Multi -azole resistant aspergillosis due to TR34/L98H Aspergillus fumigatus in a tertiary care hospital in Delhi , India , 2009-2012

Ref ID: 19489

Author:

A Chowdhary1*, S Kathuria1, C Sharma1, F Hagen2, JF Meis2,3

Author address:

1Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
2Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
3Medical Microbiology, Radboud University Medical Center,

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Aspergillus fumigatus is the commonest etiologic agent of invasive and chronic pulmonary
aspergillosis (CPA). The recent increase in itraconazole resistance has been linked to a single allele
of cyp51A, termed ’TR34/L98H’ in many European countries. However, non-cyp51A mediated
mutations are also increasingly reported especially from Manchester, United Kingdom. Apparently,
TR34/L98H mutation is now spreading, since over the past years this mutation has been reported to
occur world-wide in patients as well as in the environment. Azole resistance in A. fumigatus isolates
impacts the management of aspergillosis, since the azoles are primary agents used for prophylaxis
and therapy. The present study investigated the prevalence of azole resistance in clinical A. fumigatus
isolates and determined the effects of resistance on patient management during a 3-year retrospective
study from Delhi, India.
Methods:
A total of 260 A. fumigatus strains from 225 patients admitted to V. P. Chest Institute, Delhi, India,
during 2009-2012 were screened for azole resistance on Sabouraud dextrose agar (SDA) plates
supplemented with 4 mg/L itraconazole and 1 mg/L voriconazole. The patients underlying conditions,
diagnosis and demographic data were collected. The identification of the resistant isolates was
confirmed by calmodulin and β tubulin gene sequencing. They were investigated for susceptibility
to azoles such as itraconazole, voriconazole, posaconazole and isavuconazole using CLSI M38-A2
broth microdilution method. For detection of mutations leading to triazole resistance, all of the
resistant A. fumigatus isolates were subjected to mixed-format real-time PCR assay. Genotyping
of the resistant isolates was performed with a panel of nine short tandem repeat (STRs) and for
phylogenetic analysis Indian isolates were compared with Chinese, Dutch, German and French
isolates of A. fumigatus containing the TR34/L98H genotype.
Results:
Seven A. fumigatus strains originating from 7 patients showed growth on voriconazole (VRC+) and
itraconazole (ITC+) SDA plates. Barring one all of the 7 seven patients were azole naí¯ve. Of the
7 patients, 3 had invasive aspergillosis (IA), 3 allergic bronchopulmonary aspergillosis and one had
CPA. Of the 3 IA patients, biopsy and repeated BAL specimens yielded triazole resistant A. fumigatus
in two invasive pulmonary aspergillosis patients and in one patient with invasive sinusitis the
resected sinus tissue grew resistant A. fumigatus. Of the 4 patients with IA and CPA, 3 (75%) had
a fatal outcome which included 2 of IA and a solitary case of CPA. All of the resistant A. fumigatus
isolates had high MIC values of itraconazole (>16 mg/L), voriconazole (2 mg/L), posaconazole
(2 mg/L) and isavuconazole (8 mg/L) and exhibited a specific TR34/L98H mutations in cyp51A
gene. Phylogenetic analysis of the Indian TR34/L98H isolates showed identical STR genotypes but
were distinct from the TR34/L98H strains of Chinese, Dutch, French and German origin.
Conclusion:
The increasing rate of azole resistant A. fumigatus from 1.9% in 2005-2009 to 2.6% during
2009-2013 of TR34/L98H in clinical setting in India is alarming. TR34/L98H is the only resistant
mechanism prevalent and is consistent with a route of resistance development through exposure to
azole compounds in the environment.

Abstract Number: 17

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

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