Activity of cefquinome against extended-spectrum β-lactamase-producing Klebsiella pneumoniae in neutropenic mouse thigh model.

Abstract

Increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (K.pneumoniae) is of clinical concern. The objective of our study was to examine the invivo activity of cefquinome against ESBL-producing K.pneumoniae strain using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Dose-fractionation studies over a 24-h dose range of 2.5-320mg/kg were administered every 3, 6, 12, or 24h. The percentage of the dosing interval that the free-drug serum levels exceed the MIC (%fT>MIC) was the PK-PD index that best correlated with cefquinome efficacy (R2 =86%). Using a sigmoid Emax model, the magnitudes of %fT>MIC producing net bacterial stasis, a 1-log10 kill and a 2-log10 kill over 24h, were estimated to be 20.07%, 29.57%, and 55.12%, respectively. These studies suggest that optimal cefquinome PK/PD targets are not achieved in pigs, sheep, and cattle at current recommended doses (1˜2mg/kg). Further studies with higher doses in the target species are needed to ensure therapeutic concentration, if cefquinome is used for treatment of K.pneumoniae infection.