{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T17:48:46Z","timestamp":1772646526871,"version":"3.50.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100019590","name":"CARB-X","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019590","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Anti-Infective Research and Development"},{"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":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"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":[[2026,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Plasma pharmacokinetic\/pharmacodynamic (PK\/PD) targets are a surrogate of pulmonary exposures for pneumonia, despite potential differences in exposures. This study defined free plasma and pulmonary epithelial lining fluid (ELF) PK\/PD targets for different antibiotics against Klebsiella pneumoniae (KP) in a preclinical pneumonia model, and assessed the predicted cfu\/lung response of human exposures relative to MIC breakpoints.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>Secondary analyses were performed on previously published in vivo cfu\/lung data generated using 17 KP after administration of different dosing regimens of meropenem, cefiderocol, levofloxacin and tobramycin. Efficacy was evaluated as change in log10 cfu\/lung at 24\u2005h. Emax models were fitted to composite cfu data, and plasma and ELF targets were calculated using the Hill equation. The average human plasma and ELF exposures achieved clinically relative to MIC breakpoints were overlaid on the Emax curve to predict corresponding cfu\/lung efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All Emax models had an R2\u200a&amp;gt;\u200a0.85. ELF targets differed from plasma targets and were generally lower (meropenem, cefiderocol and tobramycin), but higher for levofloxacin. Based on average human ELF exposures, the predicted cfu\/lung responses of all four antibiotics were \u22651 log10 cfu\/lung reduction at susceptible MICs, variable at intermediate MICs and limited at resistant MICs. Based on plasma targets, both meropenem and cefiderocol predicted cfu reduction at resistant breakpoints, whereas ELF exposures predicted net growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data demonstrate the clinical translation of the pneumonia model relative to established breakpoints and emphasizes the potential limitations of relying solely on plasma exposure targets in predicting clinical efficacy for pneumonia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkaf458","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:43:38Z","timestamp":1771937018000},"source":"Crossref","is-referenced-by-count":0,"title":["Beyond plasma: defining the translation value of epithelial lining fluid exposure profiles for the treatment of pneumonia"],"prefix":"10.1093","volume":"81","author":[{"given":"Yakun","family":"Fu","sequence":"first","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J","family":"Fratoni","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, CT 06102 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6036-3263","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 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"2026030409451392700_dkaf458-B1","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.ijantimicag.2014.02.012","article-title":"Pharmacokinetic\/pharmacodynamic evaluation of sulbactam against Acinetobacter baumannii in in vitro and murine thigh and lung infection models","volume":"43","author":"Yokoyama","year":"2014","journal-title":"Int J Antimicrob Agents"},{"key":"2026030409451392700_dkaf458-B2","doi-asserted-by":"publisher","first-page":"e0080023","DOI":"10.1128\/aac.00800-23","article-title":"In vivo dose response and efficacy of the beta-lactamase inhibitor, durlobactam, in combination with sulbactam against the Acinetobacter baumannii-calcoaceticus complex","volume":"68","author":"O'Donnell","year":"2024","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B3","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1093\/jac\/dkae432","article-title":"Development and confirmation of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin in a standardized neutropenic murine pneumonia model","volume":"80","author":"Fratoni","year":"2025","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B4","doi-asserted-by":"publisher","first-page":"3142","DOI":"10.1093\/jac\/dkae333","article-title":"Quantitative performance of humanized serum and epithelial lining fluid exposures of tigecycline and levofloxacin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model","volume":"79","author":"Fratoni","year":"2024","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B5","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1093\/jac\/dkaf100","article-title":"Quantitative performance