Study: VA Clinicians Should Consider Antibiotic Risks Before Prescribing

By Brenda L. Mooney

COLUMBIA, SC — Veterans prescribed amoxicillin over a nearly 13-year period were less likely to be diagnosed with potentially fatal heart rhythms than those using either azithromycin or levofloxacin, according to new research.

The study, published recently in the Annals of Family Medicine, found that, in contrast to amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1-5, but not 6-10. Levofloxacin, usually dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.1

Researchers led by Gowtham A. Rao, MD, PhD, MPH, of the William J.B. Dorn VAMC and the University of South Carolina, both in Columbia, embarked on the study following a 2013 Food and Drug Administration warning on azithromycin use and the risk of potential fatal heart rhythms.

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“Risks and benefits of antibacterial therapies should be considered when making prescription decisions,” the authors suggested. “As compared with amoxicillin, there was higher risk of death associated with azithromycin therapy administered to U.S. veterans. There are usually multiple antibiotic choices available for older patients, especially those with cardiac comorbidities; physicians may consider prescribing medications other than azithromycin and levofloxacin.”

In 2011, outpatient prescriptions for azithromycin were written for more than 40 million patients in the United States, according to the article.

Post-marketing surveillance reports, as well as published studies, found cardiovascular risks, and the FDA approved revisions to azithromycin product labels regarding risks of QT prolongation. In March 2013, the FDA announced the warning was supported by results of a study conducted by the manufacturer of azithromycin, which found that azithromycin prolonged the QT interval.

Large Cohort of Veterans
For this study, investigators evaluated a large cohort of veterans receiving care at the VA between 1999 and 2012 seeking to determine if cardiac arrhythmia and mortality risks are observed in older male patients receiving azithromycin, amoxicillin and levofloxacin. The study analyzed more than 1.6 million unique antibiotic prescriptions, including 979,380 for amoxicillin, 201,798 for levofloxacin, and 594,792 for azithromycin.

The veterans studied were between 30 and 74 years old, averaging 56.8 years old. Most were white and male, with 78% having a history of current or prior tobacco use.

Primary and secondary endpoints were all-cause mortality and serious cardiac arrhythmia, defined as any inpatient or emergency department encounter/utilization with diagnoses such as long QT syndrome, ventricular tachycardia, ventricular fibrillation, ventricular flutter or cardiac arrest.

The three antibiotics studied were most commonly prescribed for ear-nose-throat infections, chronic obstructive pulmonary disease, respiratory infections, pneumonia and genitonurinary infections, according to the study.

Overall, the results indicated, a higher risk of death was associated with azithromycin and levofloxacin therapies compared with amoxicillin.

Specifically, the researchers found a short-course of azithromycin therapy was associated with statistically significant hazard ratios of 1.48 for mortality risks and 1.77 for serious arrhythmia risks within the first five days of treatment. That the risk of these events was not significantly increased for days 6-10 likely was explained by the traditional five-day prescription for azithromycin, the authors pointed out.

Levofloxacin also had statistically significant hazard ratios of 2.49 for mortality risk and 2.43 for serious arrhythmia risk, when compared with amoxicillin, the report notes. The increased risk lasted the full 10 days for which the antibiotic is usually prescribed.

“Our results provide support for recent safety announcements from the manufacturer and the Food and Drug Administration (FDA),” the authors wrote.

They also pointed out that past studies have been mixed on the issue — a Danish study of young and early middle age people found that azithromycin use was not associated with increased risk of death compared to penicillin, whereas a study looking at U.S. Medicaid recipients showed results in line with the VA study.

“These specialized populations may have a higher disease burden, especially cardiovascular disease, compared with the general population of Denmark,” the report said. “Taken together, the studies suggest that short courses of azithromycin may be associated with development of serious arrhythmias or sudden death in certain populations.”

Study authors also emphasized out that their report was not intended to make recommendations on antibiotic usage. “It must be kept in mind, however, that we investigated only three specific antibiotics,” they wrote. “We cannot determine from this study which alternative antibiotics might be safer.”

1Rao GA, Mann JR, Shoaibi A, Bennett CL, et. al. Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death. Ann Fam Med. March/April 2014 vol. 12 no. 2. 121-127. doi: 10.1370/afm.1601

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