{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:16:15Z","timestamp":1791504975446,"version":"4.3.4"},"reference-count":159,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170119"],"award-info":[{"award-number":["32170119"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    In the intensifying global crisis of antimicrobial resistance (AMR), the \u201cold\u201d antibiotic fosfomycin has regained prominence because of its unique mechanism of action and potent activity against numerous multidrug-resistant (MDR) pathogens. However, its clinical application is hampered by the rapid emergence of resistance during monotherapy. Rational combination therapy represents a strategic necessity to preserve and enhance the efficacy of fosfomycin. This review systematically analyzes the antibacterial and molecular mechanisms of resistance to fosfomycin, with a focus on the growing threat posed by plasmid-mediated resistance genes. The preclinical and clinical evidence of key combination regimens (including \u03b2-lactams, aminoglycosides, fluoroquinolones, polymyxins, and daptomycin) has been comprehensively evaluated, with detailed discussions of the mechanistic foundations for the observed synergistic effects. Although\n                    <jats:italic>in vitro<\/jats:italic>\n                    and animal models show substantial promise, we critically examine the translational gap between positive preclinical results and clinical realities, discussing major barriers to clinical advancement. Finally, we outline a prospective research agenda, encompassing pharmacokinetic\/pharmacodynamic (PK\/PD)-guided precision dosing, exploring non-antibiotic adjuvants, and developing more predictive preclinical models to unlock the full potential of fosfomycin-based combinations against MDR infections.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2025.1702881","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T06:23:27Z","timestamp":1763447007000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Overcoming the drug resistance barrier: progress in fosfomycin combination therapy against multidrug-resistant pathogens"],"prefix":"10.3389","volume":"16","author":[{"given":"Yan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengling","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"365","DOI":"10.5578\/mb.20239930","article-title":"[Evaluation of in vitro efficacy of meropenem\/colistin and meropenem\/fosfomycin combinations on multidrug resistant gram-negative Bacilli].","volume":"57","author":"Adaleti","year":"2023","journal-title":"Mikrobiyol. 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