Azole resistant Aspergillus fumigatus: an emerging problem.

Azole resistance has appeared recently in Aspergillus fumigatus and increased dangerously in the last decade. The main resistance mechanism is a point mutation of CYP51A, the gene encoding 14α-sterol demethylase, the target enzyme of azole antifungal drugs. This mutation can induce resistance to itraconazole alone or multi-azole resistance. CYP51A mutation can occur in two cases. The first usually concerns patients receiving long-term azole therapy, most of the time for chronic aspergillosis, and involves a wide range of mutations. The second is due to the use of azole fungicides in agriculture. The latter favors a single mutagenesis event: a substitution of leucine for histidine at codon 98 and the tandem repeat of a 34-base pair tandem sequence in the CYP51A gene promoter region. This confers cross-resistance to all azole antifungal drugs. This emerging and environmentally linked issue is of growing concern for the management of antifungal therapy. This mechanism of resistance was first described in the Netherlands and is now reported worldwide. It may have become the leading mechanism of azole resistance in A. fumigatus. Azoles are major agents for the treatment of aspergillosis, and the only oral antifungals. Infection with antifungal-resistant strains is correlated with treatment failure. This emerging phenomenon stresses the urgent need for new preventive strategies (controlled use of antifungals and azole prophylaxis), new diagnostic strategies (early detection of resistance), and new therapeutic strategies in the management of A. fumigatus infections.