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Multidrug resistance in Aspergillus fumigatus |
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Paul E. Verweij
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Invasive aspergillosis is a lethal infectious disease which occurs mainly in immunocompromised patients. In 2002 voriconazole was shown to be more efficacious than amfotericin B for the primary treatment of invasive aspergillosis, and since then the drug is commonly used for this indication. Since 2002, we observed an increase of the number of A. fumigatus isolates with elevated MICs of voriconazole (2 to >16 mg/l), itraconazole (>16 mg/l), the investigational azole ravuconazole (4 to >16 mg/l) and posaconazole (0.5 to 1 mg/l). Thirteen isolates were cultured from 9 patients from six hospitals in the Netherlands. Four patients were azole-naïve and developed primary invasive aspergillosis, while in five patients breakthrough invasive aspergillosis was diagnosed during azole prophylaxis or therapy. A novel mechanism of resistance to azole drugs, consisting of a Cyp51A amino acid substitution at codon 98 (L98H) together with a tandem repeat in the gene promoter, was found to be responsible for the azole cross-resistant phenotype. This resistance mechanism was present in 12 of 13 isolates. Genotyping of the isolates showed no evidence for clonal spread of a single resistant A. fumigatus genotype. The prevalence of resistance was compared with a previously conducted nation-wide survey of 170 A. fumigatus isolates collected from 114 patients from 21 Dutch hospitals between 1945 and 1998. In this period no patients with azole cross-resistant isolates were found as compared to 10 of 81 patients in the period since 2002 (P=0.0001). Although the emergence of this new resistance mechanism coincides with the approval of voriconazole, the factors that may explain this phenomenon remain unclear. Our observation underscores the need to make an etiologic diagnosis of invasive mould infection and to determine antifungal drug activity in clinically relevant A. fumigatus isolates. Furthermore, international surveillance programs are warranted to investigate the spread of resistance in A. fumigatus. |
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