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 warned on Wednesday.

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 U.S. 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.