University of South Carolina Study

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

1. Gowtham A. Rao, MD, PhD, MPH1,2,3,4⇑,
2. Joshua R. Mann, MD, MPH1,3,
3. Azza Shoaibi, BPharm, MPH1,2,3,4,
4. Charles Lee Bennett, MD, PhD, MPP2,3,4,
5. Georges Nahhas, MPH3,
6. S. Scott Sutton, PharmD2,4,
7. Sony Jacob, MD2 and
8. Scott M. Strayer, MD, MPH1

+ Author Affiliations

1. ¹Department of Family and Preventive Medicine, School of Medicine, University of South Carolina, Columbia, South Carolina
2. ²William J.B. Dorn Veterans Affairs Medical Center, Columbia, South Carolina
3. ³School of Public Health, Columbia, University of South Carolina, South Carolina
4. ⁴South Carolina College of Pharmacy, Columbia, South Carolina

1. CORRESPONDING AUTHOR: Gowtham A. Rao, MD, PhD, MPH, Department of Family and Preventive Medicine, School of Medicine, University of South Carolina, 3209 Colonial Dr, Columbia, SC 29203, gowtham.rao@va.gov

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.

METHODS We 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.

Key Words:

• azithromycin
• levofloxacin
• amoxicillin
• arrhythmia
• cause of death

• Received for publication May 16, 2013.
• Revision received August 30, 2013.
• Accepted for publication September 12, 2013.

• © 2014 Annals of Family Medicine, Inc.