INTRODUCTION: Fluoroquinolones can cause severe collagen-associated adverse effects, potentially impacting the pulmonary connective tissue. We investigated the association between fluoroquinolones and spontaneous pneumothorax. METHODS: A case-time-control study was performed using the nationwide French reimbursement healthcare system database (SNDS). Cases were adults ≥18 years admitted for spontaneous pneumothorax between 2017 and 2022. For each case, fluoroquinolone use was compared between the risk period immediately preceding the admission date (days -30 to -1), and three earlier reference periods (days -180 to -151, -150 to -121, -120 to -91), adjusting for time-varying confounders. OR estimates were corrected for potential exposure-trend bias using a reference group without the event (matched on age, sex, chronic obstructive pulmonary disease history, calendar time). Amoxicillin use was studied similarly to control for indication bias. RESULTS: Of the 246 pneumothorax 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 3316 amoxicillin cases (72.9% men
mean age, 39.4±17.6 years), 1210 were exposed in the 30-day risk period and 1603 in the reference ones. OR adjusted for exposure-trend and covariates was 1.59 (95% CI 1.14 to 2.22) for fluoroquinolones and 2.25 (2.07 to 2.45) for amoxicillin. CONCLUSION: An increased risk of spontaneous pneumothorax was associated with both fluoroquinolone and amoxicillin use, with an even higher 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.