新型泊沙康唑制剂在治疗白念珠菌感染中的作用：来自药代动力学-药效学模型的数据。
The Role of New Posaconazole Formulations in the Treatment of Candida albicans Infections: Data from an Pharmacokinetic-Pharmacodynamic Model.
机构信息
Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark.
出版信息
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.01292-20.
Posaconazole is more active than fluconazole against and is approved for the treatment of oropharyngeal candidiasis but not for that of invasive candidiasis (IC). Here, we explored the efficacy of posaconazole against in an pharmacokinetic/pharmacodynamic (PK/PD) model of IC and determined the probability of pharmacodynamic target attainment for the oral solution and intravenous (i.v.)/tablet formulations. Three clinical isolates (posaconazole MICs, 0.008 to 0.25 mg/liter) were studied in the PK/PD dilution model simulating steady-state posaconazole PK. The exposure-effect relationship, area under the 24-h free drug concentration curve (AUC)/MIC, was described and compared with outcome in animals with IC. PK/PD susceptibility breakpoints and trough levels required for optimal treatment were determined for EUCAST and CLSI 24-h/48-h (CLSI24h/CLSI48h) methods using the AUC/MIC associated with half-maximal activity (EI) and Monte Carlo simulation analysis for oral solution (400 mg every 12 hours [q12h]) and i.v./tablet formulations (300 mg q24h). The mean (95% confidence interval [CI]) EI was 330 (183 to 597) AUC/MIC for CLSI24h and 169 (92 to 310) for EUCAST/CLSI48h methods, which are close to the near-stasis effect. The probability of target attainment for EI was estimated; for the wild-type isolates (MIC ≤ 0.06 mg/liter), it was low for the oral solution and higher than 95% for the i.v./tablet formulations for the EUCAST/CLSI48h methods but not for the CLSI 24-h method. Non-wild-type isolates with EUCAST/CLSI48h MICs of 0.125 and 0.25 mg/liter would require trough levels of >1.2 and >2.4 mg/liter, respectively. Posaconazole i.v./tablet formulations may have a role in the therapy of invasive infections by wild-type isolates, provided that a steady state is reached quickly. A PK/PD susceptibility breakpoint at the epidemiological cutoff (ECV/ECOFF) of 0.06 mg/liter was determined.
泊沙康唑对念珠菌属比氟康唑更有效，已被批准用于治疗口咽念珠菌病，但不用于侵袭性念珠菌病（IC）。在这里，我们在 IC 的泊沙康唑药代动力学/药效学（PK/PD）模型中研究了泊沙康唑对念珠菌属的疗效，并确定了口服溶液和静脉（iv）/片剂制剂的药效学目标达标概率。在模拟稳态泊沙康唑 PK 的 PK/PD 稀释模型中研究了三种临床念珠菌属分离株（泊沙康唑 MIC 为 0.008 至 0.25mg/L）。描述了 24 小时游离药物浓度曲线下面积（AUC）/MIC 的暴露-效应关系，并与 IC 动物的结果进行了比较。使用与半最大活性（EI）相关的 AUC/MIC 并通过蒙特卡罗模拟分析，确定了 EUCAST 和 CLSI 24 小时/48 小时（CLSI24h/CLSI48h）方法的 PK/PD 敏感性断点和最佳治疗所需的谷浓度，用于口服溶液（每 12 小时 400mg [q12h]）和 iv/片剂制剂（300mg q24h）。CLSI24h 方法的 平均（95%置信区间[CI]）EI 为 330（183 至 597）AUC/MIC，EUCAST/CLSI48h 方法为 169（92 至 310），接近静止期效应。估计了 EI 的目标达标概率；对于野生型分离株（MIC≤0.06mg/L），口服溶液的概率较低，而 EUCAST/CLSI48h 方法的 i.v./片剂制剂的概率高于 95%，但 CLSI 24 小时方法则不然。EUCAST/CLSI48h MIC 为 0.125 和 0.25mg/L 的非野生型分离株分别需要谷浓度>1.2 和>2.4mg/L。如果快速达到稳态，泊沙康唑 iv/片剂制剂可能在治疗野生型念珠菌属引起的侵袭性感染方面发挥作用。确定了基于流行病学截止值（ECV/ECOFF）的 0.06mg/L 的 PK/PD 敏感性断点。
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