Azole-Resistance in Aspergillus terreus and Related Species: An Emerging Problem or a Rare Phenomenon?

Abstract

<b>Objectives:</b> Invasive mold infections associated with <i>Aspergillus</i> species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the <i>Aspergillus</i> section <i>Fumigati</i> followed by members of the section <i>Terrei</i>. The frequency of <i>Aspergillus terreus</i> and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. <b>Methods:</b> A global set (<i>n</i> = 498) of <i>A. terreus</i> and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the <i>cyp51A</i> gene. <b>Results:</b> The majority of isolates was identified as <i>A. terreus</i> (86.8%), followed by <i>A. citrinoterreus</i> (8.4%), <i>A. hortai</i> (2.6%), <i>A. alabamensis</i> (1.6%), <i>A. neoafricanus</i> (0.2%), and <i>A. floccosus</i> (0.2%). One isolate failed to match a known <i>Aspergillus</i> sp., but was found most closely related to <i>A. alabamensis</i>. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of <i>A. terreus sensu stricto (s.s.)</i> were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one <i>A. citrinoterreus</i> and one <i>A. alabamensis</i> isolate. The most affected amino acid position of the <i>Cyp51A</i> gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. <b>Conclusions:</b><i>Aspergillus terreus</i> was most prevalent, followed by <i>A. citrinoterreus</i>. Posaconazole was the most potent drug against <i>A. terreus</i>, but 5.4% of <i>A. terreus sensu stricto</i> showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all <i>A. terreus</i> isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.