AUTHOR=Huang Zhiwei , Bian Xingchen , Li Yi , Hu Jiali , Guo Beining , Yang Xinyi , Jin Yi , Zheng Shansong , Wang Xinmei , Gao Cong , Zhang Jing , Wu Xiaojie
TITLE=In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales
JOURNAL=Frontiers in Pharmacology
VOLUME=15
YEAR=2024
URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1282480
DOI=10.3389/fphar.2024.1282480
ISSN=1663-9812
ABSTRACT=Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model.
Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline.
Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT > 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1 mg/L of FL058, respectively. The PK/PD index of %fT > 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem.
Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.