In Vitro and In Vivo Efficacy of the Broad-Spectrum β-Lactamase Inhibitor APC24-7 in Combination with Meropenem Against Carbapenem-Resistant Enterobacterales

Abstract

Background: Carbapenem-resistant Enterobacterales (CRE) represent a major therapeutic challenge, driven in part by serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs). APC24-7 is a broad-spectrum β-lactamase inhibitor (BLI) designed to inhibit enzymes from both groups. Here, we evaluated the ability of APC24-7 to potentiate meropenem (MEM) activity against meropenem-resistant Escherichia coli and Klebsiella pneumoniae. Methods & Results: Checkerboard assays were performed against 31 K. pneumoniae and 17 E. coli isolates harboring a range of clinically relevant SBL and/or MBL genes. APC24-7 reduced meropenem minimum inhibitory concentrations (MICs) in an isolate- and concentration-dependent manner. At 32 mg/L APC24-7, meropenem MICs fell within the CLSI susceptible range for meropenem in 11 of 17 E. coli isolates, whereas 16 of 31 K. pneumoniae isolates remained resistant. Time-kill experiments with nine selected isolates showed bactericidal activity under active combination conditions, defined as a ≥3 log10 CFU/mL reduction from the initial bacterial count, within 3–5 h. Pharmacokinetic evaluation in infected mice showed less-than-dose-proportional systemic exposure following subcutaneous administration of APC24-7, with a maximum plasma concentration of approximately 26 mg/L after a 30 mg/kg dose. In a neutropenic murine thigh infection model, APC24-7 increased meropenem activity against four selected in vitro-responsive isolates in a dose-dependent manner. Conclusions: These findings provide preclinical proof of concept for APC24-7 as a broad-spectrum BLI capable of potentiating meropenem against Enterobacterales harboring diverse β-lactamases, while highlighting substantial isolate-dependent variability that warrants further pharmacokinetic/pharmacodynamic and resistance-mechanism studies.