Dose optimization of colistin combinations against carbapenem-resistant acinetobacter baumannii from patients with hospital-acquired pneumonia in China by using an in vitro pharmacokinetic/pharmacodynamic model

Colistin-based combination therapy has become an important strategy to combat the carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal dosage regimen selection for the combination with maximum efficacy is challenging. Checkerboard assay was employed to evaluate the synergy of colistin in combination with meropenem, rifampin, fosfomycin, and minocycline against nine carbapenem-resistant A. baumannii isolates (MIC of meropenem [MIC_MEM], 32 mg/ liter) isolated from Chinese hospital-acquired pneumonia (HAP) patients. A static time-kill assay, in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, and semimechanistic PK/PD modeling were conducted to predict and validate the synergistic effect of the most efficacious combination. Both checkerboard and static time-kill assays demonstrated the superior synergistic effect of the colistin-meropenem combination against all CRAB isolates. In the in vitro PK/PD model, the dosage regimen of 2 g meropenem daily via 3-h infusion combined with steady-state 1 mg/liter colistin effectively suppressed the bacterial growth at 24 h with a 2-log₁₀ decrease, compared with the initial inocula against two CRAB isolates. The semimechanistic PK/PD model predicted that more than 2 mg/liter colistin combined with meropenem (2 g, 3-h infusion) was required to achieve the killing below the limit of detection (LOD; i.e., 1 log₁₀CFU/ml) at 24 h with an MIC_MEM of 32 mg/liter. Colistin combined with meropenem exerted synergistic killing against CRAB even with an MIC_MEM of 32 mg/liter and MIC of colistin (MIC_CST) of 1 mg/liter. However, it is predicted that a higher concentration of colistin combined with meropenem was crucial to kill bacteria to LOD. Our study provides important PK/PD information for optimization of the colistin and meropenem combination against CRAB.