Mechanisms of Azole Resistance and Trailing in Bloodstream Isolates.

OBJECTIVES

Azole-resistant has emerged in Asia in the context of its trailing nature, defined by residual growth above minimum inhibitory concentrations (MICs). However, limited investigations in have focused on the difference of genotypes and molecular mechanisms between these two traits.

METHODS

Sixty-four non-duplicated bloodstream isolates collected in 2017 were evaluated for azole MICs by the EUCAST E.def 7.3.1 method, diploid sequence type (DST) by multilocus sequencing typing, and sequences and expression levels of genes encoding , its transcription factor, , and efflux pumps (, and ).

RESULTS

Isavuconazole showed the highest in vitro activity and trailing against , followed by voriconazole and fluconazole (geometric mean [GM] MIC, 0.008, 0.090, 1.163 mg/L, respectively; trailing GM, 27.4%, 20.8% and 19.5%, respectively; both overall < 0.001). Fourteen (21.9%) isolates were non-WT to fluconazole/voriconazole, 12 of which were non-WT to isavuconazole and clustered in clonal complex (CC) 3. Twenty-five (39.1%) isolates were high trailing WT, including all CC2 isolates (44.0%) (containing DST140 and DST98). All azole non-WT isolates carried the mutations A395T/W and/or C461T/Y, and most carried the mutation T503C/Y. These mutations were not identified in low and high trailing WT isolates. Azole non-WT and high trailing WT isolates exhibited the highest expression levels of and , 3.91- and 2.30-fold, respectively (both overall < 0.01).

CONCLUSIONS

Azole resistance and trailing are phenotypically and genotypically different in . Interference with azole binding and up-regulation confer azole resistance and trailing, respectively.