Synergistic combination of next-generation polymyxin MRX-8 and meropenem against carbapenem-resistant A. baumannii.

Abstract

MRX-8 is a new next-generation polymyxin with potent antibacterial activity against carbapenem-resistant Acinetobacter baumannii (CRAB). This study evaluated the MRX-8 and meropenem combination and their dosing regimens against CRAB in clinics. Seven CRAB strains isolated from Huashan Hospital were tested. Two strains of AB21-3881 and AB21-3759 were selected for static time-kill and the Hollow Fiber Infection Model (HFIM). Adaptive resistance to MRX-8 was assessed via population analysis profiling (PAP) at 2 mg/L of MRX-8. Multilocus sequence typing identified all seven strains as ST2. Minimum inhibitory concentration values for MRX-8 ranged from 0.5 to 1 mg/L. Synergy was observed in six out of seven (85.7%) strains. The combination of 1 mg/L MRX-8 with 1 mg/L meropenem completely inhibited bacterial growth within 24 h for both selected strains. In HFIM, the combination of MRX-8 (0.75 mg/kg q8h continuous infusion) and meropenem (1 g q6h continuous infusion) achieved synergistic killing over 72 h for AB21-3759, while single treatment of MRX-8 (0.75 mg/kg q8h continuous infusion) achieved bactericidal effect (lower than the detect limitation) over 72 h. PAP analysis demonstrated that the combinational therapy could delay the emergence of adaptive resistance sub-populations by 12-24 h. The combination of MRX-8 and meropenem demonstrated synergistic bactericidal activity by checkerboard and static time-kill curves. Additionally, in HFIM, MRX-8 at 1 mg/kg q12h combined with meropenem at 2 g q12h, as well as MRX-8 at 0.75 mg/kg q8h continuous infusion combined with meropenem at 1 g q6h continuous infusion, achieved bacteriostatic killing at 72 h compared to the initial inoculum.