Pharmacokinetic drug–drug interactions with flucloxacillin and other isoxazolyl penicillins: A systematic literature review and practical guide

Recent years have seen a notable increase in the number of publications concerning pharmacokinetic drug-drug interactions involving the isoxazolyl penicillins cloxacillin, dicloxacillin, flucloxacillin and oxacillin. Given that the findings predominantly rely on clinical observations, the interaction mechanisms and their clinical relevance remain insufficiently elucidated, thereby posing challenges for clinicians in managing these interactions. The aim of this literature review was to provide an overview of all reported pharmacokinetic drug-drug interactions involving isoxazolyl penicillins and to evaluate the plausible interaction mechanisms. We systematically searched articles reporting potential pharmacokinetic drug-drug interactions involving isoxazolyl penicillins in humans up to November 2025 in Pubmed and Embase. The quality of the articles was assessed using a self-developed risk of bias assessment tool. A modified drug-drug interaction probability assessment tool was used to objectively evaluate the probability of the reported potential interactions. A total of 33 potential victim drugs were identified across 51 articles, comprising 24 case reports or case series, 16 retrospective cohort studies and 11 prospective or crossover studies. Most of the included studies report a decreased exposure and/or efficacy of drugs during concomitant treatment with isoxazolyl penicillins. Although pointing towards induction of cytochrome P450 enzymes, diphosphate-glucuronosyltransferase enzymes and P-glycoprotein as most plausible mechanism for most interactions, the exact interaction mechanisms could not be fully elucidated due to the quality of the study designs and heterogeneity in endpoints. Clinicians should be aware of a potential clinically relevant interaction when combining isoxazolyl penicillins with drugs with a small therapeutic window that undergo extensive metabolism.