMT	Aspirin Furosemide Olsalazine Sulfasalazine NSAIDs Thiazide diuretics

 

The extent to which these agents impact drug metabolism will depend upon the dose administered and the duration of therapy. For enzyme-inhibiting drugs with a long half-life and high affinity for drug-metabolising enzymes, their effects can persist for many days after their last dose. For example, phenoconversion following chronic fluoxetine therapy is reported to persist for six weeks after discontinuation.

Other factors have also been implicated in phenoconversion. These include advanced age, frailty, obesity, cancer, inflammation, smoking, alcohol, and vitamin D exposure. However, further study of the impact of these factors is required.

Summary

Genetic variations have been implicated in an increased susceptibility to adverse reactions and reduced therapeutic efficacy. Pharmacogenetic testing may offer a means of individualising drug therapy to optimise both drug efficacy and tolerability. Unfortunately, high-level evidence for pharmacogenetic testing currently exists only for a relatively small number of genes.

The Royal College of Pathologists of Australia maintains a summary of drugs and their evidence for pharmacogenetic testing.

The Australian Commission on Safety and Quality in Healthcare recently released the Chronic Obstructive Pulmonary Disease Clinical Care Standard. This is the first national standard on chronic obstructive pulmonary disease (COPD), a common condition thought to affect around one in 13 Australians over the age of 40.

The new standard aims to reduce potentially preventable hospitalisations and improve overall outcomes for people with COPD. One of the main causes of preventable hospitalisations in this population is COPD exacerbations. An exacerbation is characterised by acute worsening of symptoms beyond what would be considered normal day-to-day variations. This may include increasing dyspnoea, worsening of chronic cough, and changes in sputum. Reducing exacerbations is a primary goal of COPD management.

Tobacco smoking is the most common risk factor for COPD. According to the Australian Burden of Disease Study 2024, tobacco contributed to 65% of the total burden from COPD. There has been a reduction in the rate of burden attributed to tobacco in Australia over the past few decades. This is likely due to the significant decrease in smoking prevalence. However, as there is a long lag time between smoking and developing disease, its contribution to disease burden is still high.

The evidence clearly demonstrates that smoking cessation is the most important intervention to prevent or minimise lung damage and reduce mortality in patients with COPD who smoke. Patients who currently smoke should be encouraged to quit smoking and offered evidence-based smoking cessation interventions.

Other interventions with evidence to support a reduction in exacerbations include:

• Optimisation of pharmacological therapies;
• Keeping up-to-date with recommended vaccinations; and
• Pulmonary rehabilitation.

Optimisation of pharmacological therapies.

Pharmacological therapies are an important part of COPD management as they can reduce symptoms and prevent exacerbations. The COPD-X Handbook provides information on a stepwise approach to therapy.

Therapy starts with a short-acting reliever that is used on an as-needed basis. This reliever may be a short-acting beta₂-agonist (SABA) or a short-acting muscarinic antagonist (SAMA). A long-acting bronchodilator, either a long-acting muscarinic antagonist (LAMA) or long-acting beta₂-agonist (LABA), may then be added. Depending on the response, a combination of LAMA + LABA may be considered. An inhaled corticosteroid may also be required for patients with moderate to severe COPD.

There are many different inhaler products and devices available. Some devices require the patient to load a capsule into the inhaler before each dose, while others are pre-loaded. Some devices, such as the metered dose inhaler, require a high level of coordination and manual dexterity. However, regardless of the type of device, optimal use of inhalers presents more challenges than most other dose forms. Therefore, patients must be trained on how to use each specific device correctly. The Lung Foundation Australia provides instructional videos for various inhaler devices.

Where possible, it is recommended to minimise the number of different inhaler devices used by a patient. Having multiple devices with different methods of use may increase the chances that the patient will not use their devices correctly. Incorrect inhaler technique is common, with reports that up to 90% of patients do not use their devices correctly. Poor inhaler technique can reduce drug delivery to the lungs, resulting in reduced efficacy and an increased risk of exacerbations. One study demonstrated a two-fold increase in the rate of severe exacerbations in the previous three months for patients with at least one critical device error compared to patients with no critical errors.

Inhaler technique should be regularly checked. In particular, it should be checked before considering an escalation of therapy, after a change in treatment, and after an exacerbation. The clinical care standard advises that all clinicians involved in a patient’s care can play a role in checking and correcting inhaler technique.

Reducing the complexity of therapy may also play a role in improving compliance with therapy. Many combination inhalers are now available, which have the potential to reduce the number of devices and doses that a patient needs to use.

Vaccinations

People with COPD are at higher risk of experiencing complications from many infections. Bacterial and viral infections are also known triggers for COPD exacerbations. Therefore, it is recommended that people with COPD are up-to-date with vaccinations for influenza, COVID-19, and pneumococcal disease.

Additional vaccines, such as a herpes zoster vaccine, may also be recommended. One meta-analysis found that people with COPD have a 41% higher risk of herpes zoster compared to healthy controls. The risk of complications may also be higher, with one study finding that COPD was associated with a 53% increased risk of post-herpetic neuralgia.

Shingrix® (varicella-zoster vaccine) is currently funded under the National Immunisation Program (NIP) for all adults 65 years of age and older, Aboriginal and Torres Strait Islander people from 50 years of age, and people 18 years of age or older with moderate to severe immunocompromise.

Pulmonary rehabilitation

Pulmonary rehabilitation has been shown to improve symptoms and reduce the risk of COPD exacerbations. These programs usually run over six to eight weeks and combine exercise, education, and self-management techniques. Patients who have completed a pulmonary rehabilitation program should be encouraged to continue with their exercise program to ensure the benefits are maintained.

The clinical care standard recommends that pulmonary rehabilitation be offered to all patients with COPD. For patients admitted to the hospital with a COPD exacerbation, the standard advises to begin within four weeks. This reduces the short-term risk of re-admission while also improving symptoms and quality of life following the exacerbation.

People with diabetes are at a greater risk of many infections. This includes infections of the urinary tract, respiratory tract, skin and soft tissues. Infections are a significant cause of morbidity and mortality in this population. While the reasons for this elevated risk are complex, impaired innate and adaptive immune responses within the hyperglycaemic environment are thought to be important factors.

