Microsatellite Typing and Resistance Mechanism Analysis of Voriconazole-Resistant
            <i>Aspergillus flavus</i>
            Isolates in South Korean Hospitals

Choi, Min Ji; Won, Eun Jeong; Joo, Min Young; Park, Yeon-Joon; Kim, Soo Hyun; Shin, Myung Geun; Shin, Jong Hee

doi:10.1128/aac.01610-18

Cited by 15 publications

(24 citation statements)

References 24 publications

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“…Microsatellite typing revealed that six of the seven non‐wild‐type isolates, which were obtained from ear specimens at four hospitals, shared the same microsatellite genotype. None of the non‐wild‐type isolates showed any cyp51 mutations associated with azole resistance, but the mean expression levels of efflux pumps ( MDR2 , atrF and mfs1 ) and target genes ( cyp51A ) exhibited significant differences between the non‐wild types and the other isolates . Continued testing of A flavus is relevant, as it is the second most common cause of IA and its burden of azole resistance has not been fully explored .…”

Section: Discussionmentioning

confidence: 99%

“…None of the non-wild-type isolates showed any cyp51 mutations associated with azole resistance, but the mean expression levels of efflux pumps (MDR2, atrF and mfs1) and target genes (cyp51A) exhibited significant differences between the nonwild types and the other isolates. 32 Continued testing of A flavus is relevant, as it is the second most common cause of IA and its burden of azole resistance has not been fully explored. 33 To the best of our knowledge, no study has yet demonstrated the association between azole-resistant clinical A flavus and environmental isolates.…”

Section: Discussionmentioning

confidence: 99%

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Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study

Chen

Kuo

Wang

et al. 2019

Mycoses

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Summary Poor clinical outcomes for invasive aspergillosis are associated with antifungal resistance. Performing antifungal susceptibility tests on clinically relevant Aspergillus isolates from patients and environmental regions with known azole resistance is recommended. The aim of the study was to assess the presence of azole resistance in clinical Aspergillus spp. isolates and those from hospital environments and farmlands within a 40 km radius of the hospital. Clinical Aspergillus spp. isolates were cultured, as well as environmental Aspergillus spp. isolates obtained from air samples. Samples were subcultured in azole‐containing agar plates. Isolates with a positive screening test were subjected to YeastOne methods to determine their minimum inhibitory concentrations of antifungals. Resistance mechanisms were investigated in the azole‐resistant Aspergillus spp. isolates. No azole‐resistant clinical or environmental A flavus, A oryaze, A niger or A terreus isolates were found in the present study. All A fumigatus clinical isolates were azole‐susceptible. Seven A fumigatus environmental isolates were associated with cyp51A mutations, including two that harboured TR34/L98H mutations with S297T/F495I substitutions, two with TR34/L98H mutations and three with TR46/Y121F/T289A mutations. One of these isolates was collected from farmland, one was from A ward and five were from B ward. The proportion of azole‐resistant A fumigatus was 10.2% (6/59) and 3.2% (1/31) in the hospital environments and the farmlands near the hospital, respectively. The results showed that azole‐resistant A fumigatus existed within hospital environments. This emphasises the importance of periodic surveillance in hospital environments and monitoring for the emergence of azole‐resistant A fumigatus clinical isolates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study

Chen

Kuo

Wang

et al. 2019

Mycoses

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“…In previous studies, A. flavus strains with MIC values higher than the epidemiological cutoff value established for voriconazole by CLSI, 1 mg/liter, were reported to sometimes harbor cyp51A, cyp51B, and cyp51C mutations, as A. flavus has three cyp51 genes. These strains presented different susceptibility patterns, as some of them had reduced susceptibility to all azoles (46) while others showed intermediate MIC values for itraconazole and posaconazole (11,13). Two A. flavus sensu stricto strains (6%) within the program were classified as itraconazole resistant, based on the EUCAST clinical breakpoint, and had high MICs against voriconazole, posaconazole, and isavuconazole.…”

