PDF(Pubmed)
Abstract：
Chromoblastomycosis (CBM) and pheohyphomycosis (PHM) are the most common implantation mycoses caused by dematiaceous fungi. In the past, flucytosine (5-FC) has been used to treat CBM, but development of resistance is common. Carmofur belongs to the same class as 5-FC and has in vitro inhibitory activity against the main agents of CBM and PHM. The aim of this study was to compare the action of these two pyrimidine analog drugs against CBM and PHM agents. The minimum inhibitory concentration (MIC) and the selectivity index based on cytotoxicity tests of these two drugs against some agents of these mycoses were determined, with carmofur presenting a higher selectivity index than 5-FC. Carmofur demonstrated here synergistic interactions with itraconazole and amphotericin B against Exophiala heteromorpha, Fonsecaea pedrosoi, Fonsecaea monophora, and Fonsecaea nubica strains. Additionally, carmofur plus itraconazole demonstrated here synergism against a Phialophora verrucosa strain. To evaluate the development of carmofur resistance, passages in culture medium containing subinhibitory concentrations of this pyrimidine analog were carried out, followed by in vitro susceptibility tests. Exophiala dermatitidis quickly developed resistance, whereas F. pedrosoi took seven passages in carmofur-supplemented medium to develop resistance. Moreover, resistance was permanent in E. dermatitidis but transient in F. pedrosoi. Hence, carmofur has exhibited certain advantages, albeit accompanied by limitations such as the development of resistance, which was expected as with 5-FC. This underscores its therapeutic potential in combination with other drugs, emphasizing the need for a meticulous evaluation of its application in the fight against dematiaceous fungi.
摘要：
嗜色真菌病(CBM)和嗜色真菌病(PHM)是由脱脂性真菌引起的最常见的着床真菌病。在过去,氟胞嘧啶（5-FC）已用于治疗CBM，但是抵抗的发展是常见的。Carmofur与5-FC属于同一类，对CBM和PHM的主要试剂具有体外抑制活性。这项研究的目的是比较这两种嘧啶类似物药物对CBM和PHM药物的作用。确定了这两种药物对这些霉菌病某些药物的最低抑制浓度（MIC）和基于细胞毒性测试的选择性指数，Carmofur的选择性指数高于5-FC。Carmofur在此证明了与伊曲康唑和两性霉素B对抗异型Exophiala的协同相互作用，Fonsecaeapedrosoi,MonophoraFonsecaea,和Fonsecaeanubica菌株。此外,卡莫富加伊曲康唑在此证明了对疣Phialophora菌株的协同作用。为了评估卡莫氟抗性的发展，在含有亚抑制浓度的嘧啶类似物的培养基中进行传代，其次是体外药敏试验。皮肤外植体迅速产生抗药性，而F.pedrosoi在补充卡莫毛的培养基中进行了7次传代以产生抗性。此外，耐药性是永久性的，但在皮氏弧菌是短暂的。因此，卡莫富有一定的优势,尽管伴随着抵抗力发展等限制，与5-FC一样。这强调了它与其他药物联合治疗的潜力，强调需要对其在对抗水性真菌中的应用进行细致的评估。
