Fluoroquinolone use predicts aortic, mitral regurgitation

People who currently take or have recently taken fluoroquinolones face higher odds of aortic and mitral regurgitation, according to a report out of Canada.

Fluoroquinolones—a common class of antibiotics that includes ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin—have long been favored over other therapies because of their spectrum of antibacterial activity and high oral absorption, Mahyar Etminan, PharmD, MSc, and colleagues wrote in the Journal of the American College of Cardiology. But recent evidence has called the safety of the drugs into question, with reports of retinal detachment, peripheral neuropathy, aortic aneurysm and cardiac arrhythmias prompting a warning label from the FDA.

“The putative mechanism behind these adverse events is fluoroquinolones’ in vitro ability to damage connective tissue and collagen throughout the body,” Etminan, lead author of the paper and an associate professor at the University of British Columbia in Vancouver, and co-authors wrote. “Like the aorta, the healthy human aortic and mitral valves are also made up of collagen and connective tissue delicately woven in its extracellular matrix that is integral to its function. When the valve connective tissue is compromised, it can lead to mitral valve prolapse and mitral regurgitation.”

Hypothesizing that fluoroquinolones might damage that connective tissue and increase patients’ risk of valvular regurgitation, the authors undertook a matched nested case-control study of 12,505 fluoroquinolone users and 125,020 controls. Current fluoroquinolone exposure was defined as an active prescription at the study’s baseline or 30 days prior to the index date; recent exposure was defined as fluoroquinolone use within 31 to 60 days of the study’s baseline.

The researchers calculated and compared rate ratios (RR) for fluoroquinolones to users of amoxicillin and azithromycin, a semisynthetic macrolide antibiotic. The adjusted RRs for current fluoroquinolone users compared with amoxicillin and azithromycin users were 2.40 and 1.75, respectively.

Adjusted RRs for recent and past fluoroquinolone users when compared with amoxicillin were 1.47 and 1.06, respectively.

“If these estimates are accurate, then given the serious nature of regurgitant valvular lesions, the existing guidance that alternative antibiotic regimens should be used when possible is further reinforced,” Robert M. Califf, MD, of the Duke University School of Medicine, wrote in an editorial comment. “On the other hand, if the many known complexities and limitations of observational analyses of spontaneous adverse event reports have led to an erroneous estimate of harm when none exists, a highly effective class of antibiotics may have been inappropriately relegated to ‘last resort’ status.”

Califf said he thought Etminan and his team “overstepped a bit” by implying their large sample size and detailed databases enabled them to overcome bias in the study, but said he appreciated they acknowledged that their findings needed to either be confirmed or refuted in future studies.

According to Califf, next steps should involve the FDA using their Sentinel system to analyze the relationship between fluoroquinolones and valvulopathy in further detail. Until then, he suggested a major reduction in the use of fluoroquinolones, calling for them “only as a last resort.”

“In the longer run, the FDA and the larger clinical ecosystem should accelerate the creation of the superior information infrastructure described in the previous text,” Califf wrote. “We are facing a critical need for an arsenal of effective, well-characterized antibiotics to deal with the evolving global problem of antibiotic resistance, and only an efficient, responsive, high-quality system of evidence generation will be able to supply it in a manner that supports a rational balance of safety and effectiveness.”