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
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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