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Macrolide Antibiotics and Ventricular Arrhythmia in Older Adults
TAKE-HOME MESSAGE
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This 11-year, population-based, cohort study of adults >65 years compared the incidence of ventricular arrhythmia within 30 days of treatment with macrolide vs non-macrolide antibiotics. Subgroup analyses were performed in patient groups with CKD, CHF, and CAD and concurrent use of a known QT interval–prolonging agent. In the overall dataset as well as across subgroups, treatment with macrolides vs non-macrolides did not increase risk for ventricular arrhythmia (0.03% vs 0.03%; RR, 1.06; 95% CI, 0.83–1.36).
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Although inconsistent with current FDA warnings, data from this study suggest relative safety of macrolide antibiotic therapy in an older adult population as compared with non-macrolide antibiotic treatment.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Many respiratory tract infections are treated with macrolide antibiotics. Regulatory agencies warn that these antibiotics increase the risk of ventricular arrhythmia. We examined the 30-day risk of ventricular arrhythmia and all-cause mortality associated with macrolide antibiotics relative to nonmacrolide antibiotics.
METHODS
We conducted a population-based retrospective cohort study involving older adults (age > 65 yr) with a new prescription for an oral macrolide antibiotic (azithromycin, clarithromycin or erythromycin) in Ontario from 2002 to 2013. Our primary outcome was a hospital encounter with ventricular arrhythmia within 30 days after a new prescription. Our secondary outcome was 30-day all-cause mortality. We matched patients 1:1 using propensity scores to patients prescribed nonmacrolide antibiotics (amoxicillin, cefuroxime or levofloxacin). We used conditional logistic regression to measure the association between macrolide exposure and outcomes, and repeated the analysis in 4 subgroups defined by the presence or absence of chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval.
RESULTS
Compared with nonmacrolide antibiotics, macrolide antibiotics were not associated with a higher risk of ventricular arrhythmia (0.03% v. 0.03%; relative risk [RR] 1.06, 95% confidence interval [CI] 0.83-1.36) and were associated with a lower risk of all-cause mortality (0.62% v. 0.76%; RR 0.82, 95% CI 0.78-0.86). These associations were similar in all subgroups.
INTERPRETATION
Among older adults, macrolide antibiotics were not associated with a higher 30-day risk of ventricular arrhythmia than nonmacrolide antibiotics. These findings suggest that current warnings from the US Food and Drug Administration may be overstated.
Additional Info
Macrolide Antibiotics and the Risk of Ventricular Arrhythmia in Older Adults
CMAJ 2016 Feb 22;[EPub Ahead of Print], MH Trac, E McArthur, R Jandoc, SN Dixon, DM Nash, DG Hackam, AX GargFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
These two studies1,2 confirm what most physicians already know regarding the cardiac safety of the macrolide and fluoroquinolone antibiotics—for the great majority of outpatients who are prescribed these important medicines, there is very little, if any, risk of cardiac arrhythmia.
Careful review of these two studies finds significant limitations in design (eg, inclusion of levofloxacin in the comparator group for macrolides and mixing several non–QT prolonging drugs such as mexiletine in the confounder analysis).1 Nevertheless, the extremely low rates of arrhythmic events in the millions of patients studied are still encouraging.
Unfortunately, the authors of one study (Trac et al2) reach conclusions regarding FDA warnings that are not justified and are not germane to their findings.
The results of these two retrospective observational studies do not negate the massive amount of evidence proving that these two classes of medications have the ability to induce a potentially lethal arrhythmia, torsades de pointes (TdP), in patients with known risk factors (a population not likely captured in these two studies). Although the studies used propensity score methods to match individual factors to balance the comparison groups, they did not focus on the relevant population with multiple risk factors for cardiac arrhythmias—patients with reduced repolarization reserve (female gender, prolonged QT, hypokalemia, hypomagnesemia, bradycardia, and/or prior myocardial infarction).
The warnings required by the FDA are based on judicious analysis of sound evidence from multiple sources and must be taken into account when physicians consider these medications for patients at high risk of TdP. Likewise, these studies do not address the larger problem with these medicines, which is that they are too often prescribed for viral illnesses when antibiotics are not appropriate and so is a practice that can result in drug-resistant infections.
Based on these and other studies, clinicians should not hesitate to prescribe the macrolide or fluoroquinolone antibiotics when they are clearly indicated. They must be aware, however, that safer alternatives are preferred in patients who have multiple risk factors for TdP.
References