Bedaquiline Drug Resistance Emergence Assessment in Multidrug-resistant-tuberculosis (MDR-TB) (DREAM) was a 5-year (2015–2019) phenotypic drug-resistance surveillance study across 11 countries. DREAM assessed the susceptibility of 5036 MDR-TB isolates of bedaquiline-treatment-naïve patients to bedaquiline and other anti-tuberculosis drugs by the 7H9 broth microdilution (BMD) and 7H10/7H11 agar dilution (AD) minimal inhibitory concentration (MIC) methods. Bedaquiline AD MIC quality control (QC) range for the H37Rv reference strain was unchanged, but the BMD MIC QC range (0.015–0.12 μg/ml) was adjusted compared with ranges from a multilaboratory, multicountry reproducibility study conforming to Clinical and Laboratory Standards Institute Tier-2 criteria. Epidemiological cut-off values of 0.12 μg/ml by BMD and 0.25 μg/ml by AD were consistent with previous bedaquiline breakpoints. An area of technical uncertainty or Intermediate category was set at 0.25 μg/ml and 0.5 μg/ml for BMD and AD, respectively. When applied to the 5036 MDR-TB isolates, bedaquiline-susceptible, intermediate and bedaquiline-resistant rates were 97.9%, 1.5% and 0.6%, respectively, for BMD, and 98.8%, 0.8% and 0.4% for AD. Resistance rates were: ofloxacin 35.1%, levofloxacin 34.2%, moxifloxacin 33.3%, 1.5% linezolid and 2% clofazimine. Phenotypic cross resistance between bedaquiline and clofazimine was 0.4% in MDR-TB and 1% in pre-extensively drug-resistant (pre-XDR-TB)/XDR-TB populations. Co-resistance to bedaquiline and linezolid, and clofazimine and linezolid, were 0.1% and 0.3%, respectively, in MDR-TB, and 0.2% and 0.4% in pre-XDR-TB/XDR-TB populations. Resistance rates to bedaquiline appear to be low in the bedaquiline-treatment-naïve population. No treatment-limiting patterns for cross-resistance and co-resistance have been identified with key TB drugs to date.

BackgroundMultidrug/extensively drug-resistant tuberculosis (M/XDR-TB) is a major public health problem, and early detection is important for preventing its spread. This study aimed to demonstrate the distribution of genetic site mutation associated with drug resistance in M/XDR-TB in the northern Thai population.MethodsThirty-four clinical MTB isolates from M/XDR-TB patients in the upper northern region of Thailand, who had been identified for drug susceptibility using the indirect agar proportion method from 2005 to 2012, were examined for genetic site mutations of katG, inhA, and ahpC for isoniazid (INH) drug resistance and rpoB for rifampicin (RIF) drug resistance. The variables included the baseline characteristics of the resistant gene, genetic site mutations, and drug susceptibility test results.ResultsAll 34 isolates resisted both INH and RIF. Thirty-two isolates (94.1%) showed a mutation of at least 1 codon for katG, inhA, and ahpC genes. Twenty-eight isolates (82.4%) had a mutation of at least 1 codon of rpoB gene. The katG, inhA, ahpC, and rpoB mutations were detected in 20 (58.7%), 27 (79.4%), 13 (38.2%), and 28 (82.3%) of 34 isolates. The 3 most common mutation codons were katG 315 (11/34, 35.3%), inhA 14 (11/34, 32.4%), and inhA 114 (11/34, 32.4%). For this population, the best genetic mutation test panels for INH resistance included 8 codons (katG 310, katG 340, katG 343, inhA 14, inhA 84, inhA 86, inhA 114, and ahpC 75), and for RIF resistance included 6 codons (rpoB 445, rpoB 450, rpoB 464, rpoB 490, rpoB 507, and rpoB 508) with a sensitivity of 94.1% and 82.4%, respectively.ConclusionThe genetic mutation sites for drug resistance in M/XDR-TB are quite variable. The distribution of these mutations in a certain population must be studied before developing the specific mutation test panels for each area. The results of this study can be applied for further molecular M/XDR-TB diagnosis in the upper northern region of Thailand.

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.

Tuberculosis disease (TB), caused by Mycobacterium tuberculosis , is a major public health issue in Thailand. The high prevalence of modern Beijing (Lineage 2.2.1) strains has been associated with multi- and extensively drug-resistant infections (MDR-, XDR-TB), complicating disease control. The impact of rarer proto-Beijing (L2.1) strains is less clear. In our study of thirty-seven L2.1 clinical isolates spanning thirteen years, we found a high prevalence of XDR-TB cases (32.4%). With ≤ 12 pairwise SNP distances, 43.2% of L2.1 patients belong to MDR-TB or XDR-TB transmission clusters suggesting a high level of clonal expansion across four Thai provinces. All XDR-TB (100%) were likely due to transmission rather than inadequate treatment. We found a 47 mutation signature and a partial deletion of the fadD14 gene in the circulating XDR-TB cluster, which can be used for surveillance of this rare and resilient M. tuberculosis strain-type that is causing increasing health burden. We also detected three novel deletion positions, a deletion of 1285 bp within desA3 (Rv3230c) , large deletions in the plcB, plcA, and ppe38 gene which may play a role in the virulence, pathogenesis or evolution of the L2.1 strain-type.

objective To assess the prevalence and risk factors of drug-resistant tuberculosis (TB), the fifth national anti-TB drug resistance survey was conducted in Thailand. methods A cross-sectional study was conducted by stratified cluster sampling with probability proportional to size of TB cases from public health facilities in 100 clusters throughout Thailand from August 2017 to August 2018. Susceptibility testing of TB isolates to first-and second-line anti-TB drugs was performed on Löwenstein-Jensen medium using the indirect proportion method. Multiple imputation was done for handling missing data using Stata 16. The proportion of TB cases with drug resistance was determined. The odds ratio was used to evaluate risk factors associated with drug-resistant TB. results Among 1501 new TB and 69 previously treated TB cases, 14.0% [95% confidence interval (CI): 12.1-16.1] and 33.4% (95% CI: 23.6-44.8), respectively, had resistance to any anti-TB drug. Multidrug-resistant TB accounted for 0.8% (95% CI: 0.5-1.4) of new TB cases and 13.0% (95% CI: 6.5-24.4) of previously treated TB cases. Drug-resistant TB was associated with prior TB treatment [odds ratio (OR), 2.9; 95% CI: 1.6-5.0], age at 45-54 years (OR, 1.6; 95% CI: 1.0-2.4), male (OR, 1.5; 95% CI: 1.0-2.1) and human immunodeficiency virus (HIV) infection (OR, 1.6; 95% CI: 1.0-2.4). conclusions The burden of drug-resistant TB remains high in Thailand. Intensified prevention and control measures should be implemented to reduce the risks of drug-resistant TB in high-risk groups previously treated, especially individuals of late middle age, males and those with coinfection of TB and HIV. keywords Mycobacterium tuberculosis, drug susceptibility testing, prevalence, risk factors, Thailand Sustainable Development Goals (SDGs): SDG 3 (good health and well-being), SDG 17 (partnerships for the goals)