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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\u2013drug interactions involving isoxazolyl penicillins and to evaluate the plausible interaction mechanisms. We systematically searched articles reporting potential pharmacokinetic drug\u2013drug interactions involving isoxazolyl penicillins in humans up to November 2025 in Pubmed and Embase. The quality of the articles was assessed using a self\u2010developed risk of bias assessment tool. A modified drug\u2013drug 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\u2010glucuronosyltransferase enzymes and P\u2010glycoprotein 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.<\/jats:p>","DOI":"10.1002\/bcp.70511","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:30:02Z","timestamp":1772991002000},"page":"1567-1583","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacokinetic drug\u2013drug interactions with flucloxacillin and other isoxazolyl penicillins: A systematic literature review and practical guide"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5499-8140","authenticated-orcid":false,"given":"Julia M.","family":"Wortman","sequence":"first","affiliation":[{"name":"Department of Hospital Pharmacy Haga Teaching Hospital  The Hague The Netherlands"},{"name":"Laboratory of Clinical Pharmacy and Toxicology AHZ Farmacie  The Hague The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiel","family":"Leegwater","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Haga Teaching Hospital  The Hague The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik B.","family":"Wilms","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Haga Teaching Hospital  The Hague The Netherlands"},{"name":"Laboratory of Clinical Pharmacy and Toxicology AHZ Farmacie  The Hague The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo G.","family":"Visser","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Department of Infectious Diseases Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cees","family":"van Nieuwkoop","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Haga Teaching Hospital  The Hague The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.4.5733.455"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1H423"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007312153"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920006775541534"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13467"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15738"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.16190"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/87912"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.32.3.340"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2001\u20100038"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2016.07.002"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-008055232-3.61500-4"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-008055232-3.61589-2"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-008055232-3.62337-2"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/bf01833876"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088\u2010197601040\u201000004"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","unstructured":"Sj\u00f6stedtN AmaezeOU van denHeuvelJJ et al.Dicloxacillin and flucloxacillin inhibit hepatic uptake transporters\u2014in vitro investigations and physiologically based pharmacokinetic modelling. bioRxiv.2025;10.1101\/2025.10.21.683780","DOI":"10.1101\/2025.10.21.683780"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.12541"},{"key":"e_1_2_10_20_1","unstructured":"WortmanJM WilmsEB Van NieuwkoopC VisserLG LeegwaterE.Systematic literature review of drug\u2010drug interactions with isoxazolyl penicillins in humans. 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