Prevalence and Molecular Characterization of Fluoroquinolone-Resistant Mycobacterium tuberculosis Isolates in China

eTo investigate the molecular characterization of multidrug-resistant tuberculosis (MDR-TB) isolates from China and the association of specific mutations conferring drug resistance with strains of different genotypes, we performed spoligotyping and sequenced nine loci (katG, inhA, the oxyR-ahpC intergenic region, rpoB, tlyA, eis, rrs, gyrA, and gyrB) for 128 MDR-TB isolates. Our results showed that 108 isolates (84.4%) were Beijing family strains, 64 (59.3%) of which were identified as modern Beijing strains. Compared with the phenotypic data, the sensitivity and specificity of DNA sequencing were 89.1% and 100.0%, respectively, for isoniazid (INH) resistance, 93.8% and 100.0% for rifampin (RIF) resistance, 60.0% and 99.4% for capreomycin (CAP) resistance, 84.6% and 99.4% for kanamycin (KAN) resistance, and 90.0% and 100.0% for ofloxacin (OFX) resistance. The most prevalent mutations among the MDR-TB isolates were katG315, inhA15, rpoB531, -526, and -516, rrs1401, eis-10, and gyrA94, -90, and -91. Furthermore, there was no association between specific resistance-conferring mutations and the strain genotype. These findings will be helpful for the establishment of rapid molecular diagnostic methods to be implemented in China.

Section: Discussionsupporting

confidence: 78%

Molecular Characterization of Multidrug-Resistant Mycobacterium tuberculosis Isolates from China

Zhao

Chen

Liu

et al. 2014

“…However, in view of enhanced moxifloxacin activity, two critical concentrations, low level (0.5 g/ml) and high level (2.0 g/ml), have been suggested by the World Health Organization since 2012 (21). Previous studies by Sirgel et al (2) and Zhang et al (22) have found that mutations at codon 94 in gyrA were linked to high-level fluoroquinolone resistance. A recent report by Kambli et al (23) also supported the view that the majority of isolates with mutations at codon 94 in gyrA were associated with a high-level resistance to MFX with MICs of 2.5 mg/ml in 76% (32/42) of isolates with a D94G mutation.…”

Section: Discussionmentioning

confidence: 99%

Mutations in gyrA and gyrB among Fluoroquinolone- and Multidrug-Resistant Mycobacterium tuberculosis Isolates

Chien

Chiu

Chien

et al. 2016

In order to correlate the mutations inside the entire gyrA and gyrB genes with the level of resistance to ofloxacin (OFX) and moxifloxacin (MFX) in isolates of multidrug-resistant Mycobacterium tuberculosis (MDR-TB), a total of 111 isolates were categorized into OFX-susceptible (MIC, <2 g/ml) and low-level (MIC, 4 to 8 g/ml) and high-level (MIC, >16 g/ml) OFX-resistant isolates and MFX-susceptible (MIC, <0.5 g/ml) and low-level (MIC, 1 to 2 g/ml) and high-level (MIC, >4 g/ml) MFXresistant isolates. Resistance-associated mutations inside the gyrA gene were found in 30.2% of OFX-susceptible and 72.5% and 72.2% of low-level and high-level OFX-resistant isolates and in 28.6% of MFX-susceptible and 58.1% and 83.9% of low-level and high-level MFX-resistant isolates. Compared with OFX-susceptible isolates, low-level and high-level OFX-resistant isolates had a significantly higher prevalence of mutations at gyrA codons 88 to 94 (17.0%, 65.0%, and 72.2%, respectively; P < 0.001) and a higher prevalence of the gyrB G512R mutation (0.0%, 2.5%, and 16.7%, respectively; P ‫؍‬ 0.006). Similarly, compared with MFXsusceptible isolates, low-level and high-level MFX-resistant isolates had a significantly higher prevalence of mutations at gyrA codons 88 to 94 (14.3%, 51.6%, and 80.6%, respectively; P < 0.001) as well as a higher prevalence of the gyrB G512R mutation (0.0%, 0.0%, and 12.9%, respectively; P ‫؍‬ 0.011). D94G and D94N mutations in gyrA and the G512R mutation in gyrB were correlated with high-level MFX resistance, while the D94A mutation was associated with low-level MFX resistance. The prevalence of mutations at gyrA codons 88 to 94 and the gyrB G512R mutation were higher among fluoroquinolone (FQ)-susceptible East Asian (Beijing) and Indo-Oceanic strains than they were among Euro-American strains, implying that molecular techniques to detect FQ resistance may be less specific in areas with a high prevalence of East Asian (Beijing) and Indo-Oceanic strains. F luoroquinolones (FQs) are used as second-line drugs for the treatment of tuberculosis (TB). These broad-spectrum antibacterial agents with bactericidal activity against Mycobacterium tuberculosis exert their bactericidal effects by inhibiting mycobacterial DNA gyrase activity, which prevents bacterial DNA from unwinding and replicating (1-3).Moxifloxacin (MFX), a "fourth-generation" FQ, has been shown to have better activity against M. tuberculosis than ofloxacin (OFX) and is recommended by the World Health Organization (WHO) for the treatment of multidrug-resistant TB (MDR-TB; defined as resistant to at least two of the most effective antituberculosis drugs, isoniazid and rifampin) (2, 3). Unfortunately, the widespread use of FQs to treat bacterial infections has led to the emergence of FQ-resistant MDR-TB and extensively drug-resistant TB (XDR-TB; defined as MDR-TB resistant to any FQ and a second-line injectable drug) (4, 5), thereby complicating patient care.Mutations in genes encoding DNA gyrase subunits gyrA and gyrB are the most common mechanism conveying ...

