Azole resistance in Aspergillus fumigatus. The first 2-year's Data from the Danish National Surveillance Study, 2018-2020

Abstract

Background: Azole resistance complicates treatment of patients with invasive aspergillosis with an increased mortality. Azole resistance in Aspergillus fumigatus is a growing problem and associated with human and environmental azole use. Denmark has a considerable and highly efficient agricultural sector. Following reports on environmental azole resistance in A. fumigatus from Danish patients, the ministry of health requested a prospective national surveillance of azole-resistant A. fumigatus and particularly that of environmental origin.

Objectives: To present the data from the first 2 years of the surveillance programme.

Methods: Unique isolates regarded as clinically relevant and any A. fumigatus isolated on a preferred weekday (background samples) were included. EUCAST susceptibility testing was performed and azole-resistant isolates underwent cyp51A gene sequencing.

Results: The azole resistance prevalence was 6.1% (66/1083) at patient level. The TR₃₄ /L98H prevalence was 3.6% (39/1083) and included the variants TR₃₄ /L98H, TR₃₄ ³ /L98H and TR₃₄ /L98H/S297T/F495I. Resistance caused by other Cyp51A variants accounted for 1.3% (14/1083) and included G54R, P216S, F219L, G54W, M220I, M220K, M220R, G432S, G448S and Y121F alterations. Non-Cyp51A-mediated resistance accounted for 1.2% (13/1083). Proportionally, TR₃₄ /L98H, other Cyp51A variants and non-Cyp51A-mediated resistance accounted for 59.1% (39/66), 21.2% (14/66) and 19.7% (13/66), respectively, of all resistance. Azole resistance was detected in all five regions in Denmark, and TR₃₄ /L98H specifically, in four of five regions during the surveillance period.

Conclusion: The azole resistance prevalence does not lead to a change in the initial treatment of aspergillosis at this point, but causes concern and leads to therapeutic challenges in the affected patients.

Keywords: Aspergillus fumigatus; TR34/L98H; antifungal susceptibility; azole resistance; environmental route; itraconazole; medical route; voriconazole.