{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:10:15Z","timestamp":1791897015147,"version":"4.3.4"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Shionogi & Co., Ltd, Japan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime\/avibactam, ampicillin\/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg\/L (previously developed resistance on therapy), n\u200a=\u200a3; 8 mg\/L, n\u200a=\u200a2; \u226532 mg\/L, n\u200a=\u200a10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol\u200a+\u200aceftazidime\/avibactam (C-CZA), cefiderocol\u200a+\u200aampicillin\/sulbactam (C-SAM) or cefiderocol\u200a+\u200ameropenem (C-MEM) HSRs. The mean change in log10 cfu\/thigh compared with starting inoculum was assessed. Resistance development on treatment was a &amp;gt;4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA \u22123.75\u200a\u00b1\u200a0.37 reduction in log10 cfu\/thigh, C-SAM produced \u22123.55\u200a\u00b1\u200a0.50 and C-MEM produced \u22122.18\u200a\u00b1\u200a1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg\/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Against cefiderocol-non-susceptible isolates, cefiderocol\u200a+\u200aceftazidime\/avibactam or ampicillin\/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime\/avibactam or ampicillin\/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime\/avibactam or ampicillin\/sulbactam against A. baumannii, including multi-drug-resistant isolates.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jac\/dkad032","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T07:04:14Z","timestamp":1676271854000},"page":"983-990","source":"Crossref","is-referenced-by-count":27,"title":["<i>In vivo<\/i>efficacy &amp; resistance prevention of cefiderocol in combination with ceftazidime\/avibactam, ampicillin\/sulbactam or meropenem using human-simulated regimens versus<i>Acinetobacter baumannii<\/i>"],"prefix":"10.1093","volume":"78","author":[{"given":"Christian M","family":"Gill","sequence":"first","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Santini","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Takemura","sequence":"additional","affiliation":[{"name":"Research Planning Department, Shionogi & Co., Ltd , 3-1-1, Futaba-cho, Toyonaka,Osaka 561-0825 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Longshaw","sequence":"additional","affiliation":[{"name":"Scientific Affairs, Shionogi B.V. , 33 Kingsway, London, WC2B 6UF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Yamano","sequence":"additional","affiliation":[{"name":"Research Planning Department, Shionogi & Co., Ltd , 3-1-1, Futaba-cho, Toyonaka,Osaka 561-0825 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Echols","sequence":"additional","affiliation":[{"name":"Infectious Disease Drug Development Consulting, LLC , 753 Westport Road, Easton, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6036-3263","authenticated-orcid":false,"given":"David P","family":"Nicolau","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 , USA"},{"name":"Division of Infectious Diseases, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,2,13]]},"reference":[{"key":"2023040308033041700_","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 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