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Clusters of Drug-Resistant Mycobacterium tuberculosis Detected by Whole-Genome Sequence Analysis of Nationwide Sample, Thailand, 2014-2017.

ABSTRACT: Multidrug-resistant tuberculosis (MDR TB), pre-extensively drug-resistant tuberculosis (pre-XDR TB), and extensively drug-resistant tuberculosis (XDR TB) complicate disease control. We analyzed whole-genome sequence data for 579 phenotypically drug-resistant M. tuberculosis isolates (28% of available MDR/pre-XDR and all culturable XDR TB isolates collected in Thailand during 2014-2017). Most isolates were from lineage 2 (n = 482; 83.2%). Cluster analysis revealed that 281/579 isolates (48.5%) formed 89 clusters, including 205 MDR TB, 46 pre-XDR TB, 19 XDR TB, and 11 poly-drug-resistant TB isolates based on genotypic drug resistance. Members of most clusters had the same subset of drug resistance-associated mutations, supporting potential primary resistance in MDR TB (n = 176/205; 85.9%), pre-XDR TB (n = 29/46; 63.0%), and XDR TB (n = 14/19; 73.7%). Thirteen major clades were significantly associated with geography (p<0.001). Clusters of clonal origin contribute greatly to the high prevalence of drug-resistant TB in Thailand.

SUBMITTER: Nonghanphithak D

PROVIDER: S-EPMC7920678 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Clusters of Drug-Resistant Mycobacterium tuberculosis Detected by Whole-Genome Sequence Analysis of Nationwide Sample, Thailand, 2014-2017.

Nonghanphithak Ditthawat D Chaiprasert Angkana A Smithtikarn Saijai S Kamolwat Phalin P Pungrassami Petchawan P Chongsuvivatwong Virasakdi V Mahasirimongkol Surakameth S Reechaipichitkul Wipa W Leepiyasakulchai Chaniya C Phelan Jody E JE Blair David D Clark Taane G TG Faksri Kiatichai K

Emerging infectious diseases 20210301 3

Multidrug-resistant tuberculosis (MDR TB), pre-extensively drug-resistant tuberculosis (pre-XDR TB), and extensively drug-resistant tuberculosis (XDR TB) complicate disease control. We analyzed whole-genome sequence data for 579 phenotypically drug-resistant M. tuberculosis isolates (28% of available MDR/pre-XDR and all culturable XDR TB isolates collected in Thailand during 2014-2017). Most isolates were from lineage 2 (n = 482; 83.2%). Cluster analysis revealed that 281/579 isolates (48.5%) fo ...[more]

PMID: 33622486

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Project description:BackgroundThe prevalence of drug-resistant tuberculosis (DR-TB) has brought severe challenges to the prevention and control of tuberculosis. Studies have explored the status of antituberculosis drug (ATD) resistance in different regions of China. However, few studies have focused on DR-TB in Sichuan to date. Due to the large population in Sichuan, detailed investigations of the DR-TB burden in Sichuan are needed. The objective of this study was to investigate the drug resistance characteristics of TB isolates from tuberculosis patients with and without HIV (TB-HIV patients and TBw/oHIV patients) in Chengdu, Sichuan, China.MethodsIsolates from respiratory samples of TBw/oHIV patients and TB-HIV patients hospitalized between January 2014 and December 2017 were collected. Nontuberculosis mycobacteria (NTM) were excluded. Drug sensitivity testing (DST) was performed according to the dilution method in microplates with 4 first-line ATDs and 8 second-line ATDs. TB strains were separated according to patient treatment history, patient age, calendar year and GeneXpert MTB/RIF (GeneXpert) assay results for further analysis.ResultsFor the 7470 patients recruited, the multidrug-resistant tuberculosis (MDR-TB) rate was 2.1-fold (14.6% vs. 6.8%) higher than the national baseline level. The repeatedly admitted patients were more likely to have a resistance profile than the first-time-admitted cases in both the TB-only group (P<0.05) and the TB-HIV corresponding group (P<0.05). Among the 7273 TBw/oHIV cases and 197 TB-HIV cases, the positivity rates of acid-fast bacilli (AFB) in the TB-HIV group were significantly lower than those in the TBw/oHIV group (P<0.05). The repeatedly admitted TB-HIV patients had lower resistance rates to INH than the repeatedly admitted TBw/oHIV patients (24.4% vs. 41.5%, P<0.05). The Rifampicin-resistant TB strains in the TBw/oHIV group were more likely to be resistant to INH in the repeatedly admitted group than those in the first-time admitted patients (P<0.05). The proportions of XDR (3.6% vs. 1.3%, P<0.05) and XDR-TB/MDR-TB (7.3% vs. 2.2%, P<0.05) in all TB-HIV patients were significantly higher than those in all TBw/oHIV patients. The ratio of XDR-TB was significantly higher in the TB-HIV group than in the TBw/oHIV group (30.4% vs. 9.0%, P<0.05) and the all TB group (9.0% vs. 10.1%, P<0.05). Regarding age, the <25-year-old TB-HIV patients (9.1% vs. 0.7%, P<0.05) and 25~44-year-old TB-HIV patients (5.2% vs. 2.4%, P<0.05) were more likely to have a higher XDR proportion than their TBw/oHIV counterparts. The ATD-resistance profile in terms of different years from high to low was 2014>2015>2016≈2017 for TBw/oHIV patients. The same trend was also observed for TB-HIV patients: 2014>2015>2016≈2017. The GeneXpert TB-positive rate in the TBw/oHIV group was higher than that in the TB-HIV group [81%(639/792) vs. 65% (13/20), P<0.05]. In TBw/oHIV cases, the agreement was 92.3% and the Kappa value was 0.75. In TB-HIV cases, the agreement was 85.0% and the Kappa value was 0.32.ConclusionIn Sichuan, ATD resistance has improved since 2014, but to date, it remains severe. The different resistance profiles of TBw/oHIV patients and TB-HIV patients indicates the need for personalized treatment plans. Specifically, the GeneXpert assay might be more suitable for TBw/oHIV patients than for TB-HIV patients.

