Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death

Abstract

PURPOSE Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithromycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin. METHODSWe studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dispensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days.RESULTS During treatment days 1 to 5, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically different. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32-2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82).CONCLUSIONS Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period. Ann Fam Med 2014;12:121-127. doi: 10.1370/afm.1601. INTRODUCTIONA zithromycin is a macrolide antibiotic commonly prescribed for outpatient treatment of respiratory infections, urinary tract infections, and sexually transmitted diseases.1 Macrolide antibiotics, primarily erythromycin and clarithromycin, are known to increase cardiac arrhythmogenic risks, including QT interval prolongation, torsades de pointes, and polymorphic ventricular tachycardia.2 Between 2001 and 2007, case reports described arrhythmias among persons receiving azithromycin. [3][4][5][6][7] In 2012, Ray et al 8 reported increased risks of cardiovascular death and all-cause mortality among adult, predominantly female, Medicaid patients in Tennessee who received azithromycin compared with amoxicillin, particularly among those with a high baseline risk for cardiovascular disease. Subsequently, the Food and Drug Administration (FDA) 10 and pharmaceutical manufacturer issued public safety notifications warning of QT prolongation risks with azithromycin. Researchers from Denmark then reported that in comparison with penicillin V, azi...

Macrolide antibiotics and the risk of ventricular arrhythmia in older adults

“…These studies vary in patient age, sex and comorbidity. Two studies reported no significant increase in the risk of ventricular arrhythmia associated with macrolide use relative to other antibiotics after 10 7 and 30 15 days of follow-up, although Rao and colleagues 7 reported an increased risk during the first 5 days of treatment only. The 7 remaining studies did not examine arrhythmia risk; however, 1 study did report a higher risk of cardiac events.…”

“…15,17,18 Similar to our results, 2 studies reported macrolide antibiotics to be associated with a lower risk of all-cause mortality than nonmacrolide antibiotics. 15,18 Rao and colleagues 7 reported an increased risk of allcause mortality during the first 5 days of treatment, but not for treatment days 6 to 10. We used the quality checklist developed by Downs and Black 55 to assess the reporting, external validity, internal validity and statistical power of the prior 9 studies (Appendix 12, available at www.cmaj.ca/lookup/ suppl/doi:10.1503/cmaj.150901 /-/DC1).…”

“…6 Findings from this study were supported by case reports and other published studies. [7][8][9][10][11][12] Other frequently used macrolide antibiotics, such as clarithromycin and erythromycin, have also been associated with QT interval prolongation. 11,13,14 Recent studies suggest that these regulatory warnings are overstated.…”

2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death

“…Leczenie kilkoma antybiotykami, takimi jak chinolony i azytromycyna, istotnie zwiększa ryzyko zgonu i zaburzeń rytmu serca [125,[745][746][747]. Wykazano, że inne antybiotyki z grupy makrolidów, w tym erytromycyna i klarytromycyna (które są również metabolizowane przez izoenzym 3A4 cytochromu P450), zwiększają ryzyko wielokształtnego VT i zgonu z przyczyn sercowych, zwłaszcza u kobiet [748].…”

Macrolides use and the risk of sudden cardiac death

“…To better examine the link between macrolide treatment and plaque formation, the duration of follow-up should be at least several months because it often takes months to years for plaque formation to occur. However, for patients taking macrolides to treat common respiratory infections or soft-tissue infections, the duration of follow-up is usually no more than 1 month [28,29]. It is difficult to identify the cardiovascular death risk related to plaque rupture in such a short time.…”