Lin Yu-Wei, Zhou Qi, Onufrak Nikolas J, Wirth Veronika, Chen Ke, Wang Jiping, Forrest Alan, Chan Hak-Kim, Li Jian
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00211-17. Print 2017 Aug.
Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice ( of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.
多粘菌素的肺部给药越来越多地用于治疗由多重耐药革兰氏阴性菌引起的呼吸道感染，如囊性纤维化患者的感染。然而，雾化多粘菌素B的药代动力学（PK）、药效学（PD）和毒性数据不足，无法为合理的剂量选择提供依据。在中性粒细胞减少的感染小鼠中研究了肺部和静脉给药后多粘菌素B的PK和PD，并通过群体PK模型分析数据。针对2.06至24.8mg碱/千克体重的每日总剂量，对ATCC 27853、PAO1和FADDI-PA022（所有三株菌的MIC为1mg/升）进行了剂量分割研究。在健康和中性粒细胞减少的感染小鼠中，于治疗后24小时进行肺组织病理学检查。上皮衬液（ELF）和血浆药物暴露均需要双室PK模型。该模型由中央室和外周室组成，并通过双向一级分布清除进行描述。曲线下面积与MIC的比值（AUC/MIC）是描述雾化多粘菌素B治疗小鼠肺部感染抗菌疗效的最具预测性的PK/PD指数（ELF为0.70至0.88，血浆为0.70至0.87）。与对这三株菌的抑菌作用相关的AUC/MIC靶点在ELF中为1326至1506，在血浆中为3.14至4.03。组织病理学结果表明，多粘菌素B气雾剂显著减轻了肺部炎症并保持了肺上皮完整性。本研究强调了多粘菌素B肺部给药在实现ELF中高药物暴露方面相对于静脉给药的有利PK/PD特性。