Project description:Genome sequencing plays a key role in understanding the genetic diversity of Mycobacterium tuberculosis (M.tb). The genotype-specific character of M. tb contributes to tuberculosis severity and emergence of drug resistance. Strains of M. tb complex can be classified into seven lineages. The Nonthaburi (NB) genotype, belonging to the Indo-Oceanic lineage (lineage 1), has a unique spoligotype and IS6110-RFLP pattern but has not previously undergone a detailed whole genome analysis. In addition, there is not much information available on the whole genome analysis of M. tb isolates from tuberculous meningitis (TBM) patients in public databases. Isolates CSF3053, 46-5069 and 43-13838 of NB genotype were obtained from the cerebrospinal fluids of TBM Thai patients in Siriraj Hospital, Bangkok. The whole genomes were subjected to high throughput sequencing. The sequence data of each isolate were assembled into draft genome. The sequences were also aligned to reference genome, to determine genomic variations. Single nucleotide polymorphisms (SNPs) were obtained and grouped according to the functions of the genes containing them. They were compared with SNPs from 1,601 genomes, representing the seven lineages of M. tb complex, to determine the uniqueness of NB genotype. Susceptibility to first-line, second-line and other antituberculosis drugs were determined and related to the SNPs previously reported in drug-resistant related genes. The assembled genomes have an average size of 4,364,461 bp, 4,154 genes, 48 RNAs and 64 pseudogenes. A 500 base pairs deletion, which includes ppe50, was found in all isolates. RD239, specific for members of Indo Oceanic lineage, and RD147c were identified. A total of 2,202 SNPs were common to the isolates and used to classify the NB strains as members of sublineage 1.2.1. Compared with 1,601 genomes from the seven lineages of M. tb complex, mutation G2342203C was found novel to the isolates in this study. Three mutations (T28910C, C1180580T and C152178T) were found only in Thai NB isolates, including isolates from previous study. Although drug susceptibility tests indicated pan-susceptibility, non-synonymous SNPs previously reported to be associated with resistance to anti-tuberculous drugs; isoniazid, ethambutol, and ethionamide were identified in all the isolates. Non-synonymous SNPs were found in virulence genes such as the genes playing roles in apoptosis inhibition and phagosome arrest. We also report polymorphisms in essential genes, efflux pumps associated genes and genes with known epitopes. The analysis of the TBM isolates and the availability of the variations obtained will provide additional resources for global comparison of isolates from pulmonary tuberculosis and TBM. It will also contribute to the richness of genomic databases towards the prediction of antibiotic resistance, level of virulence and of origin of infection.

Project description:Cambodia has one of the highest tuberculosis (TB) incidence rates in the WHO Western Pacific region. Remarkably though, the prevalence of multidrug-resistant TB (MDR-TB) remains low. We explored the genetic diversity of Mycobacterium tuberculosis (MTB) circulating in this unique setting using whole-genome sequencing (WGS). From October 2017 until January 2018, we collected one hundred sputum specimens from consenting adults older than 21 years of age, newly diagnosed with bacteriologically confirmed TB in 3 districts of Phnom Penh and Takeo provinces of Cambodia before they commence on their TB treatment, where eighty MTB isolates were successfully cultured and sequenced. Majority of the isolates belonged to Lineage 1 (Indo-Oceanic) (69/80, 86.25%), followed by Lineage 2 (East Asian) (10/80, 12.5%) and Lineage 4 (Euro-American) (1/80, 1.25%). Phenotypic resistance to both streptomycin and isoniazid was found in 3 isolates (3/80, 3.75%), while mono-resistance to streptomycin and isoniazid was identical at 2.5% (N = 2 each). None of the isolates tested was resistant to either rifampicin or ethambutol. The specificities of genotypic prediction for resistance to all drugs tested were 100%, while the sensitivities of genotypic resistance predictions to isoniazid and streptomycin were lower at 40% (2/5) and 80% (4/5) respectively. We identified 8 clusters each comprising of two to five individuals all residing in the Takeo province, making up half (28/56, 50%) of all individuals sampled in the province, indicating the presence of multiple ongoing transmission events. All clustered isolates were of Lineage 1 and none are resistant to any of the drugs tested. This study while demonstrating the relevance and utility of WGS in predicting drug resistance and inference of disease transmission, highlights the need to increase the representation of genotype-phenotype TB data from low and middle income countries in Asia and Africa to improve the accuracies for prediction of drug resistance.

Dataset Information

Clusters of Drug-Resistant Mycobacterium tuberculosis Detected by Whole-Genome Sequence Analysis of Nationwide Sample, Thailand, 2014-2017.

Publications

Clusters of Drug-Resistant Mycobacterium tuberculosis Detected by Whole-Genome Sequence Analysis of Nationwide Sample, Thailand, 2014-2017.

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