Defining Fractional Inhibitory Concentration Index Cutoffs for Additive Interactions Based on Self-Drug Additive Combinations, Monte Carlo Simulation Analysis, and In Vitro-In Vivo Correlation Data for Antifungal Drug Combinations against Aspergillus fumigatus
Defining Fractional Inhibitory Concentration Index Cutoffs for Additive Interactions Based on Self-Drug Additive Combinations, Monte Carlo Simulation Analysis, and In Vitro-In Vivo Correlation Data for Antifungal Drug Combinations against Aspergillus fumigatus
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DOI：
10.1128/aac.00999-09
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发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Walsh, Thomas J.
中科院分区：
文献类型：
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作者：
Meletiadis, Joseph;Pournaras, Spyros;Walsh, Thomas J.
在大多数抗真菌药物联合研究中，常用于定义加和性的部分抑制浓度（FIC）指数范围为0.5至4，结果显示无相互作用。这些结果可能与体内研究的结果不同，体内研究中可能观察到阳性和阴性相互作用。我们基于以下因素重新评估了该体外FIC指数范围：（i）使用多次重复的棋盘技术的实验变异，（ii）正确确定阿替西汀B（AMB）和伏立康唑（VRC）的纯加性自身药物和双药拮抗组合的能力，（iii）Monte Carlo模拟分析，和（iv）使用侵袭性肺曲霉病的实验模型针对相同的烟曲霉分离株的体外-体内相关性，基于视觉，分光光度，以及孵育24和48小时后FICs的比色测定。孵育24小时后获得的FIC范围为0.5至1.25的AMB加AMB和VRC加VRC的自药添加剂组合和2.25至4.25的AMB加VRC的拮抗剂组合。蒙特卡罗模拟分析表明，当重复FIC的95%置信区间（CI）偏离1至1.25的加和性范围时，对于> 85%的模拟FIC，自身药物组合被正确归类为加和性，而AMB加VRC组合被正确归类为拮抗性。24小时后的相互作用。体内外相关性分析显示，24 h后测定的体内协同组合阿尼芬净与VRC的FICs的95%CI均小于1，体内拮抗组合AMB与拉夫康唑的FICs的95%CI均大于1.25。通过证明24 h时一式三份FIC超出1 - 1.25的包容性加和范围，可以充分了解具有体内相关性的弱药效学相互作用。
The fractional inhibitory concentration (FIC) index range of 0.5 to 4 that is commonly used to define additivity results in no interactions in most combination studies of antifungal agents. These results may differ from those of in vivo studies, where positive and negative interactions may be observed. We reassessed this in vitro FIC index range based on (i) the experimental variation of the checkerboard technique using multiple replicates, (ii) the ability to correctly determine purely additive self-drug and two-drug antagonistic combinations of amphotericin B (AMB) and voriconazole (VRC), (iii) Monte Carlo simulation analysis, and (iv) in vitro-in vivo correlation using experimental models of invasive pulmonary aspergillosis against the same Aspergillus fumigatus isolate based on visual, spectrophotometric, and colorimetric determinations of FICs after 24 and 48 h of incubation. FICs obtained after 24 h of incubation ranged from 0.5 to 1.25 for the self-drug additive combinations of AMB plus AMB and VRC plus VRC and from 2.25 to 4.25 for the antagonistic combination of AMB plus VRC. Monte Carlo simulation analysis showed that self-drug combinations were correctly classified as additive and that the combination of AMB plus VRC was correctly classified as antagonistic for > 85% of the simulated FICs when deviation of the 95% confidence interval (CI) of replicate FICs from the additivity range of 1 to 1.25 was used to assess interactions after 24 h. In vitro-in vivo correlation analysis showed that the 95% CIs of the FICs of the in vivo synergistic combination anidulafungin plus VRC determined after 24 h were lower than 1 and the 95% CIs of the FICs of the in vivo antagonistic combination AMB plus ravuconazole were higher than 1.25. Adequate insight into weak pharmacodynamic interactions with in vivo relevance may be obtained by demonstrating that triplicate FICs at 24 h are outside an inclusive additivity range of 1 to 1.25.