of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model","volume":"80","author":"Fratoni","year":"2025","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B6","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1093\/jac\/dkae388","article-title":"Establishment of a diverse pheno-genotypic challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa suitable for use in the murine pneumonia model","volume":"80","author":"Fratoni","year":"2025","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B7","author":"CLSI"},{"key":"2026030409451392700_dkaf458-B8","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1128\/AAC.01330-10","article-title":"Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia","volume":"55","author":"Lodise","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B9","doi-asserted-by":"publisher","first-page":"2902","DOI":"10.1093\/jac\/dkab280","article-title":"Intrapulmonary pharmacokinetic profile of cefiderocol in mechanically ventilated patients with pneumonia","volume":"76","author":"Katsube","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B10","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1111\/j.1365-2125.1989.tb05431.x","article-title":"Population pharmacokinetics of tobramycin","volume":"28","author":"Aarons","year":"1989","journal-title":"Br J Clin Pharmacol"},{"key":"2026030409451392700_dkaf458-B11","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0009-9236(99)70103-7","article-title":"Tobramycin penetration into epithelial lining fluid of patients with pneumonia","volume":"65","author":"Carcas","year":"1999","journal-title":"Clin Pharmacol Ther"},{"key":"2026030409451392700_dkaf458-B12","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1128\/AAC.39.3.650","article-title":"Experience with a once-daily aminoglycoside program administered to 2,184 adult patients","volume":"39","author":"Nicolau","year":"1995","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B13","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.ijantimicag.2014.12.028","article-title":"Presence of infection influences the epithelial lining fluid penetration of oral levofloxacin in adult patients","volume":"45","author":"Kuti","year":"2015","journal-title":"Int J Antimicrob Agents"},{"key":"2026030409451392700_dkaf458-B14","author":"CLSI"},{"key":"2026030409451392700_dkaf458-B15","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1128\/AAC.00133-06","article-title":"Interpretation of antibiotic concentration ratios measured in epithelial lining fluid","volume":"52","author":"Kiem","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"issue":"Suppl 1","key":"2026030409451392700_dkaf458-B16","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.1086\/590064","article-title":"Pharmacokinetic and pharmacodynamic properties of meropenem","volume":"47","author":"Nicolau","year":"2008","journal-title":"Clin Infect Dis"},{"key":"2026030409451392700_dkaf458-B17","doi-asserted-by":"publisher","first-page":"S42","DOI":"10.1086\/344653","article-title":"Prevention of resistance: a goal for dose selection for antimicrobial agents","volume":"36","author":"Drusano","year":"2003","journal-title":"Clin Infect Dis"},{"key":"2026030409451392700_dkaf458-B18","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1093\/jac\/dkac425","article-title":"Phenotypes, genotypes and breakpoints: an assessment of beta-lactam\/beta-lactamase inhibitor combinations against OXA-48","volume":"78","author":"Asempa","year":"2023","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B19","doi-asserted-by":"publisher","first-page":"e02031-18","DOI":"10.1128\/AAC.02031-18","article-title":"In vivo pharmacodynamic study of cefiderocol, a novel parenteral siderophore cephalosporin, in murine thigh and lung infection models","volume":"63","author":"Nakamura","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B20","doi-asserted-by":"publisher","first-page":"e01558-19","DOI":"10.1128\/AAC.01558-19","article-title":"Comparative in vivo antibacterial activity of human-simulated exposures of cefiderocol and ceftazidime against stenotrophomonas maltophilia in the murine thigh model","volume":"63","author":"Chen","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B21","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.ijantimicag.2017.10.008","article-title":"Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model","volume":"51","author":"Ghazi","year":"2018","journal-title":"Int J Antimicrob Agents"},{"key":"2026030409451392700_dkaf458-B22","doi-asserted-by":"publisher","first-page":"e01022-17","DOI":"10.1128\/AAC.01022-17","article-title":"Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of Gram-negative bacteria in a murine thigh infection model","volume":"61","author":"Monogue","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B23","doi-asserted-by":"publisher","first-page":"e01767-19","DOI":"10.1128\/AAC.01767-19","article-title":"Efficacy of humanized cefiderocol exposure is unaltered by host iron overload