Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China.

Qianlin Li,Huixia Gao,Zhi Zhang,Yuling Wang,Yueyang Tian,Erhei Dai,Yuzhen Liu,Jianhua Lu,Tengfei Liu

doi:10.3389/fmicb.2019.01838

Qianlin Li, Huixia Gao + Show 7 more

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https://doi.org/10.3389/fmicb.2019.01838

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Abstract

The emergence of drug-resistant tuberculosis (TB) is involved in ineffective treatment of TB, especially multidrug resistant/extensively resistant TB (MDR/XDR-TB), leading to acquired resistance and transmission of drug-resistant strains. Second-line drugs (SLD), including both fluoroquinolones and injectable drugs, were commonly proved to be the effective drugs for treatment of drug-resistant TB. The purpose of this study was to investigate the prevalence of SLD-resistant strains and its specific mutations in drug-resistant Mycobacterium tuberculosis clinical isolates, and to acknowledge the transmission pattern of SLD resistance strains in Hebei. The genes gyrA, gyrB, rrs, eis promoter and tlyA of 257 drug-resistant clinical isolates were sequenced to identify mutations that could be responsible for resistance against fluoroquinolones and second-line injectable drugs. Each isolate was genotyped by Spoligotyping and 15-loci MIRU-VNTR. Our results indicated that 48.2% isolates were resistant to at least one of five SLD. Of them, 37.7% isolates were resistant to fluoroquinolones and 24.5% isolates were resistant to second-line injectable drugs. Mutations in genes gyrA, gyrB, rrs, eis promoter and tlyA were detected in 73 (75.3%), 7 (7.2%), 24 (38.1%), 5 (7.9%), and 3 (4.8%) isolates, respectively. The most prevalent mutations were the D94G (23.7%) in gyrA gene and the A1401G (33.3%) in rrs gene. A combination of gyrA, rrs and eis promoter can act as a valuable predicator for predicting XDR phenotype. These results highlight the development of rapid diagnosis are the effective manners for the control of SLD-TB or XDR-TB.

Highlights

Today, tuberculosis (TB) remains a major threat worldwide than any other single infectious disease
We found rrs mutations were significantly associated with the cross-resistance of second-line injectable drugs (SLID) (3.2 odds ratio (OR), 95%confidence interval (CI) [2.2, 4.6], P = 0.002), SLID (29.2 OR, 95% confidence interval (95%CI) [9.6, 89.0], P < 0.001), MDR (5.1 OR, 95%CI [2.0, 13.0], P < 0.001), and XDR (24.1 OR, 95%CI [9.4, 62.2], P < 0.001) (Figure 2D)
The majority of FQ resistance (FQr) and SLID resistance (SLIDr) strains were associated with gyrA mutation at D94G and rrs mutation at A1401G, respectively

Summary

Introduction

Tuberculosis (TB) remains a major threat worldwide than any other single infectious disease. The increasing rates of drug-resistant TB (DR-TB) worldwide and the emergence of multidrug/extensively-drug resistant TB (MDR/XDR-TB), leading to a high mortality as well as the financial burden. Estimates of the burden of DR-TB have focused on MDR-TB, there were 457,560 people (range: 396,060–523,980) developed MDR-TB (World Health Organization [WHO], 2018). Among cases of MDR-TB, 8.5% (95%CI: 6.2–11.0) were estimated to have XDR-TB (World Health Organization [WHO], 2018). MDR-TB patients ordinarily require 18 months of treatment with recommendatory second-line anti-TB drugs (SLD) that primarily include fluoroquinolones (FQ) and second-line injectable drugs (SLID). Mutations in promoter region of eis gene, encoding an aminoglycoside acetyltransferase, caused low-level KAN resistance (Bauskenieks et al, 2015; Ngo et al, 2018). CAP resistance has been correlated with mutations in tlyA gene, which encodes a putative 2 -O-methyltransferase (TlyA) (Freihofer et al, 2016; Witek et al, 2017)

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