Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Antimicrob Agents Chemother. 2012 Jan;56(1):10-6. doi: 10.1128/AAC.05088-11. Epub 2011 Oct 17.
Nine consecutive isogenic Aspergillus fumigatus isolates cultured from a patient with aspergilloma were investigated for azole resistance. The first cultured isolate showed a wild-type phenotype, but four azole-resistant phenotypes were observed in the subsequent eight isolates. Four mutations were found in the cyp51A gene of these isolates, leading to the substitutions A9T, G54E, P216L, and F219I. Only G54 substitutions were previously proved to be associated with azole resistance. Using a Cyp51A homology model and recombination experiments in which the mutations were introduced into a susceptible isolate, we show that the substitutions at codons P216 and F219 were both associated with resistance to itraconazole and posaconazole. A9T was also present in the wild-type isolate and thus considered a Cyp51A polymorphism. Isolates harboring F219I evolved further into a pan-azole-resistant phenotype, indicating an additional acquisition of a non-Cyp51A-mediated resistance mechanism. Review of the literature showed that in patients who develop azole resistance during therapy, multiple resistance mechanisms commonly emerge. Furthermore, the median time between the last cultured wild-type isolate and the first azole-resistant isolate was 4 months (range, 3 weeks to 23 months), indicating a rapid induction of resistance.
从一位患有曲霉肿的患者连续培养的 9 株同源烟曲霉分离株被用于研究唑类耐药性。第一株培养的分离株表现出野生型表型，但随后的 8 株分离株中观察到 4 种唑类耐药表型。这些分离株的 cyp51A 基因中发现了 4 个突变，导致 A9T、G54E、P216L 和 F219I 取代。先前仅证明 G54 取代与唑类耐药性相关。使用 Cyp51A 同源模型和重组实验，我们将突变引入敏感分离株，结果表明 P216 和 F219 密码子的取代均与伊曲康唑和泊沙康唑耐药相关。A9T 也存在于野生型分离株中，因此被认为是 Cyp51A 多态性。携带 F219I 的分离株进一步进化为泛唑类耐药表型，表明进一步获得了非 Cyp51A 介导的耐药机制。文献回顾表明，在治疗过程中出现唑类耐药的患者中，通常会出现多种耐药机制。此外，最后培养的野生型分离株和第一个唑类耐药分离株之间的中位时间为 4 个月（范围 3 周至 23 个月），表明耐药性迅速诱导。
