Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
J Antimicrob Chemother. 2018 Feb 1;73(2):462-468. doi: 10.1093/jac/dkx409.
The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known.
Dose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120 mg/kg/day; lung infection 5-120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later. Plasma exposure measures for unbound polymyxin B were from population pharmacokinetic analysis of single doses and plasma protein binding by ultracentrifugation. The inhibitory sigmoid dose-effect model was employed to determine the relationship between exposure and efficacy. Antibacterial activities of polymyxin B and colistin against thigh infection were compared at equimolar doses generating exposures resulting in maximal antibacterial activity.
The pharmacokinetics of polymyxin B were well described by a model comprising parallel linear and saturable pathways for absorption and elimination. Plasma binding of polymyxin B was constant (P > 0.05) over the range ∼0.9-37 mg/L; average (±SD) percentage bound was 91.4 ± 1.65. In thigh infection, antibacterial effect was well correlated with fAUC/MIC (R2 = 0.89). Target values of fAUC/MIC for stasis and 1 log10 kill were 1.22-13.5 and 3.72-28.0, respectively; 2 log10 kill was not achieved for any strain, even at the highest tolerated dose. There was no difference (P > 0.05) in antibacterial activity between polymyxin B and colistin with equimolar doses. It was not possible to achieve stasis in lung infection, even at the highest dose tolerated by mice.
The results will assist in the design of optimized dosage regimens of polymyxin B.
目前尚不清楚多黏菌素 B 针对肺炎克雷伯菌感染的药代动力学/药效学（PK/PD）关系。
采用皮下注射多黏菌素 B 的剂量分割研究，在大腿或肺部感染三种肺炎克雷伯菌的中性粒细胞减少症小鼠中进行。接种后 2 小时开始给药（大腿感染 0.5-120mg/kg/天；肺部感染 5-120mg/kg/天），24 小时后测量细菌负荷。游离多黏菌素 B 的血浆暴露量来自单次剂量的群体药代动力学分析和超速离心法的血浆蛋白结合。采用抑制型 S 型剂量效应模型来确定暴露量与疗效之间的关系。在产生最大抗菌活性的暴露量下，比较了多黏菌素 B 和黏菌素对大腿感染的抗菌活性。
多黏菌素 B 的药代动力学通过吸收和消除的平行线性和饱和途径的模型得到很好的描述。多黏菌素 B 的血浆结合率在 0.9-37mg/L 范围内保持恒定（P>0.05）；平均（±SD）结合率为 91.4 ± 1.65%。在大腿感染中，抗菌效果与 fAUC/MIC 密切相关（R2=0.89）。停滞和 1 对数杀灭的 fAUC/MIC 目标值分别为 1.22-13.5 和 3.72-28.0，任何菌株均未达到 2 对数杀灭，即使在最高耐受剂量下也是如此。在等摩尔剂量下，多黏菌素 B 和黏菌素的抗菌活性没有差异（P>0.05）。即使在小鼠耐受的最高剂量下，肺部感染也无法达到停滞状态。
这些结果将有助于设计优化的多黏菌素 B 剂量方案。
