scholarly journals Multicenter Study of the Emergence and Genetic Characteristics of Pyrazinamide-Resistant Tuberculosis in China

2016 ◽  
Vol 60 (9) ◽  
pp. 5159-5166 ◽  
Author(s):  
Dange Li ◽  
Yi Hu ◽  
Jim Werngren ◽  
Mikael Mansjö ◽  
Xubin Zheng ◽  
...  
Keyword(s):  
Multicenter Study ◽  
Multidrug Resistant ◽  
Population Based ◽  
Molecular Diagnostic ◽  
Beijing Family ◽  
First Line ◽  
Genetic Characteristics ◽  
Resistant Tuberculosis ◽  
Mdr Tb ◽  
Line Drug

ABSTRACTThe aim of this study was to investigate the epidemiology of pyrazinamide (PZA) resistance and the associated risk factors as well as to evaluate thepncAgene loci as a marker for PZA resistance in China. A population-based multicenter study of pulmonary tuberculosis (TB) cases was carried out from 2011 to 2013 in four Chinese districts/counties with different geographic and socioeconomic features. Testing for multidrug-resistant tuberculosis (MDR-TB) and susceptibility to PZA was done by the proportion method on Lowenstein-Jensen medium and Bactec MGIT 960, respectively. Mutations in thepncAgene were identified by sequencing. Among 878 culture-positive cases, 147 (16.7%) were resistant to PZA, with a significantly higher proportion among MDR isolates than among the first-line drug-susceptible isolates (30.2% versus 7.7%;P< 0.001). In total, 136 isolates had a nonsynonymouspncAmutation, with a comparable diagnostic performance between Beijing family and non-Beijing family as well as between MDR-TB and first-line drug-susceptible TB. Furthermore, the mutations in isolates with high-level PZA resistance (MIC > 500 mg/liter) were observed mainly in three regions of thepncAgene (codons 51 to 76, codons 130 to 142, and codons 163 to 180). Patients with prior treatment history had a significantly higher risk for PZA monoresistance (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.363 to 6.015) and MDR PZA resistance (OR, 6.47; 95% CI, 3.186 to 13.15), while the additional factors associated with MDR PZA resistance were the patient's age (OR, 1.02; 95% CI, 1.003 to 1.042), lung cavity (OR, 2.64; 95% CI, 1.296 to 5.391). These findings suggest that it is a priority to identify PZA resistance in MDR-TB and that a rapid molecular diagnostic test based onpncAmutations in the Chinese settings where MDR-TB prevalence is high should be developed.

scholarly journals Molecular Characterization of Multidrug-Resistant Mycobacterium tuberculosis Isolates from China

2014 ◽  
Vol 58 (4) ◽  
pp. 1997-2005 ◽  
Author(s):  
Li-Li Zhao ◽  
Yan Chen ◽  
Hai-Can Liu ◽  
Qiang Xia ◽  
Xiao-Cui Wu ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Multidrug Resistant ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Beijing Family ◽  
Phenotypic Data ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

ABSTRACTTo 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, theoxyR-ahpCintergenic region,rpoB,tlyA,eis,rrs,gyrA, andgyrB) 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 werekatG315,inhA15,rpoB531, -526, and -516,rrs1401,eis-10, andgyrA94, -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.

scholarly journals Scaling Up Molecular Diagnostic Tests for Drug-Resistant Tuberculosis in Uzbekistan from 2012–2019: Are We on the Right Track?

2021 ◽  
Vol 18 (9) ◽  
pp. 4685
Author(s):  
Sharofiddin Yuldashev ◽  
Nargiza Parpieva ◽  
Salikhdjan Alimov ◽  
Laziz Turaev ◽  
Khasan Safaev ◽  
...  
Keyword(s):  
Diagnostic Tests ◽  
Scale Up ◽  
Multidrug Resistant ◽  
Molecular Diagnostic ◽  
Drug Resistant ◽  
Second Line ◽  
First Line ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Mdr Tb

