{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:50:41Z","timestamp":1791845441648,"version":"4.3.4"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Combinations of PBP3-active \u03b2-lactams with developmental diazabicyclooctanes (DBOs), e.g. zidebactam, remain active against many MBL producers via an enhancer effect. We explored how this activity is affected by inoculum.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and methods<\/jats:title>\n                  <jats:p>MICs of zidebactam and its cefepime and ertapenem combinations (WCK 5222 and WCK 6777, respectively) were determined by BSAC agar dilution at inocula from 3\u20136\u200a\u00d7\u200a103 to 3\u20136\u200a\u00d7\u200a105\u2005cfu\/spot. Isolates, principally Klebsiella spp., were chosen as having previously tested resistant to zidebactam or its cefepime combination, and by \u03b2-lactamase type.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>MICs of zidebactam, tested alone, were strongly inoculum dependent regardless of \u03b2-lactamase type; MICs of its cefepime and ertapenem combinations likewise were strongly inoculum dependent\u2014rising \u226532-fold across the inoculum range tested\u2014but only for MBL producers. Combination MICs for isolates with non-MBLs, including those with OXA-48 (where the enhancer effect remains critical for ertapenem\/zidebactam) were much less inoculum dependent, particularly for cefepime\/zidebactam. MBL producers frequently moved between putative \u2018susceptible\u2019 (MIC\u200a\u2264\u200a8\u200a+\u200a8\u2005mg\/L) and \u2018resistant\u2019 (MIC\u200a&amp;gt;\u200a8\u200a+\u200a8\u2005mg\/L) categories according to whether the inoculum was at the high or low end of BSAC\u2019s acceptable (1\u20134\u200a\u00d7\u200a104\u2005cfu\/spot) range.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The activity of zidebactam combinations against MBL producers, which strongly depends on the enhancer effect, is inoculum dependent. Animal data suggest consistent in vivo activity even in high-inoculum pneumonia models. Contingent on this being supported by clinical experience, the combination behaviour may be best represented by the MICs obtained at the lower end of BSAC\u2019s inoculum range.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkac108","type":"journal-article","created":{"date-parts":[[2022,3,19]],"date-time":"2022-03-19T12:07:25Z","timestamp":1647691645000},"page":"1916-1922","source":"Crossref","is-referenced-by-count":10,"title":["Inoculum effects of cefepime\/zidebactam (WCK 5222) and ertapenem\/zidebactam (WCK 6777) for Enterobacterales in relation to \u03b2-lactamase type and enhancer effect, as tested by BSAC agar dilution"],"prefix":"10.1093","volume":"77","author":[{"given":"Shazad","family":"Mushtaq","sequence":"first","affiliation":[{"name":"Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, UK Health Security Agency , 61 Colindale Avenue, London NW9 5EQ , 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M","family":"Livermore","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia , Norwich NR4 7TJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"key":"2022070118383869600_dkac108-B1","doi-asserted-by":"crossref","first-page":"e00115-20","DOI":"10.1128\/CMR.00115-20","article-title":"New \u03b2-lactam-\u03b2-lactamase inhibitor combinations","volume":"34","author":"Yahav","year":"2020","journal-title":"Clin Microbiol Rev"},{"key":"2022070118383869600_dkac108-B2","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1021\/acs.jmedchem.8b00091","article-title":"Strategic approaches to overcome resistance against Gram-negative pathogens using \u03b2-lactamase inhibitors and \u03b2-lactam enhancers: activity of three novel diazabicyclooctanes WCK 5153, zidebactam (WCK 5107), and WCK 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