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

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 monobactam antibiotic 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 β-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 β-lactamase-producing strains of Enterobacteriaceae, including those expressing metallo-β-lactamases, ESBLs and serine carbapenemases, with the PK/PD driver of efficacy identified as %T>MIC.

• Authors: E J Growcott, T A Cariaga, L Morris, X Zang, S Lopez, D A Ansaldi, J Gold, L Gamboa, T Roth, R L Simmons, C S Osborne
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 74 Issue 1 Pg. 108-116 (01 01 2019) ISSN: 1460-2091 [Electronic] England
• PMID: 30325447 (Publication Type: Journal Article)

Chemical References

• Monobactams

Topics

• Animals
• Colony Count, Microbial
• Disease Models, Animal
• Enterobacteriaceae (drug effects, isolation & purification)
• Enterobacteriaceae Infections (drug therapy)
• Female
• Injections, Intramuscular
• Mice
• Microbial Sensitivity Tests
• Monobactams (administration & dosage, pharmacokinetics, pharmacology)
• Treatment Outcome