title: Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Family and Preventive Medicine, School of Medicine, University of South Carolina, Columbia, South Carolina.
authors.forename: Gowtham A
authors.initials: GA
authors.lastname: Rao
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Mann
authors.forename: Azza
authors.initials: A
authors.lastname: Shoaibi
authors.forename: Charles Lee
authors.initials: CL
authors.lastname: Bennett
authors.forename: Georges
authors.initials: G
authors.lastname: Nahhas
authors.forename: S Scott
authors.initials: SS
authors.lastname: Sutton
authors.forename: Sony
authors.initials: S
authors.lastname: Jacob
authors.forename: Scott M
authors.initials: SM
authors.lastname: Strayer
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000401:mortality; D017963:Azithromycin / Q000009:adverse effects* / Q000627:therapeutic use; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D006801:Humans; D064704:Levofloxacin / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D014728:Veterans
chemical_list: D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D017963:Azithromycin
keywords: amoxicillin; arrhythmia; azithromycin; cause of death; levofloxacin