2025/03/04 by Amaury O’Jeanson, Elisabet I. Nielsen, Lena E. Friberg · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Antibiotic Resistance in Bacteria #Antibiotics Pharmacokinetics and Efficacy #Pneumonia and Respiratory Infections
paper · pdf · doi:10.1093/jacamr/dlaf036
openalex publication_date 2025/03/04 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
Abstract Background The emergence of β-lactamase-producing bacteria limits the effectiveness of β-lactam (BL) antibiotics, and the combination with a β-lactamase inhibitor (BLI) aims to counteract this resistance. However, existing guidelines primarily focus on optimizing the dosing of BLs and do not adequately address the interaction between BLs and BLIs, leading to uncertain pharmacokinetic/pharmacodynamic (PK/PD) targets and potentially suboptimal dosing strategies. Objectives To investigate optimal PK/PD targets and dosing strategies for avibactam (BLI) combined with ceftazidime (BL) using mechanism-based PKPD models. Methods PK models for ceftazidime and avibactam were integrated with mechanism-based PKPD models for Gram-negative bacteria. Simulations explored dose regimens in mice and humans, evaluating PK/PD indices and computing the PTA for diverse dosing strategies and infusion modes. Results fAUC/MICCAZ/AVI was the most predictive index for avibactam against Enterobacteriaceae in both mice and humans, regardless of infusion mode. Against Pseudomonas aeruginosa, fT > CT predicted efficacy in mice, while fAUC/MICCAZ/AVI and fCmax/MICCAZ/AVI were more predictive in humans, particularly for continuous infusion regimens. Higher PTAs were achieved with increased avibactam doses relative to ceftazidime, particularly with 1:1 and 2:1 ceftazidime:avibactam ratios. Continuous infusion improved PTA against P. aeruginosa but had limited impact on Enterobacteriaceae. Conclusion The PK/PD indices predictive of avibactam efficacy varied by species (mice and humans), bacterial strains, and mode of infusion. Dosing simulations suggest that increasing avibactam relative to ceftazidime and using continuous infusion regimens may enhance bacterial killing. These findings highlight the importance of refining dosing strategies for both components of the combination therapy.