Whole-Genome Sequencing to Predict Mycobacterium tuberculosis Drug Resistance: A Retrospective Observational Study in Eastern China

Abstract

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). Whole-genome sequencing (WGS) holds great promise as an advanced technology for accurately predicting anti-TB drug resistance. The development of a reliable method for detecting drug resistance is crucial in order to standardize anti-TB treatments, enhance patient prognosis, and effectively reduce the risk of transmission. In this study, our primary objective was to explore and determine the potential of WGS for assessing drug resistance based on genetic variants recommended by the World Health Organization (WHO). A total of 1105 MTB strains were selected from samples collected from 2014–2018 in Zhejiang Province, China. Phenotypic drug sensitivity tests (DST) of the anti-TB drugs were conducted for isoniazid (INH), rifampicin (RFP), streptomycin, ethambutol, fluoroquinolones (levofloxacin and moxifloxacin), amikacin, kanamycin, and capreomycin, and the drug-resistance rates were calculated. The clean WGS data of the 1105 strains were acquired and analyzed. The predictive performance of WGS was evaluated by the comparison between genotypic and phenotypic DST results. For all anti-TB drugs, WGS achieved good specificity values (>90%). The sensitivity values for INH and RFP were 91.78% and 82.26%, respectively; however, they were ≤60% for other drugs. The positive predictive values for anti-TB drugs were >80%, except for ethambutol and moxifloxacin, and the negative predictive values were >90% for all drugs. In light of the findings from our study, we draw the conclusion that WGS is a valuable tool for identifying genome-wide variants. Leveraging the genetic variants recommended by the WHO, WGS proves to be effective in detecting resistance to RFP and INH, enabling the identification of multi-drug resistant TB patients. However, it is evident that the genetic variants recommended for predicting resistance to other anti-TB drugs require further optimization and improvement.

Evaluation of genetic correlation with fluoroquinolones resistance in rifampicin-resistant Mycobacterium tuberculosis isolates

“…Another study in Europe revealed that the predictive rates of WGS for LFX and MFX was 83.3 % [ 34 ]. The disparity may be attributed to the genetic diversity of investigated strains, or highly dependent on mutation sites in drug-resistance prediction analysis [ 35 ]. We found the concordance between WGS and phenotypic DST was high for both LFX and MFX, which was consistent with a study in Shanghai with the concordance of 95.3 % for MFX and 93 % for LFX [ 36 ], indicating that WGS provided a promising option for accurate identification of FQs resistant MTB.…”