Dataset Information

Multicenter Study of Azole-Resistant Aspergillus fumigatus Clinical Isolates, Taiwan¹.

ABSTRACT: In a multicenter study, we determined a prevalence rate of 4% for azole-resistant Aspergillus fumigatus in Taiwan. Resistance emerged mainly from the environment (TR₃₄/L98H, TR₃₄/L98H/S297T/F495I, and TR₄₆/Y121F/T289A mutations) but occasionally during azole treatment. A high mortality rate observed for azole-resistant aspergillosis necessitates diagnostic stewardship in healthcare and antifungal stewardship in the environment.

SUBMITTER: Wu CJ

PROVIDER: S-EPMC7101115 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Multicenter Study of Azole-Resistant Aspergillus fumigatus Clinical Isolates, Taiwan1.

Wu Chi-Jung CJ Liu Wei-Lun WL Lai Chih-Cheng CC Chao Chien-Ming CM Ko Wen-Chien WC Wang Hsuan-Chen HC Dai Ching-Tzu CT Hsieh Ming-I MI Choi Pui-Ching PC Yang Jia-Ling JL Chen Yee-Chun YC

Emerging infectious diseases 20200401 4

In a multicenter study, we determined a prevalence rate of 4% for azole-resistant Aspergillus fumigatus in Taiwan. Resistance emerged mainly from the environment (TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A mutations) but occasionally during azole treatment. A high mortality rate observed for azole-resistant aspergillosis necessitates diagnostic stewardship in healthcare and antifungal stewardship in the environment. ...[more]

PMID: 32186508

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Project description:Azoles are the primary antifungal drugs used to treat infections caused by Aspergillus fumigatus. However, the emergence of azole resistance in A. fumigatus has become a global health concern despite the low proportion of resistant isolates in natural populations. In bacteria, antibiotic resistance incurs a fitness cost that renders strains less competitive in the absence of antibiotics. Consequently, fitness cost is a key determinant of the spread of resistant mutations. However, the cost of azole resistance and its underlying causes in A. fumigatus remain poorly understood. In this observation, we revealed that the 10 out of 15 screened azole-resistant isolates, which possessed the most common azole-targeted cyp51A mutations, particularly the presence of tandem repeats in the promoter region, exhibit fitness cost when competing with the susceptible isolates in azole-free environments. These results suggest that fitness cost may significantly influence the dynamics of azole resistance, which ultimately contributes to the low prevalence of azole-resistant A. fumigatus isolates in the environment and clinic. By constructing in situ cyp51A mutations in a parental azole-susceptible strain and reintroducing the wild-type cyp51A gene into the azole-resistant strains, we demonstrated that fitness cost is not directly dependent on cyp51A mutations but is instead associated with the evolution of variable mutations related to conidial germination or other unknown development-related processes. Importantly, our observations unexpectedly revealed that some azole-resistant isolates showed no detectable fitness cost, and some even exhibited significantly increased competitive fitness in azole-free environments, highlighting the potential risk associated with the prevalence of these isolates.ImportanceAzole resistance in the human fungal pathogen Aspergillus fumigatus presents a global public health challenge. Understanding the epidemic trends and evolutionary patterns of azole resistance is critical to prevent and control the spread of azole-resistant isolates. The primary cause is the mutation of the drug target 14α-sterol-demethylase Cyp51A, yet its impact on competitive ability remains uncertain. Our competition assays revealed a diverse range of fitness outcomes for environmental and clinical cyp51A-mutated isolates. We have shown that this fitness cost is not reliant on cyp51A mutations but might be linked to unknown mutations induced by stress conditions. Among these isolates, the majority displayed fitness costs, while a few displayed enhanced competitive ability, which may have a potential risk of spread and the need to closely monitor these isolates. Our observation reveals the variation in fitness costs among azole-resistant isolates of A. fumigatus, highlighting the significant role of fitness cost in the spread of resistant strains.

Dataset Information

Multicenter Study of Azole-Resistant Aspergillus fumigatus Clinical Isolates, Taiwan¹.

Publications

Multicenter Study of Azole-Resistant Aspergillus fumigatus Clinical Isolates, Taiwan<sup>1</sup>.

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