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Pharmacodynamic Effects of Simulated Standard Doses of Antifungal Drugs against Aspergillus Species in a New In Vitro Pharmacokinetic/Pharmacodynamic Model

机译:在新的体外药代动力学/药效学模型中模拟标准剂量的抗真菌药物对曲霉菌的药效作用

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摘要

In conventional ΜΙC tests, fungi are exposed to constant drug concentrations, whereas in vivo, fungi are exposed to changing drug concentrations. Therefore, we developed a new in vitro pharmacokinetic/pharmacodynamic model where human plasma pharmacokinetics of standard doses of 1 mg/kg amphotericin B, 4 mg/kg voriconazole, and 1 mg/kg caspofungin were simulated and their pharmacodynamic characteristics were determined against three clinical isolates of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus with identical MICs (1 mg/liter for amphotericin B, 0.5 mg/liter for voriconazole) and minimum effective concentrations (0.5 mg/liter for caspofungin). This new model consists of an internal compartment (a 10-ml dialysis tube made out of a semipermeable cellulose membrane allowing the free diffusion of antifungals but not galactomannan) inoculated with Aspergillus conidia and placed inside an external compartment (a 700-ml glass beaker) whose content is diluted after the addition of antifungal drugs by a peristaltic pump at the same rate as the clearance of the antifungal drugs in human plasma. Fungal growth was assessed by galactomannan production. Despite demonstrating the same MICs, amphotericin B completely inhibited (100%) A. fumigatus but not A. flavus and A. terreus, whose growth was delayed for 7.53 and 22.8 h, respectively. Voriconazole partially inhibited A. fumigatus (49.5%) and Α. flavus (27.9%) but not Α. terreus; it delayed their growth by 3.99 h (A. fumigatus) and 5.37 h (Α. terreus). Caspofungin did not alter galactomannan production in all of the species but A. terreus. The new model simulated human pharmacokinetics of antifungal drugs and revealed important pharmacodynamic differences in their activity.
机译:在常规的M1C测试中,真菌暴露于恒定的药物浓度,而在体内真菌暴露于变化的药物浓度。因此,我们开发了一种新的体外药代动力学/药效学模型,其中模拟了标准剂量1 mg / kg两性霉素B,4 mg / kg伏立康唑和1 mg / kg卡泊芬净的人血浆药代动力学,并针对三种临床情况确定了它们的药效学特征烟曲霉,黄曲霉和土曲霉的分离物具有相同的MIC(两性霉素B为1毫克/升,伏立康唑为0.5毫克/升)和最低有效浓度(卡泊芬净为0.5毫克/升)。这个新模型包括一个内部隔室(一个由半透性纤维素膜制成的10毫升透析管,允许半乳聚糖的自由扩散,但不允许半乳甘露聚糖自由扩散),接种了曲霉的分生孢子,并置于一个外部隔室内(一个700毫升玻璃烧杯)通过蠕动泵添加抗真菌药物后,其含量被稀释,其清除率与抗血浆药物在人血浆中的清除率相同。通过半乳甘露聚糖的生产来评估真菌的生长。尽管表现出相同的MIC,但两性霉素B完全抑制(100%)烟曲霉,但不抑制黄曲霉和土曲霉,它们的生长分别延迟了7.53和22.8 h。伏立康唑部分抑制了烟曲霉(49.5%)和Α。黄褐斑(27.9%),但不是。土它使它们的生长延迟了3.99小时(烟曲霉)和5.37小时(土杆菌)。卡泊芬净并没有改变除曲霉属以外的所有物种的半乳甘露聚糖产量。新模型模拟了人类抗真菌药物的药代动力学,并揭示了其活性的重要药效学差异。

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