Cardiotoxicity of macrolide antibiotics: a pharmacovigilance study integrating FAERS and JADER databases.

Abstract

Macrolides are widely prescribed antibiotics with a well-established risk of QT prolongation, but their broader cardiotoxic profile has not been systematically compared across countries using large-scale real-world data. The aim of this study is to characterize the spectrum, drug-specific signal patterns, and clinical outcomes of macrolide-associated cardiac adverse events (cAEs) through a cross-national comparison using two independent national pharmacovigilance databases. We performed a comprehensive disproportionality analysis of macrolide-associated cardiac adverse events (cAEs) using the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) from 2016 Q1 through 2025 Q4. We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) for signal detection. Time-to-onset (TTO) was characterized using cumulative incidence curves and non-parametric Wilcoxon rank-sum tests across individual macrolides, clinical outcomes, and event types. Among 42,605 macrolide-related reports in FAERS and 4613 in JADER, cAEs accounted for 1415 (3.32%) and 128 (2.77%) reports, respectively. Azithromycin predominated in FAERS (72.3%) and clarithromycin in JADER (66.4%). Erythromycin showed the highest FAERS ROR for long QT syndrome (81.82, 95% CI 45.09-148.46), followed by azithromycin (34.71, 95% CI 25.15-47.91) and clarithromycin (18.11, 95% CI 8.61-38.08); azithromycin and clarithromycin signals were independently confirmed in JADER (ROR 24.42 and 13.17, respectively). Azithromycin was uniquely associated with heart-failure-related signals (acute right ventricular failure ROR 52.48, 95% CI 19.37-142.19), whereas clarithromycin showed the strongest ischemic heart disease signals (myocardial ischemia ROR 6.55, 95% CI 2.94-14.60; JADER coronary artery spasm ROR 10.37, 95% CI 4.25-25.33). Overall mortality among cAE cases was 10.2% in FAERS and 10.4% in JADER, with QT/torsade de pointes (TdP)-related case-fatality rates of 12.5% for clarithromycin and 10.3% for azithromycin. Most cardiac events occurred within the first 2 weeks of therapy (median time to onset, 1 day). Macrolide-associated cardiotoxicity extends beyond QT prolongation/TdP to heart failure and ischemic heart disease, with drug-specific and cross-national differences in signal pattern. As disproportionality signals, these findings are hypothesis-generating rather than causal, but support targeted cardiac monitoring in high-risk patients, particularly during the first 2 weeks of macrolide therapy.