Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniaein mouse thigh and lung infection models
Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniaein mouse thigh and lung infection models
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DOI：
10.1093/jac/dkx409
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发表时间：
2018-02-01
影响因子：
5.2
通讯作者：
Nation, Roger L.
中科院分区：
文献类型：
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作者：
Landersdorfer, Cornelia B.;Wang, Jiping;Nation, Roger L.
背景：多粘菌素 B 对抗肺炎克雷伯菌感染的药代动力学/药效 (PK/PD) 关系尚不清楚。方法：在大腿或肺部感染三种肺炎克雷伯菌菌株的中性粒细胞减少小鼠中进行皮下注射多粘菌素 B 的剂量分级研究。接种后2小时开始给药（大腿感染0.5-120毫克/公斤/天；肺部感染5-120毫克/公斤/天），24小时后测量细菌负荷。未结合的多粘菌素 B 的血浆暴露测量来自单剂量的群体药代动力学分析和通过超速离心的血浆蛋白结合。采用抑制性乙状结肠剂量效应模型来确定暴露与功效之间的关系。在等摩尔剂量下比较多粘菌素 B 和粘菌素对大腿感染的抗菌活性，产生最大抗菌活性的暴露。结果：包含平行线性和可饱和吸收和消除途径的模型很好地描述了多粘菌素 B 的药代动力学。多粘菌素 B 的血浆结合在类似于 0.9-37 mg/L 的范围内保持恒定（P > 0.05）；平均 (+/- SD) 百分比界限为 91.4 +/- 1.65。在大腿感染中，抗菌效果与 fAUC/MIC 良好相关（R-2 = 0.89）。停滞和1 log(10)杀灭的fAUC/MIC目标值分别为1.22-13.5和3.72-28.0；即使在最高耐受剂量下，任何菌株均未达到 2 log(10) 杀灭率。等摩尔剂量的多粘菌素B与粘菌素的抗菌活性无差异（P>0.05）。即使在小鼠耐受的最高剂量下，也不可能实现肺部感染的停滞。 结论：该结果将有助于设计多粘菌素 B 的优化剂量方案。
Background: The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known.Methods: 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. Results: 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 similar to 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 (R-2 = 0.89). Target values of fAUC/MIC for stasis and 1 log(10) kill were 1.22-13.5 and 3.72-28.0, respectively; 2 log(10) 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.Conclusions: The results will assist in the design of optimized dosage regimens of polymyxin B.