{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:36:23Z","timestamp":1791905783308,"version":"4.3.4"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Wockhardt Research Centre (India) and by the Ministerio de Econom\u00eda y Competitividad of Spain"},{"name":"Instituto de Salud Carlos III\u2014co-financed by the European Regional Development Fund \u2018A way to achieve Europe\u2019 ERDF","award":["RD16\/0016"],"award-info":[{"award-number":["RD16\/0016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To study the dynamics, mechanisms and fitness cost of resistance selection to cefepime, zidebactam and cefepime\/zidebactam in Pseudomonas aeruginosa.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>WT P. aeruginosa PAO1 and its \u0394mutS derivative (PAOMS) were exposed to stepwise increasing concentrations of cefepime, zidebactam and cefepime\/zidebactam. Selected mutants were characterized for change in susceptibility profiles, acquired mutations, fitness, virulence and in vivo susceptibility to cefepime\/zidebactam. Mutations were identified through WGS. In vitro fitness was assessed by measuring growth in minimal medium and human serum-supplemented Mueller\u2013Hinton broth. Virulence was determined in Caenorhabditis elegans and neutropenic mice lung infection models. In vivo susceptibility to a human-simulated regimen (HSR) of cefepime\/zidebactam was studied in neutropenic mice lung infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Resistance development was lower for the cefepime\/zidebactam combination than for the individual components and high-level resistance was only achieved for PAOMS. Cefepime resistance development was associated with mutations leading to the hyperexpression of AmpC or MexXY-OprM, combined with PBP3 mutations and\/or large chromosomal deletions involving galU. Zidebactam resistance was mainly associated with mutations in PBP2. On the other hand, resistance to cefepime\/zidebactam required multiple mutations in genes encoding MexAB-OprM and its regulators, as well as PBP2 and PBP3. Cumulatively, these mutations inflicted significant fitness cost and cefepime\/zidebactam-resistant mutants (MIC\u200a=\u200a16\u201364\u2009mg\/L) remained susceptible in vivo to the HSR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Development of cefepime\/zidebactam resistance in P. aeruginosa required multiple simultaneous mutations that were associated with a significant impairment of fitness and virulence.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jac\/dkab213","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T11:16:07Z","timestamp":1622805367000},"page":"2546-2557","source":"Crossref","is-referenced-by-count":33,"title":["<i>In vitro<\/i>evolution of cefepime\/zidebactam (WCK 5222) resistance in<i>Pseudomonas aeruginosa<\/i>: dynamics, mechanisms, fitness trade-off and impact on<i>in 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