Poor glycaemic control is associated with a higher risk of infection. One large cohort study found that, for most infection types, the rate of infections rose steadily with increasing HbA_1c. This was particularly true for patients with a HbA_1c ≥ 11%. Chronic complications of diabetes, such as neuropathy, can also predispose to infections.

The urinary tract is one of the most common sites of bacterial infections in people with diabetes. While the frequency of urinary tract infections (UTIs) is increased, this population is also likely to experience a worse prognosis. They are more likely to require hospitalisation for their UTI, and serious complications are more common.

Emphysematous pyelonephritis

Emphysematous pyelonephritis (EPN) is one of the most serious types of UTI. Although this is an uncommon condition, it is highly associated with diabetes, with around 95% of cases occurring in patients with uncontrolled diabetes mellitus.

Emphysematous pyelonephritis is an acute necrotising infection of the renal parenchyma and surrounding tissues. It is caused by bacteria that are able to ferment glucose to produce carbon dioxide. Potential causative pathogens include Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. In almost 70% of cases, E. coli is isolated on urine or pus cultures.

If not diagnosed early, this condition can be life-threatening, with mortality mostly related to septic complications. Patients may initially present with non-specific symptoms, although the clinical triad of fever, flank pain and nausea is typically seen. In severe cases, altered consciousness and shock may be apparent. Predictors of poor prognosis include thrombocytopenia, azotaemia, and high urinary red blood cell counts. Diagnosis is supported by imaging of the abdomen and pelvis, which will show the presence of intra-renal gas.

Initial treatment includes broad-spectrum antibiotics, fluid and electrolyte resuscitation, acid-base balance, percutaneous catheter drainage, and rapid glycaemic control. Empiric antibiotic therapy should target gram-negative bacteria while also considering local resistance patterns and individual patient factors. Third or fourth-generation cephalosporins or carbapenems may be considered. Factors that may favour the use of a carbapenem include hospitalisation with antibiotic use within the previous 12 months, the need for emergency haemodialysis, or the presence of disseminated intravascular coagulation. One study demonstrated that these factors had a significant correlation with cephalosporin resistance.

While emphysematous pyelonephritis is rare, it should be considered in patients with diabetes who present with pyelonephritis. Early recognition and initiation of appropriate therapy are essential to minimise mortality and potentially reduce the need for nephrectomy.

Sodium-glucose cotransporter-2 inhibitors

While diabetes itself is a risk factor for UTIs, one class of medications used to treat diabetes has been suggested to increase this risk even further. Concerns were raised about sodium-glucose cotransporter-2 (SGLT2) inhibitors and their potential to increase the risk of urinary tract and genital infections. This is related to the way in which they reduce blood glucose levels. As they work to inhibit glucose reabsorption in the proximal tubules, glucose levels in the urine are elevated. The resulting glycosuria is hypothesised to enhance bacterial growth within the urogenital environment.

Dapagliflozin and empagliflozin are SGLT2 inhibitors. They are available as single-ingredient preparations and fixed-dose combinations with metformin or linagliptin.

While urogenital infections have been reported in association with these medicines, data from large randomised clinical trials and real-world population-based studies suggest that they may not increase the risk of UTIs. One meta-analysis demonstrated that while SGLT2 inhibitors may increase the risk of genital infections, the class is not generally associated with an increased risk of UTI. However, dapagliflozin was associated with an increased risk of UTI compared to placebo when given at a dose of 10mg daily (RR 1.33, 95% CI 1.10–1.61), but not at 5mg daily. This elevated risk was not seen with empagliflozin at any dose nor with dapagliflozin when compared to active comparators.

This lack of observed UTI risk despite the favourable conditions these medicines provide for bacterial growth could be related to their diuretic effect. Therefore, the UTI risk profile may be different for patients with abnormal urinary flow.

Pathogens

Urinary tract infections occurring in people with diabetes are more likely to be caused by resistant pathogens. This includes extended-spectrum β-lactamase-positive Enterobacteriaceae, fluoroquinolone-resistant uropathogens, carbapenem-resistant Enterobacteriaceae, and vancomycin-resistant Enterococci.

The increased incidence of resistant infections in this group could be related to a general increased consumption of antibiotics for UTIs and other infections. This highlights the importance of antimicrobial stewardship initiatives to ensure that antimicrobial use is optimal in this group. For example, asymptomatic bacteriuria is more common in people with diabetes. However, this should not be treated with antibiotics unless the patient is pregnant or undergoing certain elective urological procedures. In other cases, the evidence suggests that treatment of asymptomatic bacteriuria does not reduce the incidence of symptomatic UTI or long-term complications and may increase the risk of resistant infections.

Type 2 diabetes is also a risk factor for fungal UTIs, typically with Candida spp. Fluconazole is often the agent of choice for the treatment of fungal UTIs. It has high oral bioavailability, a long half-life, and achieves adequate levels in the urine. Fluconazole is active against C. albicans and the most common non-albicans Candida species. Higher doses are typically required for infections caused by C. glabrata (recently renamed Nakaseomyces glabrata). The most recent AURA report (Antimicrobial Use and Resistance in Australia Surveillance System) finds that azole resistance among this species is 8.6% and may be increasing. Amphotericin B is a potential alternative where resistant yeasts are involved. However, liposomal formulations of amphotericin B do not achieve high urinary concentrations. Therefore, they are not suitable for lower UTIs.

Prevention

Optimal control of diabetes is essential to minimise the risk of infections as well as other diabetes complications. The Royal Australian College of General Practitioners (RACGP) make the following recommendations for the optimal management of type 2 diabetes:

• Eat according to the Australian dietary guidelines; individual dietary review is recommended if cardiovascular disease is present;
• Weight loss, if appropriate;
• At least 30 minutes of moderate physical exercise on most days (total ≥150 minutes/week);
• Cease smoking, where relevant;
• Limit alcohol intake to ≤2 standard drinks per day;
• Aim for 6–8 mmol/L fasting and 8–10 mmol/L postprandial blood glucose levels
• HbA_1c goals should be individualised, but a general goal would be ≤7% (6.5–7.5%) or ≤53 mmol/mol (48–58 mmol/mol);
• Address cardiovascular risk factors, as appropriate (i.e. blood pressure, blood lipids, etc.); and
• Consider vaccination, e.g. against seasonal influenza and pneumococcal disease.

