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Pharmacokinetics and pharmacodynamics of the novel monobactam LYS228 in a neutropenic murine thigh model of infection

Growcott, Ellena and Cariaga, Taryn and Morris, Laura and Zang, Richard and Lopez, Sara and Ansaldi, Dan and Gold, Josh and Gamboa, Luis and Roth, Theresa and 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

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