Triazole phenotypes and genotypic characterization of clinical Aspergillus fumigatus isolates in China

Abstract

This study investigated the triazole phenotype and genotypic of clinical Aspergillus fumigatus isolates from China. We determined the triazole susceptibility profiles of 159 A. fumigatus isolates collected between 2011 and 2015 from four different areas in China tested against 10 antifungal drugs using the Clinical Laboratory Standard Institute M38-A2 method. For the seven itraconazole-resistant A. fumigatus isolates identified in the study, the cyp51A gene, including its promoter region, was sequenced and the mutation patterns were characterized. The resistant isolates were genotyped by microsatellite typing to determine the genetic relatedness to isolates from China and other countries. The frequency of itraconazole resistance in A. fumigatus isolates in our study was 4.4% (7/159). Six of the seven triazole-resistant isolates were recovered from the east and southeast of China, and one from was recovered from the west of China. No resistant isolates were found in the north. Three triazole-resistant isolates exhibited the TR34/L98H mutation, two carried the TR34/L98H/S297T/F495I mutation and one harbored a G54V mutation in the cyp51A gene. Analysis of the microsatellite markers from seven non-wild-type isolates indicated the presence of five unique genotypes, which clustered into two major genetic groups. The cyp51A gene mutations TR34/L98H and TR34/L98H/S297T were the most frequently found mutations, and the G54V mutation was reported for the first time in China. The geographic origin of the triazole-resistant isolates appeared to concentrate in eastern and south-eastern areas, which suggests that routine antifungal susceptibility testing in these areas should be performed for all clinically relevant A. fumigatus isolates to guide antifungal therapy and for epidemiological purposes.

Aspergillus Species in Lower Respiratory Tract of Hospitalized Patients from Shanghai, China: Species Diversity and Emerging Azole Resistance

“…36,62 In addition, our results also suggest that echinocandins (in particular AFG) are the potent drugs against clinical isolates of Aspergillus spp., which was similar to the previous studies from the USA, India and China. 28,61,63 Therefore, our results support the current recommendation issued by the Infectious Diseases Society of America in using azoles as the primary treatment against Aspergillus spp. infections, 19 in conjunction with echinocandins and/or polyenes if needed.…”

“… 39 The sequences obtained were aligned with the sequence of a triazole-susceptible isolate (GenBank accession AF338659) using ClustalW software. 40 Specifically, we followed the steps described by Deng et al 28 and scanned the predicted cyp51A amino-acid sequence for substitutions, particularly those linked to triazole resistance as identified previously.…”

“…18,25 Geographical differences in the prevalence of different Aspergillus spp., especially in azole-resistant A. fumigatus have been observed among national and regional populations in the world, including China. 26,27 Although several studies on A. fumigatus in China have been reported, 26,28 studies focused on isolates of non-A. fumigatus spp.…”

TR34/L98H Mutation in CYP51A Gene in Aspergillus fumigatus Clinical Isolates During Posaconazole Prophylaxis: First Case in Korea

“…Also, multiple amino acid substitutions including S297T (Table 1 ) were found in our isolate. Although most of these substitutions are not clearly characterized with phenotypic relationships, a recent report has suggested that S297T substitution in TR34/L98H strains might represent a compensatory mutation showing this low VCZ MIC [ 17 ]. Although there have been no data on the azole resistance of A. fumigatus environmental and clinical isolates in Korea, our hypothesis on the resistance mechanism of the ITZ- and PCZ-resistant strain in this case is a combination of environmental acquisition and the acquired resistance from the patient, probably due to long-term PCZ exposure.…”

Antifungal Resistance: Specific Focus on Multidrug Resistance in Candida auris and Secondary Azole Resistance in Aspergillus fumigatus

“…ISV: isavuconazole; ITC: itraconazole; POS: posaconazole; VRC: voriconazole; *: Isolates with TR34/L98H/S297T/F495I changes may have lower minimum inhibitory concentrations (MICs) of voriconazole in the wild-type range. The S297T mutation might be a compensatory mutation in these cases [119,120]. …”