Knowledge Type: Clinical Articles

The management of coronavirus disease 2019 (COVID-19) continues to evolve as new therapies become available and new virus variants emerge. A recently published meta-analysis, including data from over 166,000 patients, examined the efficacy of antivirals in mild to moderate COVID-19. The analysis provides insights into the effectiveness of therapies in reducing hospital admissions.

This study ranked the following from most to least effective in reducing hospital admission:

• Nirmatrelvir + ritonavir (OR_SC 0.15 (95% CI 0.07 to 0.32)) – moderate certainty
• Remdesivir (OR_SC 0.25 (95% CI 0.07 to 0.77)) – moderate certainty
• Systemic corticosteroids (OR_SC 0.43 (95% CI 0.20 to 0.90)) – low certainty
• Molnupiravir (OR_SC 0.66 (95% CI 0.44 to 0.92)) – low certainty

Abbreviations: OR_SC, odds ratio compared with standard care; CI, credible interval

The study authors concluded that nirmatrelvir + ritonavir and remdesivir probably reduce admission to hospital, while systemic corticosteroids and molnupiravir may reduce admission to hospital. Evidence to support a mortality benefit for these agents compared to standard care is inconsistent.

Choice of therapy

The National COVID-19 Clinical Evidence Taskforce provides information on the management of COVID-19 in the Australian context. While this resource is no longer being updated, it will remain online until it no longer reflects the evidence or recommended practice.

Antivirals that target the virus that causes COVID-19 are intended to reduce the risk of severe illness and are prescribed to patients with risk factors for developing serious complications.

Risk factors for disease progression include:

• Older age (> 65 years, or > 50 years for Aboriginal and Torres Strait Islander people);
• Diabetes requiring medication;
• Obesity (BMI >30 kg/m²);
• Renal failure;
• Cardiovascular disease, including hypertension;
• Respiratory compromise, including COPD, asthma requiring steroids, or bronchiectasis; and
• Immunocompromising conditions (i.e. primary or acquired immunodeficiency or immunosuppressive therapy).

Where antivirals are considered necessary, treatment should be initiated as soon as possible after symptom onset.

Nirmatrelvir + ritonavir (Paxlovid®)

Paxlovid® is the preferred oral treatment for COVID-19, unless contraindications are present. This product contains nirmatrelvir tablets co-packaged with ritonavir tablets.

Nirmatrelvir inhibits the main protease of the SARS‑CoV‑2 virus, preventing viral replication. Ritonavir is included to increase nirmatrelvir levels by inhibiting its metabolism.

The approved indication is:

• COVID-19 in adults ≥18 years who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death.

Administration

The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet). These tablets should be taken together every 12 hours for five days. Failure to correctly take nirmatrelvir with ritonavir will result in subtherapeutic plasma levels of nirmatrelvir.

No dose adjustment is required for mild renal impairment (eGFR 60 to < 90 mL/min/1.73m²). For patients with moderate impairment (eGFR 30 to < 60 mL/min/1.73m²), the nirmatrelvir dose should be reduced to 150 mg (taken with ritonavir 100 mg) every 12 hours for 5 days. Paxlovid® is currently contraindicated in severe renal impairment as data for appropriate dosing is not yet available. Its use is also contraindicated in severe hepatic impairment, although no dose adjustment is required in mild to moderate hepatic impairment.

It is recommended that the tablets be swallowed whole without regards to food. However, studies suggest that administering nirmatrelvir + ritonavir as an oral suspension does not alter its pharmacokinetic parameters. The guidelines advise that nirmatrelvir + ritonavir tablets can be crushed or split and mixed with food or liquid, where necessary. Alternatively, they may be administered via a nasogastric tube, as indicated.

Adverse effects

Common adverse effects include taste disturbance, headache, diarrhoea, and nausea.

Nirmatrelvir and ritonavir are both metabolised by CYP3A4, and this contributes to many clinically significant drug interactions. Coadministration with medicines that induce this enzyme may reduce the concentration and efficacy of the antiviral. Use with strong CYP3A4 inducers is contraindicated as this may be associated with loss of virologic response and potential resistance. Paxlovid® may also increase the levels of medications that are metabolised by CYP3A. Use is contraindicated with medicines that are highly dependent on CYP3A for clearance and for which elevated levels may result in serious or life-threatening events.

The interactions of ritonavir can be difficult to predict, as it inhibits and induces CYP3A4 and other CYP enzymes. It also inhibits P‑glycoprotein and is a strong inducer of UGTs (which mediate glucuronidation). A full medication history should be taken before initiating therapy, ensuring that complementary and over-the-counter products are included.

Many medications are contraindicated with Paxlovid®, including:

• Drugs that may result in serious or life-threatening reactions, e.g. amiodarone, flecainide, colchicine, simvastatin, diazepam, and sildenafil.
• Drugs that may result in loss of virologic response and potential resistance, e.g. apalutamide, carbamazepine, phenytoin, rifampicin, St John’s wort.

The product information should be consulted for comprehensive advice on drug interactions.

Molnupiravir (Lagevrio®)

Molnupiravir has provisional approval for the treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death.

Molnupiravir inhibits viral replication following incorporation into viral RNA. It is less effective than nirmatrelvir + ritonavir and is not routinely recommended for the treatment of COVID-19. Molnupiravir is only recommended if an oral agent is required and the nirmatrelvir + ritonavir combination is contraindicated.

Administration

The recommended dose is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days. Doses may be taken with or without food.

Adverse effects

Diarrhoea, nausea, and dizziness were the most commonly reported adverse events in clinical trials. These were of mild to moderate severity. No serious drug-related adverse events were reported.

Molnupiravir is not a substrate of any major drug metabolising enzymes or transporters and is considered unlikely to cause drug interactions.

Remdesivir (Veklury®)

Remdesivir is an intravenously administered agent that may also be considered for patients with mild to moderate disease, as well as more severe cases where ventilation is not required.

The approved indications are for the treatment of COVID-19 in:

• Adults and paediatric patients (at least 4 weeks of age and weighing at least 3 kg) who have pneumonia due to SARS-CoV-2, and who require supplemental oxygen; and
• Adults and paediatric patients (weighing at least 40 kg) who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.

Remdesivir is metabolised to remdesivir triphosphate (an adenosine analogue). This pharmacologically active form is then incorporated into viral RNA, preventing its replication. Remdesivir is used in both outpatient and hospital settings and treatment should begin within seven days of symptom onset.

Administration:

Remdesivir is administered daily via IV infusion. For adults and patients >40kg, the usual dose is 200mg on day 1, then 100mg on subsequent days. The usual treatment duration is three days for patients who do not require supplemental oxygen, and 5-10 days for patients with pneumonia who do need supplemental oxygen.

Remdesivir is supplied as a powder for injection. The powder is reconstituted with water for injection and then further diluted with 0.9% sodium chloride. The final volume is typically 250mL, although a volume of 100mL may be used for patients with severe fluid restrictions. The infusion should run over 30-120 minutes.

Dose adjustment is not required for patients with renal impairment (including those on dialysis) or hepatic impairment.

Adverse effects

Common adverse effects include nausea, vomiting, headache, rash, increased aminotransferases, and prolonged prothrombin time (PT). While prolonged PT has been observed in clinical trials, no difference has been reported in the incidence of bleeding events compared to placebo.

Hypersensitivity reactions (including infusion-related and anaphylactic reactions) have been associated with remdesivir. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnoea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates (up to 120 minutes) may reduce the risk of these events. Remdesevir must only be administered in settings where there is immediate access to medications to treat a severe infusion or hypersensitivity reaction and access to an emergency medical response.

Table 1. Comparison of COVID-19 antiviral agents.

Drug	Route	Timing of initiation	Comments
Remdesivir	IV	≤7 days	30-120 minute infusion
Nirmatrelvir + ritonavir	Oral	≤5 days	1st line oral agent Many drug interactions + contraindications
Molnupiravir	Oral	≤5 days	Less effective

Summary

If an antiviral is considered appropriate for COVID-19, therapy should be promptly initiated following diagnosis. Where an oral agent is required, nirmatrelvir + ritonavir is preferred as it is more effective than molnupiravir. Remdesivir remains a valuable option for reducing the risk of hospitalisation. However, as it requires IV administration, its use in the community is limited.

