Global epidemiology of azole resistance in Aspergillus fumigatus.

The fungus Aspergillus fumigatus has evolved as an important cause of opportunistic fungal diseases in humans worldwide. It is the most frequent filamentous fungus colonizing the airways of patients with cystic fibrosis and can affect immunocompetent as well as immunocompromised individuals. Aspergillus disease is commonly treated with azoles, which inhibit lanosterol 14α-demethylase, a key component of the ergosterol biosynthesis pathway, essential for membrane integrity and fluidity. Lanosterol 14α-demethylase is encoded by the CYP51A gene. Azole-resistant A. fumigatus isolates often show amino acid substitutions in Cyp51A. Most prevalent mutations have a tandem repeat (TR) in the promoter and point mutations in the gene (e.g. TR34/L98H and TR46/Y121F/T289A). In addition to TRs, isolates with single point mutations developed and are widespread around the world (e.g. M220I, G54R). To date, azole-resistant isolates have been found on every continent except Antarctica. This review will summarize the epidemiology and prevalence of Azole-resistant A. fumigatus worldwide including the history of different mutations found and highlights important gaps as data are missing in several parts of the world.