Other preventative measures that may be considered to reduce the risk of UTIs include adequate hydration, avoidance of constipation, and attention to hygiene.

Antiemetics can be used to treat or prevent nausea and vomiting due to a range of causes. Their use can significantly improve quality of life and prevent complications such as dehydration and electrolyte disturbances.

Several neural pathways are involved in the development of nausea and vomiting. These include dopaminergic, serotonergic, histaminergic, cholinergic, neurokinin and cannabinoid receptor-mediated pathways. No antiemetic is universally effective, as no agent acts on all of these receptors.

The choice of antiemetic is influenced by the cause of nausea and vomiting, severity of symptoms, preferred route of administration, and the patient’s previous response to therapy. If a poor response occurs to one agent, a medication from a different class may be considered. Combination therapy using antiemetics with different mechanisms of action may also be considered.

Dopamine antagonists

Dopamine acts on D2 receptors in the chemoreceptor trigger zone (CTZ) to induce nausea and vomiting. Dopamine antagonists treat and prevent nausea and vomiting by blocking these receptors. Domperidone and metoclopramide also have prokinetic effects, which may be useful if symptoms are due to gastroparesis.

While dopamine is involved in the development of nausea and vomiting, it has a number of other functions in the brain. These include motor control, cognitive function, pleasure/reward, and hormonal control. Therefore, dopamine antagonists are associated with adverse effects, such as extrapyramidal side effects (EPSE) and elevation of prolactin levels.

The risk of EPSE is greatest with high doses and rapid intravenous administration of dopamine antagonists. Caution should be used in patients who are elderly as they may be more sensitive to the adverse effects of this class. These agents should generally be avoided in patients with Parkinson’s disease as they can cause significant exacerbation of parkinsonian symptoms. Of the dopamine antagonists, domperidone is least likely to cause this issue as it does not readily cross the blood-brain barrier.

Domperidone

Domperidone is indicated for the short-term treatment of intractable nausea and vomiting from any cause. Domperidone has been associated with an increased risk of serious ventricular arrhythmias and sudden cardiac death. This risk may be higher in patients taking doses greater than 30mg a day and in those over 60 years of age. Domperidone is contraindicated in patients with pre-existing prolongation of cardiac conduction intervals, significant electrolyte disturbances, or underlying cardiac conditions such as congestive heart failure.

Domperidone is primarily metabolised via CYP3A4. To minimise adverse effects, domperidone is contraindicated with potent inhibitors of CYP3A4 (e.g. azole antifungals, macrolide antibiotics, diltiazem, verapamil, amiodarone, aprepitant, fosamprenavir, ritonavir, saquinavir).

Metoclopramide

Metoclopramide is used to control nausea and vomiting associated with medications, uraemia, radiation sickness, malignancy, labour, infectious disease, and postoperative vomiting.

Metoclopramide is available as an oral tablet and an injection for intramuscular or intravenous use. The onset of effect is 1-3 minutes following an IV dose, 10-15 minutes for an IM dose, and 30-60 minutes following an oral dose; effects persist for 1-2 hours.

To minimise the risk of EPSE, metoclopramide is recommended for short-term use only (up to five days). Children are also at greater risk of EPSE with metoclopramide and it should be avoided in patients younger than 20 years.

Prochlorperazine

Prochlorperazine is used for the treatment of nausea and vomiting due to various causes and is available as a tablet and an injection. In addition to its action on dopamine receptors, prochlorperazine also has antagonist effects at α-adrenoceptors, histamine receptors, and cholinergic receptors, and potentiates noradrenaline. This may result in adverse effects such as orthostatic hypotension, reflex tachycardia, sedation, dry mouth, and constipation.

Droperidol

Droperidol can be used to prevent or treat postoperative nausea and vomiting. It is available as an injectable for IV or IM use. The usefulness of droperidol is limited by its sedating tendency and risk of EPSE.

5HT₃ antagonists

5-HT₃ antagonists block serotonin peripherally (in the gastrointestinal system) and centrally in the CTZ. It is thought that chemotherapeutics and radiotherapy can cause the release of 5-HT in the small intestine to trigger a vomiting reflex. These agents are effective in managing nausea and vomiting associated with cancer therapy and surgery.

The 5-HT₃ antagonists available in Australia are:

• Granisetron;
• Ondansetron;
• Palonosetron; and
• Tropisetron.

All of these agents appear to be similarly effective overall. However, palonosetron is more effective for preventing postoperative vomiting than ondansetron. When used for chemotherapy-induced nausea and vomiting, 5-HT₃ antagonists are more effective for acute rather than delayed symptoms.

5-HT₃ antagonists have a favourable side effect profile; common adverse effects include constipation, headache, and dizziness.

These agents are available in a range of presentations, including tablets/capsules, orally disintegrating tablets, oral liquid, and injections.

Substance P antagonists

Substance P antagonists prevent the binding of substance P to the neurokinin type 1 receptor (NK-1R) in the CTZ. This class includes:

• Aprepitant;
• Fosaprepitant;
• Fosnetupitant (only available in combination with the 5-HT₃ antagonist, palonosetron)
• Netupitant (only available in combination with palonosetron).

Fosnetupitant and fosaprepitant are phosphorylated pro-drugs of netupitant and aprepitant, respectively. This improves their water solubility. Following IV administration, they are rapidly converted to their active form.

Substance P antagonists are indicated for the prevention of acute and delayed nausea and vomiting associated with chemotherapy. For this purpose, they are typically administered in combination with a 5-HT₃ antagonist and a corticosteroid (e.g. dexamethasone). Aprepitant is also indicated for the prevention of postoperative nausea and vomiting.

