Azole resistance in Aspergillus fumigatus isolates from respiratory specimens in Lyon University Hospitals, France: prevalence and mechanisms involved

Int J Antimicrob Agents. 2021 Oct 4:106447. doi: 10.1016/j.ijantimicag.2021.106447. Online ahead of print.

ABSTRACT

Aspergillus fumigatus resistance to triazoles is increasingly reported in Europe. As few data are available in Southern France, our objectives were to assess the burden of A. fumigatus isolates with azole resistance from clinical specimens in Lyon and explore the involved resistance mechanisms. In this retrospective cross-sectional study, 221 consecutive A. fumigatus isolates from respiratory samples were identified during an eight-month period from 195 patients attending the Pulmonary Medicine Departments of Lyon University Hospitals. Morphological identification was confirmed by sequence analysis of the β-tubulin gene. Itraconazole, voriconazole, posaconazole, and isavuconazole susceptibilities were tested for all samples with concentration gradient strips and confirmed with EUCAST broth microdilution method. The resistance mechanisms were investigated by sequencing of the cyp51A gene and its promoter, and by expression analysis of cyp51 and genes encoding several efflux transporters. Four isolates exhibited azole resistance. Three isolates presented with polymorphisms in an intronic region of cyp51A and one with simultaneously the F46Y, M172V and E427K polymorphisms. No mutation was identified in the cyp51A promoter, but significant inductions of cyp51A and cyp51B gene expression were observed for all four and three isolates, respectively. Significant inductions of atrF and cdr1B gene expression were observed for two and three isolates, respectively. No significant induction of MDR1/2/3/4, MFS56 and M85 gene expression was observed. To conclude, the observed prevalence of azole resistance was 2.1%. Significant inductions of the expression of the cyp51 genes and two genes encoding efflux transporters were evidenced, underlying the diversity of resistance mechanisms to be explored.

PMID:34619334 | DOI:10.1016/j.ijantimicag.2021.106447