Section: Discussionmentioning

confidence: 99%

“…Most A. fumigatus triazole resistance cases are explained by point mutations in the cyp51A gene, which encodes the 14␣-sterol-demethylase of the ergosterol biosynthesis pathway (10). Point muta-tions associated with azole resistance have also been reported in cyp51A in Aspergillus terreus and in cyp51C in Aspergillus flavus (11)(12)(13)(14)(15). Resistance in Aspergillus has also been described in cryptic or sibling species, which can only be identified to the species level using molecular tools and are classified in "complex" of closely related species when convenient identification techniques are not performed (16).…”

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confidence: 99%

Molecular Identification, Antifungal Susceptibility Testing, and Mechanisms of Azole Resistance in Aspergillus Species Received within a Surveillance Program on Antifungal Resistance in Spain

Rivero-Menéndez

Soto-Debrán

Medina

et al. 2019

Antimicrob Agents Chemother

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Antifungal resistance is one of the major causes of the increasing mortality rates for fungal infections, especially for those caused by Aspergillus spp. A surveillance program was established in 2014 in the Spanish National Center for Microbiology for tracking resistance in the most prevalent Aspergillus species. A total of 273 samples were included in the study and were initially classified as susceptible or resistant according to EUCAST breakpoints. Several Aspergillus cryptic species were found within the molecularly identified isolates. Cyp51 mutations were characterized for Aspergillus fumigatus, Aspergillus terreus, and Aspergillus flavus sensu stricto strains that were classified as resistant. Three A. fumigatus sensu stricto strains carried the TR34/L98H resistance mechanism, while two harbored G54R substitution and one harbored the TR46/Y121F/T289A mechanism. Seventeen strains had no mutations in cyp51A, with ten of them resistant only to isavuconazole. Three A. terreus sensu stricto strains harbored D344N substitution in cyp51A, one of them combined with M217I, and another carried an A249G novel mutation. Itraconazole-resistant A. flavus sensu stricto strains harbored P220L and H349R alterations in cyp51A and cyp51C, respectively, that need further investigation on their implication in azole resistance.

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“…Recently, A. flavus isolates with in vitro azole resistance have been described and azole resistance mechanisms in these strains are being analyzed. To date, different A. flavus Cyp51 point mutations have been described [ 22 , 23 , 24 , 25 , 26 ], however their role in azole resistance cannot be assumed since most of them were eventually described in azole susceptible strains. To date, only one point mutation (Y319H) in A. flavus Cyp51C seems to be related to azole resistance although it needs further confirmation [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus

Lúcio

González-Jiménez

Rivero-Menéndez

et al. 2020

Genes

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Infections caused by Aspergillus species are being increasingly reported. Aspergillus flavus is the second most common species within this genus causing invasive infections in humans, and isolates showing azole resistance have been recently described. A. flavus has three cyp51-related genes (cyp51A, cyp51B, and cyp51C) encoding 14-α sterol demethylase-like enzymes which are the target of azole drugs. In order to study triazole drug resistance in A. flavus, three strains showing reduced azole susceptibility and 17 azole susceptible isolates were compared. The three cyp51-related genes were amplified and sequenced. A comparison of the deduced Cyp51A, Cyp51B, and Cyp51C protein sequences with other protein sequences from orthologous genes in different filamentous fungi led to a protein identity that ranged from 50% to 80%. Cyp51A and Cyp51C presented several synonymous and non-synonymous point mutations among both susceptible and non-susceptible strains. However, two amino acid mutations were present only in two resistant isolates: one strain harbored a P214L substitution in Cyp51A, and another a H349R in Cyp51C that also showed an increase of cyp51A and cyp51C gene expression compared to the susceptible strain ATCC2004304. Isolates that showed reduced in vitro susceptibility to clinical azoles exhibited a different susceptibility profile to demethylation inhibitors (DMIs). Although P214L substitution might contribute to azole resistance, the role of H349R substitution together with changes in gene expression remains unclear.

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Microsatellite Typing and Resistance Mechanism Analysis of Voriconazole-Resistant Aspergillus flavus Isolates in South Korean Hospitals

Cited by 15 publications

References 24 publications

Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study

Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study

Molecular Identification, Antifungal Susceptibility Testing, and Mechanisms of Azole Resistance in Aspergillus Species Received within a Surveillance Program on Antifungal Resistance in Spain

Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus

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