Exploring the Synergy of CB-618 and Meropenem: Insights from In Vitro Pharmacokinetic-Pharmacodynamic Studies

The rise of bacteria that produce β-lactamase poses a significant threat to the efficacy of β-lactam antimicrobial drugs. This has spurred a renewed focus on developing broad-spectrum inhibitors of β-lactamase. The study in question presents findings from dose fractionation and dose-ranging experiments conducted using an in vitro one-compartment infection model. The aim was to identify the exposure measure for CB-618, a new β-lactamase inhibitor, that best predicts its effectiveness when combined with meropenem. The study involved a variety of Enterobacteriaceae clinical strains known to produce multiple types of β-lactamase enzymes. Human drug concentration profiles were simulated, and samples were taken to measure drug levels and bacterial densities.

Data from the dose fractionation studies were used along with a Klebsiella pneumoniae strain to examine the correlation between the change in log10 CFU/ml at 24 hours and various measures of CB-618 exposure, including the area under the concentration-time curve over 24 hours (AUC0–24), the maximum concentration (Cmax), and the time that CB-618 levels remained above a certain threshold, all in conjunction with meropenem administered at 2 g every 8 hours.

The exposure measures that showed the strongest association with CB-618's efficacy when used with meropenem were the AUC0–24 and Cmax. By using the AUC0–24 adjusted to the CB-618-potentiated meropenem MIC value, the study evaluated the relationship between the change from baseline in log10 CFU/ml at 24 hours and the AUC0–24/MIC ratio using data from five challenge isolates. The AUC0–24/MIC ratio that corresponded to bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 hours were identified as 27.3, 86.1, and 444.8, respectively. These findings provide a pharmacokinetic and pharmacodynamic foundation for assessing potential dosing strategies for CB-618 in combination with meropenem in future research.