“…There are several potential explanations for this observation. First, due to the high efficacy and low occurrence of adverse effects, FQs have been widely used in the treatment of undiagnosed respiratory bacterial infections for more than 2 decades in China (11). Hence, the overuse of FQs may be the major reason for an increase in the proportion of MOX-resistant TB cases in China.…”

Section: Discussionmentioning

confidence: 99%

“…Due to its high sterilizing capacity in vivo, PZA plays an essential role in shortening the duration of TB therapy from the previous 9 months to 6 months (10). In addition to PZA, moxifloxacin (MOX), a member of the new generation of fluoroquinolones (FQs), has been widely used in the therapy of MDR-TB (11). Considering the potential central role of PZA and MOX in the treatment of tuberculosis, it is critically important to understand the prevalence of PZA and MOX resistance.…”

mentioning

confidence: 99%

Genotyping and Prevalence of Pyrazinamide- and Moxifloxacin-Resistant Tuberculosis in China, 2000 to 2010

Pang

Zhang

Wang

et al. 2017

Self Cite

We investigated the prevalence, trends, and risk factors for pyrazinamide (PZA) and moxifloxacin (MOX) resistance among tuberculosis (TB) cases in China and also analyzed the population structure of Mycobacterium tuberculosis strains. All the M. tuberculosis strains enrolled in this study were collected from the national TB prevalence surveys. Each strain was genotyped by analyzing the regions of RD105 and IS6110 in the NTF region. The Bactec MGIT 960 system was used to detect the drug susceptibility of M. tuberculosis isolates to PZA and MOX. Based on the genotyping results, 241 (66.4%) strains were classified as Beijing genotype in 2000, which was significantly lower than in 2010 (76.2%, P Ͻ 0.01). The proportion of the modern Beijing genotype increased significantly from 49.6% in 2000 to 68.1% in 2010 (P Ͻ 0.01), while no significant difference was observed in the rate of ancient Beijing genotype between 2000 and 2010 (P ϭ 0.676). In addition, we found that the proportion of PZA resistance in 2010 (15.0%) was significantly higher than that in 2000 (9.6%, P ϭ 0.04). For MOX, there were more MOX-resistant isolates detected in 2010 (7.7%) than in 2000 (3.0%). In conclusion, our data demonstrate that the Beijing genotype was the predominant M. tuberculosis lineage during the past decade. The proportion of Beijing genotype isolates significantly increased from 2000 to 2010, largely due to an increase in the modern Beijing sublineage. In addition, resistance to PZA and MOX increased significantly in China between 2000 and 2010.