Zhou Yu-Feng, Tao Meng-Ting, Huo Wei, Liao Xiao-Ping, Sun Jian, Liu Ya-Hong
National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Antimicrob Agents Chemother. 2017 Apr 24;61(5). doi: 10.1128/AAC.02691-16. Print 2017 May.
Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC)/MIC ratio was the PD index most closely linked to efficacy ( = 0.96). The mean free-drug AUC/MIC ratios required to achieve net bacterial stasis, a 1-log kill, and a 2-log kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving .
安妥沙星是一种正在研发的新型广谱氟喹诺酮类药物，用于治疗由多种细菌引起的感染。我们通过使用中性粒细胞减少小鼠肺部感染模型，探究了安妥沙星对7株分离菌的药效学（PD）特征和靶点。在单剂量皮下注射2.5、10、40和160mg/kg体重的情况下进行了血浆和支气管肺药代动力学（PK）研究。小鼠经气管内感染，并使用总剂量以2倍递增的安妥沙星进行治疗，总剂量范围为2.5至160mg/kg/24h，分1、2、3或4次给药。使用希尔方程对剂量反应数据进行建模。安妥沙星能够穿透肺上皮衬液（ELF），其药代动力学与血浆中的相似，在该剂量范围内消除半衰期呈线性。所有研究菌株的细菌载量均降低了3个对数或更多，抗生素后效应（PAEs）延长，范围为3.2至5.3小时。剂量分割反应曲线较陡，24小时内浓度-时间曲线下的游离药物面积（AUC）/MIC比值是与疗效最密切相关的PD指标（r = 0.96）。每种分离菌实现净细菌停滞、1个对数杀灭和2个对数杀灭所需的平均游离药物AUC/MIC比值分别为52.6、89.9和164.9。当与人体PK数据整合时，这些PD靶点可为进一步优化给药方案提供框架。这可能使安妥沙星成为治疗涉及[具体细菌]的呼吸道感染的有吸引力的选择。