INTRODUCTION:

Migraine headaches impose a substantial level of pain and disruption to a person’s quality of life. (Malmberg-Ceder, Soinila et al. 2022) Common triggers for migraine included physical activity, poor sleep hygiene, physical and mental fatigue, and emotional anxiety and stress. (Aderinto, Olatunji et al. 2024)

The age-adjusted prevalence of migraine is observed to be 21% in women, which is twice the rate of 10.7% seen in men (Burch, Rizzoli et al. 2021) and the economic burden is substantial. Starting from 2020 as a baseline, over the next 10 years migraine is predicted to have a in health-care costs of AU$1.67 billion, or AU$1313 per person. There could also be AU$68.13 billion loss to the GDP.(Tu, Liew et al. 2020)

Historically, acute migraine treatment has involved triptans as the leading clinical option. Preventive treatments include propranolol, metoprolol, amitriptyline and anti-epileptics such as sodium valproate and topiramate (Zobdeh, Ben Kraiem et al. 2021) as well as botulinum toxin.  (Kępczyńska and Domitrz 2022).

More recently a new class of drugs, the calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs), have become available as an effective preventative treatment for chronic migraine. (Ray, Dalic et al. 2024) In Australia eptinezumab, fremanezumab, galcanezumab and erenumab are available. The first three act directly against CGRP whilst erenumab acts against the CGRP receptor. (de Vries, Villalón et al. 2020). They are collectively referred to as CGRP antagonists. (AMH, 2025).

Briefly, the pathophysiology of migraine involves the triggering of the trigeminovascular system. Divisions of the trigeminal nerve innervate the face and as well as the meninges, which also includes intracranial blood vessels and the dura. These nerve branches release calcitonin-gene related peptide (CGRP), which acts as a potent vasodilator of cerebral and dural vessels, leading to neurogenic inflammation, and CGRP facilitates pain transmission from trigeminal vessels to the CNS.(Pescador Ruschel and De Jesus 2025)

Proof of concept for the role of CGRP has been demonstrated by the venous infusions of CGRP which results in migraine-like headaches. (de Vries, Villalón et al. 2020). Calcitonin gene-related peptide is reported to be most potent known vasodilator of both cerebral and peripheral blood vessels. (ACOG. 2022)

It is important to note that CGRP monoclonal antibodies (mAbs), due to their molecular size, exhibit only 0.1% presence in the brain as they are unable to cross the blood-brain barrier. Therefore, their mechanism of action primarily involves the trigeminal network located outside the brain. (Edvinsson and Warfvinge 2019). Two studies using radiolabelled mAbs have confirmed that these drugs act mainly peripherally, due to their large size.(Labastida-Ramírez, Caronna et al. 2023)

USE IN LACTATION:

For lactating mother’s, the current approved product information for erenumab (Aimovig) in eMIMS (2025) states:

“It is not known whether Aimovig is present in human milk. There are no data on the effects of Aimovig on the breastfed child or the effects of Aimovig on milk production. Because drugs are excreted in human milk and because of the potential for adverse effects in nursing infants from Aimovig, a decision should be made whether to discontinue nursing or discontinue Aimovig, taking into account the potential benefit of Aimovig to the mother and the potential benefit of breast feeding to the infant.”

However, a more forensic analysis of the pharmacokinetics of CGRP drugs, understood as the timeline of the drug’s absorption, bioavailability, distribution, metabolism and excretion, is important in assessing the suitability of administering these drugs to pregnant and lactating mothers. (Ernstmeyer and Christman 2023)

THE RESEARCH:

Erenumab (Aimovig), a biosynthetic immunoglobulin G monoclonal antibody (mAb), is a large protein molecule with a weight of 150,000 Da. (Bussiere, Davies et al. 2019, Kothari, Wanjari et al. 2024).

Because of the size of erenumab, presentation via maternal milk to a newborn infant faces a number of physical barriers.

First, erenumab (and other mAbs) must cross the mammary epithelium from maternal blood into milk. A review of the research by LaHue, Anderson et al. (2020) of 155 women using the mAbs certolizumab, rituximab or natalizumab across 30 studies reported that “a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.”

These researchers applied the relative infant dose (RID), a metric comparing the infant and maternal drug dose, where <10% is generally considered safe, and found that certolizumab and rituximab were present in maternal milk at <1%.

A second “barrier’ is the digestion of a mAb in the infants GIT. A study of the IgG1 mAb palivizumab presence in neonatal intestinal fluid found a variably level of destruction of 50%. (Sah, Lueangsakulthai et al. 2020) As a guide to understanding the poor GI abruption, “native” IgG is only 0.01% absorbed intact from the GIT. (Anderson 2021)

Other “barriers” to infant exposure include the extent to which the drug is bound by maternal plasma proteins, the degree of drug ionisation, lipid solubility and most pertinently, the molecular weight of the drug, which for CGRP drugs is 150,000 Da. (Hotham and Hotham 2015).

Once a CRGP drug enters the infant GIT there are added impediments to the drug entering its bloodstream. These include the infant gut immune barrier (GIB) (Daneman and Rescigno 2009), as well as infant acidic denaturing. (Tashima 2021). 

The implications of this low rate of infant GI tract absorption of mAbs is readily demonstrated by another mAb, natalizumab, for which there is considerable pharmacokinetic data.

Natalizumab is given at a 300mg dose and, according to the official information, will achieve an average patient plasma concentration of 110mg/L. Applying the aforementioned 0.01% GIT absorption and an estimated volume of distribution of 0.25L (Anderson 2021), the infant would be exposed to a concentration of approximately 0.04% of the mother’s serum level.

This is a trivial level when measured against the WHO Working Group of experts of drug use during breastfeeding, who consider an infant: maternal ratio of less than 10% to be safe.

Indeed, many medicines enter breast milk, but usually the amount received by the infant is less than 10% of the maternal dose.(Amir, Pirotta et al. 2011)

In summary, Rayhill (2022) has noted: “The large size of monoclonal antibodies could theoretically reduce the degree that these medications are expressed in breast milk, although this has not been adequately studied.”

PREGNANCY IMPLICATIONS:

The positive implications associated with a putative low foetal concentration are supported by a 2021 analysis of WHO pharmacovigilance date for erenumab, galcanezumab and fremanezumab when given during pregnancy and lactation. (Noseda, Bedussi et al. 2021) The researchers reported that there were “no specific maternal toxicities, patterns of major birth defects or increased reporting of spontaneous abortion…”

There are various case reports of erenumab given during pregnancy. For example, Vig, Garza et al. (2022) referenced a case of a woman who used erenumab for migraine through her pregnancy with no harm to her child.

In another report of three pregnancies with gestational exposure to erenumab, two women ceased erenumab during the first trimester with no adverse sequalae for their babies.

One woman ceased erenumab 1 month before conception and experienced a first trimester spontaneous abortion due to gestational trophoblastic neoplasia, however a subsequent pregnancy was uneventful. No plausible drug-related explanation could be offered by the authors for the spontaneous abortion. (Bonifácio, de Carvalho et al. 2022)

An updated safety analysis on erenumab, galcanezumab, fremanezumab and eptinezumab use in pregnancy by  Noseda, Bedussi et al. (2023) “ showed no signals of foeto-maternal toxicity according to VigiBase® safety reports.”

A case series and literature review by Elosua-Bayes, Alpuente et al. (2024) focused on the periconceptional period of CGRP therapies that were ceased prior to conception. They reported that “database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates.”

They concluded that “CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.”

A reasonable explanation for foetal safety is that mAbs likely do not cross the blood brain barrier secondary to their molecule size. (de Vries, Villalón et al. 2020).

In contrast to these positive reports, Rayhill (2022) advise that CGRP mAbs should be ceased 5-6 months pre-conception due to their long half-life and a lack of safety data.

EFFICACY:

All four CGRP therapies have been reported to possess long-term safety, making them “effective and well-tolerated for the prevention of migraines.” (Muddam, Obajeun et al. 2023)

Summarising the current research, Oliveira, Gil-Gouveia et al. (2024) reported that “Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6–61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29–88% of the patients stopped medication overuse.”

CONCLUSION:

Based upon the preceding literature review, the use of erenumab and other CGRP medications in lactation is an option that can be positively considered by a clinician when balancing the maternal benefits against potential foetal harms. However caution is necessary because longer-term studies are still required, (Burch, Rizzoli et al. 2021) notably in its cardiovascular impact, since CGRP has protective properties in cardiovascular disease. (González-Hernández, Marichal-Cancino et al. 2016).

