Abstract
Resistance to the azole antifungals itraconazole, voriconazole, and posaconazole in
Aspergillus species is a growing concern. This is especially alarming for A. fumigatus, where acquired resistance has been documented in patients with invasive disease
caused by this species that were exposed to these agents, as well as in azole-naive
individuals. The primary mechanisms of resistance that have been described in clinical
strains include different point mutations in the CYP51A gene, which encodes the enzyme responsible for converting lanosterol to ergosterol
via demethylation. Some resistant isolates also contain a tandem repeat in the promoter
region of this gene that causes increased expression. These mutations, including TR34/L98H and TR46/Y121F/T289A have also been found in the environment in several areas of the world
and have been demonstrated to cause resistance to azole fungicides used in agriculture,
thus raising the concern of environmental spread of resistance. Treatment options
are limited in patients with infections caused by azole-resistant isolates and include
amphotericin B formulations or combination therapy involving an echinocandin. However,
there are few clinical data available to help guide therapy, and infections caused
by resistant A. fumigatus isolates have been reported to have high mortality rates.
Keywords
Aspergillus fumigatus
- azole resistance - aspergillosis - voriconazole - itraconazole - posaconazole -
CYP51A