Common side effects for this class include diarrhoea, fatigue, headache, and dizziness. There are many potential drug interactions with this class due to their effects on cytochrome P450. Aprepitant inhibits, induces and is metabolised by CYP3A4, and is also a moderate inducer of CYP2C9. Caution is required when administering with other medicines metabolised by these enzymes as therapeutic effect may be altered and adverse effects may be increased. Combination with pimozide, terfenadine, astemizole, or cisapride is contraindicated.

Netupitant is metabolised by, and moderately inhibits, CYP3A4. Combined use with a strong CYP3A4 inducer should be avoided as netupitant levels may reduce significantly. Caution should be used when combining netupitant with medicines that rely on CYP3A4 for metabolism as their levels may rise, increasing the risk of adverse effects. It is worth noting that netupitant has a long half-life (~88 hours), so this inhibitory effect may last for four days or more.

Antihistamines

Antihistamines reduce nausea and vomiting by blocking the effects of histamine in the CTZ. Cyclizine and promethazine are the antihistamines typically used for the management of nausea and vomiting in the hospital setting. Agents such as levomepromazine are not marketed in Australia but may be accessed via the Special Access Scheme. Other antihistamines are available over the counter for the management of motion sickness (e.g. dimenhydrinate in a fixed-dose combination with hyoscine).

Antihistamines can cause sedation. Due to their anticholinergic properties, they may also cause side effects such as dry mouth and constipation. Promethazine also has some anti-serotonin effects.

Promethazine is available as tablets and as an injection. It is a known vesicant, and the manufacturer recommends deep intramuscular injection into a large muscle as the preferred method of parenteral administration. Intravenous or inadvertent intra-arterial or subcutaneous administration can result in complications that may be severe (e.g. thrombophlebitis, venous thrombosis, phlebitis, nerve damage, abscess, tissue necrosis, and gangrene). However, care is required wherever injectable promethazine is used, as all administration routes can result in tissue damage. The Institute for Safe Medication Practices (ISMP) strongly advises against the use of injectable promethazine in favour of safer alternatives, such as 5-HT₃ antagonists.

Summary

A summary of commonly used antiemetics is shown in Table 1. If a poor response occurs to one agent, a drug from a different class may be considered. Alternatively, combination therapy using antiemetics with different mechanisms of action may also be considered.

Table 1. Overview of antiemetic agents

Drug	Form	Usual dosing	Notes
Dopamine antagonists
Domperidone	Tablets	3 times daily	Can cause EPSE Avoid in Parkinson’s disease
Droperidol	Injection	Single dose
Metoclopramide	Tablets, injection	3 times daily
Prochlorperazine	Tablets, injection	3 times daily
5-HT3 antagonists
Granisetron	Tablets, injection	Daily
Ondansetron	Tablets, wafer, oral liquid, injection	2-3 times daily
Palonosetron	Injection	Single dose	Long half-life (~40 hours)
Tropisetron	Injection	Daily
Substance P antagonists
Aprepitant	Capsule	Single dose	Many clinically significant drug interactions
Fosaprepitant	Injection	Single dose
Fosnetupitant + palonosetron	Injection	Single dose
Netupitant + palonosetron	Capsule	Single dose
Antihistamines
Cyclizine	Tablets, injection	Up to 3 times daily	May cause sedation
Promethazine	Tablets, oral liquid, injection	Up to 4 hourly

 

 

The scheduling of paracetamol will change on 1 February 2025, affecting pack sizes and how paracetamol-containing products can be accessed. These changes are intended to minimise harm related to intentional paracetamol overdose while also maintaining appropriate access for therapeutic use.

The upcoming changes are summarised in Table 1. These restrictions apply to all paracetamol-containing products, including combination products with additional active ingredients (e.g. paracetamol-containing cold and flu tablets).

Table 1. Summary of changes to paracetamol scheduling

	Current rules	Rules from 1st February 2025
Immediate-release tablets and capsules
Unscheduled (i.e. non-pharmacy retailers)	Maximum pack size of 20	Maximum pack size of 16
Schedule 2 (Pharmacy Only)	Maximum pack size of 100	Maximum pack size of 50*
Schedule 3 (Pharmacist Only)	N/A	Pack sizes up to 100
Schedule 4 (Prescription Only)	No change
Packaging for general sale	Blister or bottle	Blister packaging only
Other forms
Modified-release tablets	No change
Paracetamol liquid	No change

* Poisons regulations governing the storage and display of Schedule 2 medicines differ slightly in Queensland and Western Australia. In these states, the maximum pack size available for self-selection in a pharmacy will be 16 tablets or capsules; packs of 16 to 100 will be stored behind the counter.

Implementation of changes

Non-pharmacy retailers must comply with these new pack limits from 1 February 2025. They are also encouraged to restrict sales to a single pack at a time.

Pharmacies will also need to implement these changes for the storage and supply of paracetamol products from 1 February 2025. Manufacturers have already begun to supply wholesalers with products that are compliant with the new restrictions in terms of pack size and updated labelling. However, pharmacies have been granted a 12-month labelling exemption. During this period, pharmacies may continue to supply paracetamol-containing products with the existing labelling as long as they comply with the new storage and supply conditions.

Why are these changes being made?

While paracetamol has an excellent safety profile when used therapeutically, it is hepatotoxic and potentially fatal in overdose. Given the ready availability of paracetamol, it is perhaps not surprising to know that it is commonly involved in overdoses. Recent Australian evidence shows that paracetamol is:

• The most common cause of severe acute liver injury;
• The most common reason for calls to Poisons Information Centres;
• One of the most common medications involved in deliberate self-poisoning;
• Involved in a large percentage of accidental paediatric exposures; and
• Involved in a significant number of overdoses with therapeutic intent.

The Therapeutic Goods Administration (TGA) estimate that around 225 people are hospitalised with liver injury, and 50 people die from paracetamol overdose each year in Australia.

The final decision to make these changes was the result of a lengthy consultation period. This included an independent expert report examining the incidence of serious injury and death from intentional paracetamol overdose; advice from the Advisory Committee on Medicines Scheduling (ACMS); and submissions from individuals, and organisations representing consumers, healthcare practitioners, and industry.

