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
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
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DOI：
10.1093/jac/dkv267
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发表时间：
2015-12-01
影响因子：
5.2
通讯作者：
Nation, Roger L.
中科院分区：
文献类型：
--
作者：
Cheah, Soon-Ee;Wang, Jiping;Nation, Roger L.
目的：本研究调查了血浆中未结合的粘菌素与小鼠大腿和肺部感染的抗菌活性之间的确定-反应关系。剂量分割研究（皮下硫酸粘杆菌素，1.25-160 mg/kg/天）在血小板减少小鼠中进行，其中感染（3株铜绿假单胞菌和3株鲍曼不动杆菌）已经通过大腿肌肉注射或气雾剂肺部递送产生。在开始粘菌素治疗后24小时测量细菌负荷。通过快速平衡透析和超离心测定血浆蛋白结合率。结果：在2-50 mg/L的浓度范围内，血浆中粘杆菌素的结合率是恒定的。所有浓度的平均+/- SD结合百分比为92.9 +/- 3.3%（超离心法）和90.4 +/- 1.1%（平衡透析法）。在大腿模型中，在所有六种菌株中，粘菌素的抗菌作用与fAUC/MIC良好相关（对于铜绿假单胞菌，R-2 = 0.82-0.94;对于曲霉菌，R-2 = 0.84-0.95。鲍曼不动）。对于铜绿假单胞菌和曲霉菌，2 log（10）杀灭的fAUC/MIC目标值分别为7.4-13.7和7.4-17.6。鲍曼不动杆菌。在肺模型中，只有两株铜绿假单胞菌和一株A.即使在小鼠耐受的最高粘菌素剂量下，也可能达到2 log 10杀灭（fAUC/MIC目标值36.8-105）。该剂量对另外两株A.结论：多粘菌素对肺部感染的疗效显著降低。药代动力学/药效学目标值将有助于优化剂量方案的设计。
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 similar to 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 log(10) 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.