Their use in pregnancy currently has contradicting research findings.   (Elosua-Bayes, Alpuente et al. 2024) (Moisset, Demarquay et al. 2024)

The Heart Foundation and the Cardiac Society of Australia and New Zealand have released the new Australian clinical guideline for diagnosing and managing acute coronary syndromes 2025. This new guideline replaces National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016.

Acute coronary syndrome (ACS) includes acute myocardial infarction (AMI) and unstable angina. Around 160 Australians experience an acute coronary event each day and these events remain a leading cause of morbidity and mortality.

The new guideline contains updated evidence-based recommendations and practical advice that is intended to improve patient outcomes overall and reduce disparities in care for people experiencing ACS across Australia.

Changes relating to pharmacotherapy include new recommendations and guidance on secondary prevention measures, as follows:

• More detailed advice on post-discharge care (e.g. medicines and adherence strategies, vaccinations, mental health screening);
• Treatment algorithms to enable more tailored prescribing of antiplatelet and anticoagulation therapies;
• A new recommended treatment target for low density lipoprotein cholesterol (LDL-C) of <1.4 mmol/L and a reduction of at least 50% from baseline; and
• New recommendations on select medicines, including beta blockers and the PCSK9 inhibitors, alirocumab and evolocumab.

Vaccinations

Viral respiratory infections are a well-documented trigger for AMI. Various mechanisms have been proposed for this increased risk. The systemic inflammatory response to a viral infection may destabilise atherosclerotic plaques. These plaques contain inflammatory cells that can be activated by several cytokines present in a pro-inflammatory state. This can lead to activation of the coagulation cascade, thereby increasing the risk of AMI. Hypoxaemia associated with severe respiratory infections can also increase the risk of AMI. The reduced oxygen supply, coupled with the increased metabolic needs during systemic inflammation, can create an imbalance in oxygen supply and demand.

One study conducted in patients with angiographically confirmed AMI found a 17-fold increased risk of AMI within seven days of a respiratory infection. Other studies looking at individual viruses found an elevated risk for influenza, respiratory syncytial virus, and COVID-19.

The relationship between viral infections and cardiovascular events suggests that vaccination could play a role in preventing AMI in patients with cardiovascular disease. Evidence for the benefits of vaccination in this setting is particularly strong for influenza. Vaccination against influenza has also been shown to reduce the risk of further cardiac complications following ACS. The evidence demonstrates that influenza vaccination is safe and effective when administered within 72 hours of an invasive coronary procedure or hospitalisation for AMI.

The benefits of vaccination in these patients likely go beyond prevention of cardiovascular events. People with cardiovascular disease are at higher risk of severe viral infection, making preventative measures particularly important.

The guidelines recommend:

• Annual influenza vaccination
• Pneumococcal vaccination per the immunisation schedule
• RSV vaccination for patients with coronary artery disease (CAD) who are 60 years of age or older.
• Consideration of additional doses of COVID-19 vaccine for all patients with chronic cardiac conditions.

Antiplatelet therapy

Some of the recommendations for antiplatelet therapy have been updated. The recommended duration for dual antiplatelet therapy (DAPT) in patients discharged following an ACS is now:

• High ischaemic and/or low bleeding risk
  • DAPT for 6-12 months.
  • P2Y₁₂ inhibitor preferred over aspirin for continuation of long-term therapy.
  • Long-term (>12 months) DAPT may be considered for patients who remain at high ischaemic and low bleeding risk.
• Low ischaemic risk and/or high bleeding risk
  • DAPT may be ceased at 1-3 months, with single antiplatelet therapy continued.
• Indication for long-term oral anticoagulant therapy (e.g. atrial fibrillation)
  • Continue anticoagulant and DAPT for 1-4 weeks, then cease aspirin.
  • Cease antiplatelet therapy at 6-12 months and continue anticoagulant alone.

Available P2Y₁₂ receptor inhibitors are:

• Clopidogrel;
• Prasugrel; and
• Ticagrelor.

The choice of P2Y₁₂ receptor inhibitor will depend on different patient factors. Ticagrelor and prasugrel are considered more potent than clopidogrel and are also associated with less interpatient variability. Clopidogrel is preferred for older adults with higher bleeding risk. Some patients may prefer the convenience of once daily dosing with clopidogrel and prasugrel, compared to ticagrelor which is taken twice a day.

Gastroprotection

A proton pump inhibitor (PPI) is recommended for patients receiving DAPT who have a high risk of gastrointestinal bleeding and for patients receiving triple antithrombotic therapy.

Available PPIs are:

• Esomeprazole;
• Lansoprazole;
• Omeprazole;
• Pantoprazole; and
• Rabeprazole.

All PPIs have similar safety and efficacy. However, there are some differences in their potential to cause drug interactions. For example, esomeprazole and omeprazole inhibit CYP2C19 and may increase the plasma levels of medications that are substrates of this enzyme (e.g. warfarin, citalopram, diazepam).

Lipid-modifying therapy

A reduction in LDL-C of 1.0 mmol/L can reduce the risk of AMI, stroke, coronary revascularisation and vascular death. Statins are the first-line lipid-modifying agents. They have established efficacy and a low rate of serious adverse effects.

The guidelines recommend the initiation of statin therapy prior to hospital discharge following ACS. If the patient was already on lipid-lowering therapy, this should be reviewed with consideration of intensifying therapy. Statin therapy should be continued indefinitely at the highest tolerated dose, unless contraindicated or the patient is not tolerant.

Available statins are:

• Atorvastatin;
• Fluvastatin;
• Pravastatin;
• Rosuvastatin; and
• Simvastatin.

All statins are associated with a reduced risk of cardiovascular events. However, it is the extent of LDL-C reduction that is important, and this is determined by the potency of the statin and the dose used. High-potency statins, such as atorvastatin and rosuvastatin, are preferred following an ACS.

One other consideration when selecting a statin is the potential for drug interactions. Fluvastatin, pravastatin and rosuvastatin are associated with fewer interactions compared to atorvastatin and simvastatin.

Additional non-statin therapies are often required to achieve target lipid levels. Medications that may be added to statin therapy include:

• Ezetimibe;
• PCSK9 inhibitors. This class includes alirocumab, evolocumab, and inclisiran. These medications are administered by subcutaneous injection every 2-4 weeks (alirocumab and evolocumab) or up to six-monthly (inclisiran); or
• Icosapent ethyl (for elevated triglyceride levels).

Beta blocker therapy

The guidelines recommend the use of a beta blocker for patients with ACS and left ventricular (LV) impairment. In this cohort, they are associated with a reduced risk of recurrent AMI. Their efficacy in patients with preserved ejection fraction is less clear.

For patients with confirmed LV impairment, the guidelines recommend use of a beta blocker with proven benefit in heart failure with reduced ejection fraction. This includes bisoprolol, carvedilol, metoprolol, and nebivolol.

Renin-angiotensin antagonist therapies

Angiotensin converting enzyme (ACE) inhibitors are associated with a reduced risk of early mortality and further cardiovascular events following AMI. Angiotensin receptor blockers (also known as sartans) exhibit similar effects to ACE inhibitors. However, angiotensin receptor–neprilysin inhibitors (i.e. sacubitril + valsartan) have not demonstrated any benefit in this population.

Adjunct medications

The new version of the guidelines also contains recommendations regarding colchicine and semaglutide. These medications were not included in the previous version of the guidelines.

Colchicine

Colchicine may reduce the risk of recurrent ischaemic events in ACS by reducing the persistent inflammation that occurs in these patients. Studies have evaluated doses ranging from 0.5 mg to 1.0 mg per day. A recent meta-analysis suggests that doses at the lower end of this range may be effective in reducing recurrent ischaemic events. Higher doses are associated with an increased risk of gastrointestinal adverse events and may not offer any additional benefits. However, colchicine was not associated with a significant reduction in all-cause mortality or cardiovascular death. Further research is required to clarify the role of colchicine post-ACS.

The most common side effects are gastrointestinal, e.g. diarrhoea, nausea, vomiting, and abdominal pain. Colchicine is metabolised by CYP3A4 and is a substrate of P‑glycoprotein. Therefore, combination with CYP3A4 inhibitors (e.g. amiodarone, ciclosporin, ticagrelor, grapefruit juice) or P‑ glycoprotein inhibitors (e.g. carvedilol, clarithromycin, verapamil) may increase colchicine concentration. This can lead to increased adverse effects and is particularly important to consider in patients with renal impairment.

