Compared with amoxicillin, azithromycin is associated with an 82 percent higher risk of death from cardiovascular causes within five days of exposure and a 2.17-fold increased risk of death from other causes, according to a study published in June 2020 in JAMA Network Open. “For azithromycin and related macrolide antibiotics such as clarithromycin, prior reports have indicated that these drugs can alter the normal flow of electricity within the heart muscle and increase the risk of life threatening arrhythmias (irregular heartbeats),” says lead study author Jonathan Zaroff, MD, a staff cardiologist at Kaiser Permanente San Francisco Medical Center and an adjunct investigator for the Kaiser Permanente Division of Research. Results from previous studies have been mixed, however, with some pointing to an increased risk and others finding no connection between azithromycin and heart-related fatalities. Many earlier studies also were unable to examine other factors that might independently influence the risk of death from cardiovascular causes, such as the type of infection being treated with antibiotics, or determine the exact cause of death, Dr. Zaroff says.

Mixed Results From Previous Studies

An earlier study published in The New England Journal of Medicine found taking azithromycin for five days was associated with a 2.9-fold greater risk of cardiovascular death than taking no antibiotics at all, as well as an 85 percent higher risk of death from all causes. Based in part on safety concerns raised by this study, the U.S. Food and Drug Administration (FDA) warned against prescribing azithromycin to patients with known risk factors for ventricular arrhythmia, a type of abnormal heart rhythm. Since then, several other studies have linked azithromycin to an increased risk of cardiovascular-related deaths, serious heart rhythm abnormalities, or heart attacks, Zaroff and colleagues point out in their own paper. For example, one study of older patients with pneumonia published in the Journal of the American Medical Association tied azithromycin to a 17 percent increased risk of heart attacks. However, other studies have found the opposite — that there wasn’t any connection between azithromycin and cardiac deaths. For example, a study of Medicare beneficiaries published in April 2018 in the Journal of the American Heart Association found no link between macrolides, the family of antibiotics that includes azithromycin, and the risk of having or dying from cardiac events like heart attacks, strokes, or heart rhythm abnormalities. “Compared with prior studies, the current study had a greater ability to control for confounding factors such as the type of infection being treated with azithromycin, and we were also able to determine the exact cause of death in many cases,” Zaroff says.

While the absolute increased risk of cardiovascular-related death was small — only about 13 additional fatalities for every million azithromycin prescriptions — doctors should still weigh this risk against the benefits of azithromycin for pneumonia and other common infections, Zaroff says. “Physicians should individualize their recommendations based on whether or not a patient has heart disease and the nature and severity of the infection,” Zaroff says. For the study, researchers examined data on a total of 7.82 million antibiotic prescriptions through Kaiser Permanente in California from 1998 to 2014. This included 1.74 million azithromycin prescriptions and 6.09 million amoxicillin prescriptions for a total of 2.93 million individuals. A total of 485 people died within 10 days of getting a prescription for azithromycin or amoxicillin, including 256 individuals who died of cardiovascular causes. Among people who didn’t die of cardiovascular causes, the most common causes of death were lung disease, infection, cancer, and diabetes.

Limitations of the Study

The study wasn’t a controlled experiment designed to prove that azithromycin directly causes heart problems or fatalities. One limitation of the study is that it’s possible that the severity of infections treated with antibiotics impacted both the decision about whether to use azithromycin and the risk of cardiac-related deaths, the study team notes. Even so, the results add to a body of evidence suggesting that clinicians should avoid azithromycin for patients who are predisposed to certain kinds of heart rhythm problems, says Salim Virani, MD, PhD, a professor and director of the cardiology fellowship training program at Baylor College of Medicine in Houston, who wasn’t involved in the current study. Azithromycin can cause what’s known as a prolonged QT interval, when the electrical system in the heart takes longer than it should to recharge between beats. This delay is visible on an EKG, and can lead to a potentially fatal abnormal heart rhythm, says Dr. Virani. “This risk is especially high in those with preexisting heart disease and as one would expect,” Virani says. Even though the overall risk of heart-related deaths with azithromycin is relatively low, heart disease is quite common, making it crucial that patients are aware of this potential side effect, Virani adds. “If a patient has some form of heart disease or they are on any medications that can affect heart rhythm, they should mention it to the clinician,” Virani advises. “In most cases, there can be other medications that could be prescribed as there are many choices available.”

Testing Azithromycin for COVID-19

Despite potential heart risks, some scientists are currently conducting clinical trials to see if giving azithromycin to patients recently diagnosed with COVID-19 might help prevent severe infections that require hospitalization. Researchers at the University of California in San Francisco are recruiting 2,500 adults for a trial investigating azithromycin for this purpose. The study team said it’s possible that macrolides — the family of antibiotics that includes azithromycin — might help curb inflammation and viral replication in people with mild COVID-19 infections. But the National Institute for Allergy and Infectious Diseases (NIAID) halted another trial testing azithromycin in combination with hydroxychloroquine shut down early because not enough people enrolled. In a statement announcing the end of this trial, scientists said a move by the FDA to revoke emergency approval for hydroxychloroquine for hospitalized COVID-19 patients may have curbed participation in the NIAID study. RELATED: Scientists Fast-Track Research for Coronavirus Treatment and Vaccine And, an analysis of research to date on azithromycin and hydroxychloroquine for COVID-19 published in May 2020 in Circulation concluded that both medicines may independently increase the risk of potentially fatal heart rhythm disorders in COVID-19 patients. Patients given both drugs together had an even higher risk of these heart issues, researchers reported. In an article published in May 2020 in the Open Forum for Infectious Diseases, Jennifer Lighter, MD, and Vanessa Raabe, MD, of New York University School of Medicine in New York City, argue that heart risks make it unethical to test azithromycin for COVID-19 patients. “There is no justifiable preclinical or clinical evidence to suggest that the benefits of azithromycin for COVID-19 outweigh the risks of treatment,” they wrote.