First isolations in India of multiple-triazole resistant Aspergillus fumigatus strains, carrying the TR/L98H mutations in the cyp51A gene

A Chowdhary1, S Kathuria1, HS Randhawa1, SN Gaur2, CH Klaassen3, JF Meis3

Author address: 

1Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India 2Department of Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India 3Department of Medical Microbiology and In


Purpose: Aspergillus fumigatus is the commonest etiologic agent of invasive and chronic pulmonary aspergillosis. Azole resistance in Aspergillus fumigatus isolates impacts the management of aspergillosis since the azoles are primary agents used for prophylaxis and therapy. We report the emergence of resistance to triazoles in two A. fumigatus isolates from patients in Delhi, India.

Methods: One hundred and three A. fumigatus isolates, collected from 85 patients suspected of bronchopulmonary aspergillosis, admitted to the Clinical Research Centre of V. P. Chest Institute (VPCI), Delhi, India, during 2005-2010 were investigated for susceptibility to itraconazole, voriconazole, posaconazole and isavuconazole using CLSI M38-A2 broth microdilution method. Identification of the resistant isolates was confirmed by internal transcribed spacer (ITS) sequencing. We undertook mixed-format real-time PCR assay for detection of mutations leading to triazole resistance in A. fumigatus. Genotyping was performed with a panel of nine short tandem repeats. For phylogenetic analysis, 25 Dutch clinical and environmental isolates of A. fumigatus containing the TR/L98H genotype were included along with the Indian isolates.

Results: Of the 103 A. fumigatus isolates tested, only two had high MIC values of itraconazole (>16 mg/L), voriconazole (2 mg/L), posaconazole (2 mg/L) and isavuconazole (8 mg/L). The resistant A. fumigatus isolates exhibited the TR/L98H genotype and showed identical patterns by microsatellite typing but were different from 25 Dutch TR/L98H isolates. Isolate VPCI 1042/09 originated from sputum of a 55-year-old, male outpatient of VPCI, diagnosed with chronic obstructive pulmonary disease with bilateral bronchiectasis and cor pulmonale. The second multiple-triazole resistant A. fumigatus isolate, VPCI 942/09, originated from sputum of a 22-year- old male labourer who presented to the outpatient department of VPCI with complaints of productive cough since two years and fever on and off since one year. His diagnosis included pulmonary tuberculosis and allergic bronchopulmonary aspergillosis.

Conclusion: To our knowledge, this is the first report from India on the occurrence of multiple-triazole resistant A. fumigatus isolates, carrying the TR/L98H genotype, in patients with chronic respiratory diseases. The TR/L98H mutation associated with pan-azole resistance in A. fumigatus has been reported so far only from Europe and recently from China. In the present study, 1.9% (2/103) of the A. fumigatus clinical isolates were multiple-triazole resistant, whereas in Dutch hospitals, the corresponding figure is 6-12.8%. As both of our triazole-resistant A. fumigatus isolates were epidemiologically unrelated but showed identical STR genotypes, and were obtained from patients without history of exposure to azoles or of travel to Europe, it is highly likely that the resistance was acquired from the environment in India. Keeping in mind the emergence of azole resistance in environmental strains, continued surveillance of resistance in clinical A. fumigatus strains is desirable for successful therapy of aspergillosis.


abstract No: 


Full conference title: 

5th Advances Against Aspergillosis
    • AAA 5th (2012)