在小鼠大腿和肺部感染模型中，对全身性给予多粘菌素治疗铜绿假单胞菌和鲍曼不动杆菌的新的药代动力学/药效学研究：肺部感染中的反应较小。
New pharmacokinetic/pharmacodynamic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: smaller response in lung infection.
作者信息
Cheah Soon-Ee, Wang Jiping, Nguyen Van Thi Thu, Turnidge John D, Li Jian, Nation Roger L
机构信息
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia.
Departments of Pathology and Paediatrics and School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
出版信息
J Antimicrob Chemother. 2015 Dec;70(12):3291-7. doi: 10.1093/jac/dkv267. Epub 2015 Aug 27.
OBJECTIVES
This study investigated the exposure-response relationships between unbound colistin in plasma and antibacterial activity in mouse thigh and lung infections.
METHODS
Dose fractionation studies (subcutaneous colistin sulphate at 1.25-160 mg/kg/day) were conducted in neutropenic mice in which infection (three strains of Pseudomonas aeruginosa and three strains of Acinetobacter baumannii) had been produced by intramuscular thigh injection or aerosol lung delivery. Bacterial burden was measured at 24 h after initiation of colistin treatment. Plasma protein binding was measured by rapid equilibrium dialysis and ultracentrifugation. The inhibitory sigmoid dose-effect model and non-linear least squares regression were employed to determine the relationship between exposure to unbound colistin and efficacy.
RESULTS
Plasma binding of colistin was constant over the concentration range ∼2-50 mg/L. The average ± SD percentage bound for all concentrations was 92.9 ± 3.3% by ultracentrifugation and 90.4 ± 1.1% by equilibrium dialysis. In the thigh model, across all six strains the antibacterial effect of colistin was well correlated with fAUC/MIC (R(2) = 0.82-0.94 for P. aeruginosa and R(2) = 0.84-0.95 for A. baumannii). Target values of fAUC/MIC for 2 log10 kill were 7.4-13.7 for P. aeruginosa and 7.4-17.6 for A. baumannii. In the lung model, for only two strains of P. aeruginosa and one strain of A. baumannii was it possible to achieve 2 log10 kill (fAUC/MIC target values 36.8-105), even at the highest colistin dose tolerated by mice. This dose was not able to achieve bacteriostasis for the other two strains of A. baumannii.
CONCLUSIONS
Colistin was substantially less effective in lung infection. The pharmacokinetic/pharmacodynamic target values will assist in the design of optimized dosage regimens.
目的
本研究调查了血浆中游离多黏菌素与小鼠大腿和肺部感染抗菌活性之间的暴露-反应关系。
方法
对中性粒细胞减少的小鼠进行剂量分割研究（皮下注射硫酸多黏菌素，剂量为1.25 - 160 mg/kg/天），通过肌肉注射到大腿或雾化吸入到肺部制造感染（三种铜绿假单胞菌菌株和三种鲍曼不动杆菌菌株）。在多黏菌素治疗开始后24小时测量细菌载量。通过快速平衡透析和超速离心法测量血浆蛋白结合率。采用抑制性S形剂量效应模型和非线性最小二乘法回归来确定游离多黏菌素暴露与疗效之间的关系。
结果
多黏菌素在约2 - 50 mg/L的浓度范围内血浆结合率恒定。通过超速离心法，所有浓度下结合的平均±标准差百分比为92.9±3.3%，通过平衡透析法为90.4±1.1%。在大腿模型中，对于所有六种菌株，多黏菌素的抗菌效果与fAUC/MIC密切相关（铜绿假单胞菌的R² = 0.82 - 0.94，鲍曼不动杆菌的R² = 0.84 - 0.95）。对于2 log10杀灭率，铜绿假单胞菌的fAUC/MIC目标值为7.4 - 13.7，鲍曼不动杆菌为7.4 - 17.6。在肺部模型中，即使在小鼠耐受的最高多黏菌素剂量下，仅对两种铜绿假单胞菌菌株和一种鲍曼不动杆菌菌株能够实现2 log10杀灭率（fAUC/MIC目标值为36.8 - 105）。该剂量无法对其他两种鲍曼不动杆菌菌株实现抑菌作用。
结论
多黏菌素在肺部感染中的效果显著较差。药代动力学/药效学目标值将有助于优化给药方案的设计。
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