{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T03:21:07Z","timestamp":1772680867540,"version":"3.50.1"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019590","name":"CARB-X","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021704","name":"Administration for Strategic Preparedness and Response","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100021704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["75A50122C00028"],"award-info":[{"award-number":["75A50122C00028"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["WT224842"],"award-info":[{"award-number":["WT224842"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Germany\u2019s Federal Ministry of Education and Research"},{"name":"UK Department of Health and Social Care"},{"name":"Global Antimicrobial Resistance Innovation Fund"},{"DOI":"10.13039\/100011094","name":"Public Health Agency of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011094","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill & Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The COMBINE murine neutropenic pneumonia model looks to standardize an important element of preclinical development and provide interlaboratory uniformity. Herein we provide quantitative bacterial density in lung benchmark efficacy data of humanized exposures of meropenem, cefiderocol and tobramycin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In accordance with the COMBINE protocol, human-simulated regimens (HSRs) based on both plasma and ELF exposures of meropenem, cefiderocol (both as 2\u2005g q8h as 3\u2005h infusions) and tobramycin 7\u2005mg\/kg as 30\u2005min infusions were tested against K. pneumoniae and P. aeruginosa isolates. The 24\u2005h change in cfu\/lung for each HSR was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Meropenem HSRs demonstrated &amp;gt;1\u2005log10 kill against all P. aeruginosa isolates with MICs of \u226416\u2005mg\/L, but only against K. pneumoniae isolates with MICs of \u22642\u2005mg\/L as isolates with MICs of &amp;gt;2\u2005mg\/L generally harboured carbapenemases. Cefiderocol HSRs uniformly achieved &amp;gt;1\u2005log10 kill against both species at MICs of \u22648\u2005mg\/L, with net growth and extensive variability in P. aeruginosa isolates with MICs of 16\u2005mg\/L. All tobramycin-susceptible isolates demonstrated &amp;gt;1\u2005log10 kill, while non-susceptible isolates did not. Differences in cfu\/lung magnitude between the plasma and ELF HSRs were most pronounced around the clinical breakpoints.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In the COMBINE pneumonia model, administration of plasma and ELF HSRs of meropenem, cefiderocol and tobramycin demonstrated 24\u2005h cfu\/lung within reason of expectation given known PK\/PD properties and existing clinical breakpoints.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaf100","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T23:52:42Z","timestamp":1748908362000},"page":"1552-1559","source":"Crossref","is-referenced-by-count":2,"title":["Quantitative performance of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin against a challenge set of <i>Klebsiella pneumoniae<\/i> and <i>Pseudomonas aeruginosa<\/i> in a standardized neutropenic murine pneumonia model"],"prefix":"10.1093","volume":"80","author":[{"given":"Andrew J","family":"Fratoni","sequence":"first","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alissa M","family":"Padgett","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, CT ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin M","family":"Duffy","sequence":"additional","affiliation":[{"name":"CARB-X , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4148-0165","authenticated-orcid":false,"given":"David P","family":"Nicolau","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , Hartford, 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