Macrolide Antibiotics: No Link With Increased Risk of Ventricular Arrhythmia, Mortality in Cohort Study

Use of a macrolide antibiotic, including azithromycin, clarithromycin, or erythromycin, is not associated with an increased risk of ventricular arrhythmia or mortality at 30 days when compared with nonmacrolide antibiotics, according to the results of a large cohort study.  

The new findings challenge a 2013 announcement from the US Food and Drug Administration warning of an increased risk of QT-interval prolongation and torsades de pointes with azithromycin.

“Although caution should be exercised when prescribing macrolide antibiotics to high-risk patients in whom drug clearance or electrical activity of the heart is impaired and outcomes less predictable, our study findings and examination of the current literature suggest that the risk of ventricular arrhythmia and death from macrolide antibiotic use may be overstated,” write Mai Trac, MSc, of Western University (London, Canada), and colleagues February 22, 2016, in the Canadian Medical Association Journal.

Commonly prescribed to treat community-acquired respiratory tract infections, concerns about the drug class were first raised in 2012 following a study published in the New England Journal of Medicine. In that observational study, patients prescribed a 5-day course of azithromycin had an increased risk of cardiovascular and all-cause mortality compared with those receiving amoxicillin or no antibiotics. The increased risk observed with azithromycin was supported by case reports and other studies. As a result, the azithromycin drug labels were updated to warn of the risk of QT interval prolongation and torsades de pointes. In other reports, clarithromycin and erythromycin were also linked with QT-interval prolongation.

The increased risk with the macrolide antibiotics, and the subsequent FDA warning, was later challenged by other studies, however, with one showing that mortality was no higher at 90 days in patients treated with azithromycin compared with those who received other antibiotics. In another study, researchers reported that the 5-day risk of cardiovascular death was similar among patients treated with azithromycin and penicillin.

Given these conflicting findings, the researchers conducted a population-based cohort study, analyzing data from men and women aged 65 years and older prescribed azithromycin, clarithromycin, or erythromycin and pairing them with individuals prescribed a nonmacrolide antibiotic. In total, 503,612 individuals treated with a macrolide antibiotic were propensity matched with individuals prescribed nonmacrolide antibiotics, including amoxicillin, cefuroxime, or levofloxacin.

At 30 days, there was no difference in the number of patients reporting to the hospital for ventricular arrhythmia, with 0.03% of patients in both drug classes developing ventricular tachycardia or ventricular fibrillation. The result was consistent across multiple subgroups, including those with chronic kidney disease, heart failure, coronary artery disease, and those taking a QT-interval-prolonging drug. All-cause mortality was lower among patients treated with a macrolide antibiotic, with 0.62% of patients dead at 30 days compared with 0.76% of patients treated with a nonmacrolide antibiotic (RR 0.82; 95% CI 0.78-0.86). 

In an email to TCTMD, senior investigator Amit Garg, MD, also of Western University, said the findings should reassure healthcare providers who prescribe macrolide antibiotics to their patients. He points out that hundreds of millions of adults are prescribed a macrolide antibiotic each year—more than 57 million prescriptions were written in 2010—and that given the lack of harm observed in their analysis, the FDA should review all available clinical evidence to determine if a change in the warning is necessary.
 

Sources: 
1. Trac MH, McArthur E, Jandoc R, et al. Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. CMAJ 2016;Epub ahead of print.
2. Food and Drug Administration. FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and risk of potentially fatal heart rhythms. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM343347.pdfhttp:/www.fda.gov/downloads/Drugs/DrugSafety/UC M343347.pdf. Published: March 12, 2013. Accessed: February 24, 2016.