Posaconazole Pharmacodynamic Target Determination against Wild-Type and Cyp51 Mutant Isolates of Aspergillus fumigatus in an In Vivo Model of Invasive Pulmonary Aspergillosis
Posaconazole Pharmacodynamic Target Determination against Wild-Type and Cyp51 Mutant Isolates of Aspergillus fumigatus in an In Vivo Model of Invasive Pulmonary Aspergillosis
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DOI：
10.1128/aac.01279-12
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发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Andes, David R.
中科院分区：
文献类型：
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作者：
Lepak, Alexander J.;Marchillo, Karen;Andes, David R.
侵袭性肺曲霉病是免疫功能低下患者的一种毁灭性疾病。抗真菌药物治疗IPA的药效学（PD）检查是可能改善结局的一种策略。当前的研究探索了泊沙康唑在IPA抗10 A免疫功能低下小鼠模型中的PD靶点。烟曲霉菌株，包括4个Cyp 51野生型菌株和6个携带Cyp 51突变的菌株，赋予唑抗性。泊沙康唑的MIC范围为0.25至8 mg/L。感染后，小鼠每天口服泊沙康唑0.156至160 mg/kg体重，持续7天。通过肺匀浆的定量PCR（qPCR）和存活率评估疗效。在治疗开始时，小鼠肺匀浆中的曲霉孢子当量（CE）为5.59 +/- 0.19 log（10）/ml，未治疗动物的肺匀浆中的CE增加至7.11 +/- 0.29 log（10）/ml。在对照小鼠中，在研究终点之前，感染是一致致死的。使用Hill型剂量反应函数对泊沙康唑游离药物浓度-时间曲线下面积（AUC）/MIC和qPCR肺负荷之间的关系进行建模。静态剂量范围为1.09 - 51.9 mg/kg/24 h。菌株组的游离药物AUC/MIC PD目标为1.09 +/- 0.63。1-log无杀灭药物AUC/MIC为2.07 +/- 1.02。野生型和突变生物体组的PD目标无显著差异。死亡率反映了qPCR结果，在产生静态或杀灭活性的相同给药方案下观察到存活率的最大改善。考虑到人体药代动力学数据和当前静态剂量PD目标，预测临床MIC阈值为0.25至0.5 mg/L。
Invasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10 A. fumigatus isolates, including 4 Cyp51 wild-type isolates and 6 isolates carrying Cyp51 mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy, mice had 5.59 +/- 0.19 log(10) Aspergillus conidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 +/- 0.29 log(10) CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 +/- 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 +/- 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results, with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 to 0.5 mg/liter.