Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.

Abstract

OBJECTIVES:

Little is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment.

METHODS:

Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance.

RESULTS:

Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03-5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance.

CONCLUSIONS:

A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.

• Authors: Yi Hu, Xubin Zheng, Lina Davies Forsman, Zhu Ning, Cheng Chen, Yazhou Gao, Zhengdong Zhang, Wei Lu, Jim Werngren, Judith Bruchfeld, Sven Hoffner, Biao Xu
• Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases (Clin Microbiol Infect) Vol. 27 Issue 12 Pg. 1805-1813 (Dec 2021) ISSN: 1469-0691 [Electronic] England
• PMID: 33895338 (Publication Type: Journal Article, Multicenter Study, Observational Study)
• Copyright: Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antitubercular Agents

Topics

• Antitubercular Agents (pharmacology, therapeutic use)
• China (epidemiology)
• Coinfection (drug therapy)
• Diabetes Mellitus, Type 2
• Drug Resistance, Multiple, Bacterial
• Humans
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, genetics)
• Prospective Studies
• Reinfection
• Tuberculosis, Multidrug-Resistant (drug therapy, epidemiology)
• Whole Genome Sequencing