Department of Medicine and Medical Microbiology and Immunology, Section of Infectious Disease, University of Wisconsin, MFCD, Room 5211, 1685 Highland Ave., Madison, WI 53705, USA.
Antimicrob Agents Chemother. 2011 May;55(5):2113-21. doi: 10.1128/AAC.01430-10. Epub 2011 Feb 7.
Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.
棘白菌素类药物已成为侵袭性念珠菌病 (IC) 的一线治疗药物。使用 IC 患者的 3 期临床试验数据，研究了米卡芬净疗效的药代动力学-药效学 (PK-PD) 关系。使用群体药代动力学模型估算米卡芬净的暴露量，并使用单变量和多变量逻辑回归来确定与结果相关的因素，包括米卡芬净浓度-时间曲线下面积 (AUC)/MIC 比值。蒙特卡罗模拟用于评估达到与疗效相关的 AUC/MIC 比值的概率。可评估病例的微生物学和临床成功率分别为 89.4%和 90.9%。对念珠菌属抑制的 MIC50 和 MIC90 分别为 0.008 和 0.5 毫克/升。中位 AUC/MIC 比值为 15511（范围，41.28 至 98716）。单变量分析显示 AUC/MIC 比值与微生物学反应之间存在显著关系，AUC/MIC 比值较低（≤3000）的患者反应最差（P=0.005）。对于近平滑念珠菌患者，AUC/MIC 比值≥285 与较高的微生物学反应相关（P=0.11）。多变量逻辑回归表明 AUC/MIC 比值、APACHE II 评分和皮质类固醇使用史是良好反应的独立预测因素。PK-PD 目标达成分析表明，对于 MIC 为 0.03 毫克/升的 AUC/MIC 比值≥3000 和 MIC 为<0.5 毫克/升的 AUC/MIC 比值≥285，分别有 76.7%和 100%的患者将达到目标。与其他念珠菌属相比，对近平滑念珠菌设定较低的 AUC/MIC 比值目标表明，需要考虑特定物种的棘白菌素药敏折点和低于监管机构目前批准的数值。
