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Associations between use of seen in observational studies could be largely explained by confounding, researchers said, though they acknowledged the possibility of harm still remains.

One study published Tuesday in clarified the issues of confounding by underlying infection type and surveillance bias, while another in the same journal highlighted risks from coexisting infections in developing AA or AD.

In light of the earlier studies linking fluoroquinolones with aortic disorders, the FDA in December 2018 recommended against using these antibiotics in patients with AA or AD, or those at risk for them.

"Observational studies reflect real-world experience, but for rare outcomes, results are sensitive to design parameters, especially to the choice of appropriate comparison groups," according to an accompanying editor's note from Raphaela DeGette, MD, of University of California San Francisco, and Richard Grant, MD, MPH, of Kaiser Permanente Northern California in Oakland, California.

"While clinicians may choose to avoid use of fluoroquinolones in patients with aortic abnormalities, a strong causal association between fluoroquinolones and AA/AD remains unproven," DeGette and Grant wrote.

Excess Risk in Pneumonia, But Not UTI?

Joshua Gagne, PharmD, ScD, of Brigham and Women's Hospital in Boston, and colleagues made the case that the excess risk of AA or AD when taking a fluoroquinolone over a comparator medication could be related to confounding and surveillance bias, based on data from a large U.S. commercial claims database.

Indeed, people treated with fluoroquinolones for pneumonia had increased rates of AA or AD compared with initiators of the macrolide antibiotic azithromycin (0.03% vs 0.01%, HR 2.57, 95% CI 1.36-4.86).

Yet fluoroquinolone use in urinary tract infections was not associated with greater AA or AD risk compared with combined trimethoprim/sulfamethoxazole treatment (<0.01% for both groups, HR 0.99, 95% CI 0.62-1.57).

Moreover, patients receiving fluoroquinolones, compared with those receiving amoxicillin, did show a greater incidence of AA/AD (HR 1.54, 95% CI 1.33-1.79) -- but when baseline imaging was required to address differences in detection of AA/AD before antibiotic use, the link between fluoroquinolones and AA/AD was no longer significant (0.06% vs 0.05% with amoxicillin, HR 1.13, 95% CI 0.96-1.33).

"Taken together, our results suggest that fluoroquinolones may increase a person's risk of AA/AD, although unmeasured confounding or differential surveillance cannot be ruled out since we observed too few events to implement the imaging restriction in the pneumonia cohort," the authors said. "The absolute rates of AA/AD were low across all cohorts (i.e., <0.1%); thus, given a clear indication for antibiotic use, the benefits of choosing an appropriate antibiotic in terms of coverage may outweigh a small potential increased risk for AA/AD."

Gagne and colleagues had accessed the IBM MarketScan database to create two matching cohorts of people age 50 or older: those with a diagnosis of pneumonia ≤3 days before initiating treatment with a fluoroquinolone or azithromycin (n=279,554; mean age 63.7, 53.6% women), and another group that had a UTI diagnosis ≤3 days before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole (n=948,364; mean age 62.1 years, 86.9% women).

"Using heart failure hospitalizations and hospitalization for acute MI as negative control outcomes suggested that the primary analyses in the pneumonia and UTI cohorts were robust; however, the secondary analyses in the amoxicillin cohort may have been affected by residual confounding even when requiring baseline imaging," the investigators acknowledged.

Other limitations include the inclusion of relatively young patients and the lack of certain clinical data to adjust for other risk factors for AA/AD (e.g., family history). In addition, the findings may not apply to people who receive fluoroquinolones for longer than the short course typically prescribed for pneumonia or UTI.

Risk Not Related to Choice of Antibiotic?

A separate study suggested the infections for which fluoroquinolones were prescribed may have been the true risk factor for AA or AD.

It was common for people to have had an infection in which fluoroquinolones were a reasonable treatment option in the 60 days prior to visiting the hospital with disorders of the aorta (18.6% vs 5.9% for controls presenting for other reasons, adjusted OR 1.73, 95% CI 1.66-1.81).

However, in the group of people with indicated infections, AA/AD patients were not more likely than controls to have taken fluoroquinolones in place of combined amoxicillin-clavulanate or combined ampicillin-sulbactam (adjusted OR 1.01, 95% CI 0.82-1.24) or with extended-spectrum cephalosporins (adjusted OR 0.88, 95% CI 0.70-1.11), according to Yaa-Hui Dong, PhD, of National Yang-Ming University School of Pharmaceutical Science in Taipei, Taiwan, and colleagues.

"Infection was found to be a risk factor for AA/AD after we adjusted for baseline covariates and concomitant antibiotic use. In contrast, fluoroquinolones were not associated with an elevated risk of AA/AD vs antibiotics with similar indication profiles after accounting for coexisting infections. The null findings did not change materially in different subgroup and sensitivity analyses," Dong's team wrote.

"This study's results emphasize the importance of considering coexisting infections while examining the safety of antibiotics using real-world data. Concern about AA/AD should not preclude patients with indicated infections from necessary treatment with fluoroquinolones," the investigators noted.

The retrospective study was based on a Taiwanese population-based health insurance claims database. Some 29,000 patients with AA/AD were each matched by birth year, sex, and follow-up duration to 10 people with other conditions. Mean age was 67.4 years and 71.4% were men.

Compared with controls, AA/AD patients were at particularly high risk of septicemia (adjusted OR 3.16, 95% CI 2.63-3.78) and intra-abdominal infection (adjusted OR 2.99, 95% CI 2.45-3.65) -- two conditions that "may independently damage aortic endothelium," suggested DeGette and Grant.

Study authors noted the potential of miscoding in their dataset, as well as the lack of granular clinical details for adjustment.

As such, "we could not fully rule out an actual causal relation between fluoroquinolones and AA/AD in certain patients," they cautioned.