Azithromycin and the Risk of Cardiovascular Death

Abstract

BACKGROUND Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death. METHODS We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score–matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions). RESULTS During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P = 0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P = 0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P = 0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin. CONCLUSIONS During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.)

Principles of Judicious Antibiotic Prescribing for Upper Respiratory Tract Infections in Pediatrics

“…[49][50][51] A recent study highlighted risk of sudden death in adults treated with azithromycin, likely related to drug-associated prolongation of the QT interval. 24 Azithromycin is not a firstline antibiotic for any pediatric URI and is the antibiotic most likely to be used inappropriately (inadequate coverage for the most common pathogens causing AOM and sinusitis). 1 The incidence of C difficile colitis in hospitalized children has increased substantially during the past decade.…”

“…In recent years, several high-quality randomized controlled trials, meta-analyses, and new and updated clinical guidelines have been published that better define the effectiveness of antibiotic use for selected URIs, including AOM and acute bacterial sinusitis. [14][15][16][17][18][19][20][21][22][23] At the same time, new evidence highlighting the extent to which antibiotics lead to adverse events requiring medical attention [4][5][6] or potentially life-threatening events 24,25 has emerged.…”

Long-term macrolide treatment for chronic respiratory disease

“…This risk is particularly high in older COPD patients who are more likely both to have cardiac disease and to be taking other drugs that prolong the QTc interval. Although erythromycin and clarithromycin have been most commonly associated with cardiac arrhythmias [113], azithromycin should also be avoided in subjects with a high risk of baseline cardiovascular disease [114]. Macrolides also inhibit the cytochrome P450 (CYP)3A4 isoenzyme, resulting in increased serum levels of other drugs metabolised by this enzyme, such as statins, warfarin and amiodarone.…”

Macrolides use and the risk of sudden cardiac death

“…Although they have been in use for decades, macrolides are proposed to have the greatest potential among antibiotics to cause QT interval prolongation, torsades de pointes (TdP), and sudden cardiac death [3,4]. Although the absolute risk of sudden cardiac death is small, widespread macrolide use may lead to a considerable excess of sudden cardiac death [5].…”