The Independent expert report on the risks of intentional self-poisoning with paracetamol was commissioned by the TGA to examine the reasons for the increasing rate of intentional paracetamol overdoses. In particular, the report focussed on the rising prevalence in young people involving paracetamol sourced from non-pharmacy settings (i.e. supermarkets and convenience stores).

This report found that the majority of paracetamol self-poisonings are impulsive but with suicidal intent. This was true across all age groups. The paracetamol taken was present in the home in more than half of all cases, with only around 10% of individuals reporting a recent paracetamol purchase. Where purchases were made, one or two packs were typically bought. The pack sizes most commonly involved were 20/24s and 96/100s; unscheduled products were involved in between 25% and 30% of events.

The largest pack size available is often consumed in an intentional self-poisoning. Therefore, the idea of reducing pack sizes is often suggested as a harm minimisation strategy. Evidence shows that the introduction of reduced pack sizes is associated with reduced harm from self-poisoning. For example, the United Kingdom made changes to the scheduling of paracetamol in 1998. This has been associated with a 43% reduction in paracetamol-related deaths, a 61% reduction in registration for liver transplants due to paracetamol-induced hepatotoxicity, and a reduction in the median number of tablets taken in an intentional overdose (from 50 to 20 tablets for males and from 20 to 16 tablets for females). However, while there has been a significant reduction in the severity of paracetamol poisonings, the frequency of reported cases has not decreased.

Treatment of paracetamol overdose

While paracetamol overdose is common, severe liver injury and death are not common outcomes. This is due to the efficacy of therapies, although this is dependent upon the time to initiation of therapy.

The management of a paracetamol overdose will depend upon the context. For example:

• Overdose involving immediate-release compared to modified-release products;
• Unintentional overdoses in children younger than six years; and
• Unintentional overdose with therapeutic intent (also referred to as repeated supratherapeutic ingestion [RSTI]).

For example, activated charcoal may be used for gastrointestinal decontamination in patients presenting early (i.e. within two hours of ingesting immediate-release preparations and four hours for modified-release). However, this would not be useful in RSTI, where the paracetamol ingestion occurs over a long period.

Acetylcysteine:

Acetylcysteine is a paracetamol antidote used for patients at risk of hepatotoxicity. It is highly effective when given early, particularly within eight hours of ingestion. The therapeutic effect of acetylcysteine occurs via several mechanisms.

When administered in therapeutic quantities, paracetamol is primarily metabolised via glucuronidation and sulfation. Less than 5% is oxidised by cytochrome P450 to generate the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Glutathione present in the liver can normally detoxify the small amounts of NAPQI produced, thereby preventing cellular injury. This occurs via irreversible conjugation of NAPQI to the sulfhydryl groups of glutathione.

However, when excessive amounts of paracetamol are taken, the glucuronidation and sulfation pathways become saturated. Metabolism via the CYP450 pathway then increases with a greater quantity of NAPQI produced. This leads to the depletion of glutathione reserves and the accumulation of toxic metabolites, which are the causes of hepatic injury.

Acetylcysteine is a sulfhydryl donor which can directly conjugate with NAPQI to prevent hepatic injury. Other possible mechanisms include providing cysteine (an essential precursor of glutathione) and increasing blood flow and oxygen delivery to the liver.

The Updated Guidelines for the Management of Paracetamol Poisoning in Australia and New Zealand provide details of the protocols recommended for various clinical situations. Expert advice is recommended in the following cases as the risk of hepatotoxicity and complications is greater:

• Overdoses involving more than 50g or 1g/kg (whichever is less);
• High paracetamol levels (>3 times the nomogram line);
• Overdoses involving IV paracetamol;
• Hepatotoxicity (i.e. ALT > 100 IU/L); and
• Neonatal poisonings.

Advice can be sought from a clinical toxicologist or from a Poisons Information Centre (13 11 26).

Summary

These changes to paracetamol scheduling are intended to minimise the harm related to intentional overdoses. There have been no changes to treatment guidelines or dosing recommendations. Patients can be assured that paracetamol remains a safe medication when used appropriately.

Additional steps that can be taken to minimise paracetamol-related harm include:

• Encouraging patients to avoid stockpiling medication;
• Encouraging patients to store all medicines out of the reach of children;
• Educating patients to be aware of the active ingredients in the medications they use. This can avoid inadvertent overdosing from taking more than one paracetamol-containing product at the same time; and
• Educating patients on the correct dose and dosing interval for paracetamol.

“Health literacy means being able to access, understand, appraise and use information and services in ways that promote and maintain good health and well-being.” WHO 2024

The term “health literacy” has a long history. It was first used by Scott K. Simonds in 1974 in a monograph entitled “Health Education as Social Policy”.

Many permutations of the concept of health literacy (HL) have emerged since then, with an easy and elegant definition from Kendir and Breton (2020) which states that “Health literacy (HL) is increasingly hailed as a strategy to improve the control individuals have over their health.”

The application of this generic concept to dementia, in the form of dementia literacy (DL), has also undergone various revisions with no consensus on the agreed definition. (Lo 2020). However, a comprehensive definition has been suggested by Fernandez Cajavilca and Sadarangani 2024:

“Dementia literacy is defined as the ability to acquire dementia-related knowledge to inform decision-making, self-identify gaps in caregiving support, and secure access to necessary resources to enable long-term care, all while maintaining relationships with an interdisciplinary team of specialized providers.” (Fernandez Cajavilca and Sadarangani 2024).

As can be seen, this definition is strongly patient-centred. It, therefore, encourages active engagement by persons living with dementia in their own healthcare, disease prevention, health promotion and activities of daily living. (Sørensen et al., 2012).

Does DL improve the lives of people living with dementia?

In brief, the answer is yes. According to  Nguyen, Phan et al. 2022: “There is evidence for the positive impact of dementia literacy interventions on different groups of non-health-professionals.”

Importantly, knowledge of dementia has been shown to be significantly associated with the psychological wellbeing of caregivers.  As has been noted by Fernandez Cajavilca and Sadarangani 2024, DL for caregivers “can potentially buffer many of the adverse consequences of caregiving such as emotional distress and chronic illness.” (Fernandez Cajavilca and Sadarangani 2024).

