Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models
Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models
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DOI：
10.1093/jac/dki241
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发表时间：
2005-08-01
影响因子：
5.2
通讯作者：
Lame, ME
中科院分区：
文献类型：
--
作者：
Girard, D;Finegan, SM;Lame, ME
目的：由于阿奇霉素的半衰期延长和独特的药代动力学和药效学（PK-PD）特征，正在评估用于治疗社区获得性感染的较短给药方案。为了提供进一步的支持，较短的给药方案，阿奇霉素的疗效进行了测定，在临床前感染模型比较单与多剂量regiments.Methods：阿奇霉素的单与多剂量方案的疗效进行了比较，在小鼠肺炎，急性腹膜炎，并arrhenic大腿感染模型和沙鼠模型流感嗜血杆菌急性中耳炎。阿奇霉素在第一个治疗日单次口服给药，或在2个治疗日分两次给药，或在3个治疗日分三次给药。阿奇霉素的药代动力学分析单剂量和多剂量方案与单剂量数据拟合到EM，模型来表征的PK-PD的阿奇霉素。结果：在小鼠疗效模型，单剂量阿奇霉素的管理产生上级的生存率和细菌清除率相比，相同的总剂量分为2或3天。在沙鼠模型中，单次剂量使中耳绝育，并更快地清除H。流感。药代动力学评价证实，三种方案的血清和肺组织中的总暴露量（AUC）相似。PK-PD参数和抗菌效果的相关性证实了浓度依赖性和剂量无关的关系阿奇霉素。结论：这些数据是一致的，从临床研究报告的数据，并表明，单剂量方案将至少是有效的相同剂量的管理超过几天。
Objectives: As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens.Methods: The efficacy of single versus multi-dose regimens of azithromycin was compared in mouse pneumonia, acute peritonitis, and neutropenic thigh infection models and in a gerbil model of Haemophilus influenzae acute otitis media. Azithromycin was administered as a single oral dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days. The pharmacokinetics of azithromycin was profiled following single and multi-dose regimens with the single dose data fit to an Em,, model to characterize the PK-PD of azithromycin.Results: In the mouse efficacy models, administration of single-dose azithromycin produced superior rates of survival and bacterial clearance compared with the same total dose divided over 2 or 3 days. In the gerbil model, a single dose sterilized the middle ear and more rapidly cleared H. influenzae. The pharmacokinetic evaluation confirmed similar total exposure (AUC) in serum and pulmonary tissue for the three regimens. Correlation of PK-PD parameters and antimicrobial efficacy confirmed a concentration-dependent and dosing-independent relationship for azithromycin.Conclusions: These data are consistent with data reported from clinical studies and indicate that a single-dose regimen would be at least as effective as the same dose administered over several days.