Research & Development

Understanding resistance mechanisms in azole resistant Aspergillus fumigatus

Azoles are the mainstay of oral therapy for all forms of aspergillosis, and so widespread azole resistance would be devastating. This project was designed to assess the experience of azole resistance at our facility. The frequency of itraconazole resistance in the RMLM clinical culture collection between 1992 - 2007 (519 A. fumigatus) was found to be 7%, a high rate compared to other reports in the literature. Furthermore, incidence has increased significantly since 2004. 58% and 66% of itraconazole resistant isolates were also cross-resistant to voriconazole and posaconazole respectively. To date, azole resistance has been reported infrequently and few resistance mechanisms in A. fumigatus have been described. Cyp51A amino acid alterations are known to cause resistance, we found eighteen diverse Cyp51A alterations in our collection, some novel. We also found evidence of the emergence of azole resistance and evolution within the lung; with mutants arising from originally susceptible strains (probably associated with azole treatment), different cyp51A mutations found in the same strain, and alterations in microsatellite repeat number.