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Mixing antibiotic may be risky
Sep 9, 2004
Doctors have known for years that the antibiotic erythromycin can, in rare cases, spark an abnormal and sometimes fatal heartbeat. But combining it with several common drugs may dramatically increase that risk, researchers have warned.
Their analysis of 1,476 sudden deaths in Tennessee found a fivefold increase in the chance of dropping dead from a heart attack among people taking erythromycin plus one of a handful of drugs.
Yet even erythromycin, if used alone, doubled the risk of sudden death, said the team, led by Wayne Ray of the Vanderbilt University School of Medicine in Nashville.
"We were very surprised. We were expecting maybe a slight increase in deaths, if anything," he told Reuters.
The drug is a general-purpose antibiotic that is commonly prescribed. Between 1970 and 1996, 49 cases of erythromycin-related fatal or life-threatening heart rhythm problems were reported to the US Food and Drug Administration.
More recently, research has shown that some drugs can double the time it takes for the body to break down erythromycin, increasing the risk that the antibiotic will disrupt the heart's rhythm.
But until the new study, published in this week's edition of the New England Journal of Medicine, the scope of the erythromycin risk had not been assessed.
"People knew that, in theory, this might pose a problem, but this is the first study to document serious outcomes," Ray said.
Two of the drugs found to interact with erythromycin are fairly common.
One is diltiazem, also known as Cardizem, which is prescribed to fight the chest pain of angina, lower high blood pressure and, at times, restore circulation to fingers and toes in people with Raynaud's syndrome. Diltiazem is also sold under the brand names Tiazac and Dilacor.
The second drug is verapamil, sold under brand names like Calan and Isoptin. It is also used for heart and blood pressure problems, but can be prescribed for migraines, asthma, manic depression, and panic attacks.
The problem also applies to fungus-fighting drugs that contain nitromidazole. Once seldom used, those medicines are often given to people with HIV, the AIDS virus. They have generic names like fluconazole, ketoconazole and itraconazole, Ray said.
But it's not just the drugs that enhance the risk of erythromycin, Ray said. Drinking grapefruit juice also keeps the antibiotic in the body longer and may pose a risk.
"The typical person and their doctor should just avoid these combinations whenever possible," he said.
ABSTRACT
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.
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.
Source Information
From the Division of Pharmacoepidemiology, Department of Preventive Medicine (W.A.R., S.M., K.H.), and the Departments of Medicine and Pharmacology, Divisions of Cardiology (K.T.M.), Clinical Pharmacology (K.T.M., S.S.N., C.M.S.), and Rheumatology (C.M.S.), Vanderbilt University School of Medicine; and the Geriatric Research, Education, and Clinical Center, Nashville Veterans Affairs Medical Center (W.A.R.) — both in Nashville.
Address reprint requests to Dr. Ray at cindy.naron@vanderbilt.edu.
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