Isavuconazole Nonwildtype Aspergillus fumigatus Isolates from a Global Surveillance Study Display Alterations in Multiple Genes Involved in the Ergosterol Biosynthesis Pathway Not Previously Associated with Resistance to Other Azoles

Mycoses. 2021 Mar 11. doi: 10.1111/myc.13267. Online ahead of print.


We evaluated 35 azole-nonwildtype A. fumigatus isolates that were collected during 2017-2018 using whole genome sequencing (WGS) to detect alterations in the genes involved in the ergosterol biosynthesis as well as other genes associated with azole resistance. Among 297 A. fumigatus isolates collected worldwide, 36 isolates displayed nonwildtype MIC values to isavuconazole, itraconazole or voriconazole when tested by the CLSI reference broth microdilution method. Isolates were submitted to WGS and results were compared to 2 azole-wildtype isolates. Among the 35 sequenced isolates (1 failed to produce quality sequences), 29 were nonwildtype to isavuconazole, 16 to itraconazole and 9 to voriconazole (CLSI M59Ed2 criteria). A total of 9 isolates carried Cyp51A TR34/L98H alterations (8 from Italy and 1 from Belgium) and had nonwildtype MIC values for ≥2 azoles. A Cyp51B Q42L mutation was detected in 3 isolates, 1 voriconazole- and 2 isavuconazole-nonwildtype. Three isolates harboured multiple mutations in Cyp51A (F46Y, M172V, E427K ± N248T, D255E), including 1 with the Cyp51B Q42L. Mutations causing frameshifts, early termination, and duplications were observed among several genes and were more prevalent in isavuconazole nonwildtype isolates (66.7%) than in isolates nonwildtype to 1 or 2 other azoles (22.2%). Nine isolates harbored frameshift mutations in an ERG25 homologue usually associated with changes in other genes and should be further evaluated. Cyp51A L98H/TR34 was the most common alteration observed among azole-nonwildtype A. fumigatus from a large surveillance; however, isolates only nonwildtype to isavuconazole had alterations in multiple analysed genes that deserve further evaluation.

PMID:33705591 | DOI:10.1111/myc.13267