In vivo pharmacodynamic profiling of doripenem against Pseudomonas aeruginosa by simulating human exposures
In vivo pharmacodynamic profiling of doripenem against Pseudomonas aeruginosa by simulating human exposures
复制标题
DOI：
10.1128/aac.01252-07
复制
发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
Nicolau, David P.
中科院分区：
文献类型：
--
作者：
Kim, Aryun;Banevicius, Mary Anne;Nicolau, David P.
多尼培南是一种新型广谱碳青霉烯类药物，具有对抗一系列革兰氏阴性病原体的活性，包括铜绿假单胞菌等非发酵细菌。本研究的目的是使用中性粒细胞减少的小鼠大腿感染模型，针对 24 种具有广泛 MIC 的临床铜绿假单胞菌分离株，评估模拟人体暴露于多尼培南的情况。小鼠给药方案的设计接近于人类每 8 小时 500 mg 多尼培南 1 小时或 4 小时静脉输注观察到的高于 MIC 的自由时间 (fT > MIC)。最大抗菌杀灭效果与多尼培南暴露量 >= 40% fT > MIC 相关；抑菌效果约为 20% fT > MIC。模拟1小时输注对MIC=8μg/ml的分离株具有杀菌作用，通常观察到再生。在 1 小时内每 8 小时输注 500 mg 多尼培南的模拟剂量证明了对铜绿假单胞菌分离株的抗菌杀灭作用，MIC 为 0.125 至 8 μg/ml。暴露于 >= 40% fT > MIC 时会产生最明显的杀菌效果，而当暴露于 20% 至 30% fT > MIC 时，杀灭作用是可变的。输注剂量超过 4 小时可增强对选定假单胞菌分离株的功效，MIC 为 4 μg/ml。
Doripenem is a new broad-spectrum carbapenem with activity against a range of gram-negative pathogens, including nonfermenting bacteria such as Pseudomonas aeruginosa. The objective of this study was to evaluate simulated human exposures to doripenem using a neutropenic murine thigh infection model against 24 clinical P. aeruginosa isolates with a wide range of MICs. Dosing regimens in mice were designed to approximate the free time above MIC (fT > MIC) observed with 500 mg doripenem every 8 h given as either a 1-h or 4-h intravenous infusion in humans. Maximal antibacterial killing was associated with doripenem exposures of >= 40% fT > MIC; bacteriostatic effects were noted at approximate to 20% fT > MIC. The simulated 1-h infusion provided bactericidal effects for isolates with MICs of = 8 mu g/ml, regrowth was generally observed. Simulated doses of 500 mg doripenem every 8 h infused over 1 h demonstrated antibacterial killing for P. aeruginosa isolates with MICs of 0.125 to 8 mu g/ml. Exposures of >= 40% fT > MIC resulted in the most pronounced bactericidal effects, while killing was variable for 20 to 30% fT > MIC. Infusing doses over 4 h enhanced efficacy against selected pseudomonal isolates with an MIC of 4 mu g/ml.