Drug resistance gene mutations and treatment outcomes in MDR-TB: A prospective study in Eastern China

PLoS Negl Trop Dis. 2021 Jan 20;15(1):e0009068. doi: 10.1371/journal.pntd.0009068. eCollection 2021 Jan.

Abstract

Background: Multidrug-resistant tuberculosis (MDR-TB) poses a serious challenge to TB control. It is of great value to search for drug resistance mutation sites and explore the roles that they play in the diagnosis and prognosis of MDR-TB.

Methods: We consecutively enrolled MDR-TB patients from five cities in Jiangsu Province, China, between January 2013 and December 2014. Drug susceptibility tests of rifampin, isoniazid, ofloxacin, and kanamycin were routinely performed by proportion methods on Lowenstein-Jensen (LJ) medium. Drug resistance-related genes were sequenced, and the consistency of genetic mutations and phenotypic resistance was compared. The association between mutations and treatment outcomes was expressed as odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Among 87 MDR-TB patients, 71 with treatment outcomes were involved in the analysis. The proportion of successful treatment was 50.7% (36/71). The rpoB gene exhibited the highest mutation rate (93.0%) followed by katG (70.4%), pncA (33.8%), gyrA (29.6%), eis (15.5%), rrs (12.7%), gyrB (9.9%) and rpsA (4.2%). Multivariable analysis demonstrated that patients with pncA gene mutations (adjusted OR: 19.69; 95% CI: 2.43-159.33), advanced age (adjusted OR: 13.53; 95% CI: 1.46-124.95), and nonstandard treatment (adjusted OR: 7.72; 95% CI: 1.35-44.35) had a significantly higher risk of poor treatment outcomes.

Conclusions: These results suggest that Mycobacterium tuberculosis gene mutations may be related to phenotypic drug susceptibility. The pncA gene mutation along with treatment regimen and age are associated with the treatment outcomes of MDR-TB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases
  • Adult
  • Amidohydrolases
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / genetics
  • Catalase
  • China
  • DNA Gyrase
  • DNA-Directed RNA Polymerases / genetics
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Female
  • Humans
  • Isoniazid / therapeutic use
  • Kanamycin / therapeutic use
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Mutation Rate*
  • Mutation* / drug effects
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics*
  • Odds Ratio
  • Ofloxacin / therapeutic use
  • Prospective Studies
  • Rifampin / therapeutic use
  • Sequence Analysis, DNA
  • Treatment Outcome
  • Tuberculosis, Multidrug-Resistant / genetics*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • rpoB protein, Mycobacterium tuberculosis
  • Kanamycin
  • Ofloxacin
  • Catalase
  • katG protein, Mycobacterium tuberculosis
  • Acetyltransferases
  • Eis protein, Mycobacterium tuberculosis
  • DNA-Directed RNA Polymerases
  • Amidohydrolases
  • PncA protein, Mycobacterium tuberculosis
  • DNA Gyrase
  • Isoniazid
  • Rifampin

Grants and funding

This study was supported by the National Nature Science Foundation of China 81973103(JW), 82003516(QL)], Medical Research Project of Jiangsu Health Commission (ZDB2020013)(JW), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX19-1131)(QL), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)(JW). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.