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

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) <i>Enterobacterales</i> (CPE) and <i>Acinetobacter baumannii</i> (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 (%<i>f</i>T>C_T) was a good predictor of activity against serine- and metallo-CPE and CPAB based on coefficients of determinations (R² = 0.5-0.8) and a visual inspection of the plots showing %<i>f</i>T>C_T against the change in log₁₀ CFU/thigh, although the area under the 24-h free drug concentration time-curve yielded similar R² values. The required values for %<i>f</i>T>C_T at 0.25-4 μg/mL were 20.4%-4.2% (stasis) and 45.1%-14.1% (1-log₁₀ kill) for serine-CPE and 48.6%-13.3% (stasis) and 97.9%-42.3% (1-log₁₀ kill) 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, the <i>in vivo</i> efficacy 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.