Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence.
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DOI：
10.1371/journal.pone.0010080
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发表时间：
2010-04-09
期刊：
影响因子：
3.7
通讯作者：
Verweij PE
中科院分区：
文献类型：
--
作者：
Arendrup MC;Mavridou E;Mortensen KL;Snelders E;Frimodt-Møller N;Khan H;Melchers WJ;Verweij PE
对来自一名慢性肉芽肿病（CGD）患者的四种连续分离的烟曲霉进行了研究，该患者最终在唑类-棘白菌素联合治疗中失败。前两个分离株（1 和 2）对抗真菌唑类药物敏感，但后两个分离株（3 和 4）发现伊曲康唑、伏立康唑和泊沙康唑 MIC 增加。微卫星分型显示4个分离株是同基因的，表明患者在唑类治疗期间获得了耐药性。免疫功能低下的小鼠模型证实，体外耐药性与治疗失败相对应。受到耐药分离株 4 攻击的小鼠对泊沙康唑治疗没有反应，而被敏感分离株 2 感染的小鼠则有反应。泊沙康唑-阿尼芬净联合疗法对接受分离株 4 攻击的小鼠有效。四种分离株的 Cyp51A 基因未发现突变。然而，Cyp51A 的表达实验表明，与唑敏感分离株相比，抗性分离株中的表达增加。四个分离株的微观形态相似，但与分离株 1 和 2 以及不相关的野生型对照相比，观察到径向生长的明显变化以及固体和肉汤培养基中抗性分离株的生长速率显着降低。在小鼠模型中，与易感菌株和野生型对照相比，分离株 3 和 4 的毒力降低。首次描述了 CGD 患者尽管接受唑类-棘白菌素联合治疗，但仍获得唑类耐药性，并且该耐药性被证明与毒力的显着变化直接相关。
Four sequential Aspergillus fumigatus isolates from a patient with chronic granulomatous disease (CGD) eventually failing azole-echinocandin combination therapy were investigated. The first two isolates (1 and 2) were susceptible to antifungal azoles, but increased itraconazole, voriconazole and posaconazole MICs were found for the last two isolates (3 and 4). Microsatellite typing showed that the 4 isolates were isogenic, suggesting that resistance had been acquired during azole treatment of the patient. An immunocompromised mouse model confirmed that the in vitro resistance corresponded with treatment failure. Mice challenged with the resistant isolate 4 failed to respond to posaconazole therapy, while those infected by susceptible isolate 2 responded. Posaconazole-anidulafungin combination therapy was effective in mice challenged with isolate 4. No mutations were found in the Cyp51A gene of the four isolates. However, expression experiments of the Cyp51A showed that the expression was increased in the resistant isolates, compared to the azole-susceptible isolates. The microscopic morphology of the four isolates was similar, but a clear alteration in radial growth and a significantly reduced growth rate of the resistant isolates on solid and in broth medium was observed compared to isolates 1 and 2 and to unrelated wild-type controls. In the mouse model the virulence of isolates 3 and 4 was reduced compared to the susceptible ones and to wild-type controls. For the first time, the acquisition of azole resistance despite azole-echinocandin combination therapy is described in a CGD patient and the resistance demonstrated to be directly associated with significant change of virulence.
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