Growcott, Ellena, Cariaga, Taryn, Morris, Laura, Zang, Richard, Lopez, Sara, Ansaldi, Dan, Gold, Josh, Gamboa, Luis, Roth, Theresa, Simmons, Bob and Osborne, Colin (2019) Pharmacokinetics and pharmacodynamics of the novel monobactam LYS228 in a neutropenic murine thigh model of infection. Journal of Antimicrobial Chemotherapy, 74 (1). pp. 108-116. ISSN 14602091

Abstract

Objectives: The neutropenic murine thigh infection model and a dose-fractionation approach were used to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of LYS228, a novel monobactamantibiotic with activity against Enterobacteriaceae including carbapenem-resistant strains. Methods: Mice (n"4 per group) were inoculated with Enterobacteriaceae strains via intramuscular injection. Two hours post-bacterial inoculation, treatment with LYS228 was initiated. Animals were euthanized with CO2 24 h after the start of therapy and bacterial counts (log10 cfu) per thigh were determined. PK parameters were calculated using free (f) plasma drug levels. Results: Following a dose-fractionation study, non-linear regression analysis determined that the predominant PK/PD parameter associated with antibacterial efficacy of LYS228 was the percentage of the dosing interval that free drug concentrations remained above the MIC (%fT.MIC). In a dose-dependent manner, LYS228 reduced the thigh bacterial burden in models established with Enterobacteriaceae producing b-lactamase enzymes of all classes (e.g. ESBLs, NDM-1, KPC, CMY-2 and OXA-48). The range of the calculated static dose was 86-649 mg/kg/ day for the isolates tested, and the magnitude of the driver of efficacy was 37-83%fT.MIC. %fT.MIC was confirmed as the parameter predominantly driving efficacy as evidenced by a strong coefficient of determination (r2"0.68). Neutrophils had minimal impact on the effect of LYS228 in the murine thigh infection model. Conclusions: LYS228 is efficacious in murine thigh infection models using b-lactamase-producing strains of Enterobacteriaceae, including those expressing metallo-b-lactamases, ESBLs and serine carbapenemases, with the PK/PD driver of efficacy identified as%T.MIC.

Item Type:	Article
Date Deposited:	05 Feb 2020 00:45
Last Modified:	05 Feb 2020 00:45
URI:	https://oak.novartis.com/id/eprint/36941