In vitro interaction of flucytosine combined with amphotericin B or fluconazole against thirty-five yeast isolates determined by both the fractional inhibitory concentration index and the response surface approach
In vitro interaction of flucytosine combined with amphotericin B or fluconazole against thirty-five yeast isolates determined by both the fractional inhibitory concentration index and the response surface approach
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DOI：
10.1128/aac.46.9.2982-2989.2002
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发表时间：
2002-09-01
影响因子：
4.9
通讯作者：
Mouton, JW
中科院分区：
文献类型：
--
作者：
Dorsthorst, DTAT;Verweij, PE;Mouton, JW
联合治疗可能有利于治疗侵袭性酵母菌感染。然而，体外相互作用的研究相对较少，并且由于使用的定义不同，对分数抑制浓度（FIC）指数的解释可能相互矛盾；并不是所有相互作用研究的信息都被用于索引中，不同类别的药物存在不同的MIC终点。将相互作用模型拟合到整个响应面并估计相互作用系数α (icα)将克服这些缺点，并且具有获得相互作用置信区间的额外优点。采用微量肉液稀释棋盘法研究氟胞菌素（5FC）联合两性霉素B （AB）和氟康唑（FCZ）对35株分离酵母（白色念珠菌[n = 9]、光秃念珠菌[n = 9]、克鲁氏念珠菌[n = 9]、新型隐球菌[n = 8]）的抑菌效果，并用分光光度计测定48 h后的生长情况。测定FIC指数和ICalpha，后者由Greco等人（W. R. Greco， G. Bravo, and J. C. Parsons, Pharmacol）描述的响应面法估计。（启示录47:31 -385,1995）通过使用为此目的而开发的计算机程序。对于5FC-FCZ组合，由ic α确定的相互作用与FIC指数确定的相互作用基本一致，但对于5FC-AB组合，两种方法之间存在较大差异。这主要可以由FIC方法的缺点来解释。5FC-AB的体外相互作用表现出不同的结果，这取决于所测试的念珠菌分离株。总体上，5FC-FCZ组合对念珠菌具有拮抗作用，但对部分念珠菌有协同作用。对于新型C菌，两种组合的相互作用高度依赖于被测分离物和使用的方法。响应面法是测定抗真菌药物之间相互作用的另一种方法。通过使用这种方法，克服了FIC遇到的一些问题。
Combination therapy could be of benefit for the treatment of invasive yeast infections. However, in vitro interaction studies are relatively scarce and the interpretation of the fractional inhibitory concentration (FIC) index can be contradictory due to various definitions used; not all information on the interaction study is used in the index, and different MIC end points exist for different classes of drugs. Fitting an interaction model to the whole response surface and estimation of an interaction coefficient alpha (ICalpha) would overcome these objections and has the additional advantage that confidence intervals of the interaction are obtained. The efficacy of flucytosine (5FC) in combination with amphotericin B (AB) and fluconazole (FCZ) was studied against 35 yeast isolates in triplicate (Candida albicans [n = 9], Candida glabrata [n = 9], Candida krusei [n = 9], and Cryptococcus neoformans [n = 8]) using a broth microdilution checkerboard method and measuring growth after 48 h by a spectrophotometer. The FIC index and ICalpha were determined, the latter by estimation from the response surface approach described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) by using a computer program developed for that purpose. For the 5FC-FCZ combination, the interactions determined by the ICalpha generally were in concordance with the interactions determined by the FIC index, but large discrepancies were found between both methods for the 5FC-AB combination. These could mainly be explained by shortcomings in the FIC approach. The in vitro interaction of 5FC-AB demonstrated variable results depending on the tested Candida isolate. In general, the 5FC-FCZ combination was antagonistic against Candida species, but for some Candida isolates synergism was found. For C neoformans the interaction for both combinations was highly dependent on the tested isolate and the method used. Response surface approach is an alternative method for determining the interaction between antifungal agents. By using this approach, some of the problems encountered with the FIC were overcome.