{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:29:56Z","timestamp":1785511796189,"version":"3.56.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Carbapenem-resistant (CR) Gram-negative pathogens are classified by the WHO as critical threats due to limited therapeutic options. Cefiderocol (CFD), a novel siderophore cephalosporin, shows promise but remains unapproved in China. This study investigated the prevalence, clinical impact, and genetic mechanisms of cefiderocol heteroresistance (CFD-HR) in CR and ESBL-producing clinical isolates from China, where CFD remains unapproved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 407 CR and ESBL-producing isolates were analyzed. CFD-HR was identified by population analysis profiles (PAPs). Clinical relevance was assessed through disk diffusion susceptibility testing, time-kill assays, and a murine peritonitis model. Genetic mechanisms and stability were elucidated by whole-genome sequencing (WGS) and fitness cost assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CFD-HR prevalence was 17.4% (16\/92) in carbapenem-resistant <jats:italic>A. baumannii<\/jats:italic> (CRAB), 27.9% (24\/86) in carbapenem-resistant <jats:italic>P. aeruginosa<\/jats:italic> (CRPA), 23.8% (10\/42) in carbapenem-resistant <jats:italic>E. coli<\/jats:italic> (CRE), and \u226410% (1\/10 in ESBL-producing <jats:italic>P. aeruginosa<\/jats:italic> and 8\/177 in ESBL-producing <jats:italic>E. coli<\/jats:italic>). Although 72.9% (43\/59) of HR isolates were classified as CFD-susceptible by disk diffusion, time-kill assays showed that 66.7% (4\/6) of HR strains required \u22658 mg\/L CFD (vs. 4 mg\/L for non-HR) to prevent regrowth. <jats:italic>In vivo<\/jats:italic>, CFD achieved 100% (3\/3) survival in non-HR infections but only 16.7% (4\/6) in HR-infected mice. WGS identified transient genetic alterations in HR subpopulations, including <jats:italic>sitABCD<\/jats:italic> duplications (CRE), <jats:italic>oprD<\/jats:italic> mutations (CRAB), and <jats:italic>vgrG<\/jats:italic> SNPs (CRPA), which reverted after antibiotic withdrawal. Fitness cost assays revealed unstable growth deficits in 33.3% (2\/6) of HR subpopulations, correlating with genetic instability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings highlight the clinical significance of CFD-HR, even in susceptible isolates, and underscore the need for improved diagnostic methods to detect HR and monitor cross-resistance, offering critical insights for regions transitioning to CFD implementation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2025.1496514","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:34:15Z","timestamp":1746768855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Carbapenem-resistant Gram-negative bacteria exhibiting clinically undetected cefiderocol heteroresistance leads to treatment failure in a murine model of infection"],"prefix":"10.3389","volume":"16","author":[{"given":"Hongwei","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingfeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/s41579-019-0218-1","article-title":"Mechanisms and clinical relevance of bacterial heteroresistance","volume":"17","author":"Andersson","year":"2019","journal-title":"Nat. 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