PR002321 (Project)

Description: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 strains harbouring genes that encode various carbapenemases or ESBLs (extended spectrum beta-lactamases). 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. Metabolomic analysis: Mechanistical investigation of the PD interaction between ceftazidime/avibactam-tigecycline was studied in a selected clinical isolate of E. coli (strain JUM_JEA) using metabolomic analyses in mono- and combination treatment scenarios. Time-kill assays were conducted for ceftazidime/avibactam and tigecycline concentrations of 4 x MIC (minimum inhibitory concentration) as well as combinations of both antibiotics at 4 x MIC CZA – 4 x MIC TGC and growth controls as four replicates over 4 h with samples at 0, 2 and 4 h. 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.