{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:29:03Z","timestamp":1788535743741,"version":"build-2803163510"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019590","name":"CARB-X","doi-asserted-by":"publisher","award":["75A50122C00028"],"award-info":[{"award-number":["75A50122C00028"]}],"id":[{"id":"10.13039\/100019590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["WT224842"],"award-info":[{"award-number":["WT224842"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Germany\u2019s Federal Ministry of Education and Research"},{"name":"UK Department of Health and Social Care as part of the 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":"The 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":[[2024,12,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Lack of uniformity in infection models complicates preclinical development. The COMBINE protocol has standardized the murine neutropenic pneumonia model. Herein we provide benchmark efficacy data of humanized exposures of tigecycline and levofloxacin 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>Following the COMBINE protocol, plasma and ELF human-simulated regimens (HSRs) of tigecycline 100\u2005mg followed by 50\u2005mg q12h and levofloxacin 750\u2005mg once daily were developed and confirmed in the murine neutropenic pneumonia model. Tigecycline HSRs were tested against seven K. pneumoniae isolates. Levofloxacin HSRs were assessed against 10 K. pneumoniae and 9 P. aeruginosa. The change in cfu\/lung over 24\u2005h for each treatment 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>Tigecycline 1.8 and 3\u2005mg\/kg q12h achieved humanized exposures of serum and ELF, respectively. Levofloxacin 120 and 90\u2005mg\/kg q8h led to fAUC exposures in plasma and ELF similar to in humans. Both tigecycline regimens were ineffective across the MIC range. Levofloxacin regimens achieved multilog kill against susceptible isolates, and no appreciable cfu\/lung reductions in isolates with an MIC of \u226532\u2005mg\/L. Differences in cfu\/lung were evident between the levofloxacin plasma and ELF HSRs against isolates with MICs of 4 and 8\u2005mg\/L.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Administering HSRs of tigecycline and levofloxacin based on both serum\/plasma and ELF in the COMBINE pneumonia model resulted in cfu\/lung values reasonably aligned with MIC. These data serve as translational benchmarks for future investigations with novel compounds.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkae333","type":"journal-article","created":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T02:53:22Z","timestamp":1725677602000},"page":"3142-3149","source":"Crossref","is-referenced-by-count":4,"title":["Quantitative performance of humanized serum and epithelial lining fluid exposures of tigecycline and levofloxacin 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":"79","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 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa M","family":"Padgett","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M","family":"Duffy","sequence":"additional","affiliation":[{"name":"CARB-X , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 , 80 Seymour Street, Hartford, CT 06102 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