Evaluation of in vitro pharmacodynamic drug interactions of ceftazidime-avibactam with tigecycline in ESBL- and carbapenemase producing Escherichia coli and Klebsiella pneumoniae

Abstract

Background: Combination therapy offers a promising option to enhance efficacy and prevent resistance. A comprehensive and quantitative assessment of the last-resort combination of ceftazidime/avibactam and tigecycline is not available.

Objective: This study systematically investigated the pharmacodynamic interaction between ceftazidime/avibactam and tigecycline in clinical and isogenic Escherichia coli and Klebsiella pneumoniae strains harbouring genes that encode various carbapenemases or ESBLs.

Methods: An adaptive in vitro 'dynamic' checkerboard design and pharmacometric modelling were employed for the evaluation of pharmacodynamic interactions in fifteen bacterial isolates. Additionally, time-kill assays and metabolomic analyses were used to provide mechanistic insights.

Results: Antagonistic drug interactions between ceftazidime/avibactam and tigecycline were identified in the majority of tested strains. Time-kill assays confirmed antagonistic interactions, with tigecycline limiting ceftazidime/avibactam total killing. Metabolomic analyses of mono and combined drug exposure to bacteria revealed matching metabolomes in tigecycline alone and the combination with ceftazidime/avibactam, corroborating the identified antagonism between these drugs.

Conclusions: Our study reveals that the antagonistic interaction between ceftazidime/avibactam and tigecycline can undermine ceftazidime/avibactam's efficacy, suggesting limited clinical benefit in combining these antibiotics. Therefore, further research is encouraged to explore this and alternative combinations or approaches that may offer better clinical outcomes.

Keywords: Carbapenemases; Ceftazidime-avibactam; Combination therapy; Pharmacodynamic interactions; Tigecycline.