in the thigh infection model","volume":"64","author":"Kidd","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B24","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1093\/jac\/dkac221","article-title":"Evolution of beta-lactamase-mediated cefiderocol resistance","volume":"77","author":"Fr\u00f6hlich","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2026030409451392700_dkaf458-B25","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.jgar.2020.07.009","article-title":"Reduced susceptibility mechanism to cefiderocol, a siderophore cephalosporin, among clinical isolates from a global surveillance programme (SIDERO-WT-2014)","volume":"22","author":"Kohira","year":"2020","journal-title":"J Glob Antimicrob Resist"},{"key":"2026030409451392700_dkaf458-B26","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1089\/mdr.2021.0095","article-title":"Defining baseline mechanisms of cefiderocol resistance in the Enterobacterales","volume":"28","author":"Simner","year":"2022","journal-title":"Microb Drug Resist"},{"key":"2026030409451392700_dkaf458-B27","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1086\/383320","article-title":"Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia","volume":"189","author":"Drusano","year":"2004","journal-title":"J Infect Dis"},{"key":"2026030409451392700_dkaf458-B28","author":"LEVAQUIN (levofloxacin)"},{"key":"2026030409451392700_dkaf458-B29","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1128\/AAC.43.3.623","article-title":"Optimizing aminoglycoside therapy for nosocomial pneumonia caused by Gram-negative bacteria","volume":"43","author":"Kashuba","year":"1999","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B30","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1111\/j.1365-2125.1995.tb05719.x","article-title":"A suggested approach to once-daily aminoglycoside dosing","volume":"39","author":"Begg","year":"1995","journal-title":"Br J Clin Pharmacol"},{"key":"2026030409451392700_dkaf458-B31","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1093\/jat\/28.3.187","article-title":"Gentamicin and tobramycin binding to human serum in vitro","volume":"28","author":"Bailey","year":"2004","journal-title":"J Anal Toxicol"},{"key":"2026030409451392700_dkaf458-B32","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1007\/s00134-007-0688-x","article-title":"Reliability of mini-bronchoalveolar lavage for the measurement of epithelial lining fluid concentrations of tobramycin in critically ill patients","volume":"33","author":"Boselli","year":"2007","journal-title":"Intensive Care Med"},{"key":"2026030409451392700_dkaf458-B33","doi-asserted-by":"publisher","first-page":"988725","DOI":"10.3389\/fmicb.2022.988725","article-title":"Expert workshop summary: advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections","volume":"13","author":"Arrazuria","year":"2022","journal-title":"Front Microbiol"},{"key":"2026030409451392700_dkaf458-B34","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/S1473-3099(20)30731-3","article-title":"Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial","volume":"21","author":"Wunderink","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"2026030409451392700_dkaf458-B35","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/S0149-2918(03)80091-7","article-title":"Levofloxacin compared with imipenem\/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label study","volume":"25","author":"West","year":"2003","journal-title":"Clin Ther"},{"key":"2026030409451392700_dkaf458-B36","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1093\/cid\/ciu219","article-title":"A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia","volume":"59","author":"Awad","year":"2014","journal-title":"Clin Infect Dis"},{"key":"2026030409451392700_dkaf458-B37","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.1128\/AAC.02292-12","article-title":"Monte Carlo simulations based on phase 1 studies predict target attainment of ceftobiprole in nosocomial pneumonia patients: a validation study","volume":"57","author":"Muller","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"2026030409451392700_dkaf458-B38","doi-asserted-by":"publisher","first-page":"3294","DOI":"10.1128\/AAC.00144-09","article-title":"Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole","volume":"53","author":"Rodvold","year":"2009","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/81\/4\/dkaf458\/67226724\/dkaf458.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/81\/4\/dkaf458\/67226724\/dkaf458.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T14:45:22Z","timestamp":1772635522000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/doi\/10.1093\/jac\/dkaf458\/8505764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,3,4]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkaf458","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,3,4]]},"article-number":"dkaf458"}}