Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, Netherlands.
Antimicrob Agents Chemother. 2018 Apr 26;62(5). doi: 10.1128/AAC.02322-17. Print 2018 May.
The lack of a quantifiable marker for echinocandin activity hinders pharmacokinetic/pharmacodynamic (PK/PD) studies for spp. We developed an PK/PD model simulating the pharmacokinetics of anidulafungin and assessing its pharmacodynamics against with a new, easily quantifiable, sensitive, and reproducible marker. Two clinical isolates previously used in animals (AZN8196 and V52-35) with identical anidulafungin EUCAST (0.03 μg/ml) and CLSI (0.015 μg/ml) minimal effective concentrations (MEC) and one isolate (strain AFU79728) with an MEC of >16 μg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane (DM) tube inoculated with 10 CFU/ml. During anidulafungin exposure, two types of fungal forms were observed inside the DM tube: floating conidia that were quantified by cultures and aberrant mycelia that were quantified by the vertical height of the mycelia attached on the DM tube. No aberrant mycelia were found for the resistant isolate or in the drug-free controls. An exposure-effect relationship was similar to that found in animals using survival as an endpoint, with a free-drug area under the concentration-time curve from 0 to 24 h (AUC) associated with 50% of maximal activity of 2.21 (range, 1.81 to 2.71) mg · h/liter versus 2.62 (range, 1.88 to 3.65) mg · h/liter ( = 0.41). The hillslopes were also similar, with 1.96 versus 1.34 ( = 0.29). Analysis of each isolate separately showed increased antifungal susceptibility between AZN8196 and V52-35 ( < 0.001) even though they have the same CLSI and EUCAST MECs, but the strains have two 2-fold dilutions lower MICs using Etest and the XTT {2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide} method. Dose fractionation studies with all three echinocandins showed that their activities are best described by AUC and not the maximum concentration of free drug (). The new marker correlated with outcome and can be used for PK/PD studies exploring the pharmacodynamics of echinocandins against spp.
棘白菌素活性缺乏定量标志物，这阻碍了棘白菌素类药物的药代动力学/药效学（PK/PD）研究。我们开发了一种 PK/PD 模型，模拟了安尼卡fungin 的药代动力学，并使用新的、易于定量、敏感和可重复的标志物来评估其对棘白菌素类敏感性的药效学。以前在动物中使用的两种临床分离株（AZN8196 和 V52-35）具有相同的棘白菌素 EUCAST（0.03 μg/ml）和 CLSI（0.015 μg/ml）最小有效浓度（MEC），而一个分离株（菌株 AFU79728）的 MEC ＞16 μg/ml，在包含透析膜（DM）管的两室 PK/PD 透析/扩散封闭模型中进行了测试，该 DM 管中接种了 10 CFU/ml 的真菌。在安尼卡fungin 暴露期间，在 DM 管内观察到两种真菌形式：通过培养量化的漂浮孢子，以及通过附着在 DM 管上的菌丝的垂直高度量化的异常菌丝。在耐药分离株或无药物对照中均未发现异常菌丝。暴露-效应关系与使用生存作为终点的动物研究相似，游离药物 AUC 0-24 h 的 AUC 与 50%最大活性相关，为 2.21（范围，1.81 至 2.71）mg·h/L 对 2.62（范围，1.88 至 3.65）mg·h/L （=0.41）。坡度也相似，为 1.96 对 1.34（=0.29）。单独分析每个分离株表明，AZN8196 和 V52-35 之间的抗真菌敏感性增加（<0.001），尽管它们具有相同的 CLSI 和 EUCAST MEC，但它们的 MIC 用 Etest 和 XTT{2,3-双（2-甲氧基-4-硝基-5-磺苯基）-5-[(苯氨基）羰基]-2H-四唑]氢氧化物}方法降低了 2 倍。三种棘白菌素的剂量分割研究表明，其活性最好通过 AUC 描述，而不是游离药物的最大浓度（）。新标志物与结果相关，可用于研究棘白菌素类药物对棘白菌素类敏感性的药效学。
