Macrolide Antibiotics, Prolonged QTc, and Ventricular Dysrhythmias

Written by Anand Swaminathan REBEL EM Medical Category: Cardiovascular

Background: When it comes to treating community acquired respiratory tract infections, macrolide antibiotics (azithromycin, clarithromycin, and erythromycin) are a common choice of agent. In 2010, 57.4 million macrolide prescriptions were written in the U.S. with azithromycin being the most commonly prescribed individual antibiotic agent overall with ~51.5 million prescriptions (Hicks 2013).

With more and more patients being prescribed macrolide antibiotics, an increasing amount of research has been put forth dealing with the safety concerns regarding these medications; specifically the thought that azithromycin use can lead to fatal ventricular arrhythmias. In addition to case reports a 2012 observational study published in the New England Journal of Medicine highlighted an association between azithromycin use and higher rate of both cardiovascular death and all-cause mortality (Ray 2012). This prompted the US Food and Drug Administration to issue warnings about the use of azithromycin and potential QT-interval prolongation and fatal ventricular dysrhythmias.

However, recent studies suggest that these concerns and warnings may not be accurate. A retrospective cohort study comparing older patients hospitalized with pneumonia that were treated with azithromycin to those who received other guideline appropriate antibiotics actually showed a lower risk of 90-day mortality in the azithromycin group. Further, there was no significant difference between the 2 groups in regards to risk of arrhythmia, heart failure or any cardiac event. (Mortensen 2014).

Article:

Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. CMAJ 2016; 188(7): E120-9. Trac MH et al.CMAJ 2016; 188(7): E120-9. PMID: 26903359

Clinical Question:

Are the use of macrolide antibiotics (azithromycin, clarithromycin, or erythromycin) associated with a higher 30-day risk of ventricular dysrhythmias than the use of non-macrolide antibiotics (amoxicillin, cefuroxime or levofloxacin)?

Study Design:

Population-based retrospective cohort study

Population:

Patients age >65, who were dispensed new outpatient prescription for macrolide antibiotic between April 2002 – March 2013 compared with similar group prescribed non-macrolide antibiotics (amoxicillin, cefuroxime, or levofloxacin). Patients from each group matched in 1:1 ratio, creating 2 groups without meaningful differences in 106 measured baseline characteristics.

Exclusion Criteria:

Those in first year of eligibility for prescription drug coverage (age 65), those without standard drug doses for respiratory tract infections, those with multiple antibiotic prescriptions. All exclusions performed before matching

Outcomes:

Primary : Hospital encounter (presentation to ED or hospital admission) with ventricular dysrhythmia (ventricular tachycardia or ventricular fibrillation) within 30 days after a new prescription.

Secondary: All-cause mortality within 30-days.

Results:

503,612 patients taking macrolide antibiotics were successfully matched with an equal number of patients taking non-macrolide antibiotics.

Subgroup analysis showed that presence or absence of CKD, CHF, CAD or use of other QT-prolonging drugs did not significantly modify the primary/secondary outcomes.

Similar results found when looking at a 14-day endpoint as well.

Strengths:

Large database allowing for representative sample of patients

Assessed clinically important, patient centered adverse events (hospital encounter with ventricular arrhythmia and death)

Compared patients with similar indications for treatment to reduce bias (chose antibiotics that would be used commonly for URIs)

Limitations:

Retrospective data collection using diagnosis codes from prior records as opposed to prospective data collection

No guarantee that patients actually took the medications they were prescribed

Presentations for dysrhythmia or even death may not have been captured

No cardiac rhythm tracings available

Unable to determine exact indication for antibiotics

Results may have been confounded if prescribers were deliberately avoiding prescribing macrolide antibiotics to those at high risk for ventricular arrhythmia

Author’s Conclusions: “Among older adults prescribed macrolide antibiotics compared with nonmacrolide antibiotics, we found no difference in risk of a hospital encounter with ventricular arrhythmia within 30 days of a new prescription and a lower risk of 30-day all- cause mortality. These findings are reassuring for health care providers who prescribe macrolide antibiotics to a wide range of patients in routine care”

Our Conclusions: This study, while not without its limitations, is another piece of evidence that suggests that the risk of ventricular dysrhythmias and death secondary to macrolide antibiotic use may not be as high as once thought. The authors of this study provided a very large sample size, with clinically important outcomes.

Potential Impact to Current Practice: This study may make ED physicians more comfortable in prescribing macrolide antibiotics, although it appears that this is already the case.

Clinical Bottom Line: While this study is another step towards determining the risks of macrolide antibiotics and clinically relevant outcomes, caution should still be exercised when prescribing them to high-risk patients with poor drug clearance or with already impaired electrical activity of the heart.

References:

Hicks LA et al. US outpatient antibiotic prescribing, 2010. NEJM 2013;368:1461-2. PMID: 23574140 Mortensen EM et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA 2014; 311:2199-208. PMID: 24893087 et al. Azithromycin and the risk of cardiovascular death. NEJM 2012; 366:1881-90. Ray WAet al. Azithromycin and the risk of cardiovascular death. NEJM 2012; 366:1881-90. PMID: 22591294

For More on this Topic Checkout:

Guest Post By:

Kurt MacDonald, PGY4

NYU/Bellevue Emergency Medicine Residency Program

Post Peer Reviewed By: Salim R. Rezaie (Twitter: @srrezaie)