{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:04:33Z","timestamp":1790827473270,"version":"4.1.0"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Evopoint Biosciences Co., Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Imipenem\/funobactam (formerly XNW4107) is a novel \u03b2-lactam\/\u03b2-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic\/pharmacodynamic (PK\/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem\/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem\/funobactam MICs 0.25\u201316 mg\/L) was assessed as 24 h change in log10cfu\/thigh.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu\/thigh versus %fT\u200a&amp;gt;\u200aMIC were poorly predictive of efficacy; bactericidal activity was observed at %fT\u200a&amp;gt;\u200aMIC\u200a=\u200a0%. Across different threshold plasma funobactam concentrations (CTs), %fT\u200a&amp;gt;\u200aCT(1 mg\/L) had the highest correlation with efficacy. Normalizing the %fT\u200a&amp;gt;\u200aCT\u200a=\u200a1 mg\/L index to the respective isolate imipenem\/funobactam MIC ([%fT\u200a&amp;gt;\u200aCT]\/MIC) allowed integration of the isolate\u2019s susceptibility, which further enhanced the correlation. Median (%fT\u200a&amp;gt;\u200aCT[1 mg\/L])\/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT\u200a&amp;gt;\u200aCT[1 mg\/L])\/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem\/funobactam 500\/250 mg q6h 1 h infusion HSR produced &amp;gt;1-log kill against 6\/7 A. baumannii, 4\/4 P. aeruginosa and stasis against 4\/4 K. pneumoniae.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Imipenem\/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK\/PD index (%fT\u200a&amp;gt;\u200aCT)\/MIC appeared to best describe in vivo activity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkad242","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T16:46:07Z","timestamp":1690217167000},"page":"2343-2353","source":"Crossref","is-referenced-by-count":24,"title":["Imipenem\/funobactam (formerly XNW4107)\n                    <i>in vivo<\/i>\n                    pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing"],"prefix":"10.1093","volume":"78","author":[{"given":"Andrew J","family":"Fratoni","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":"Angela V","family":"Berry","sequence":"additional","affiliation":[{"name":"Center for 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for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 , USA"},{"name":"Division of Infectious Diseases, 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 , 80 Seymour Street, Hartford, CT 06102 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"2023090502540374400_dkad242-B1","doi-asserted-by":"crossref","first-page":"ofx176","DOI":"10.1093\/ofid\/ofx176","article-title":"Prevalence of carbapenem-resistant gram-negative infections in the United States predominated by Acinetobacter baumannii and Pseudomonas aeruginosa","volume":"4","author":"Cai","year":"2017","journal-title":"Open Forum Infect 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