Aspergillus fumigatus is a saprophytic mould that causes a range of diseases in humans. The spectrum of diseases includes allergic conditions, aspergilloma and acute and chronic invasive aspergillosis. Acute invasive aspergillosis occurs typically in patients with compromised host defenses such as those receiving treatment for leukemia. The management of invasive aspergillosis is very difficult as the diagnostic tools often lack sensitivity and the number of antifungal agents effective against the infection is limited. The azoles are the most important class of agents used for the treatment and prevention of invasive aspergillosis. Since 1998 resistance to medical triazoles has emerged in the Netherlands in clinical A. fumigatus isolates. These isolates commonly showed a multi-azole resistant phenotype and patients with azole-resistant aspergillosis failed to respond to azole therapy. The mortality rate of azole-resistant invasive aspergillosis was 88%. In more than 90% of resistant isolates a combination of changes in the target gene Cyp51A was found: a substitution at codon 98 and a 34 bp tandem repeat in the promoter region (TR34/L98H). As person-to-person transmission is highly unlikely in invasive aspergillosis, the dominance of a single resistance mechanism could not be explained by resistance development in azole-treated patients. Surveys in the environment showed that A. fumigatus isolates resistant to medical triazoles could be recovered from the environment, especially from cultivated soil. The resistance mechanisms in these isolates were identical to those found in clinical isolates. Molecule alignment studies identified 5 triazole fungicides that showed highly similar molecule structures to the medical triazoles. These 5 fungicides have been authorized between 1990 and 1996, thus preceding the isolation of the first resistant clinical A. fumigatus isolate. TR34/L98H is increasingly reported in European countries, India, China and Iran. Recently a new azole-resistance mechanism was found in Dutch patients and in the environment. The resistance mechanism again consisted of a combination of changes in the Cyp51A-gene: TR46/Y121F/T289A. This new resistance mechanism has spread in addition to TR34/L98H in the Netherlands, and has also been reported in the neighboring country Belgium. The selection of multiple azole resistance mechanisms in the environment posses a threat for the use of azole drugs in the management of Aspergillus diseases in humans. Research that investigates the selection of azole resistance in A. fumigatus in the environment is urgently warranted.
Full conference title:
27th Fungal Genetics Conference
- Fungal Genetics Conference 27th (2013)