Background: 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 the maximum efficacy is challenging.
Method: Checkerboard assay was employed to evaluate the synergy of colistin in combination with meropenem, rifampicin, fosfomycin and minocycline against nine carbapenem-resistant A. baumannii (Minimum inhibitory concentration of meropenem [MICMEM]≥32 mg/L) isolated from Chinese hospital-acquired pneumonia (HAP) patients. Static time-kill assay, in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model and semi-mechanistic PK/PD modeling were conducted to predict and validate the synergistic effect of the most efficacious combination.
Results: Both checkerboard and static time-kill assays demonstrated superior synergistic effect of 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/L colistin effectively suppressed the bacterial growth at 24 h with 2-log10 decrease, compared to the initial inocula against two CRAB isolates. The semi-mechanistic PK/PD model predicted that more than 2 mg/L 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 MICMEM ≥32 mg/L.
Conclusions: Colistin combined with meropenem exerted synergistic killing against CRAB even with MICMEM ≥32 mg/L and MICCST ≤1 mg/L. However, it is predicted that higher concentration of colistin combined with meropenem was crucial to kill bacteria to <LOD. Our study provides important PK/PD information for optimization of colistin and meropenem combination against CRAB.
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