{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:08:05Z","timestamp":1791331685560,"version":"4.3.1"},"reference-count":155,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This article reviews resistance to ceftazidime\/avibactam as an aspect of its primary pharmacology, linked thematically with recent reviews of the basic in vitro and in vivo translational biology of the combination (J Antimicrob Chemother 2022; 77: 2321\u201340 and 2341\u201352). In Enterobacterales or Pseudomonas aeruginosa, single-step exposures to 8\u00d7\u200a MIC of ceftazidime\/avibactam yielded frequencies of resistance from &amp;lt;\u223c0.5\u200a\u00d7\u200a10\u22129 to 2\u20138\u200a\u00d7\u200a10\u22129, depending on the host strain and the \u03b2-lactamase harboured. \u03b2-Lactamase structural gene mutations mostly affected the avibactam binding site through changes in the \u03a9-loop: e.g. Asp179Tyr (D179Y) in KPC-2. Other mutations included ones proposed to reduce the permeability to ceftazidime and\/or avibactam through changes in outer membrane structure, up-regulated efflux, or both. The existence, or otherwise, of cross-resistance between ceftazidime\/avibactam and other antibacterial agents was also reviewed as a key element of the preclinical primary pharmacology of the new agent. Cross-resistance between ceftazidime\/avibactam and other \u03b2-lactam-based antibacterial agents was caused by MBLs. Mechanism-based cross-resistance was not observed between ceftazidime\/avibactam and fluoroquinolones, aminoglycosides or colistin. A low level of general co-resistance to ceftazidime\/avibactam was observed in MDR Enterobacterales and P. aeruginosa. For example, among 2821 MDR Klebsiella spp., 3.4% were resistant to ceftazidime\/avibactam, in contrast to 0.07% of 8177 non-MDR isolates. Much of this was caused by possession of MBLs. Among 1151 MDR, XDR and pandrug-resistant isolates of P. aeruginosa from the USA, 11.1% were resistant to ceftazidime\/avibactam, in contrast to 3.0% of 7452 unselected isolates. In this case, the decreased proportion susceptible was not due to MBLs.<\/jats:p>","DOI":"10.1093\/jac\/dkac449","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T02:53:31Z","timestamp":1674788011000},"page":"569-585","source":"Crossref","is-referenced-by-count":11,"title":["The primary pharmacology of ceftazidime\/avibactam: resistance<i>in vitro<\/i>"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3305-6388","authenticated-orcid":false,"given":"Wright W","family":"Nichols","sequence":"first","affiliation":[{"name":"Microbiology Consulting , Didsbury, Manchester , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushmita D","family":"Lahiri","sequence":"additional","affiliation":[{"name":"Infectious Diseases and Vaccines, Johnson & Johnson , Cambridge, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1285-2978","authenticated-orcid":false,"given":"Patricia A","family":"Bradford","sequence":"additional","affiliation":[{"name":"Antimicrobial Development Specialists, LLC , Nyack, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory G","family":"Stone","sequence":"additional","affiliation":[{"name":"Global Product Development, Pfizer , Groton, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"2023030208090220700_","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.mib.2011.07.026","article-title":"Diazabicyclooctanes (DBOs): a potent new class of non-\u03b2-lactam \u03b2-lactamase inhibitors","volume":"14","author":"Coleman","year":"2011","journal-title":"Curr Op 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