Thie impact on caregivers must not be diminished in importance. In 2020, it was estimated that 57 million people were currently living with dementia and by 2050, it is predicted that this number will increase by nearly 300%, most rapidly in low- and middle-income countries.  Unfortunately, the impact on caregivers is substantial with 75% reporting that they had one or more physical or emotional effects due to the caring role.

Aside from the benefits to caregivers, continuously improving DL is also vital for all members of the clinical health care team.

Community pharmacist:

Because of their training and ready availability, community pharmacists are an ideal point of contact for cognitive impairment screening. The pursuit of ongoing education in dementia-related factors and issues would improve this screening and referral capacity. (Ramos, Moreno et al. 2021)

Doctors:

Turner, Iliffe et al. (2004) have suggested that “Educational support for general practitioners should concentrate on epidemiological knowledge, disclosure of the diagnosis and management of behaviour problems in dementia. The availability and profile of support services, particularly social care, need to be enhanced, if earlier diagnosis is to be pursued as a policy objective in primary care.”

Aged care staff:

Aged care staff are in the front line of those who care for people living with dementia as 52% of people living in Australian Residential Aged Care Facilities (RACFs) have dementia.

Pleasingly, the DL of RACF staff is significant, with approximately 77% (n = 137) aware of dementia-specific education, and 66% (n = 115) completing education in the previous 2 years. However, on a negative note “only 27% of staff had accessed dementia‐specific services, and only two thirds (66%) had accessed dementia‐specific education in the previous 2 years.” (Williams, Ockerby et al. 2021)

An excellent starting point for all who are involved in the care of people living with dementia is the “Understanding Dementia” Massive Open Online Course (MOOC), which has been developed by Wicking Dementia Research and Education Centre at the University of Tasmania. It is a free nine-week online course that builds upon the latest in international research on dementia.

The curriculum draws upon the expertise of neuroscientists, clinicians and dementia care professionals at the Wicking Centre.  I completed this course in September 2024 and strongly endorse it.

World Antimicrobial Resistance (AMR) Awareness Week is celebrated each year from the 18th to the 24th of November. This campaign aims to raise awareness and understanding of AMR, with the ultimate goal of improving antimicrobial use to limit the impact of AMR.

Antimicrobial resistance poses a significant threat to global health. It is estimated that 4.95 million deaths were associated with bacterial AMR in 2019 alone. At the United Nations General Assembly High-Level Meeting on AMR held in September this year, world leaders committed to decisive action. The goal set at this meeting was to reduce AMR-related deaths by 10% by 2030.

In regards to human health, one of the actions that has been suggested to reach this target is to ensure that at least 70% of antibiotics used globally belong to the World Health Organization (WHO) Access group of antibiotics.

The WHO has grouped antibiotics into the following three categories based on their clinical importance and potential for the selection of AMR:

1. Access antibiotics have a narrow spectrum of activity, are generally well tolerated and have a lower potential for AMR. These agents should be widely available and are often listed in guidelines for the empiric treatment of common infections;
2. Watch antibiotics typically have a higher risk of selection for AMR, and their use should be carefully monitored to avoid inappropriate use; and
3. Reserve antibiotics are considered last resort antibiotics that should be reserved for treating severe infections caused by multi-drug resistant pathogens.

This is known as the AWaRE (Access Watch Reserve) classification system and can indirectly indicate the appropriateness of antibiotic use. Examples of antibiotics belonging to each group are shown in Table 1.

Group	Example medications
Access	Amikacin Amoxicillin, amoxicillin + clavulanic acid, ampicillin, benzathine benzylpenicillin, benzylpenicillin, phenoxymethylpenicillin, procaine benzylpenicillin Cefalexin, cefazolin Chloramphenicol Clindamycin, Doxycycline Gentamicin Metronidazole Nitrofurantoin Sulfamethoxazole + trimethoprim Trimethoprim
Watch	Azithromycin Cefotaxime, ceftazidime, ceftriaxone, cefuroxime Ciprofloxacin Clarithromycin Meropenem Piperacillin + tazobactam Vancomycin
Reserve	Ceftazidime + avibactam Colistin Fosfomycin Linezolid Polymyxin B*

*Only available via special access scheme (SAS)

Table 1. Examples of antibiotics included in the AWaRE groupings

The WHO publishes the AWaRe Antibiotic Book, which provides guidance on antibiotic choice (including drug, formulation, dose, and duration) in hospital and primary healthcare settings. Importantly, the book also includes guidance on when not to use antibiotics.

Allergy labelling

When looking at the Access group of antibiotics, we can see that beta-lactams feature quite prominently. This is because the penicillins and cephalosporins in that group are among the most effective and safe antibiotics for many infections. However, alternatives to these medications may be needed in the case of allergy.

Penicillin allergy is commonly reported in Australia, with around 10% of the population stating that they are allergic to penicillin. However, studies demonstrate that less than 10% of people reporting a penicillin allergy have a true allergy upon skin testing. There are many possible reasons for this apparent discrepancy. Patients may confuse common adverse effects, such as diarrhoea or nausea, with an allergy. In other cases, a viral rash may be misinterpreted as an allergy if the patient happens to be taking a penicillin at the same time.

Incorrect labelling of penicillin allergy has been identified as a major public health concern. Potential outcomes associated with this include:

• Increased use of alternative antibiotics, which are often broader spectrum;
  • Broader spectrum alternatives are associated with an increased risk of AMR and iatrogenic infections, such as Clostridioides difficile-associated diarrhoea.
  • Alternative antibiotics are typically more expensive.
  • Alternative antibiotics may not be as well tolerated
• Treatment delays; and
• Longer hospital stays.

Accurate documentation of patient allergies is, therefore, crucial. A detailed clinical history should be taken whenever an antibiotic allergy is reported. Patients should be asked about the nature and severity of the reaction, when it occurred, how it was managed, and if other antibiotics have since been tolerated.

