Differential In Vivo Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without FKS Resistance Mutations
Differential In Vivo Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without FKS Resistance Mutations
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DOI：
10.1128/aac.06369-11
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发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Hope, William
中科院分区：
文献类型：
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作者：
Arendrup, Maiken Cavling;Perlin, David S.;Hope, William
我们最近观察到，一些光滑念珠菌fks热点突变分离株的米卡芬净MIC升高低于其他棘白菌素，表明米卡芬净的疗效可能与此类突变有差异。三个临床C。分别对具有或不具有（S3）fks热点突变R83（Fks 2 p-S663 F）和RR 24（Fks 1 p-S629 P）以及低、中和高棘白菌素MIC的光滑菌株进行评价，以评估使用三种剂量的每种棘白菌素在免疫活性小鼠模型中的体内功效。通过高效液相色谱法（HPLC）测定血浆和肾脏中的药物浓度。使用药代动力学-药效学数学模型定义产生半数和近最大活性的浓度-时间曲线下面积（AUC）。米卡芬净对S3和R83分离株同样有效。诱导半数最大效应（E（50）s）的每种棘白菌素的AUC估计值分别为194.2和53.99 mg。h/L。相反，卡泊芬净对S3的最大效应（E-max）高于R83，但E-50的估计值相似（187.1和203.5 mg . h/升）。阿尼芬净未能诱导任何分离株的>= 1-log减少（AUC范围，139至557 mg . h/升）。尽管毒力较低（最大生长降低、延迟期延长和肾脏负荷降低），但在用RR 24分离株攻毒的小鼠中，棘白菌素均无效。除米卡芬净和R83分离株外，所有药物-剂量-细菌组合的半数最大效应相关AUC均高于平均人体暴露量。总之，米卡芬净MIC的差异与动物模型中不同的抗真菌活性相关。这项研究可能对临床实践和棘白菌素断点确定有意义，需要进一步研究。
We recently observed that the micafungin MICs for some Candida glabrata fks hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical C. glabrata isolates with or without (S3) fks hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the in vivo efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half-and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E(50)s) were 194.2 and 53.99 mg . h/liter, respectively. In contrast, the maximum effect (E-max) for caspofungin was higher against S3 than R83, but the estimates for E-50 were similar (187.1 and 203.5 mg . h/liter, respectively). Anidulafungin failed to induce a >= 1-log reduction for any of the isolates (AUC range, 139 to 557 mg . h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.