Association of fluoroquinolones with the risk of spontaneous pneumothorax

Background: Fluoroquinolones can cause severe collagen-associated adverse effects, including tendon rupture, or aortic aneurysm or dissection. The pulmonary connective tissue could also be affected, potentially exposing to a risk of spontaneous pneumothorax.

Objectives: To investigate the association between fluoroquinolone and spontaneous pneumothorax.

Methods:

Design: Case-time-control study, using an active comparator (amoxicillin) to control for potential indication bias. Setting: Data from the nationwide French reimbursement healthcare system database (SNDS). Participants: Among 22,423 eligible patients admitted for spontaneous pneumothorax between 2017 and 2022, cases were inpatients exposed to either fluoroquinolone, either amoxicillin within the 180 days before admission (246 fluoroquinolone; 3,316 amoxicillin). To control for exposure-trend bias, they were individually matched on sex, age, COPD history and calendar time to patients free of the event (1,846 time-trend controls for fluoroquinolone; 32,494 for amoxicillin). Exposures: Each participant was assessed for antibiotic exposure during the risk period immediately before admission date for cases or selection date for time-trend controls (days -30 to -1) and three earlier reference periods (days -180 to -151, -150 to -121, -120 to -91). Main outcomes measures: Adjusting for time-varying confounders, association Odds Ratio (OR) was assessed comparing for each case antibiotic exposure between the risk period and the reference periods. A similar estimation was performed in time-trend controls; the associations to the risk of pneumothorax in cases were finally corrected for the exposure-trend estimations.

Results: Of the 246 cases exposed to fluoroquinolones (63.8% men; mean age, 43.0±18.4 years), 63 were exposed in the 30-day risk period preceding pneumothorax and 128 in the reference periods. Of the 3,316 amoxicillin cases (72.9% men; mean age, 39.4±17.6 years), 1,210 were exposed in the risk period and 1,603 in the reference ones. OR adjusted for exposure-trend and covariates was 1.59 (95%CI: 1.14-2.22) for fluoroquinolones and 2.25 (2.07-2.45) for amoxicillin.

Conclusions: Increased risk of spontaneous pneumothorax was associated to both fluoroquinolone and amoxicillin use, with an equal or stronger association for amoxicillin. This strongly suggests the role of the underlying infections rather than a causal effect of the individual antibiotics and can be considered reassuring regarding a potential lung connective-toxicity of fluoroquinolones.