In some cases, de-labelling a reported penicillin allergy may be possible after appropriate assessment (i.e. allergy history reconciliation or allergy testing). Studies have found that penicillin allergy de-labelling is associated with reduced AMR, reduced patient morbidity and mortality, and lower treatment costs. Just as importantly, detailed patient assessment also allows for verification of true penicillin allergy.

Allergy testing may be considered for some patients. The Australasian Society of Clinical Immunology and Allergy (ASCIA) recommends that penicillin allergy testing be prioritised for the following patient groups:

• Patients who have frequent infections and require antibiotics several times per year;
• Patients who have infections for which penicillins are the most appropriate antibiotic;
• Patients who are allergic or intolerant to other antibiotics in addition to penicillins;
• Patients with risk factors for infections requiring frequent antibiotic use (e.g. immunodeficiency, significant immunosuppressive therapy, bronchiectasis); and
• Patients with asplenia or who are undergoing splenectomy.

Antimicrobial resistance continues to be a significant health concern. However, there are actions that can be taken to help minimise the impact. Accurate documentation of adverse reactions is just one simple way that healthcare professionals can play their part in reducing AMR, while also directly improving patient outcomes.

To learn more about AMR, head to the WHO campaign page.

In January 2024, the Therapeutic Goods Administration (TGA) approved the first respiratory syncytial virus vaccine – Arexvy®. ATAGI (Australian Technical Advisory Group on Immunisation) issued guidelines recommending the vaccine for all people ≥ 75 years of age. ATAGI has also recommended the vaccination for people 60-74 years of age with medical conditions (RSV infection increases risk of severe disease) and Aboriginal and Torres Strait Islander people over the age of 60 years.

Arexvy® is highly effective as it reduces the incidence of lower respiratory tract infections by 83% and severe RSV infections by 94%. Arexvy® is currently not available on the Pharmaceutical Benefits Scheme (PBS). However, there is an expectation that it will be added to the National Immunisation Program, in time.

RSV is a common respiratory disease that causes cold-like symptoms. In severe cases, infection can spread and cause pneumonia or bronchiolitis. It is very common in children. Virtually all children are infected before the age of two. However, in recent years there has been a greater awareness of RSV infection in adults, particularly those over the age of 60. Immunocompromised individuals regardless of age are also at a higher risk of getting RSV and having a more severe infection requiring hospitalisation.

RSV has been around for a long time, but it’s been under recognised and only became a notifiable disease in 2021. It is a very contagious virus. Infected individuals are likely to infect three other people. Natural immunity to RSV is very short lived and hence repeated infections are typical throughout life. The virus is spread through aerosol droplets formed from coughs or sneezes.

Most adults over 60 would probably have had RSV 6-10 times. But it may have been interpreted as a common cold or influenza as their symptoms may have been mild.
Triple combination rapid antigen tests (RATs) incorporating influenza A and B, RSV and COVID-19 are available at pharmacies. Polymerase chain reaction (PCR) tests for influenza A and B, RSV, COVID 19, adenovirus, and others are also available.

Like the common cold, there is no specific medication for RSV. Treatment is symptom based. In temperate and colder climates, RSV has a late autumn to winter season, similar to influenza. In subtropical areas, it can be earlier because of the warmer weather. In Northern Territory, it can be in the wet season. However, anytime is a good time to get vaccinated against RSV. A need for revaccination has not been established yet as per the product information.

RSV infections can exacerbate existing medical conditions. For older Australians with co-morbidities like asthma, diabetes, chronic obstructive pulmonary disease (COPD), heart failure, chronic kidney disease, and coronary artery disease, vaccination is particularly important as they are more likely to be hospitalised. Among patients with COPD, 80% experienced an exacerbation during an RSV associated hospitalisation.

About 25% of people aged over 60 who are hospitalised with RSV will require home care when discharged. And about 25% will be readmitted to hospital within 3 months. About 33% of people aged 75 years and older will die within one year of admission to hospital with RSV. Many people do not get back to their normal function level. It can really impact on people’s quality of life, their emotional, physical and cognitive functioning, and their sleep. It’s a bit similar to the long-term effects we’re seeing after COVID 19 infection.

Diarrhoea is a common adverse effect associated with antibiotic therapy. Almost all antibiotics can cause diarrhoea due to disruption of the normal microflora of the gut. However, antibiotics with the greatest risk are those that are broad-spectrum and those with activity against anaerobic bacteria.

Antibiotics with a particularly high risk of causing diarrhoea include:

• Lincosamides (i.e. clindamycin, lincomycin)
• Aminopenicillins (i.e. amoxicillin, ampicillin)
• Aminopenicillin + clavulanic acid combinations
• Cephalosporins
• Quinolones

Other factors that may increase the risk of antibiotic-associated diarrhoea include older age (i.e. over 65 years), immunosuppression, prolonged hospitalisation, and the concomitant use of a proton pump inhibitor.

Antibiotic-associated diarrhoea is often mild, with symptoms generally resolving soon after the course is finished. In many cases, no specific treatment is required. However, severe presentations can occur that require medical intervention.

Severe presentations

Clostridioides difficile (previously known as Clostridium difficile) is a major pathogen involved in antibiotic-associated diarrhoea. This anaerobic spore-forming bacteria is thought to be responsible for up to 25% of all antibiotic-associated diarrhoea and almost all cases of pseudomembranous colitis.

Pseudomembranous colitis is a severe inflammation of the intestinal lining and a serious complication of antibiotic use. This condition results from disruption of the normal microbiome, which allows for the overgrowth of C. difficile. This bacterium can produce toxins, most notably toxin A (TcdA) and toxin B (TcdB).

While both toxin A and toxin B are cytotoxic, toxin B is between 100 and 1,000 times as potent as toxin A. Up to 12% of strains infecting humans also produce a third toxin, known as binary toxin or C. difficile transferase (CDT). The presence of CDT is usually associated with higher virulence, which may be related to enhanced adherence of C. difficile to the intestinal epithelium.

The clinical presentation of pseudomembranous colitis typically includes profuse, watery or mucoid diarrhoea, fever, and abdominal cramps. Blood may also be present in the stool. On endoscopic examination, pseudomembranes can be seen. Potential complications include toxic megacolon, colonic perforation, and shock.

