Is it still safe to use azithromycin?

The Therapeutic Goods Administration has issued a warning after receiving reports possibly associating azithromycin with cardiovascular death in four patients, leading to death.

The patients, who were of both sexes, ranged in age from 26 to 84. However, most were over 60 years of age.

Both the Product Information and Consumer Medicine Information has been updated to describe an increased short-term risk of cardiovascular death with using azithromycin, compared with other antibiotics, such as amoxicillin. While rare, the risk appears to be higher within the first 5 days of treatment. This is in addition  to the existing warning for azithromycin of ventricular arrhythmias associated with prolonged QT interval.

Healthcare professionals such as pharmacists must be able to balance the benefits of azithromycin with the rare but serious risk of sudden cardiac death.

Australian Pharmacist spoke with Karl Winckel, Advanced Practice credentialed pharmacist and conjoint pharmacist at the School of Pharmacy, University of Queensland, and the Princess Alexandra Hospital in Brisbane, to find out how the risk/benefit should be assessed. 

How much heed should be taken?

The risk of sudden cardiovascular death associated with azithromycin has been known for some time through observational studies, said Mr Winckel. 

‘The problem is that the people who [are prescribed] azithromycin for pneumonia or any other infection [are often] sicker and frailer with multiple comorbidities,’ he said. 

‘That’s because azithromycin, by its very nature, is there to cover the atypical bacteria that simpler antibiotics don’t cover. This is usually only required in sicker cohorts of patients.’

As a result, there have been ongoing questions about whether cardiac deaths linked to the medicine are real effects, or whether this patient cohort is just at higher risk of these events.

But given cardiovascular events have occurred in patients using other antibiotics in the same class, such as erythromycin, it’s important to take note of, said Mr Winckel.

‘We’ve definitely had cases where people’s QT has been prolonged on azithromycin,’ he said. ‘Everyone’s always careful, particularly with intravenous high-dose erythromycin, around QT prolongation.’

Once a medicine gets labelled as a cardiac risk, the reputation is difficult to shake.

‘Anytime anyone has a sudden cardiac death, it gets attributed to the drug – particularly when used early on in the initiation of the drug,’ he explained. ‘But antibiotics are initiated right at a time when patients have events that put them at risk of sudden cardiac death, such as severe pneumonia or other types of severe infections.’ 

Yet, Mr Winckel said it does need to be acknowledged that the cardiovascular risk associated with azithromycin is real. Initially it was thought that azithromycin would be less likely to prolong the QT interval because it doesn’t bind to potassium channels in the myocardium as potently as erythromycin does.

‘When it was brought out, it was thought that azithromycin would be a cardiac-safe antibiotic,’  said Mr Winckel. ‘But surprise, surprise, it’s associated with the same adverse effects.’

Who is at risk of the cardiac effect?

The risk factors for QT prolongation occurring with medicines associated with this effect are quite well established.

Mr Winckel said these include:

• the female sex – who have lower safe reference ranges for QT intervals than males
• older people – who are more likely to experience changed pharmacokinetics of medicines such as reduced clearance, and increased rates of myocardial ischemia
• ischaemic heart disease or heart failure – for example where there are left or right bundle branch blocks, which creates increased risk where there’s slow propagation through the ventricles.

Two big risk factors for QT prolongation are hypokalemia or hypomagnesemia – low serum levels of potassium and magnesium. 

‘The patients our toxicologist sees with torsades de pointes (TdP) almost always have low serum electrolytes,’ he said. ‘There’s a bit of a double whammy with heart failure patients, who might also be on high-dose diuretics such as furosemide that lower their electrolytes.’

People with a slow heart rate (bradycardia) are also at much higher risk of TdP from QT prolongation.

‘Tachycardia is actually protective of TdP in QT prolongation,’ said Mr Winckel. ‘This is relevant with azithromycin, because if used for patients with severe pneumonia, those patients may be tachycardic – which does give them some protection against TdP.’

How can pharmacists help to reduce risks?

A key takeaway for pharmacists to reduce cardiac risks in patients prescribed azithromycin is to ensure that: 

• patients’ serum electrolytes aren’t low
• electrolytes are sufficiently replaced when needed
• patients are not bradycardic.

‘If a patient is on a big dose of a beta blocker that’s renally cleared, and they’re a frail older woman, [pharmacists] should check their heart rate and ensure they’ve had blood tests to check their electrolytes – if you think there’s a good reason to believe they would be low,’ he said. ‘[For example] if they haven’t been checked in over 6 months, and they’re on furosemide or a medicine that reduces potassium.’

For patients with a high risk of a prolonged QT interval who have been prescribed azithromycin, pharmacists should consider contacting the prescriber to discuss precautionary ECG screening.

‘If a patient has a prolonged baseline QT, then they’re at much higher risk of TdP with any further prolongation,’ said Mr Winckel.

Modifying cardiovascular risk factors by ensuring potassium and magnesium is replete, and encouraging dietary intake if there’s a reason to think they might be low should be a key area of focus for pharmacists.

‘A key thing is to ensure patients are eating,’ said Mr Winckel. ‘Because if they are not eating anything [and/or] they are nauseous or vomiting, there will be zero intake of potassium and magnesium, and they’re going to be deficient.’

An important caveat

Despite the cardiac risk linked to azithromycin, it should be noted that overall, the risk of death from severe respiratory infections such as pneumonia is more significant, said Mr Winckel.

But what pharmacists should keep an eye on is the duration of treatment.

‘What sometimes happens, particularly in hospitals, is that people get prescribed azithromycin for too long,’ he said. 

‘A key role for pharmacists is to make sure patients are only using 3-day courses, because sometimes prescribers don’t realise it has a long half-life, and you don’t need to continue to dose after that period of time.’