In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model
In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model
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DOI：
10.1128/aac.01061-07
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发表时间：
2008-02-01
影响因子：
4.9
通讯作者：
Hou, J.
中科院分区：
文献类型：
--
作者：
Andes, D.;Diekema, D. J.;Hou, J.
多项体内研究已经确定了三唑类和多烯类抗真菌药物的药效学特征。很少有研究调查棘白菌素类药物的药效学关系。我们使用中性粒细胞减少的小鼠模型播散白色念珠菌，热带念珠菌和光滑念珠菌感染来表征新的棘白菌素的活性时间过程。药代动力学-药效学（PK-PD）指数（药物浓度高于MIC的时间百分比，0-24 h浓度-时间曲线下面积[AUC(0-24)]与MIC的比值，以及最大血清药物浓度[C-max]与MIC的比值）与体内疗效相关，这些指标是通过治疗96 h后肾脏培养物中的生物体数量来测量的。观察了中性粒细胞减少感染小鼠腹腔注射阿尼拉芬素后的动力学。峰值水平和auc在16倍剂量范围内呈线性关系。血清中的药物消除半衰期为14至24小时。单剂量真菌效应研究表明，在血清anidulafungin水平降至MIC以下后，对生物体再生的抑制时间延长。在研究的四个给药间隔中，间隔较宽的给药方案治疗最有效，这表明C-max/MIC比是最能预测疗效的PK-PD指数。非线性回归分析表明，C-max/MIC和AUC/MIC比值对治疗成功有很强的预测作用。然后对另外13株白色念珠菌、热带念珠菌和光滑念珠菌进行了研究，这些念珠菌对阿杜拉芬的敏感性不同（这些菌株的阿杜拉芬的MIC为0.015至2.0 μ g/ml），以确定这些菌株的C-max/MIC和AUC(0-24)/MIC比值是否与疗效相关。在不同种类的念珠菌中，与药效相关的抗霉素暴露是相似的。
Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC(0-24)] to the MIC, and the ratio of the maximum serum drug concentration [C-max] to the MIC were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C-max/MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C-max/MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 mu g/ml) to determine if similar C-max/MIC and AUC(0-24)/MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.