期刊
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
卷 55, 期 2, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ijantimicag.2019.10.019
关键词
beta-lactamase inhibitor; Carbapenemase; AmpC; KPC; Lung epithelial lining fluid
资金
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
- Department of Health and Human Services
- Office of the Assistant Secretary for Preparedness and Response
- Biomedical Advanced Research and Development Authority [HHSO100201600038C]
Nacubactam is a novel non-beta-lactam diazabicyclooctane beta-lactamase inhibitor under development for the treatment of serious Gram-negative infections. This study assessed the efficacy of human-simulated epithelial lining fluid (ELF) exposure of nacubactam in combination with meropenem against AmpC-overproducing (n=4) and Klebsiella pneumoniae carbapenemase (KPC)-expressing (n=3) Pseudomonas aeruginosa isolates in the neutropenic murine lung infection model. Meropenem, nacubactam and meropenem-nacubactam (1:1 concentration ratio) minimum inhibitory concentrations (MICs) were determined in triplicate using broth microdilution. Regimens that provided ELF profiles mimicking those observed in humans given nacubactam 2 g q8h (1.5-h infusion) alone and in combination with a subtherapeutic ELF exposure of meropenem were administered 2 h after inoculation. Efficacy was assessed as the change in log 10 colony-forming units (CFU)/lung at 24 h compared with 24-h meropenem monotherapy. Meropenem, nacubactam and meropenem-nacubactam MICs were 8->64, 128->256 and 2-16 mg/L, respectively. Meropenem and nacubactam monotherapy groups demonstrated bacterial growth over 24 h for each isolate. Against AmpC-overproducing and KPC-expressing P. aeruginosa isolates, meropenem-nacubactam resulted in -2.73 +/- 0.93 and -4.35 +/- 1.90 log 10 CFU/lung reduction, respectively, relative to meropenem monotherapy. Meropenem-nacubactam showed promising in-vivo activity against meropenem-resistant P. aeruginosa, indicative of a potential role for the treatment of infections caused by these challenging pathogens. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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