乌鸦传媒

Exposure to fluoroquinolone antibiotics is linked to a heightened risk of left-sided valvular regurgitation, analysis of adverse event reporting data showed.

Fluoroquinolones overall held a significant 45% higher likelihood of valvular regurgitation events reported to the FDA Adverse Events Reporting Systems (FAERS) than did other drugs from 2004 to 2018, reported Mahyar Etminan, PharmD, MSc, of the University of British Columbia in Vancouver, and colleagues in the .

Current users of fluoroquinolone antibiotics carried, for example:

• 2.40 times greater risk of developing mitral and aortic regurgitation, compared to patients on the narrow-spectrum, penicillin-group antibiotic amoxicillin
• 1.75 times greater risk when compared to patients on azithromycin (Zithromax), a broad-spectrum, macrolide-type antibiotic used for more severe infections

"Patients with aortic regurgitation should not be prescribed an fluoroquinolone unless absolutely necessary where benefits outweigh risks," Etminan told 乌鸦传媒.

"Further studies are needed to fully characterize the incremental risk of valvular heart disease and other adverse events in patients treated with fluoroquinolones," the authors concluded.

The FDA should use its database of insurance and electronic health record data to assess the connection between valvulopathy and fluoroquinolones in detail, noted Robert Califf, MD, of Duke University School of Medicine in Durham, North Carolina, in an .

Until this work is complete, there should be a considerable reduction in fluoroquinolone use, and these prescriptions should only be used as a last resort, he added.

But there's a bigger issue too, the former FDA commissioner argued. "What does it say about our system when a class of drugs -- one that has been on the market for over 20 years -- continues to have new, concerning information emerge in the face of 32.5 million outpatient prescriptions in the United States in 2015 alone?"

Although the FDA has warned about aortic dissection or aneurysm and other risks that appear to arise from disruption of collagen and connective tissue by the fluoroquinolones, Califf suggested that further such surprises are likely given the use of accelerated development and approval pathways.

"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," Califf wrote.

The researchers evaluated 125,020 control subjects and 12,505 cases. The cohort was 56.3% male, and mean age was 58.1 years. For the matched nested case-control study, the investigators used the U.S. PharMetrics Plus database (IQVIA), a nationwide insurance claims database of more than 150 million individuals. For the disproportionality analysis, they collected information from the FDA's adverse reporting system database on 102 valvular regurgitation events with fluoroquinolones and 6,099 reports of these with other drugs.

Current fluoroquinolone exposure was determined by an active prescription at index or 30 days before the event date. Recent fluoroquinolone exposure was considered as fluoroquinolone use from 31 to 60 days, while past exposure was from 61 to 365 days before the event date.

Recent fluoroquinolone use (31 to 60 days after exposure) was significantly linked to valvular regurgitation (adjusted RR 1.47, 95% CI 1.03-2.09), whereas past use beyond 60 days was not (aRR 1.06, 95% CI 0.91-1.21).

Patients with myocarditis, strep throat, endocarditis, rheumatic fever, mitral stenosis, rheumatic aortic stenosis, rheumatic heart disease, disease of tricuspid valve, and other diseases of mitral valve were excluded.

Limitations of the study included that the study cohort can only be generalized to those that are able to afford private health insurance. Etminan and colleagues also noted a disproportionality assessment usually cannot demonstrate cause and effect associations, primarily due to its possible reporting bias and cross-sectional nature, so they used this method to identify potential case reports and to assess a potential signal that could later be tested using a case-control study.

Another limitation was that even though the adjusted crude rate ratios were similar, showing that the findings were robust to measured confounders, the researchers did not have data on unmeasured confounders, they continued.

Califf cautioned that the large population size and deep clinical detail of the dataset used in the study wouldn't fully overcome bias from potential confounders, and he agreed with the researchers in their call for further research to refute or verify the results.