Surveillance and analysis of drug resistance and drug resistance levels in multidrug resistant tuberculosis on the tropical islands of China.

OBJECTIVE

Multidrug-resistant tuberculosis (MDR-TB) remains a major public health challenge in China. Hainan, China's largest tropical island, possesses distinct socio-geographical features. However, the drug resistance patterns and molecular epidemiology of MDR-TB in this region have not been fully elucidated. This study aimed to assess the correlation between drug resistance genotypes and phenotypic resistance levels in multidrug-resistant Mycobacterium tuberculosis (MDR-MTB) strains collected from Hainan Island, using whole-genome sequencing (WGS) and phenotypic drug susceptibility testing (DST).

METHODS

MDR-MTB strains isolated from patients on Hainan Island (2019-2021) were analyzed. Minimum inhibitory concentrations (MIC) for 15 anti-TB drugs were determined by broth microdilution (BMD). Whole-genome sequencing (WGS) was performed using Illumina NovaSeq 6000. Genotypic resistance was predicted via TB-Profiler, and correlations between resistance mutations and MIC levels were assessed.

RESULTS

A total of 209 MDR-MTB strains were analyzed. Strains of lineage 2.2 exhibited significantly higher resistance to ethambutol (EMB) compared to non-lineage 2 strains (P < 0.05). The sensitivity of WGS in predicting resistance to first-line drugs isoniazid (INH), rifampicin (RIF), EMB, and pyrazinamide (PZA) was 94.7%, 99.0%, 96.5%, and 80.8%, respectively. However, specificity for EMB and PZA was lower at 60.2% and 79.4%. WGS also demonstrated high sensitivity and specificity (> 95%) for second-line injectable aminoglycosides (amikacin [AMK], capreomycin [CPM], and kanamycin [KM]), but sensitivity for other second-line drugs except for fluoroquinolone drug moxifloxacin (MOX, 94.4%) was below 80.0%. Notably, mutations in katG_S315T, rpoB_S450L, and gyrA_D94G were strongly associated with high-level resistance, while mutations in fabG1, ahpC, embA promoters, and gyrA at codon 90 were linked to low-level resistance.

CONCLUSIONS

This study quantitatively demonstrates the relationship between specific drug resistance genotypes and resistance levels. It is the first to characterize the regional resistance spectrum of MDR-MTB strains on Hainan Island. These findings offer a novel foundation for MIC-based dose adjustment and the optimization of treatment strategies in this region.  TRIAL REGISTRATION: MR-46-23-020530. Date of registration:2023-07-03.