{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:25:16Z","timestamp":1791523516192,"version":"4.3.4"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T00:00:00Z","timestamp":1649721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015511","name":"Wockhardt Bio AG","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100015511","id-type":"DOI","asserted-by":"crossref"}]}],"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>Ertapenem has proven to be an effective antimicrobial; however, increasing enzyme-mediated resistance has been noted. Combination with zidebactam, a \u03b2-lactam enhancer, is restorative. Human-simulated regimens (HSRs) of ertapenem and zidebactam alone and in combination (WCK 6777; 2\u2005g\/2\u2005g q24h) were assessed for efficacy against carbapenemase-producing Klebsiella pneumoniae (CP-KP) in the pneumonia model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Infected ICR mice were rendered neutropenic and exposed to various doses of ertapenem and zidebactam alone and in combination to develop the HSRs that were subsequently confirmed in additional pharmacokinetic studies. Twenty-one CP-KP (KPC or OXA-48-like producers) with WCK 6777 MICs of 1\u20138\u2005mg\/L were utilized. Mice were treated for 24\u2005h with saline or HSRs of ertapenem, zidebactam and WCK 6777. Efficacy was defined as change in mean lung bacterial density relative to 0\u2005h.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Confirmatory pharmacokinetic analysis showed agreement between predicted human exposures (%fT&amp;gt;MIC) and those achieved in vivo for all three HSRs. The 0\u2005h bacterial density across all isolates was 6.69\u200a\u00b1\u200a0.31\u2005log10 cfu\/lungs. At 24\u2005h, densities increased by 2.57\u200a\u00b1\u200a0.50, 2.2\u200a\u00b1\u200a0.60 and 2.05\u200a\u00b1\u200a0.71\u2005log10 cfu\/lungs in the 24\u2005h control, ertapenem HSR and zidebactam HSR groups, respectively. Overall, 18\/21 of the isolates exposed to the WCK 6777 HSR displayed a killing profile that exceeded the translational benchmark for efficacy of a 1\u2005log10 cfu reduction. Among the remaining three isolates, two displayed \u223c0.5\u2005log10 kill and stasis was observed in the third.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Human-simulated exposures of WCK 6777 demonstrated potent in vivo activity against CP-KP, including those with WCK 6777 MICs up to 8\u2005mg\/L.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkac110","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T04:13:26Z","timestamp":1648008806000},"page":"1931-1937","source":"Crossref","is-referenced-by-count":12,"title":["<i>In vivo<\/i> efficacy of WCK 6777 (ertapenem\/zidebactam) against carbapenemase-producing <i>Klebsiella pneumoniae<\/i> in the neutropenic murine pneumonia model"],"prefix":"10.1093","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7455-4709","authenticated-orcid":false,"given":"Matthew","family":"Gethers","sequence":"first","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamilia","family":"Abdelraouf","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P","family":"Nicolau","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT , USA"},{"name":"Division of Infectious Diseases, Hartford Hospital , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,13]]},"reference":[{"key":"2022070118372829100_dkac110-B1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/ciy745","article-title":"2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy","volume":"68","author":"Norris","year":"2019","journal-title":"Clin Infect Dis"},{"issue":"Suppl 2","key":"2022070118372829100_dkac110-B2","first-page":"83","article-title":"Ertapenem: a new opportunity for outpatient parenteral antimicrobial therapy","volume":"53","author":"Tice","year":"2004","journal-title":"J Antimicrob Chemother"},{"key":"2022070118372829100_dkac110-B3","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1093\/jac\/dkq152","article-title":"Ertapenem administered as outpatient parenteral antibiotic therapy for urinary tract infections caused by extended-spectrum-\u03b2-lactamase-producing Gram-negative organisms","volume":"65","author":"Bazaz","year":"2010","journal-title":"J Antimicrob Chemother"},{"key":"2022070118372829100_dkac110-B4","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1128\/AAC.02721-14","article-title":"Safety and efficacy of long-term outpatient ertapenem therapy","volume":"58","author":"Qureshi","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2022070118372829100_dkac110-B5","doi-asserted-by":"crossref","first-page":"3917","DOI":"10.1128\/AAC.00070-11","article-title":"Susceptibility of Klebsiella pneumoniae isolates from intra-abdominal infections and molecular characterization of ertapenem-resistant isolates","volume":"55","author":"Hawser","year":"2011","journal-title":"Antimicrob Agents 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