Study: Common antibiotic can trigger cardiac deaths
The Associated Press
A common antibiotic prescribed for 50 years to treat everything from strep throat to syphilis dramatically increases the risk of cardiac arrest, especially when taken with certain newer, popular drugs, a study found.
The study shows the need for continuing research on the safety of older medicines such as the widely prescribed drug, erythromycin, including how they interact with newer medicines, said researcher Wayne A. Ray, a professor of preventive medicine at Vanderbilt University School of Medicine in Nashville.
In patients taking erythromycin along with other drugs that increase its concentration in the blood, the risk of cardiac death was more than five times greater, Ray and his colleagues found. That translates to six deaths for every 10,000 people taking erythromycin for the typical two weeks while on the other drugs.
"This is an unacceptably high risk," Ray said.
Nobody realized the magnitude of the problem before, said Dr. Muhamed Saric, a cardiologist and director of the electrocardiology laboratory at University of Medicine and Dentistry of New Jersey in Newark. "It was thought that erythromycin is a generally safe drug."
Most heart doctors knew erythromycin alone carried a slight risk because of some individual reports on patient deaths, mostly in people who took the drug intravenously. However, family doctors are less likely to know about it, Saric said.
This study, in Thursday's New England Journal of Medicine, was the first to systematically document the risk. It focused on much more commonly used erythromycin pills — usually sold as a generic — along with certain medicines for infections and calcium channel blockers for high blood pressure.
Ray said the danger seems to come from other drugs slowing the breakdown of erythromycin, which increases its concentration. At high levels it traps salt inside resting heart muscle cells, prolonging the time until the next heartbeat starts, and sometimes triggering an abnormal, potentially fatal, rhythm.
The findings show doctors should choose an alternative antibiotic, Ray said, at least when prescribing the drugs that interact. Amoxicillin, another popular antibiotic, showed no cardiac risk.
"There are other antibiotics that provide the same antimicrobial activity without building up in the blood the way erythromycin does," Ray said.
Ray's team of doctors and nurses spent years studying detailed medical records of 4,404 Medicaid patients from Tennessee who apparently died of cardiac arrest from 1988-93. The team confirmed 1,476 cases of cardiac arrest, then studied Medicaid's records of each patient's medication use.
Only a small number of patients had taken both erythromycin and any of the antibiotics or heart drugs carrying a risk.
Still, three of them died. Statistically, it was extremely unlikely those deaths were due to chance, according to Ray and other experts.
The deaths were in patients taking verapamil or diltiazem, both blood pressure drugs sold as generics and also under various brand names: Verelan and Isoptin for verapamil, Cardizem and Tiazac for diltiazem.
Other drugs posing a risk with erythromycin, Ray said, include the antibiotic clarithromycin, sold under the Biaxin brand; fluconazole, or Diflucan, for vaginal yeast infections; and the antifungal drugs ketoconazole (Nizoral) and itraconazole (Sporanox). Pills and injections of the drugs, but not topical forms, carry the risk.
"People may be taking these medications for years, and they develop a throat infection and someone gives them erythromycin, and that's it," Saric said.
The AIDS drugs called protease inhibitors and grapefruit juice also should be avoided, Ray said, because they, too, can boost blood levels of erythromycin.
Erythromycin, in turn, boosts blood levels of verapamil and diltiazem, which slow heart rate, and thus can worsen abnormal rhythms, said American Heart Association spokeswoman Dr. Nieca Goldberg. The findings show why people should keep a list of medications they take and share them with all their doctors, said Goldberg, chief of women's cardiac care at Lenox Hill Hospital in New York City.
About 340,000 Americans die each year of cardiac arrest, also called sudden cardiac death, according to the heart association. The condition is caused by abnormal heart rhythm, usually when the heart begins beating too rapidly or too chaotically to efficiently pump blood.
Goldberg noted the once-blockbuster nonsedating allergy drug Seldane was taken off the market, in 1998, after reports linking it to sudden cardiac death due to the same types of abnormal heart rhythms.
The study was funded by the Food and Drug Administration, two other federal health agencies and the drug company Janssen Pharmaceutica, which makes Nizoral and Sporanox. Ray and two other researchers have received consulting fees from other pharmaceutical or health products companies.
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Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes
Wayne A. Ray, Ph.D., Katherine T. Murray, M.D., Sarah Meredith, M.B., B.S., Sukumar Suguna Narasimhulu, M.B., B.S., M.P.H., Kathi Hall, M.S., and C. Michael Stein, M.B., Ch.B.
ABSTRACT
Background Oral erythromycin prolongs cardiac repolarization and is associated with case reports of torsades de pointes. Because erythromycin is extensively metabolized by cytochrome P-450 3A (CYP3A) isozymes, commonly used medications that inhibit the effects of CYP3A may increase plasma erythromycin concentrations, thereby increasing the risk of ventricular arrhythmias and sudden death. We studied the association between the use of erythromycin and the risk of sudden death from cardiac causes and whether this risk was increased with the concurrent use of strong inhibitors of CYP3A.
Methods We studied a previously identified Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. The CYP3A inhibitors used in the study were nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin; each doubles, at least, the area under the time–concentration curve for a CYP3A substrate. Amoxicillin, an antimicrobial agent with similar indications but which does not prolong cardiac repolarization, and former use of erythromycin also were studied, to assess possible confounding by indication.
Results The multivariate adjusted rate of sudden death from cardiac causes among patients currently using erythromycin was twice as high (incidence-rate ratio, 2.01; 95 percent confidence interval, 1.08 to 3.75; P=0.03) as that among those who had not used any of the study antibiotic medications. There was no significant increase in the risk of sudden death among former users of erythromycin (incidence-rate ratio, 0.89; 95 percent confidence interval, 0.72 to 1.09; P=0.26) or among those who were currently using amoxicillin (incidence-rate ratio, 1.18; 95 percent confidence interval, 0.59 to 2.36; P=0.65). The adjusted rate of sudden death from cardiac causes was five times as high (incidence-rate ratio, 5.35; 95 percent confidence interval, 1.72 to 16.64; P=0.004) among those who concurrently used CYP3A inhibitors and erythromycin as that among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications. In contrast, there was no increase in the risk of sudden death among those who concurrently used amoxicillin and CYP3A inhibitors or those currently using any of the study antibiotic medications who had formerly used CYP3A inhibitors.
Conclusions The concurrent use of erythromycin and strong inhibitors of CYP3A should be avoided.
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