Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles

Abstract

We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

Azole-Resistant Aspergillus fumigatus Isolate with the TR34/L98H Mutation in Both a Fungicide-Sprayed Field and the Lung of a Hematopoietic Stem Cell Transplant Recipient with Invasive Aspergillosis

“…TR34/L98H strains were first detected in the Netherlands and then subsequently in numerous European countries and in Asia. The other recently described fungicide-driven route of the resistance mechanism TR46 Y121F/T289A, also found in hematology patients with IA, can easily spread further (13). Since more and more immunocompromised patients are outpatients and given the growing use of the five molecules involved in such mutations, we can expect a higher risk of inhaling azole-resistant isolates and an increase in IA with azole-resistant isolates.…”

Mechanisms of Antifungal Drug Resistance

“…The position and nature of the alteration within the protein structure influence cross-resistance within the drug class, with proximity to the heme-binding site affecting the binding of any azole drug (Xiao et al 2004;Snelders et al 2010;Fraczek et al 2011). To date, all known mutations confer resistance to itraconazole, whereas resistance to voriconazole and/or posaconazole depend on the specific modification (Verweij et al , 2009Howard and Arendrup 2011;van der Linden et al 2011;Camps et al 2012b). Resistance has also been identified in azole-naïve patients, which is environmentally derived and appears to be driven by the agricultural use of azoles (Snelders et al 2012;Bowyer and Denning 2013;Verweij et al 2013).…”

“…Strains bearing these alterations have emerged across Europe and beyond Chowdhary et al 2012). Further, a new resistance mutation selected from the environment, TR46/Y121F/T289A, is also being reported among patients in the Netherlands (van der Linden et al 2013). …”

Immunotherapy for opportunistic infections: Current status and future perspectives

“…[14][15][16][17][18][19][20] Therefore, it is attractive if we could be able to induce specific anti-pathogen specific immunity to control the infections after allo-HSCT. In terms of viral infections, it is well established that T cells play an important role.…”