In Vitro and In Vivo Efficacy of the Broad-Spectrum β-Lactamase Inhibitor APC24-7 in Combination with Meropenem Against Carbapenem-Resistant Enterobacterales.
4 affiliations
- 1Bacteria, Parasites & Fungi, Statens Serum Institut (SSI), 2300 Copenhagen, Denmark.
- 2CANDOR Simulation, 8270 Højbjerg, Denmark.
- 3AdjuTec Pharma AS, 0349 Oslo, Norway.
- 4Department of Pharmacy, The University of Oslo, 0371 Oslo, Norway.
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.
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BibTeX
@article{matias2026vitro,
title = {{In Vitro and In Vivo Efficacy of the Broad-Spectrum β-Lactamase Inhibitor APC24-7 in Combination with Meropenem Against Carbapenem-Resistant Enterobacterales.}},
author = {Carina Sofia Silva Matias and Klaus Skovbo Jensen and Henrik Hasman and Kasper Thystrup Karstensen and Bjørg Bolstad and Bjørn Klem and Pål Rongved and Carina Vingsbo Lundberg and Jon Ulf Hansen},
journal = {Antibiotics (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/antibiotics15101011},
url = {https://europepmc.org/article/MED/42938753},
note = {CC BY},
}
RIS
TY - JOUR
TI - In Vitro and In Vivo Efficacy of the Broad-Spectrum β-Lactamase Inhibitor APC24-7 in Combination with Meropenem Against Carbapenem-Resistant Enterobacterales.
AU - Carina Sofia Silva Matias
AU - Klaus Skovbo Jensen
AU - Henrik Hasman
AU - Kasper Thystrup Karstensen
AU - Bjørg Bolstad
AU - Bjørn Klem
AU - Pål Rongved
AU - Carina Vingsbo Lundberg
AU - Jon Ulf Hansen
PY - 2026
DA - 2026/10/12
JO - Antibiotics (Basel, Switzerland)
DO - 10.3390/antibiotics15101011
UR - https://europepmc.org/article/MED/42938753
AB - 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.
SN - 2079-6382
ER -