Real-World Safety Signals of Fluoroquinolone-Associated Peripheral Neuropathy: Analysis of US and Canadian Databases Combined with Mechanistic Exploration.

BACKGROUND:The association between fluoroquinolones (FQs) and peripheral neuropathy (PN) poses a severe challenge to patient safety. This study aimed to characterize PN signals for ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin using large-scale pharmacovigilance databases and explore potential mechanisms. METHODS:Pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS, 2004-2025) were analyzed and corroborated with the Canada Vigilance Adverse Reaction Database (CVARD). Signal detection utilized four disproportionality algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). Time-to-onset, subgroup analysis, and logistic regression were performed on FAERS data to identify clinical patterns. Network toxicology was employed to explore potential mechanisms. RESULTS:In FAERS (n=6,451), all FQs exhibited significant signals across all four algorithms. In the CVARD validation set, signals were confirmed for ciprofloxacin, levofloxacin, and moxifloxacin, while ofloxacin did not reach significance due to limited data. Within FAERS, ciprofloxacin (OR=2.71) and levofloxacin (OR=1.88) exhibited significantly higher reporting odds compared to moxifloxacin (p<0.001). PN onset was typically rapid (median 4-5 days). Logistic regression identified extended treatment duration and concomitant nitrofurantoin use as important factors associated with higher reporting odds. Mechanistic exploration suggested a potential association with pathways such as neuroactive ligand-receptor interaction. CONCLUSION:This study provides a comprehensive pharmacovigilance characterization of FQ-associated PN, revealing significant differences in reporting frequencies among FQs. These results underscore the need for a careful benefit-risk assessment when prescribing FQs, particularly for long-term oral therapy, and highlight the importance of further research to validate these associations.