Lin Yu-Wei, Zhou Qi Tony, Cheah Soon-Ee, Zhao Jinxin, Chen Ke, Wang Jiping, 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, Purdue University, West Lafayette, Indiana, USA
Antimicrob Agents Chemother. 2017 Feb 23;61(3). doi: 10.1128/AAC.02025-16. Print 2017 Mar.
Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR) However, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against three strains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (AUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection ( = 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). The AUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDR lung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy.
多粘菌素通常通过吸入和/或肠胃外途径给药，用于治疗由多重耐药（MDR）菌引起的呼吸道感染。然而，目前可用于指导吸入多粘菌素给药方案优化的药代动力学（PK）和药效学（PD）数据有限。在本研究中，在中性粒细胞减少的肺部感染小鼠中气管内递送单剂量多粘菌素溶液后，测定了上皮衬液（ELF）和血浆中多粘菌素的PK。在中性粒细胞减少的小鼠肺部感染模型中，检测了气管内递送多粘菌素对三株菌（ATCC 27853、PAO1和FADDI-PA022；所有菌株的最低抑菌浓度均为1毫克/升）的抗菌效果。进行了剂量分割研究，剂量范围为2.64至23.8毫克/千克体重/天。采用抑制性S型模型来确定最能描述肺部递送多粘菌素抗菌效果的PK/PD指数。在ELF和血浆中，游离浓度-时间曲线下面积与最低抑菌浓度的比值（AUC/MIC）是最能描述小鼠肺部感染抗菌效果的PK/PD指数（ELF为0.60至0.84，血浆为0.64至0.83）。对这三株菌实现抑菌所需的AUC/MIC靶点在ELF中为684至1050，在血浆中为2.15至3.29。组织病理学数据显示，尽管多粘菌素在健康小鼠中会引起轻度肺部炎症，但肺部递送多粘菌素可减轻感染引起的肺部炎症并保持肺上皮的完整性。本研究表明，肺部递送多粘菌素对MDR菌肺部感染的抗菌效果优于肠胃外给药。我们的结果首次为优化吸入多粘菌素治疗提供了重要的临床前PK/PD信息。
