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Oral Erythromycin and the Risk of Sudden Death From Cardiac Causes

Background: Erythromycin is a very common macrolide antibiotic often used for upper respiratory infections. Clinical trials have demonstrated that Erythromycin can prolong the QT interval resulting in torsades de pointes and possibly even sudden cardiac death.

Objectives: The objective of this study was to evaluate the use of erythromycin in association with the development of ventricular tachyarrhythmia that resulted in sudden cardiac death. The question that was posed in the study was whether or not the risk of sudden cardiac death was increased from the use of Erythromycin and whether this use was altered by the combination of Erythromycin and CYP 3A inhibitors.

Methods: This was a cohort study that was conducted to include patient information from January 1, 1988 to December 31, 1993. The patients that were selected for this study were cohorts of Tennessee Medicaid enrollees. The inclusion criteria is as follows:

Tennessee Medicaid enrollees who were enrolled for at least 365 consecutive days, patients between the ages of 15 and 84, no evidence of a life-threatening cardiac illness, and the study cases that were involved should include a witnessed collapse or evidence that the person was alive within 24 hours before the death was reported. Exclusion criteria included patients who took both amoxicillin and erythromycin within 1 year, persons with pre-existing cardiac conditions, residence in a long term care facility, administration of IV erythromycin, and patients receiving protease inhibitors.

Results: The study had 5305 patient years of current use of Erythromycin and 111,779 patient-years of former use. As well as 6846 patient-years of current use of Amoxicillin. The mean age of the patient population was 45 years. The results were reported with 95% confidence intervals- estimated with the use of Poisson regression models. The rate of sudden death from cardiac causes was twice as high among current users of erythromycin incidence-rate ratio of 2.01 (95% CI 1.08 to 3.75) p=0.03) when compared to those who did not use any of the study antibiotics. There appeared to be no significant increase in risk of sudden death among former users incidence-rate ratio 0.89 (95% CI 0.72 to 1.09) p=0.26. or current users of amoxicillin- incidence-rate 1.18 (95% CI 0.59 to 2.36) p=0.65. There was however a marked increase in risk of sudden death between those who used Erythromycin AND CYP 3a inhibitors. Incidence-rate ratio was 5.35. (95% CI 1.72 to 16.64) p=0.004.

Strengths: Some of the strengths of the study include the editorial board that reviewed the study, the limitations of the study are addressed, inclusion and exclusion criteria are well defined, the baseline characteristics were similar between patients and patient selection is well defined.

Weaknesses: The study was conducted as a cohort study rather than a controlled randomized clinical trial, thus results aren’t as strong as they would have been for an experimental study. The study data did not include information regarding behavioral factors such as smoking, high cholesterol, lack of physical activity, or higher body-mass index. The sample size was insufficient to study the independent association of the drugs that were evaluated. It is difficult from the details given from the Medicaid databases to assess compliance.

Conclusion: In my opinion, the study results are not very convincing. I do feel that caution should be taken when giving Erythromycin with a CYP 3A inhibitor; however this has been a subject of concern for quite some time. The study design lacked conviction and there should be better-designed studies conducted before making conclusions regarding the administration of erythromycin.

Reference: Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral Erythromycin and the risk of sudden death from cardiac causes. New England Journal of Medicine 2004;351:1089-96.

Aimee Cross, PharmD. Candidate