A New Risk with an Older Drug

Summarized by Robert W. Griffith, MD
October 29, 2004

Introduction

Erythromycin is the main representative of a class of broad-spectrum antibiotics called macrolides, which have been widely used since the 1950s. It's always been considered largely free of side effects. Occasionally, however, cases of 'torsades de pointes' have been reported with its use. Torsades de pointes means, literally, 'twisting of the points', something which appears on the electrocardiogram (EKG) tracing. Its occurrence is associated with another EKG change - prolongation of the time between the Q wave and the T wave. Most cases of torsades de pointes are hereditary, but it has also been linked to the use of several drugs.

Torsades de pointes is a cardiac arrhythmia, that is to say, a disorder of the normal rhythmic contraction of the heart muscle. Its presence is linked to incidents of sudden death. This has led researchers in Tennessee to try to estimate the possible risk to patients taking erythromycin by mouth of developing cardiac arrhythmia and sudden cardiac death. They were particularly interested to see if there was an increased risk if the patient was taking another type of drug (CYP3A inhibitors) in addition to erythromycin.¹ Their findings are published in the New England Journal of Medicine, and summarized here.

What was done

A large number of Tennessee Medicaid enrollees were identified who had their medical records analyzed between 1988 and 1993. Records of their medications were available, as well as their cause of death, if they had died.

Attention was focused on the intake of oral erythromycin and strong CYP3A inhibitors (antifungal agents, two antihypertensive calcium antagonists [diltiazem and verapamil], and troleandomycin - another antibiotic). In addition, the use of amoxicillin, another broad spectrum antibiotic, was noted.

What was found

There were approximately 1,250,000 person-years of follow-up, i.e. this was the total number of years that at least one person was studied. During this period, there were 1476 cases of sudden death from cardiac causes.

The rate of sudden death from cardiac causes was twice as high in patients who were currently using erythromycin as among those not using the antibiotic. On the other hand, there was no increase in sudden death in former users of erythromycin, or in those taking amoxicillin. When the risk of sudden death was estimated in people using erythromycin together with one of the CYP3A inhibitors, it was found to be five times greater. There was no increased risk, however, in people using amoxicillin together with a CYP3A inhibitor drug.

What do these findings teach us?

First, this study shows that doctors should be cautious in prescribing erythromycin to anyone taking a drug that's also a strong CYP3A inhibitor. This isn't very likely to happen, in fact, because doctors and pharmacists receive plenty of information on possibly dangerous drug interactions, and drugs with such an action (CYP3A inhibition) are all generally labeled as such.

Second, the use of erythromycin should probably be reduced. There are today few indications for its use where another broad spectrum antibiotic couldn't be prescribed instead.

Finally, the surprising results uncovered by this study show that, even fifty years after a drug's introduction, its full side-effect profile may not be a complete picture. There are no therapeutic roses without thorns, and absolute safety of medications is a myth. It's up to everyone concerned to be aware of the risks, as they become discovered, and react accordingly - balancing the known benefits against the known risks.

Source

• Oral erythromycin and the risk of sudden death from cardiac causes. WA. Ray, KT. Murray, S. Meredith,  et al., N Engl J Med, 2004, vol. 351, pp. 1089--1096

Footnotes
1. Erythromycin is broken down (metabolized) in the liver by the enzyme cytochrome P-450 3A (CYP3A). This process may be slowed by drugs which have a CYP3A-inhibiting action, allowing erythromycin to accumulate and reach 'toxic' levels.

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