Emergence of Echinocandin Resistance Due to a Point Mutation in the fks1 Gene of Aspergillus fumigatus in a Patient with Chronic Pulmonary Aspergillosis

Abstract

We have identified the first case of an fks1 hot spot 1 point mutation causing echinocandin resistance in a clinical Aspergillus fumigatus isolate recovered from a chronic pulmonary aspergillosis patient with an aspergilloma who first failed azole and polyene therapy and subsequently failed micafungin treatment.

Keywords: Aspergillus fumigatus; chronic pulmonary aspergillosis; echinocandin resistance; fks1 mutation; micafungin.

FIG 1

(A) Timeline for patient antifungal therapy. Collection of the Aspergillus species isolates for the current microbiological study is shown (triangles). (B) Isolates recovered from the patient grown for 2 days at 37°C on a PDA plate. (C) A. fumigatus clinical isolates 24053A and 24053B grown for 4 days at 37°C on PDA plates. Isolate 24053B grows at a lower rate and sporulates very poorly compared to the rest of isolates collected from the patient.

FIG 2

Echinocandin kinetic inhibition profiles for wild-type ATCC 13073 and clinical isolate 24053B. Product-entrapped β-(1,3)-glucan synthase complexes were assessed by incorporation of [³H]-UDP-glucose into radiolabeled product and evaluated using a sigmoidal-response (variable-slope) curve. Echinocandin inhibition kinetics yielding 50% inhibitory concentrations (IC₅₀s) are expressed in nanograms per milliliter.