Introduction. Cefuroxime is an important antibiotic to treat several serious infections. Rapid elimination through the kidneys and the variation in MICs of various susceptible pathogens such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae give rise to dosing issues, especially in otherwise healthy patients. Aim. To investigate the probability of target attainment (PTA) for obtaining the optimal dosage regimens for cefuroxime in healthy young people. Methodology. Two weeks apart 750 and 1500 mg cefuroxime were administered as an intravenous bolus to 20 healthy volunteers (mean age: 27 years). Population modelling and simulation studies were done based on the obtained data for cefuroxime plasma concentration. Results. With a target value of time above MIC (T _>MIC) greater than 50 % the simulations revealed that a PTA of >99 % is obtained for S. pneumoniae with a dosage regimen of 750 mg q12h. For E. coli and K. pneumoniae the PTA was <90 % even with the highest, simulated dosage of 1500 mg q6h. For S. aureus a dosage of 1500 mg q8h gave a PTA above 97 %. Conclusions. S. pneumoniae is most likely treatable with a two-daily dose of 750 mg cefuroxime. Not treatable are K. pneumoniae and E. coli . For S. aureus 1500 mg q8h constitutes an optimal dosing schedule.

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.