The synergistic activity of tigecycline-based combinations against multidrug-resistant Acinetobacter baumannii-caused bloodstream infections.

Abstract

Objectives: Bloodstream infections (BSIs) caused by MDR Acinetobacter baumannii (MDRAB) have become a serious threat. Tigecycline is one of the last-resort agents for MDRAB, but its monotherapy in BSIs is limited by insufficient serum exposure. Certain combination strategies can enhance anti-infection ability via a synergistic effect, thus achieving acceptable antimicrobial efficacy at a relatively lower concentration. Therefore, this study was conducted to explore tigecycline-based combinations with synergistic activity against MDRAB BSIs.

Methods: Four clinically isolated MDRAB strains were investigated. The FIC index (FICI) of tigecycline in combination with clinical common antibiotics was assessed to screen synergistic combination strategies through chequerboard assays. The synergistic effect was then evaluated by an in vitro pharmacokinetics/pharmacodynamics (PK/PD) model through simulating human drug serum concentration-time profiles. Finally, a lethal BSI murine model was used to verify the synergistic efficacy of selected combination strategies in vivo.

Results: Tigecycline combined with meropenem showed the strongest synergistic effect, with an FICI of ≤0.5 for all MDRAB strains, and was consequently selected for subsequent experiments. In the in vitro PK/PD model, high-dose tigecycline combined with meropenem showed excellent synergistic activity against tigecycline-susceptible but not against non-susceptible MDRAB strains. In a lethal BSI murine model induced by tigecycline-susceptible MDRAB, strong synergistic activity was verified in the high-dose tigecycline + meropenem group, with mortality reduced to zero and the bacterial load of blood, liver, lung and kidney significantly decreased (P < 0.05).

Conclusions: High-dose tigecycline combined with meropenem displayed an excellent synergistic effect against BSIs caused by tigecycline-susceptible but not non-tigecycline-susceptible MDRAB, therefore providing a promising treatment choice for tigecycline-susceptible MDRAB BSIs in the clinic.