Semaglutide

For people with ACS who are overweight or obese, a glucagon-like peptide-1 (GLP-1) receptor agonist may improve outcomes. The SELECT trial demonstrated that the cardiovascular benefits associated with semaglutide in people with diabetes were also seen in patients without diabetes.

The SELECT trial enrolled people without diabetes who were overweight or obese and had pre-existing cardiovascular disease (defined as previous AMI or stroke, or symptomatic peripheral arterial disease). Participants were randomly assigned to receive weekly semaglutide or placebo. Semaglutide was found to be superior to placebo in reducing the incidence of non-fatal AMI and stroke as well as death from cardiovascular causes.

Semaglutide is not currently subsidised on the Pharmaceutical Benefits Scheme (PBS) for people without diabetes.

Further information

The Heart Foundation provides a range of useful resources for healthcare professionals and free access to the MyHeart MyLife support program for patients.

 

The Australian Institute of Health and Welfare (AIHW) recently released the report, Injury among women 2022-23. This report shows that unintentional falls are the leading cause of injury hospitalisation and death for women.

In the year 2022-23, falls injuries in women were responsible for:

• 122,826 hospitalisations;
• 57% of injury hospitalisations; and
• 3,437 deaths.

While males are more likely to be injured and hospitalised across most causes, falls are one of the few exceptions. The rate of falls in males is reported to be 730 per 100,000, while the rate in females is around 770 per 100,000. The AIHW reports that the death rates for falls is currently the highest of the last decade.

The increasing incidence of falls may be related to population ageing. In Australia, women represent an increasing proportion of older adults. Factors that increase the risk of falls in older adults include musculoskeletal decline, osteoporosis, and cognitive decline. Dementia increases the risk of falls almost three-fold due to effects on balance and gait control. Research also suggests that medications are a significant contributing factor to falls.

Effect of medications on falls risk

The impact that medications play in falls is difficult to quantify. One study looking at elderly patients admitted to hospital with hip fractures found that medications were a likely contributing factor in 41% of cases.

Polypharmacy is an important consideration, with studies finding a significant increase in falls risk for patients taking more than four medications. As the population ages and chronic disease management becomes more complex, the prevalence of polypharmacy has risen in Australia.

Some medications have been identified as being of particularly high risk of causing falls. These are sometimes referred to as fall-risk increasing drugs (FRIDs), and they appear to be more strongly related to falls than polypharmacy alone. Medications classified as FRIDs include many medicines that act on the central nervous system, i.e. sedatives and hypnotics, neuroleptics and antipsychotics, antidepressants, and opioids.

There is a range of ways in which a medication may increase the risk of falls, including:

• Sedation;
• Cognitive impairment;
• Orthostatic hypotension;
• Muscle weakness; and
• Impaired vision or balance.

Some medications may contribute to falls via multiple mechanisms. For example, anticholinergics can cause sedation, cognitive impairment, and visual disturbances. Drug interactions may also increase a person’s falls risk by amplifying adverse effects. This could be due to additive effects (e.g. increased sedation when a benzodiazepine is combined with an opioid) or due to changes in serum levels as a result of altered metabolism.

Anticholinergic medications are well known for their additive effects. There are many tools available that attempt to quantify the overall anticholinergic effect of a medication regime. The anticholinergic cognitive burden (ACB) scale categorises drugs into three levels:

• Level 1 – drugs with low anticholinergic effect that may still contribute to overall burden (e.g. atenolol, digoxin)
• Level 2 – Drugs with moderate anticholinergic effect that may produce noticeable cognitive effects (e.g. carbamazepine, pethidine)
• Level 3 – Drugs with high anticholinergic activity and a greater risk of cognitive impairment (e.g. clozapine, paroxetine)

The ACB scale can be used to score a patient’s overall risk of anticholinergic adverse effects. A score of greater than three is considered significant, with the risk further increasing as the score increases.

One large retrospective study of older adults with mild cognitive impairment or dementia sought to determine whether drugs with different anticholinergic ratings contribute proportionately to the anticholinergic burden. The study found differing levels of risk for patients with the same ACB score. The evidence suggested that patients taking level 2 and level 3 drugs had a higher risk of falls compared to patients with the same ACB score who were only taking level 1 drugs.

Medicines with strong anticholinergic properties are considered potentially inappropriate for older individuals as the risks typically outweigh the benefits. In addition to falls, these medicines are associated with other serious adverse events, including cognitive impairment and delirium.

Some examples of highly anticholinergic medicines and potential alternatives are shown in Table 1.

Table 1. Highly anticholinergic medicines and potential alternatives

Indication	Highly anticholinergic medicines (avoid where possible)	Potential alternatives (no or lower anticholinergic effects)
Allergic rhinitis	Chlorpheniramine Promethazine	Cetirizine Loratadine Intranasal corticosteroids
Major depression	Amitriptyline Doxepin	Sertraline Venlafaxine
Urinary urge incontinence	Solifenacin Oxybutynin	Mirabegron
Psychoses	Chlorpromazine Clozapine	Amisulpride Risperidone Ziprasidone
Pain	Tramadol	Paracetamol
Nausea and vomiting	Cyclizine	Domperidone Metoclopramide

Medication review

As medications are a significant modifiable risk factor for falls, regular review is recommended for older adults. Reviews can be used to identify medications with a high risk of harm or a lack of benefit for the individual patient.

Deprescribing may be considered for some patients identified as high risk, particularly if the harms of the medication outweigh the potential benefits for the patient at their current stage of life.

Medication review and deprescribing have been shown to reduce hospital readmission rates in older adults. Studies highlight the particular benefit that reducing the use of potentially inappropriate medications has in preventing readmission.

Other falls prevention strategies

It is thought that around 40% of falls could be preventable. However, the causes of falls are typically multifactorial. Therefore, addressing multiple risk factors will be more beneficial than relying on a single intervention.

In addition to medication optimisation, other falls prevention strategies may include:

• Exercise – a large review found that exercise of any type may reduce the risk of falls by 23%. The benefits may be even higher for exercise programs combining balance and functional exercises with resistance exercises;
• Home hazard assessment and modification;
• Vision correction;
• Mobility aids; and
• Encouraging the use of non-pharmacological therapies where appropriate, e.g. the Therapeutic Guidelines considers psychological and behavioural interventions as first-line options for the treatment of insomnia.

Falls can have significant outcomes for older adults, including serious injury and loss of independence. Individualised assessment of patient risk factors along with the implementation of appropriate interventions can reduce the risk of falls in older adults.

Dapagliflozin and empagliflozin are sodium-glucose co-transporter 2 (SGLT-2) inhibitors. These medications inhibit SGLT-2 in the renal proximal convoluted tubules.

The SGLT-2 protein is responsible for the resorption of around 90% of the glucose from the glomerular filtrate. This makes SGLT-2 an attractive target for diabetes therapies as inhibition of SGLT-2 increases the amount of glucose removed by the kidneys. As the name suggests, SGLT-2 also transports sodium. Therefore, SGLT-2 inhibitors also increase the amount of sodium that is removed via the kidneys. This produces natriuresis and a mild diuresis that is associated with a moderate and sustained reduction in blood pressure.

Significant improvements in glycaemic control can be achieved with SGLT-2 inhibitors, and these medications were originally only indicated for the management of type 2 diabetes. However, studies have demonstrated cardiorenal protective effects and SGLT-2 inhibitors now also have a place in the management of heart failure and chronic kidney disease (CKD).

Indications

The current approved indications for SGLT-2 inhibitors in Australia are:

• Dapagliflozin
  • Type 2 diabetes – glycaemic control
  • Type 2 diabetes – reduce risk of hospitalisation for heart failure in patients with established cardiovascular disease or risk factors for cardiovascular disease
  • Heart failure – as an adjunct to standard therapy
  • Chronic kidney disease – to reduce the risk of disease progression in patients with proteinuric CKD.
• Empagliflozin
  • Type 2 diabetes – glycaemic control
  • Type 2 diabetes – prevention of cardiovascular death in patients with established cardiovascular disease
  • Heart failure – as an adjunct to standard therapy
  • Chronic kidney disease – to reduce the risk of disease progression.

Studies have demonstrated that the cardiorenal benefits become evident soon after randomisation. The mechanisms responsible for these benefits are not fully understood. However, these effects appear to be independent of glucose lowering and are apparent in patients with and without diabetes.

