Disproportionality and Case-Based Evidence for a Possible Association Between Fluoroquinolones and Kounis Syndrome

Background/Objectives: Drug-induced hypersensitivity and cardiotoxicity are important yet often underrecognized clinical concerns, and fluoroquinolones are widely used antibiotics with well-documented safety issues. Given the limited systematic evidence and underreporting in pharmacovigilance databases, this study explored a potential association between fluoroquinolones and Kounis syndrome (KS) and the possibility of a class-related effect. Methods: This retrospective descriptive study analyzed individual case safety reports from VigiBase, complemented by published case reports to capture additional cases not recorded in the database. All fluoroquinolones reported as suspected drugs in KS cases were included, and a systematic search of major literature databases was undertaken to identify further case-level evidence. Quantitative data were explored using VigiLyze, while qualitative clinical data were extracted for case characterization. Literature cases underwent Naranjo assessment, and the overall body of evidence was evaluated using a qualitative Bradford Hill framework. Results: A descriptive disproportionality signal for fluoroquinolones was identified in VigiBase (IC₀₂₅ = 1.3). Seventeen cases of fluoroquinolone-associated KS were identified across VigiBase and the published literature, all originating from unsolicited sources. Most cases involved ciprofloxacin and levofloxacin, whereas other fluoroquinolones were only rarely reported. Across cases, a consistent clinical pattern was observed, including a clear temporal relationship between drug exposure, allergic manifestations, and acute coronary events, compatible with hypersensitivity-mediated coronary involvement. Conclusions: KS cases associated with several fluoroquinolones were identified in pharmacovigilance data and the published literature, with the most consistent evidence observed for ciprofloxacin and levofloxacin. Although a class effect was not confirmed, a potential association cannot be excluded. These findings should be interpreted as hypothesis-generating, and further research is required to clarify underlying mechanisms, drug-specific risks, and clinical relevance.