The widely used antibiotic erythromycin increases the risk of sudden cardiac death, particularly when taken at the same time as medicines including protease inhibitors, antifungals and antidepressants, that are metabolised using the cytochrome P-450 3A pathway, according to a United States study published in the September 9th edition of the New England Journal of Medicine.
Erythromycin is a broad-based antibiotic and oral doses of the drug are used to treat a wide range of bacterial infections across the population, including in HIV-positive individuals. The drug is considered to have a good safety profile, the most widely reported side-effects being stomach cramps, nausea and diarrhoea.
However, there have been case reports of sudden cardiac deaths in patients treated with both oral and intravenous doses of erythromycin. The antibiotic prolongs cardiac repolarisation, which can cause potentially fatal arrhythmias.
Drug interactions may increase the risk of sudden cardiac death amongst individuals taking erythromycin. Erythromycin is metabolised using the P-450 3A (CYP3A) pathway which is also used by protease inhibitors, antifungal agents including fluconazole, ketoconazole, and intraconaole (all of which are widely used in HIV-positive individuals), and some antidepressants. These agents can increase plasma concentrations of erithromycin.
Investigators from the US conducted a retrospective review of the medical records of individuals using Medicaid in Tennessee between 1988 and 1993. The investigators wished to determine if the oral use of erythromycin increased the risk of suddent cardiac death, and if the use concurrent use of drugs that use P-450 3A (CYP3A) to be metabolised increase the risk further. The study identified 5305 person-years of erithromycin use during 1,249,943
person-years of follow-up.
HIV-positive individuals were excluded from the investigators’ analysis, however, they emphasise that “protease inhibitors are potent CYP3A inhibitors.”
They identified 1476 cases of sudden cardiac death that occurred outside hospitals, having excluded all deaths in individuals with an underlying heart condition and those where another potential cause of sudden cardiac arrest, such as pneumonia, had been recorded. Where sufficient information about medical history and the circumstances was lacking, deaths were excluded from the analysis.
Amongst all patients who received erithromycin, there were ten sudden cardiac deaths during 5305 person-years of follow-up. Among patients using CYP3A inhibitors at the same time as erithromycin, there were three sudden cardiac deaths during 194 person-years of follow-up, or 15.5 deaths per 1000 person-years. The incidence of sudden cardiac death across the whole cohort was 1.2 deaths per 1000 person-years, and the difference in the rate of sudden cardiac death between the whole cohort and those who received both erithromycin and a CYP3A inhibitor was highly significant (p = 0.004) despite the small number of deaths recorded.
The risk of sudden cardiac death amongst patients currently using erythromycin was twice as high as that for individuals not taking the drug (incidence-rate ratio 2.01, p = 0.03). Neither past use of the drug, nor use of amoxicillin, another broad-based antibiotic were associated with an increased risk of sudden cardiac death.
However, the investigators found that the risk of sudden cardiac death amongst concurrent users of erythromycin and other medication that inhibited CYP3A was five times higher (incidence-rate ratio 5.35, p = 0.004). Concurrent use of amoxicillin and CYP3A inhibitors did not increase the risk of sudden cardiac death.
The investigators conclude that the concurrent use of erythromycin and inhibitors of CYP3A should be avoided.
Ray WA et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 351: 1089-1096, 2004.