Tochigi, Japan—For more than a dozen years, the FDA has required “black-box” warnings that fluoroquinolone antibiotics can increase risk of tendinitis and tendon rupture in some patients. 

New studies are raising questions on how universal that concern should be.

A recent investigation from Japan looked at whether use of third-generation fluoroquinolones is associated with occurrence of Achilles tendon rupture. The study, published in Annals of Family Medicine, used a case series analysis in which patients served as their own control.

Jichi Medical University researchers used administrative claims data to identify 504 residents in a single Japanese prefecture who were enrolled in National Health Insurance and Elderly Health Insurance from April 2012 to March 2017 and were diagnosed with Achilles’ tendon rupture after receiving an antibiotic prescription.

The study team categorized antibiotics into three groups: first- and second-generation fluoroquinolones, third-generation fluoroquinolones, and nonfluoroquinolones.

Analysis was based on 504 patients with Achilles tendon rupture who had received antibiotic prescriptions. Risk of rupture was not significantly elevated during exposure to third-generation fluoroquinolones (IRR = 1.05; 95% CI, 0.33-3.37) and nonfluoroquinolones (IRR = 1.08; 95% CI, 0.80-1.47).

On the other hand, researchers report that risk was significantly elevated during exposure to first- and second-generation fluoroquinolones (IRR = 2.94; 95% CI, 1.90-4.54). Sex and recent corticosteroid use did not appear to affect the results.

“Our analysis showed that third-generation fluoroquinolone use was not associated with an increased risk of Achilles tendon rupture,” the authors wrote. “These antibiotics may be a safer option for patients in whom this risk is elevated, such as athletes.”

A retrospective observational study late last year from the National Library of Medicine sought to assess the association of fluoroquinolone use with tendon ruptures compared with no fluoroquinolone and that of the four most commonly prescribed nonfluoroquinolone antibiotics in the United States.

To do that, researchers focused on more than a million Medicare fee-for-service beneficiaries, reviewing inpatient and outpatient, prescription-medication records.

Information about use of seven oral antibiotics—fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) and amoxicillin, amoxicillin-clavulanate, azithromycin and cephalexin—was extracted. The study team also looked at all tendon ruptures combined, and three types of tendon ruptures by anatomic site, Achilles tendon rupture, rupture of rotator cuff, and other tendon ruptures that occurred in 2007–2016.

Results published in BMJ Open indicate that, of three fluoroquinolones, only levofloxacin was associated with a significant increased risk of tendon ruptures—16% (HR = 1.16; 95% CI, 1.06-1.28) and 120% (HR = 2.20; 95% CI, 1.50-24) for rotator cuff and Achilles’ tendon rupture, respectively, in the 30-day or less window. Ciprofloxacin (HR = 0.96; 95% CI, 0.89-1.03) and moxifloxacin (HR = 0.59; 95% CI, 0.37-0.93) exhibited no increased risk of tendon ruptures combined, however, the researchers report.

An important finding was that, among the nonfluoroquinolone antibiotics, cephalexin use was linked to increased risk of combined tendon ruptures (HR = 1.31; 95% CI, 1.22-1.41) and modest-to-large risks across all anatomic rupture sites (HRs: 1.19-1.93) during the time period. “Notably, the risk of levofloxacin never exceeded the risk of the non-fluoroquinolone, cephalexin in any comparison,” the authors advise.

“In our study, fluoroquinolones as a class were not associated with the increased risk of tendon ruptures,” the researchers point out. “Neither ciprofloxacin nor moxifloxacin exhibited any risk for tendon ruptures. Levofloxacin did exhibit significant increased risk. Cephalexin with no reported effect on metalloprotease activity had an equal or greater risk than levofloxacin; so we question whether metalloprotease activity has any relevance to observed associations with tendon rupture.”

They add, “Confounding by indication bias may be more relevant and should be given more consideration as explanation for significant associations in observational studies of tendon rupture.”

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