Abstract
OBJECTIVE: This study aimed to investigate whether the introduction of β-lactamase inhibitors (BLIs) alters the adverse event (AE) profiles of parent penicillin antibiotics, using real-world pharmacovigilance data. METHODS: A disproportionality analysis was conducted using reports from the FDA Adverse Event Reporting System database (2004-2024). The research compared the safety profiles of amoxicillin versus amoxicillin-clavulanate (ACP) and ampicillin versus ampicillin-sulbactam (ASS) by employing multiple statistical methods, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). The signals were considered significant only when meeting multiple algorithm criteria (Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, Empirical Bayesian Geometric Mean). Subgroup analyses by age and gender were performed. RESULTS: Analysis of over 200,000 reports revealed distinct AE spectra. ACP demonstrated a significantly stronger association with hepatobiliary disorders (e.g., drug-induced liver injury, ROR 35.41) compared to amoxicillin alone (ROR 4.98). In contrast, amoxicillin monotherapy showed stronger signals for certain immune-mediated skin reactions. For ampicillin, monotherapy was strongly linked to pregnancy/perinatal events, whereas ASS showed higher risks for gastrointestinal disorders (e.g., hemorrhagic enterocolitis), specific skin reactions, and allergic events. Subgroup analyses indicated that hepatobiliary and renal risks with ACP were more prominent in males and the elderly (≥60 years), while severe skin reactions with ampicillin were more frequent in females. CONCLUSION: The addition of BLIs significantly may modify the AE profiles of parent penicillins, introducing distinct organ-specific risks. These findings underscore the necessity for personalized risk assessment and monitoring in clinical practice, tailored to the specific combination agent and patient demographics.