Ceftazidime/avibactam: a potent arsenal against multidrug-resistant Pseudomonas aeruginosa-unveiling in vitro and in vivo strategies

Abstract

Background: Ceftazidime/avibactam (CZA) is recognized as an efficacious treatment modality against multidrug-resistant Pseudomonas aeruginosa. Nevertheless, it encounters the challenge of escalating antimicrobial resistance. Employing combination regimens involving ceftazidime/avibactam may confer advantages.

Methods: Checkerboard titration, time-kill assays, and an in vitro pharmacodynamic model were employed to investigate the effectiveness of ceftazidime/avibactam alone and in combination in vitro. Additionally, an intraperitoneal infection mouse model was established to assess the efficacy of combination therapy in vivo.

Results: In the in vitro pharmacodynamic model, administration of ceftazidime/avibactam plus polymyxin B resulted in a significant reduction in colony-forming units of all four strains, whereas ceftazidime/avibactam plus aztreonam only reduced the colonies of three strains. Significant or trending declines in mortality and tissue colony counts of infected mice were observed in groups treated with ceftazidime/avibactam plus polymyxin B. Conversely, ceftazidime/avibactam combined with aztreonam only reduced mortality and tissue colonies in MBL-positive P.aeruginosa-infected mice.

Conclusion: Combining ceftazidime/avibactam with polymyxin B might represent a potentially effective option against MDR-P.aeruginosa. Although the synergistic effect in vitro might not be readily apparent due to the potent bactericidal effect of aztreonam alone, the combination of ceftazidime/avibactam and aztreonam demonstrated promising synergistic effects on MBL-positive P.aeruginosa strains in vivo.