Some mechanisms that have been suggested include:

• Modulation of the renin-angiotensin-aldosterone (RAAS) system
• Osmotic diuresis and natriuresis to reduce preload;
• Vascular effects, such as improved endothelial function, to reduce afterload;
• Inhibition or reversal of adverse cardiac remodelling; and
• Improved myocardial metabolism to improve cardiac efficiency.

Evidence

Cardiovascular outcomes

The EMPA-REG OUTCOME trial evaluated cardiovascular outcomes of empagliflozin in patients with type 2 diabetes and high cardiovascular risk. Over 7,000 patients were randomised to receive empagliflozin or placebo. The empagliflozin group demonstrated significantly lower rates of death from cardiovascular causes (3.7% vs. 5.9%), hospitalisation for heart failure (2.7% vs 4.1%), and death from any cause (5.7% vs 8.3%).

Similar findings were reported for dapagliflozin in the DECLARE-TIMI trial. This was a larger study with more than 17,000 patients with type 2 diabetes at risk of atherosclerotic cardiovascular disease. Patients randomised to the dapagliflozin group had a lower rate of hospitalisation for heart failure compared to placebo (2.5% vs 3.3%).

The cardiovascular benefits of these studies prompted their investigation in people without diabetes. Studies such as the DAPA-HF and EMPEROR-Reduced trials demonstrated that SGLT-2 inhibitors may provide cardiovascular benefits for patients with heart failure regardless of their diabetes status.

Renal outcomes

In the initial cardiovascular outcomes trial, EMPA-REG OUTCOME, patients in the empagliflozin group were significantly less likely to experience a rapid decline in renal function over a median exposure period of 2.6 years. The potential renal benefits of SGLT-2 inhibitors were further investigated in the following trials:

• CREDENCE
  • Drug – canagliflozin (no longer available in Australia)
  • Population – type 2 diabetes and kidney disease
  • Outcome – 32% lower relative risk of end-stage kidney disease
• DAPA-CKD
  • Drug – dapagliflozin
  • Population – patients with CKD
  • Outcome – hazard ratio for the primary outcome (composite of sustained decline in the eGFR of ≥ 50%, end-stage kidney disease, or death from renal causes) was 0.56 (95% CI: 0.45 to 0.68).
• EMPA-KIDNEY trials
  • Drug – empagliflozin
  • Population – patients with CKD
  • Outcome – hazard ratio for the progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 mL/min/1.73 m², a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) was 0.71 (95% CI: 0.62 to 0.81).

A recently published umbrella review of network meta-analyses provided further support for the use of SGLT-2 inhibitors in CKD. This study compared the safety and efficacy of SGLT-2 inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) in patients with CKD. The authors concluded that all three classes of medication are associated with significant reductions in the risk of major cardiovascular events and the progression of CKD compared to placebo. Furthermore, indirect evidence suggests that SGLT-2 inhibitors may be the most attractive option when considering efficacy together with safety.

Adverse effects

As SGLT-2 inhibitors increase the amount of glucose in the urine, they are associated with an increased risk of genital infections (e.g. vulvovaginal candidiasis, balanitis). Other common adverse effects include polyuria, dysuria, thirst, and constipation. Hypoglycaemia can occur, particularly when used in combination with a sulfonylurea or insulin.

Serum creatinine may rise initially (potentially related to volume depletion). This is sometimes referred to as the “GFR dip”. This acute reduction in eGFR is reversible and typically followed by a partial recovery. The slower decline in eGFR compared to placebo then becomes apparent.

Ketoacidosis

Ketoacidosis has been rarely associated with the use of SGLT-2 inhibitors. A large cohort study from Canada and the United Kingdom found that SGLT-2 inhibitors significantly increased the risk of diabetic ketoacidosis (DKA) compared to dipeptidyl peptidase 4 (DPP-4) inhibitors. The hazard ratio was 1.86 for dapagliflozin and 2.52 for empagliflozin.

Diabetic ketoacidosis can occur in the setting of carbohydrate deficit. Under these conditions, serum insulin levels are low, and the body reduces the use of glucose and increases the use of fat as an energy source. Increased lipolysis, increased free fatty acid generation, and ketoacidosis can occur.

Hyperglycaemia is a classic component of DKA diagnosis. However, in patients taking SGLT-2 inhibitors, blood glucose levels can be normal or mildly elevated. This unusual presentation has been associated with delays in diagnosis.

There are many potential risk factors for the development of this adverse event. This includes acute illness or infection, surgery or trauma, dehydration, low carbohydrate intake, and alcohol abuse. Hospitalised patients are at greater risk as predisposing factors are more common in this population. To reduce the risk, SGLT-2 inhibitors should be avoided in patients on low carbohydrate diets and should be withheld during acute illness and prior to elective procedures.

The recommendation to withhold SGLT-2 inhibitors prior to elective surgery is directed towards patients with diabetes. There is currently a lack of evidence to guide recommendations for patients without diabetes who are taking an SGLT-2 inhibitor. While the risk of ketoacidosis in this group is thought to be significantly lower, the Council of Australian Therapeutic Advisory Groups currently recommends that the guidelines for patients with diabetes can also be followed for patients without diabetes. If the SGLT-2 inhibitor is withheld for surgery, it can be restarted once the patient is eating and drinking normally and kidney function has returned to baseline.

While SGLT-2 inhibitors have shown some promise as an adjunct therapy in type 1 diabetes, they are currently not recommended to be used in this population. This is due to an increased risk of DKA.

Recommendations

Heart failure

The Therapeutic Guidelines recommend dapagliflozin or empagliflozin for patients with heart failure, unless contraindicated. This should be used in addition to standard care (i.e. a renin-angiotensin system inhibitor, beta blocker and mineralocorticoid receptor antagonist for patients with heart failure with reduced ejection fraction).

Chronic kidney disease

The Chronic Kidney Disease (CKD) Management in Primary Care handbook recommends the use of an SGLT-2 inhibitor for patients with CKD and proteinuria (with or without diabetes) to reduce the risk of progressive decline in kidney function. The handbook advises against initiating an SGLT-2 inhibitor in patients with an eGFR <25mL/min/1.73m².

Potassium is an electrolyte which is essential for regulating nerve and muscle function, including cardiac muscle function. Disturbances in serum (blood) potassium affect the activity of Na/K – ATP pumps in the muscle tissue, leading to inappropriate muscle contractions.

The potassium concentration in the serum is around 3.5-5.2 mmol/L. This range describes the values between which 95% of the healthy population’s levels are expected to be. It does not necessarily mean that patients with results outside the reference range are at risk of complications. It also does not mean that all patients with levels within the reference ranges have an optimal concentration.

Hypokalaemia is a concentration of potassium in the blood below the reference range. Mild cases of hypokalaemia with serum potassium levels of 3-3.5 mmol/L can be asymptomatic, while severe cases with serum potassium of <2.5 mmol/L can lead to life threatening complications.

Healthy young patients with potassium levels slightly outside the reference ranges rarely experience problems. Older patients with acute cardiac conditions like rapid atrial fibrillation or acute myocardial infarction may require tighter potassium concentrations than the standard range to achieve optimal outcomes.

Laboratories can have different reference ranges due to different techniques used to collect and analyse specimens. This should be considered when reviewing results.

In the general population hypokalaemia is estimated to occur in 1-3% of people. People with malnutrition or on diuretics have a higher risk of developing hypokalaemia.

Symptoms of hypokalaemia include muscle weakness or cramps, lethargy, constipation, palpitations, nausea or vomiting, tingling or numbness in the limbs. In severe cases hypokalaemia can cause cardiac arrhythmias and cardiac arrest.

Common causes of hypokalaemia include

• Increased aldosterone levels caused by primary hyper aldosteronism or untreated heart failure. Aldosterone is the primary hormone regulating renal potassium excretion.
• Medicines, including loop and thiazide diuretics, nebulised or oral beta agonists and amphotericin B.

Mild cases of hypokalaemia in young patients without cardiac complications can often be managed with oral potassium supplements. Intravenous potassium supplementation could be required when the potassium concentration is <3 mmol/L with associated paralysis, hypokalaemia is associated with a cardiac rhythm disturbance, or oral supplementation is not possible. Concomitant oral and IV potassium supplementation should be considered when the patient’s potassium concentration is <3 mmol/L.

The actual increase in serum potassium from supplements is variable and depends on several factors like kidney disease or heart failure, and the presence of medicines such as diuretics, ACE Inhibitors and angiotensin receptor blockers.

