High-frequency Triazole Resistance Found In Nonculturable Aspergillus fumigatus from Lungs of Patients with Chronic Fungal Disease

Denning, David W.; Park, Steven; Lass‐Flörl, Cornelia; Fraczek, Marcin G.; Kirwan, Marie; Gore, Robin; Smith, Jaclyn A.; Bueid, Ahmed S.; Moore, Caroline B.; Bowyer, Paul; Perlin, David S.

doi:10.1093/cid/cir179

Cited by 273 publications

(255 citation statements)

References 43 publications

(53 reference statements)

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“…Thus, case detection is likely to be incomplete. Detectable Aspergillus desoxyribonucleic acid (DNA) in respiratory samples 36 could suggest CPA, prior to A. fumigatus IgG antibodies being requested.…”

Section: Cpa Case Ascertainmentmentioning

confidence: 99%

Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis

Denning¹,

Pleuvry²,

Cole³

2011

Bull World Health Org

351

366

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Section: Cpa Case Ascertainmentmentioning

confidence: 99%

Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis

Denning¹,

Pleuvry²,

Cole³

2011

Bull World Health Org

351

366

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“…A. fumagatis is a ubiquitous fungal antigen and the most common fungus in the airway, inhaled at a rate of several hundred conidia per day. [76][77][78] Although studies in mice found that a single exposure to A. fumagatis induced increases in Treg numbers and function in the lung, repeated exposure models, more akin to the exposure humans experience, was found to shift T-cell responses toward a pathogenic Th2-Th17 phenotype. 79 The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25[OH]D 3 ) has been shown in multiple disease states to induce Tregs.…”

Section: Potential Causes Of Treg Dysfunctionmentioning

confidence: 99%

The Role of Regulatory T Cells in the Regulation of Upper Airway Inflammation

Palmer

Mulligan

Smith

et al. 2017

Am J Rhinol�Allergy

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“…All the primers were selected based on pervious study [10]. Wild type strains A. fumigatus Cyp51A gene (GenBank accession number AF338659.1) and A. niger Cyp51A gene (GenBank accession number JF450900) were used as reference.…”

Section: Primers For Pcr Assays and Sequencingmentioning

confidence: 99%

Determination of Azole Antifungal Drug Resistance Mechanisms Involving Cyp51a Gene in Clinical Isolates of Aspergillus fumigatus and Aspergillus niger

Rajendran¹,

Khaithir²,

Santhanam³

2016

Mycology

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Aims: The main aim of this research is to investigate azole resistance mechanisms in A. fumigatus and A. niger which involve Cyp51A gene that encodes 14-α sterol demethylase enzyme. Methodology and results:Itraconazole susceptibility was determined through E-test method. A conventional PCR method was used to amplify and sequence Cyp51A gene in fungal DNA, to detect the presence of gene mutations. Real-time PCR method was applied to determine overexpression of Cyp51A gene in A. fumigatus and A. niger isolates. Susceptibility test found that 3/13 (23.1%) A. fumigatus and 7/23 (30.4%) A. niger isolates were resistant to Itraconazole, with minimum inhibitory concentrations (MICs) of 2.5 µg/ml to 3.0 µg/ml. Sequencing of A. fumigatus DNA showed presence of L98H mutation in 7/13 (53.8%) and M220 mutation in 3/13 (23%) isolates. Whereas, sequencing of A. niger DNA detected the presence of G427S mutation in 3/23 (13%) isolates. Tandem Repeat mutation was not detected in all A. fumigatus and A. niger isolates. Only M220 mutation showed significant correlation (r (13)=0.041038, p<0.05) with Itraconazole antifungal resistance in A. fumigatus isolates while L98H mutation was not involved. G427S mutation also showed correlation (r (15)=0.038434, p<0.05) with Itraconazole antifungal resistance in A. niger isolates. A higher level of Cyp51A gene expression was detected in 4/8 (50%) A. fumigatus isolates and 7/12 (58.3%) A. niger isolates. Resistant isolates more often showed higher level of Cyp51A gene expression compared to susceptible isolates; however the difference in level of expression between resistant isolates and susceptible isolates is not significant. This may be due to similar MIC values in resistant and susceptible isolates.Conclusion, significance and impact of study: In conclusion the level of azole resistance in A. fumigatus and A. niger isolates in Malaysia is low and mutations in Cyp51A gene may contribute towards Itraconazole antifungal resistance, however other factors may also be involved.

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High-frequency Triazole Resistance Found In Nonculturable Aspergillus fumigatus from Lungs of Patients with Chronic Fungal Disease

Abstract: The very low organism burdens of fungi causing infection have previously prevented direct culture and detection of antifungal resistance in clinical samples. These findings have major implications for the sustainability of triazoles for human antifungal therapy.

Cited by 273 publications

References 43 publications

Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis

Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis

The Role of Regulatory T Cells in the Regulation of Upper Airway Inflammation

Determination of Azole Antifungal Drug Resistance Mechanisms Involving Cyp51a Gene in Clinical Isolates of Aspergillus fumigatus and Aspergillus niger

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