The link between fluoroquinolone antibiotics and aortic aneurysm (AA) was further strengthened by analysis of a U.S. commercial claims database.
Incidence of AA formation or dissection reached 7.5 per 10,000 prescription fills for fluoroquinolones at 90 days compared with 4.6 per 10,000 fills for comparator antibiotics (HR 1.20, 95% CI 1.17-1.24), according to Melina Kibbe, MD, and colleagues of the University of North Carolina at Chapel Hill. The study was published online in JAMA Surgery, where Kibbe is an editor.
Patients filling prescriptions for these medications were also more likely to undergo aneurysm repair (HR 1.88 vs other antibiotics, 95% CI 1.44-2.46).
The study suggests "fluoroquinolone use should be pursued with caution in all adults, not just in high-risk individuals" as recommended by the current FDA black box warning, Kibbe's group wrote.
"We wholeheartedly agree with the authors ... and we encourage the FDA to broaden their warning recommendations," argued Amanda Filiberto, MD, and Gilbert Upchurch, Jr., MD, both of the University of Florida in Gainesville, in an accompanying commentary.
In December 2018, the FDA updated its warning against fluoroquinolone use in people at increased risk of aortic disease based on cases reported to the FDA Adverse Event Reporting System and in four international epidemiological studies.
However, two studies published in September 2020 suggested that confounding -- by underlying infection type, surveillance bias, or coexisting infections -- may account for the perceived relationship between fluoroquinolones and AA in observational analyses.
Aneurysms would not be the only danger of these frequently prescribed drugs: fluoroquinolones carry warnings about associations with Clostridium difficile infection, nerve damage, mental health issues, and hypoglycemic coma.
For the present study, Kibbe and colleagues performed a retrospective analysis of IBM MarketScan health insurance claims from 2005 to 2017 for adults ages 18 to 64.
They found more than 47 million antibiotic fills, with the most common indications being upper respiratory tract infection, urinary tract infection, and skin or soft tissue infection.
One in five antibiotic fills were for fluoroquinolones (largely ciprofloxacin [Cipro] and levofloxacin [Levaquin]).
In total, there were 27,827,254 unique U.S. adults included, all with no known previous AA or dissection, no recent antibiotic exposure, and no recent hospitalization. Baseline differences between fluoroquinolone recipients (median age 47 years, 61.3% women) and controls (43 years, 59.5% women) largely dissipated after weighting.
Fluoroquinolone fills were tied specifically to excess abdominal AAs (HR 1.31, 95% CI 1.25-1.37) and iliac artery aneurysms (HR 1.60, 95% CI 1.33-1.91) but not significantly for aortic dissection (HR 1.09, 95% CI 0.95-1.24) or thoracic aortic aneurysm (HR 1.05, 95% CI 0.98-1.13).
More research is needed on why an aneurysm might grow in one physiologic location over another, Kibbe's group said. "As such, regional differences in the etiology, incidence, and clinical management of aortic disease in the thoracic vs abdominal aorta should be carefully considered."
Her group also reported an interaction between the effect of fluoroquinolones and age: Adults over 35 had a significant increase in AA risk on fluoroquinolones not seen in younger cohorts.
Study authors acknowledged that their dataset did not capture undiagnosed aneurysms nor several risk factors associated with aneurysm development (e.g., smoking). Additionally, abdominal imaging was not routinely performed, so some incident aneurysms might have predated fluoroquinolone use.
It is also possible that comparator antibiotics might actually have inhibited aneurysm formation, Filiberto and Upchurch suggested.
"Almost regardless, this large cohort study of a U.S. population suggests it is time once again to rethink the use of this class of antibiotics for patients with or without aortic disease," they wrote.
Disclosures
Kibbe, Filiberto, and Upchurch had no disclosures.
The study was supported by an award from the National Institute of General Medical Sciences of the NIH.
Primary Source
JAMA Surgery
Source Reference: Newton ER, et al "Association of fluoroquinolone use with short-term risk of development of aortic aneurysm" JAMA Surg 2021; DOI: 10.1001/jamasurg.2020.6165.
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