Intravenous potassium supplementation should be administered at a rate of no greater than 20 mmol/hr and ideally at a rate of no greater than 10 mmol/hr when administered via a peripheral cannula. Faster rates can be administered via central lines terminating in high flow veins, such as the vena cava, in monitored settings such as an ICU.

Most people need 1mmol/kg of potassium per day to replace physiological losses. In patients who are unable to meet daily potassium requirements (e.g. patients who are nil by mouth) or when there are ongoing potassium losses (e.g. patients on large doses of loop diuretic), supplementation doses should account for this.

Aldosterone antagonists, such as spironolactone and eplerenone, are not used for management of acute hypokalaemia. They are however useful in the ongoing management of hypokalaemia secondary to hyperaldosteronism due to their aldosterone antagonist effects. They are also used in patients with recurrent hypokalaemia from loop diuretics. This includes patients with heart failure and cirrhotic liver disease.

Hypomagnesaemia can cause potassium wasting in the kidneys. Hence patients with hypokalaemia resistant to potassium supplementation should have magnesium levels assessed, and magnesium supplementation initiated where necessary.

Many foods e.g. bananas, baked potatoes, edamame, raisins and salmon are rich in potassium. Individuals with chronic hypokalaemia should have dietitian input to increase dietary potassium.

 

Staphylococcus aureus is a gram-positive pathogen and is one of the major human pathogens with a tendency to develop resistant strains to antibiotics. A penicillin-binding protein, PBP-2a, is responsible for mediating the resistance and allows division and growth of the organism in the presence of methicillin, resulting in strains of methicillin-resistant Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus is one of the major causes of hospital-acquired and community-acquired infections including skin and soft tissue infections, bacteraemia, pneumonia, surgical site infections, and sepsis(1). Higher rates of mortality and morbidity have been associated with infections involving methicillin resistant strains of Staphylococcus aureus. According to a national Australian study, it was identified that MRSA accounted for about 24% of all S. aureus bacteraemia infections. The study also showed that the all-cause 30-day mortality for methicillin-susceptible strains was only 17.7% whereas for MRSA, it was 30% (2).

Initiation of an appropriate antimicrobial therapy is significant for the treatment of methicillin-resistant Staphylococcus aureus bacteraemia. Intravenous vancomycin is the drug of choice for MRSA. However, increasing resistance against vancomycin monotherapy and owing to some limitations of vancomycin (poor tissue penetration, slower bactericidal effect, and high rates of mortality of MRSA bacteraemia), research is being conducted to determine other effective antimicrobial regimens. A number of other antimicrobial agents have been identified including linezolid, daptomycin, and ceftaroline. Although these agents have shown effectiveness against MRSA infections, the effects were not superior to vancomycin and most of these agents are associated with higher cost of therapy and/or serious adverse effects (2).

In recent years, several studies have been conducted to evaluate the effectiveness of combination therapy of vancomycin with β-lactam antibiotics. An inverse relationship (seesaw effect) was identified between vancomycin and β-lactam sensitivity in some MRSA strains that drew attention towards combination therapy of vancomycin with β-lactam antibiotics. Vancomycin showed synergistic effect when combined with different β-lactam antibiotics in several experimental models. Truong et al conducted a study in which a significant reduction in clinical failure was observed when combination therapy of vancomycin and various β-lactams were used (MIC < 2mg/l) (3).

In 2011, a pilot, open label, multicentre, parallel group clinical trial (CAMERA1) was performed in which patients with MRSA bacteraemia were randomly treated with either monotherapy with vancomycin intravenously at the standard dose, or combination therapy of vancomycin with flucloxacillin 2 gram every 6-hours for the first week. A total of 60 patients were enrolled in the study in which standard therapy group (29 participants) were given vancomycin alone and combination group (31 participants) were given vancomycin plus flucloxacillin. The results showed that the combination therapy resulted in shorter duration of bacteraemia 1.94 (SD 1.79) days as compared to 3.00 (SD 3.35) days in the group receiving standard therapy. It was indicated that the mean time for bacteraemia to resolve was 65% in the combination group as compared to that of the standard therapy group (RR 0.65, 95%CI, 0.41–1.02 p=0.06). 90% of patients in the combination group showed clearance of bacteraemia in four days, in contrast to nine days in the standard therapy group. However, in terms of the 28-day mortality (RR1.33, 95%CI 0.52–3.41, p=0.52), 90-day mortality (RR1.1, 95%CI 0.50-2.42, p=0.81) and complications (liver toxicity, nephrotoxicity, sepsis, need for ICU or other complications), no noteworthy difference was identified between the two groups (2).

Another study, CAMERA-2 was designed to further study the effect of combination therapy of β-lactam antibiotics with vancomycin in patients. Similar results were identified in this study regarding shortening of bacteraemia duration. However, incidence of higher rates of acute kidney injury (AKI) identified in the combination therapy resulted in the early termination of the study (3).

Combination therapy of β-lactam antibiotics with vancomycin in MRSA bacteraemia may shorten the duration of bacteraemia, however, no clinically significant effect on the rate of mortality and morbidity has been identified which necessitates further studies to explore the efficacy and safety of other combination therapies for MRSA bacteraemia.

Pharmacists being the expert of medicines, are an important part of multidisciplinary healthcare teams to manage the use of medicines in patients. Pharmacists, with other healthcare stakeholders, work together towards medication safety and for the Quality Use of Medicines including antimicrobial stewardship. Implementation of antimicrobial stewardship for MRSA bacteraemia is essential due to its high mortality and morbidity rates. A patient-directed approach is highly essential to effectively manage MRSA bacteraemia in hospital and community settings. Following are some of the areas where pharmacists can contribute their role:

• Contribution in developing local procedure and guideline by effectively utilising national standard guidelines such as Therapeutic Guidelines and by reviewing recent research evidence.
• Providing input on appropriate selection of antibiotic, dose, and duration of therapy.
• Involve in therapeutic drug monitoring of vancomycin to achieve the target trough levels for vancomycin.
• Monitoring the outcome of treatment.
• Monitoring the safety profile of vancomycin (Nephrotoxicity).
• Monitoring of drug-drug interactions.

Vulvovaginal candidiasis is a type of fungal infection characterized by inflammation of vagina and vulva caused by candida species. It is the second most common cause of vaginitis after bacterial vaginosis. Clinical presentation includes intense vaginal itching, irritation, feeling of burning and soreness and dyspareunia, curdy “cheese”-like discharge, and oedema with normal vaginal pH. Most common causative pathogen is Candida albicans that accounts for 80 to 90% of infection and Candida glabrata is the second highest causative specie. Authors have classified vulvovaginal candidiasis into two major categories: uncomplicated and complicated vulvovaginal candidiasis (VVC). Infections with mild to moderate symptoms and less than four episodes in a year caused by Candida albicans are mainly classified as uncomplicated vulvovaginal candidiasis. While infections caused by other pathogens or with more severe symptoms are classified as complicated vulvovaginal candidiasis. Infections in women where more than 4 episodes occur in a year and have risk factors are classified as complicated recurrent vulvovaginal candidiasis (RVVC). It is estimated that nearly three quarters of all women (70-75%) will develop this infection at least once in their life and half of these women will have another episode (50%), whereas about 5-10% may develop recurrent vulvovaginal candidiasis in their lives (1).

Self-diagnosis or miss-diagnosis makes it difficult to determine prevalence of Vulvovaginal candidiasis. Symptoms of vaginal infections including dysuria, redness, itchiness, vaginal discharge, and pain etc are highly non-specific and often result in over-diagnosis or under-diagnosis by women based on these symptoms (2). Consideration to differential diagnosis is highly important to consider other diagnosis such as bacterial vaginosis, dermatoses, atrophic vaginitis, trichomonas vaginalis. Also, the availability of most antifungal drugs without a prescription and their increase usage makes it difficult to correctly perform epidemiology studies (3).

There are multiple risk factors which account for recurrent vulvovaginal candidiasis in women and are broadly classified as host related factors and behavioural factors.

