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

Abstract

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

Cryptic species of Aspergillus section Terrei display essential physiological features to cause infection and are similar in their virulence potential in Galleria mellonella

“…terreus s.s., A. citrinoterreus and A. hortai are the most common found species in clinically samples [17,21,29]. These three species were found to exhibit highest growth and germination rates at 30°C and 37°C, which might partially explain their high frequency in clinical specimen [17,21,29]. A. terreus s.s. is the most Figure 5.…”

“…A prospective international Aspergillus terreus study revealed that A. terreus s.s. was found to be the most frequently isolated species from clinical specimens (86.8%) followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). Frequencies of cryptic species vary with geographical origin [21]. A French study found similar occurrence of cryptic species [29], suggesting that cryptic species might be underdiagnosed in less experienced centers due to their morphological indifference.…”

“…Therefore, primary treatment for the majority of patient cohorts is based on triazoles [20]. But, similar to A. fumigatus, posaconazole resistance is emerging in A. terreus with resistance rates ranging from 0% to 13.7%, depending on geographical origin and patient cohort [21].…”

Routine comprehensive Aspergillus screening of bronchoalveolar lavage samples in lung transplant recipients

“…If aspergillosis was suspected, the patient was switched from itraconazole to voriconazole. The rationale for this switch is that voriconazole is considered the drug of choice for IA and has better absorption than itraconazole, coupled with the low prevalence of azole‐resistant strains in Israel . Additional antimicrobials included nystatin mouth washes for 1 month, valganciclovir 450 mg daily for 6 months, and trimethoprim/sulfamethoxazole 160/800 mg three times per week.…”

Blood Aspergillus PCR: The Good, the Bad, and the Ugly

“…Aspergillus fumigatus (A. fumigatus) is the most common cause for IA [33,34] and most prior studies have focused on the evaluation of PCR assays for this species. Epidemiology of IA globally varies and species other than A. fumigatus are increasing in prevalence [35]. Additionally, non-Aspergillus molds occur more frequently due to the increasing use of antifungal prophylaxis and more intensive immunosuppressive therapies [36].…”