C. difficile infection can occur at any time during antibiotic use and for some months after completing the course.

Treatment of C. difficile infection

Any antibiotics implicated in causing the antibiotic-associated diarrhoea should be ceased wherever possible. The timely discontinuation of causative antibiotic therapy is associated with a reduced risk of recurrence and may also improve symptoms.

The Therapeutic Guidelines make the following recommendations for the treatment of adults with a first episode of C. difficile disease:

Mild to moderate disease

• Metronidazole 400mg orally or enterally, 8-hourly for 10 days OR
• Vancomycin 125mg orally or enterally, 6-hourly for 10 days.

Severe disease

• Vancomycin 125mg orally or enterally, 6-hourly for 10 days.
  • In complicated cases, add metronidazole 500mg IV, 8-hourly for 10 days
  • In the presence of ileus, consider adding vancomycin 500mg in 10mL sodium chloride 0.9%. Administer as a retention enema every 6 hours.

Expert advice is required for all patients with severe disease. A patient would be considered to have severe disease if they have leucocytosis, severe abdominal pain, elevated serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction.

Vancomycin must be given orally or enterally for the treatment of C. difficile infection. Intravenous vancomycin is ineffective in these cases as it has poor penetration into the lumen of the colon. It is also worth noting that vancomycin has poor oral absorption. Therefore, the oral route is not appropriate for the treatment of any systemic infection.

Vancomycin is available as a capsule for oral administration. The capsules may be given without regard to food but should be swallowed whole. As the capsules contain a semi-solid material, they are not appropriate for administration via an enteral feeding tube. Alternatively, the injectable form can be given orally or enterally. For example, a 500mg vial of vancomycin powder for injection can be dissolved in 10mL of water for injection to give a 50mg/mL solution. Vancomycin does have a very unpleasant taste; flavouring syrups may be added prior to administration to improve palatability.

Other therapies

• Fidaxomicin

Fidaxomicin is sometimes used for the treatment of recurrent or refractory disease. The Therapeutic Guidelines do not currently recommend fidaxomicin for the treatment of severe disease due to a lack of data in this setting. However, some international guidelines do recommend fidaxomicin as a first-line option for initial infections. For example, the 2021 update to the Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).

Fidaxomicin is a novel antibiotic known as a macrocycle. It has a narrow spectrum of activity, being bactericidal against C. difficile and minimally active against other flora of the gastrointestinal tract. Due to its poor oral absorption, its activity is predominantly confined to the intestinal lumen.

Two randomised controlled trials comparing fidaxomicin and oral vancomycin found similar rates of diarrhoea resolution at ten days (88% vs 86%, respectively). However, sustained clinical response was superior for fidaxomicin (71% vs 57%).

The usual dose is 200mg orally twice daily for 10 days. Tablets can be taken without regard to food and may be crushed if required. Patients who are allergic to macrolide antibiotics (e.g. azithromycin, clarithromycin) may have a higher risk of fidaxomicin hypersensitivity.

• Rehydration

When treating C. difficile infection, the importance of rehydration in addition to antibiotic therapy should not be underestimated. Oral rehydration may be sufficient for patients with minimal or no dehydration. However, parenteral rehydration is recommended if ileus or features of severe dehydration are present.

A variety of oral rehydration products are available. While some are ready to use, many require reconstitution. Incorrect preparation of these products can worsen dehydration. Therefore, it is important that they are always prepared exactly as directed.

Sodium chloride 0.9% or lactated Ringer solution are often used for intravenous rehydration. If the intravenous route is not appropriate, sodium chloride 0.9% may be administered via the subcutaneous route.

• Antimotility agents

Antimotility agents have traditionally been avoided in patients with active C. difficile infection. This is due to the belief that these agents may increase the risk of complications by prolonging the intestinal contact time of bacterial toxins.

Some small studies have challenged this idea, suggesting that antimotility agents may be safe for C. difficile infection when administered in conjunction with appropriate antimicrobial therapy. However, larger randomised studies are required to confirm what place antimotility agents may have. The product information for loperamide and diphenoxylate cites pseudomembranous colitis as a contraindication to their use.

Antimicrobial optimisation

Antimicrobial resistance has been highlighted as one of the causes of epidemic outbreaks of C. difficile. Polymerase chain reaction (PCR) ribotyping is a molecular typing technique often used with C. difficile to facilitate surveillance and outbreak investigations. C. difficile ribotype 027 has been found to have reduced susceptibility to many antibiotics, including metronidazole, rifampicin, moxifloxacin, clindamycin, and imipenem. This strain is also considered to be hypervirulent, with higher morbidity and mortality rates compared to other strains. Outbreaks of ribotype 027 have occurred in Australia and many countries worldwide.

Antimicrobial stewardship (AMS) is a crucial strategy to limit the emergence of antimicrobial resistance. The goal of AMS programs is to promote and support the optimal use of antimicrobials. Activities that fall under the AMS umbrella include audits, formulary restrictions, therapeutic drug monitoring, and education. One meta-analysis demonstrated that AMS activities could reduce the incidence of C. difficile infections by 32% in hospital patients.

The Australian Commission on Safety and Quality in Healthcare (the Commission) has been monitoring the national burden of C. difficile infection in Australian public hospitals since 2016. The most recent data published by ACSQHC shows that separations with a diagnosis of C. difficile infection increased by 29% from 2020 to 2021.

However, the rate of healthcare-associated hospital-onset infection has been declining over recent years. This suggests that hospital-based strategies to prevent C. difficile infection are effective. The implementation of effective AMS programs is thought to be one of the most important strategies in reducing the risk of C. difficile. The Commission notes that reducing the inappropriate prescribing of antimicrobials has significantly impacted the incidence of hospital-associated infection. Other effective measures highlighted by the Commission are early detection and appropriate testing, environmental cleaning programs, the use of single rooms and en-suites, and transmission-based precautions in addition to standard precautions for symptomatic patients.

Optimising infection control measures and minimising unnecessary antibiotic use should be prioritised within the hospital environment to reduce the burden of C. difficile disease.