Occurrence of recurrent vulvovaginal candidiasis in diabetic women is more common than non-diabetic women. High levels of glucose results in the impairment of defensive mechanism and promote adhesion of Candida specie to the vaginal wall. It has been estimated that in diabetic women, the prevalence of vulvovaginal candidiasis is between 32 to 76.5% whereas as only 11 to 23% in women without diabetes (4). Also, women with a history of gestational diabetes mellitus during pregnancy are at higher risk of developing type 2 diabetes particularly in women greater than 35 years of age. A prospective cohort study was conducted in which the risk of developing type 2 diabetes was assessed using the reproductive histories of women. Results showed increased risk of type 2 diabetes mellitus in women with history of gestational diabetes and multiple pregnancies with a hazard ratio of 3.87 (95% CI 2.60-5.75). The American Diabetes Association recommends the screening of women with a history of gestational diabetes at 4-12 weeks postpartum and then at least every 3 years (5).

Some authors have also identified the use of oral contraceptives as one of the risk factors for vulvovaginal candidiasis. Some studies have reported that the incidence of vulvovaginal candidiasis is higher (39-58% versus 20-38%) when women are using oral contraceptive pills as contraception than in women not taking oral contraceptive pills. Also, the prevalence of recurrent vulvovaginal candidiasis is found to be more in women using oral contraceptives pills for longer time. Oral contraceptives are made of higher hormonal dose of synthetic estrogen and progesterone that promote Candida growth by increasing glycogen in vagina and increase the available carbohydrate as nutrients for candida specie. It also stimulate Candida hormone receptors that increases the adhesion of candida to the vaginal walls (1).

The first step in the management of recurrent vulvovaginal candidiasis is to confirm the diagnosis by microbial investigation and identification of the specie. Also, attempts should be made to identify the triggering or precipitating factor such as screening for diabetes or discontinuation of the combined oral contraceptive(6).

After excluding the possibility of other vaginal infections and taking the vaginal swab for cultures and sensitivities, if cultures confirm the presence of Candida albicans then the Therapeutic Guidelines recommends treatment course with fluconazole with a dosage of 150mg on Day 1, 4 and 7 and followed by once-a-week dosing of 150mg fluconazole for a further 6 months. In case of pregnancy or if the patient is planning to conceive, oral fluconazole is not recommended as it is TGA category D drug. Alternative choice in case of pregnancy or planning for pregnancy would be clotrimazole 1% cream administered as 1 applicatorful intravaginally at night for 14 consecutive nights then once a week administration of clotrimazole 500mg pessary inserted vaginally at bedtime for the next 6 months. If cultures indicate the presence of Candida glabrata and azole-resistant species, then therapeutic guidelines recommend the treatment course with nystatin 100000 units/5g vaginal cream to be applied intravaginally with applicator once daily at night-time for 2 weeks (14 nights) in a month for a total of 6 months (3).

Treatment regimen consisting of induction and maintenance regimen has shown to reduce the symptoms and recurrences of recurrent vulvovaginal candidiasis. The intention of maintenance therapy is to supress the symptoms and does not target the elimination of infection therefore chances of recurrence is 50% after the maintenance therapy is stopped which is considered as challenge in the management of recurrent vulvovaginal candidiasis. Also, the emergence of azole-resistant strains due to repeated use of fluconazole imposes another challenge. In case of azole-resistance, other agents that can be used are boric acid vaginal suppositories or capsules, nystatin vaginal suppositories, amphotericin B vaginal suppositories or cream, or flucytosine cream (2).

Also, patient counselling on general management is also important that includes avoiding the use of harsh soaps and perfumes to avoid vulvar irritation. Also, keeping the vaginal area clean and dry and avoiding long exposure to hot tub use. Cool bath may sooth the irritation and provide some relief (7).

The response to the treatment can be monitored by looking at the positive outcomes of the treatments that includes resolution of the symptoms and reduction in the number of reoccurrences. If the desired response is not achieved to the treatment regimen for recurrent vulvovaginal candidiasis, then microbiological cultures can be repeated to assess the development of resistance to the treatment. Also, reassessment of the alternative causes of the symptoms can be done if no adequate clinical response is achieved.

A new boxed warning is being added to the product information and consumer medicine information documents of systemic fluoroquinolone products. This warning advises that “fluoroquinolones… have been associated with disabling and potentially irreversible serious adverse reactions involving different body systems that have occurred together in the same patient.”

Fluoroquinolones are broad-spectrum antibiotics. Medications in this class that are currently available for systemic use include:

• Ciprofloxacin (oral, parenteral);
• Moxifloxacin (oral, parenteral); and
• Norfloxacin (oral).

In the majority of cases, fluoroquinolones are not first-line antibiotics. They are typically reserved for infections where alternative agents are ineffective or contraindicated. This is due to the rising level of resistance to this antibiotic class around the world. Judicious use is recommended to extend their clinical life. Another reason to be cautious about the use of these medicines is the potential for serious and long-lasting adverse reactions.

The European Medicines Agency (EMA) conducted a review of this issue in 2018. This review found that fluoroquinolones are associated with prolonged, serious, and disabling reactions. These reactions may affect several systems, organ classes and senses and may, in some cases, be irreversible.

These reactions include:

• Tendonitis;
• Tendon rupture;
• Arthralgia;
• Pain in the extremities;
• Gait disturbance;
• Neuropathies associated with paraesthesia;
• Depression;
• Fatigue;
• Memory impairment;
• Sleep disorders; and
• Impaired hearing, vision, taste, and smell.

These reactions have been associated with the use of fluoroquinolones via the oral, parenteral, and inhalation routes.

Effects on tendons

Tendonitis and tendon rupture are known adverse events associated with fluoroquinolones. Any tendon can be affected, but the Achilles tendon is most commonly implicated. The estimated incidence is between 0.14% and 2%. Onset can occur within days of initiating a fluoroquinolone, and almost all reported cases have occurred with one month. However, a longer latency of up to six months has been reported.

Risk factors for tendon effects may include older age, obesity, and physical exertion. As long-term use of glucocorticoids is independently implicated in tendinopathies, the concomitant use of a glucocorticoid may potentiate the risk with fluoroquinolones.

Adverse events affecting tendons can lead to prolonged disability or the need for surgical repair. If a patient develops tendon pain or inflammation, it is recommended that the fluoroquinolone be discontinued, and the affected limb rested.

Nervous system effects

Mononeuropathies and polyneuropathy have been reported in association with fluoroquinolone use. The resultant sensory disturbances can have a significant impact on functional ability and quality of life.

A large nested case-control study evaluated the risk of peripheral neuropathy with fluoroquinolones compared to amoxicillin + clavulanic acid. This study found that current fluoroquinolone use was associated with a significantly higher risk of peripheral neuropathy (adjusted incidence rate ratio [aIRR]: 1.47; 95% CI: 1.13-1.92). The risk was found to increase with increasing duration of fluoroquinolone use. There was no significant association with amoxicillin + clavulanic acid (aIRR: 1.10; 95% CI: 0.86-1.40).

Peripheral neuropathy is likely a rare adverse event. Risk factors may include high body mass index, alcohol abuse, amyloidosis, Sjögren syndrome, and shingles. For patients who develop symptoms of neuropathy during fluoroquinolone therapy, discontinuation of the fluoroquinolone is recommended to avoid the development of an irreversible condition. Symptoms that could indicate neuropathy include burning, tingling, numbness, and weakness.

Psychiatric adverse effects

Fluoroquinolones are associated with psychiatric adverse effects. These may be mild and include confusion, restlessness, and insomnia. Severe events such as catatonia, psychosis, and suicidal depression have also been reported. The usual reported incidence is 1% to 4.4%. However, one study reported an incidence of 13.6% in patients over 80 years with a history of neurologic or psychiatric disorders.

The potential for fluoroquinolones to cause these effects is thought to be related to their structural similarity to gamma-aminobutyric acid (GABA) and their high permeability across the blood-brain barrier. This allows access to the central nervous system (CNS) where these drugs may inhibit GABAergic neurotransmission.

A recent retrospective analysis of US data found that the class is associated with a range of psychiatric effects, although there are some key differences for the individual drugs. Ciprofloxacin was more frequently associated with adverse events of anxiety, depression, and suicidal ideation compared to other fluoroquinolones. Moxifloxacin may have a lower risk of depression and suicidal ideation but was more strongly associated with delirium. The study authors suggest that moxifloxacin may be preferred over ciprofloxacin for patients with pre-existing depression.

Risk factors for psychiatric adverse events appear to include high fluoroquinolone dose and a history of neurological or psychiatric disorders. However, it should be noted that psychiatric adverse events have been reported in patients with no relevant psychiatric history. Patient age may also be a significant variable with patients under 65 years experiencing more adverse events related to affective disorders, and older adults more likely to experience psychosis and delirium.

