Synergistic killing by meropenem and colistin combination of carbapenem-resistant Acinetobacter baumannii isolates from Chinese patients in an in vitro pharmacokinetic/pharmacodynamic model.
Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important clinical threat. Combination therapy that exerts a synergistic effect has become a potential solution to combat CRAB. However, choosing an optimal combination regimen is challenging. A dynamic in vitro pharmacokinetic/pharmacodynamic (PK/PD) model that can simulate the pharmacokinetic profiles of antibiotics provides a powerful tool to compare antibacterial responses to different clinical dosage regimens. In this study, the synergistic effect of the combination of meropenem and colistin was tested in 12 clinical CRAB isolates from Chinese patients using the chequerboard technique. The antibacterial effect was investigated in an in vitro PK/PD diffusion model by simulating different dosage regimens: meropenem monotherapy (0.5 g with 0.5-h infusion or 1 g with 3-h infusion); colistin monotherapy (fixed unbound concentration maintained at 0.25, 0.5 or 1 mg/L); and combination of meropenem and colistin. The chequerboard method showed that the combination of meropenem and colistin had synergistic effects against all 12 isolates, with fractional inhibitory concentration indices (FICIs) of ≤0.5. Moreover, the dynamic in vitro PK/PD model demonstrated that for clinical CRAB isolates with a meropenem MIC of 128 mg/L, the combination (meropenem 1 g with 3-h infusion combined with colistin maintained at 1 mg/L) could achieve 3.8 log10killing after 24 h, whereas monotherapy was unable to provide such an antibacterial effect. Taken together, these results suggest that the combination of meropenem and colistin might be a promising therapy against CRAB.
Institute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China; Roche Innovation Center Shanghai, Shanghai 201203, China.
Xiaofen
X
Liu
Institute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China.
Miao
M
Zhao
Institute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China.
Yuancheng
Y
Chen
Shanghai Normal University, Shanghai 200234, China.
Xingchen
X
Bian
Roche Innovation Center Shanghai, Shanghai 201203, China.
Yunfei
Y
Li
Roche Innovation Center Shanghai, Shanghai 201203, China.
Jun
J
Shi
Institute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China. Electronic address: zhangj_fudan@aliyun.com.
Jing
J
Zhang
D000151:Acinetobacter Infections / Q000382:microbiology*; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D044466:Asian People; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology; D003091:Colistin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D008954:Models, Biological; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D018440:beta-Lactam Resistance
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D000077731:Meropenem; D003091:Colistin
Carbapenem-resistant Acinetobacter baumannii; Colistin; Combination therapy; In vitro; Meropenem; PK/PD model