Sources of multi-drug resistance in patients with previous isoniazid resistant tuberculosis identified using whole genome sequencing: A longitudinal cohort study.
AuthorSrinivasan, V; Ha, VTN; Vinh, DN; Thai, PVK; Ha, DTM; Lan, NH; Hai, HT; Walker, TM; Thu, DDA; Dunstan, SJ; ...
Source TitleClinical Infectious Diseases
PublisherOxford University Press (OUP)
University of Melbourne Author/sDunstan, Sarah
Document TypeJournal Article
CitationsSrinivasan, V., Ha, V. T. N., Vinh, D. N., Thai, P. V. K., Ha, D. T. M., Lan, N. H., Hai, H. T., Walker, T. M., Thu, D. D. A., Dunstan, S. J., Thwaites, G. E., Ashton, P. M., Caws, M. & Thuong, N. T. T. (2020). Sources of multi-drug resistance in patients with previous isoniazid resistant tuberculosis identified using whole genome sequencing: A longitudinal cohort study.. Clin Infect Dis, 71 (10), pp.e532-e539. https://doi.org/10.1093/cid/ciaa254.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744982
BACKGROUND: Meta-analysis of patients with isoniazid-resistant tuberculosis given standard first-line anti-tuberculosis treatment indicated an increased risk of multi-drug resistant tuberculosis (MDR-TB) emerging (8%), compared to drug-sensitive tuberculosis (0.3%). Here we use whole genome sequencing (WGS) to investigate whether treatment of patients with pre-existing isoniazid resistant disease with first-line anti-tuberculosis therapy risks selecting for rifampicin resistance, and hence MDR-TB. METHODS: Patients with isoniazid-resistant pulmonary TB were recruited and followed up for 24 months. Drug-susceptibility testing was performed by Microscopic observation drug-susceptibility assay (MODS), Mycobacterial Growth Indicator Tube (MGIT) and by WGS on isolates at first presentation and in the case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine the genomic relatedness between initial and subsequent isolates. De novo emergence of MDR-TB was assumed where the genomic distance was five or fewer single nucleotide polymorphisms (SNPs) whereas reinfection with a different MDR-TB strain was assumed where the distance was 10 or more SNPs. RESULTS: 239 patients with isoniazid-resistant pulmonary tuberculosis were recruited. Fourteen (14/239, 5.9%) patients were diagnosed with a second episode of tuberculosis that was multi-drug resistant. Six (6/239, 2.5%) were identified as having evolved MDR-TB de novo and six as having been re-infected with a different strain. In two cases the genomic distance was between 5-10 SNPs and therefore indeterminate. CONCLUSIONS: In isoniazid-resistant TB, de novo emergence and reinfection of MDR-TB strains equally contributed to MDR development. Early diagnosis and optimal treatment of isoniazid resistant TB are urgently needed to avert the de novo emergence of MDR-TB during treatment.
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