Recommendations:

The potential for fluoroquinolones to cause severe and long-lasting adverse events, combined with increasing levels of resistance, means that the use of this class should be restricted. These antibiotics are reserved for infections where alternative therapies are ineffective or contraindicated. In general, fluoroquinolones should not be used to treat infections that are non-severe or self-limiting. Their use should also be avoided in patients who have previously experienced severe adverse effects with a fluoroquinolone, unless there are no other appropriate alternatives.

Prior to initiating a fluoroquinolone, individual risk factors should be considered. As fluoroquinolones are cleared via the kidneys, renal impairment may increase the risk of adverse effects. Dose alteration is required for ciprofloxacin and norfloxacin when used in renal impairment.

Treatment with a fluoroquinolone be discontinued at the first signs of musculoskeletal, neurological, or psychiatric adverse effects.

An updated consensus statement on the management of Buruli ulcer has recently been published. Buruli ulcer is a skin infection caused by the bacteria Mycobacterium ulcerans. This condition is named after the Buruli district in Uganda where many of the earliest documented cases occurred. The condition is sometimes also referred to as Bairnsdale or Daintree ulcer.

The M. ulcerans bacterium produces the mycolactone toxin which can cause significant tissue damage. Infection typically begins with a dermal papule or subcutaneous nodule. Over the following weeks or months, these painless lesions can develop into necrotic ulcers. Less common presentations are plaques without ulceration or atypical cellulitis involving all or part of a limb.

While Buruli ulcer is considered a tropical or subtropical condition around the world, it does occur in cooler regions of Australia. In Australia, outbreaks have previously been limited to coastal regions of Victoria and north Queensland. However, infections have now been reported in many suburbs of Melbourne, coastal regions of New South Wales, and the Northern Territory. The spread into new areas of Australia has been accompanied with an increased incidence of infection.

Treatment includes effective wound care in combination with antibiotics. Surgery may be required in some cases.

Antibiotic therapy

The complex cell wall structure of the Mycobacterium species makes them intrinsically resistant to many antibiotics. Many antibiotics commonly used for skin and soft tissue infections, such as flucloxacillin and cefalexin, are not effective in the treatment of Buruli ulcer.

Dual antibiotic therapy is recommended for the treatment of Buruli ulcer. This increases the effectiveness of therapy and minimises the risk of resistance emerging. Observational data supports the use of rifampicin with either clarithromycin or a quinolone in Australian cases. A Victorian study demonstrated that this therapy was associated with excellent cosmetic outcomes and a cure rate of 99.2%. In this study, cure was defined as healing within 12 months.

The current consensus guidelines recommend the following oral therapies:

• Rifampicin 10 mg/kg per day (up to 600 mg daily)

PLUS one of:

• Clarithromycin 7.5 mg/kg twice daily (up to 500 mg every 12 hours) OR
• Moxifloxacin 400 mg once daily OR
• Ciprofloxacin 500 mg every 12 hours.

Clarithromycin and ciprofloxacin doses should be adjusted according to renal function. If rifampicin is contraindicated or not tolerated, clarithromycin may be prescribed in combination with a quinolone.

Rifampicin

Rifampicin belongs to the rifamycin class of antibiotics. It is broad-spectrum with activity against Mycobacteria, most Gram-positive bacteria, and some Gram-negative bacteria.

Doses are typically given once a day and should be taken on an empty stomach, either half an hour before meals or two hours after a meal. To avoid unnecessary concern, patients should be advised that rifampicin can cause a red-orange discolouration of urine, faeces, sweat, and tears. This can cause permanent staining of soft contact lenses.

Rifampicin is implicated in many clinically important drug interactions. It is a potent inducer of various drug metabolising enzymes and transporters, including cytochrome P450 enzymes and P-glycoprotein. Rifampicin can accelerate the metabolism of some co-administered medicines which may result in reduced efficacy. For example, rifampicin has been shown to decrease lurasidone exposure by 81% and this combination is contraindicated. Conversely, in the case of pro-drugs, it may increase their efficacy and risk of adverse events by accelerating their metabolic activation. For example, rifampicin increases the conversion of clopidogrel to its active metabolite. This combination should be avoided as it may increase the risk of bleeding.

Rifampicin can cause liver dysfunction. Caution is required in patients with liver disease and patients receiving other hepatotoxic agents.

Clarithromycin

Clarithromycin is a macrolide antibiotic. The consensus statement advises that clarithromycin plus rifampicin is preferred for patients who are pregnant.

Clarithromycin has many clinically relevant drug interactions. It is a strong inhibitor of CYP3A4 and inhibits P-glycoprotein and organic anion transporting polypeptide (OATP) 1B1. The manufacturer contraindicates use with many drugs including colchicine, domperidone, oral midazolam, ticagrelor, and simvastatin. As simvastatin is extensively metabolised by CYP3A4, concomitant use of clarithromycin can lead to increased simvastatin levels and a higher risk of myopathy. Caution is also required with other statins. Fluvastatin and pravastatin are safer options as their metabolism is not dependent on CYP3A4.

Azithromycin is another antibiotic in this class that may have activity against M. ulcerans. However, there is less experience with azithromycin in this setting.

Quinolones

Moxifloxacin and ciprofloxacin belong to the quinolone class of antibiotics. It is preferable for ciprofloxacin to be taken on an empty stomach. However, both of these agents may be taken without regards to meals. Co-administration with food does delay absorption but there is not a substantial impact on the extent of absorption.

Important points:

• Photosensitivity – ciprofloxacin may cause photosensitivity reactions. Patients should be advised to avoid direct exposure to sunlight and to wear protective clothing and a broad-spectrum sunscreen when outdoors. Moxifloxacin has not been associated with phototoxicity.
• Driving ability – quinolones can cause dizziness, light-headedness, and visual disturbances. Patients should be advised that these medications may affect their ability to drive or operate machinery.
• Tendinopathies – quinolones can cause tendinopathies. Factors that may increase the risk include older age, strenuous physical activity, renal impairment, and coadministration with corticosteroids. Patients should be advised to consult their doctor if they develop any signs of tendonitis.
• Neuropathy – quinolones are rarely associated with peripheral neuropathy. The antibiotic should be discontinued at the first symptoms of neuropathy to prevent the development of a potentially irreversible reaction.

General information

It is recommended that full blood examination, and hepatic and renal function be checked at baseline and repeated periodically where required. Alcohol should be avoided during therapy to minimise the risk of liver injury.

Prolongation of the QT interval can occur with clarithromycin and the quinolone antibiotics. An electrocardiogram is recommended at baseline and again two weeks later for patients at increased risk, i.e. patients with pre-existing cardiac disease and those taking another medication associated with QT prolongation. Many medications are associated with prolongation of the QT interval, including hydroxychloroquine, domperidone, and methadone. A complete list is maintained at www.qtdrugs.org.

Drug interactions are very common with these antibiotics. Patients should be advised to check with their healthcare professional before starting any new medication, including alternative and over-the-counter medicines.

Buruli ulcer lesions are notoriously slow to heal and may even enlarge upon initiation of antibiotic therapy. Evidence supports a treatment duration of eight weeks in most cases. There is some evidence to support a six-week duration in patients with small lesions at low risk of relapse, and a four-week course for patients who have undergone surgical excision. As the median time to heal is around four to five months, patients should be warned that ulcers may not have healed completely by the time the antibiotic course is finished.

Paradoxical reactions can occur during or after antibiotic therapy. These reactions, also known as immune reconstitution inflammatory reactions, are associated with increased tissue necrosis and delayed healing. These reactions are common, affecting around one in five patients treated with antibiotics. Older adults and those with oedematous lesions may be at greater risk. Early identification of paradoxical reactions is important to prevent significant tissue loss.

Prevention

The exact mode of transmission of M. ulcerans is not currently understood, which makes it difficult to implement effective preventative strategies. However, there is increasing evidence that mosquitos, possums, and environmental factors play a role in transmission in Australia.

Based on this information, the consensus statement makes the following recommendations to reduce the risk of Buruli ulcer:

• Avoid mosquito bites (i.e. mosquito repellents, protective clothing, fly screens, etc.);
• Minimise potential mosquito breeding sites (i.e. remove sources of still water around the home);
• Wear gloves and protective clothing when gardening or working outdoors;
• Keep any cuts and abrasions clean and use effective wound management practices; and
• Minimise contact with possums and their excreta.