Pharmacokinetics/pharmacodynamics of KSP-1007 in combination with meropenem against carbapenemase-producing gram-negative bacteria in a neutropenic murine thigh infection model.

Abstract

KSP-1007 is a novel bicyclic boronate-based broad-spectrum β-lactamase inhibitor that improves meropenem (MEM) efficacy against gram-negative bacteria (GNB) producing serine- and metallo-type carbapenemases. We investigated which pharmacokinetics (PK)/pharmacodynamics (PD) parameters of KSP-1007 correlated with MEM/KSP-1007 efficacy against carbapenemase-producing (CP)(CPE) and(CPAB) in a neutropenic murine thigh infection model. Infected neutropenic mice were subcutaneously treated with MEM every 3 h for 24 h alone or in combination with KSP-1007 administered at 3-, 6-, 12-, or 24-h dosing intervals. The bacterial burden in the thigh was assessed 2 h and 26 h after infection. The percentage of the dosing interval at which the free drug concentration exceeded the threshold concentration (%T>C) was a good predictor of activity against serine- and metallo-CPE and CPAB based on coefficients of determinations (R= 0.5-0.8) and a visual inspection of the plots showing %T>Cagainst the change in logCFU/thigh, although the area under the 24-h free drug concentration time-curve yielded similar Rvalues. The required values for %T>Cat 0.25-4 μg/mL were 20.4%-4.2% (stasis) and 45.1%-14.1% (1-logkill) for serine-CPE and 48.6%-13.3% (stasis) and 97.9%-42.3% (1-logkill) for metallo-CPE. The corresponding values for CPAB at thresholds of 0.5-8 μg/mL were 15.3%-4.3% and 33.9%-8.7%. Frequent dosing of KSP 1007 maximized its potentiation of MEM activity against most of the tested CP-GNB strains. Therefore, theefficacy of KSP-1007 with MEM against CP-GNB was not dependent on the peak free drug concentration of KSP-1007, making KSP-1007 an optimal partner for MEM, which exhibits time-dependent activity.