Uzbekistan has a large burden of drug-resistant tuberculosis (TB). To deal with this public health threat, the National TB Program introduced rapid molecular diagnostic tests such as Xpert MTB/RIF (Xpert) and line probe assays (LPAs) for first-line and second-line drugs. We documented the scale-up of Xpert and LPAs from 2012–2019 and assessed whether this led to an increase in patients with laboratory-confirmed multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) and extensively drug-resistant TB (XDR-TB). This was a descriptive study using secondary program data. The numbers of GeneXpert instruments cumulatively increased from six to sixty-seven, resulting in annual assays increasing from 5574 to 107,330. A broader use of the technology resulted in a lower proportion of tests detecting Mycobacterium tuberculosis with half of the positive results showing rifampicin resistance. LPA instruments cumulatively increased from two to thirteen; the annual first-line assays for MDR-TB increased from 2582 to 6607 while second-line assays increased from 1435 in 2016 to 6815 in 2019 with about one quarter to one third of diagnosed patients showing second-line drug resistance. Patient numbers with laboratory-confirmed MDR-TB remained stable (from 1728 to 2060) but there was a large increase in patients with laboratory-confirmed XDR-TB (from 31 to 696). Programmatic implications and ways forward are discussed.

Molecular Characterization of Levofloxacin, Moxifloxacin, Bedaquiline, Linezolid, Clofazimine, and Delamanid against Multidrug-resistant Tuberculosis in Southwest of China

2021 ◽  
Author(s):  
Huiwen Zheng ◽  
Wencong He ◽  
Weiwei Jiao ◽  
Hui Xia ◽  
Lin Sun ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Southwest China ◽  
Resistance Mutation ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Resistance Rate ◽  
Genetic Characteristics ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Abstract Objectives: To explore the drug susceptibility of levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ) and delamanid (DLM) against multidrug resistant tuberculosis (MDR-TB) isolates from drug resistance survey of southwest China, and to illustrate the genetic characteristics of MDR-TB isolates with acquired drug resistance. Methods: A total of 339 strains were collected from smear-positive TB patients in the drug resistance survey of southwest China between January 2014 and December 2016. The MICs were determined for MDR-TB identified by conventional drug susceptibility testing. Genes related to drug resistance were amplified with their corresponding pairs of primers. Results: MDR was observed in 88 (26.0%; 88/339) isolates. LFX had the highest resistance rate (50.0%; 44/88), followed by MFX (38.6%; 34/88). The resistance rate to LZD, CFZ, and DLM was 4.5% (4/88), 3.4% (3/88), and 4.5% (4/88), respectively, and the lowest resistance rate was observed in BDQ (2.3%; 2/88). Of the 45 isolates resistant to LFX and MFX, the most prevalent resistance mutation was found in gyrA with the substitution of codon 94 (34/45, 75.6%). All two CFZ - BDQ cross resistant strains had a mutation in the Rv0678 gene. Two of four LZD resistant isolates carried mutations in rplC gene. Of the four isolates resistant to DLM, one isolate with the mutations in codon 318 of fbiC gene and two isolates in codon 81 of ddn gene. Conclusion: This study provided evidence for further application of new anti-TB drugs in the treatment of MDR-TB in China.

scholarly journals Citywide Transmission of Multidrug-resistant Tuberculosis Under China’s Rapid Urbanization: A Retrospective Population-based Genomic Spatial Epidemiological Study

2019 ◽  
Vol 71 (1) ◽  
pp. 142-151
Author(s):  
Qi Jiang ◽  
Qingyun Liu ◽  
Lecai Ji ◽  
Jinli Li ◽  
Yaling Zeng ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Population Based ◽  
Case Finding ◽  
Transmission Risk ◽  
Rapid Urbanization ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Recent Transmission ◽  
Mdr Tb ◽  
Genomic Clusters

Abstract Background Population movement could extend multidrug-resistant tuberculosis (MDR-TB) transmission and complicate its global prevalence. We sought to identify the high-risk populations and geographic sites of MDR-TB transmission in Shenzhen, the most common destination for internal migrants in China. Methods We performed a population-based, retrospective study in patients diagnosed with MDR-TB in Shenzhen during 2013–2017. By defining genomic clusters with a threshold of 12–single-nucleotide polymorphism distance based on whole-genome sequencing of their clinical strains, the clustering rate was calculated to evaluate the level of recent transmission. Risk factors were identified by multivariable logistic regression. To further delineate the epidemiological links, we invited the genomic-clustered patients to an in-depth social network investigation. Results In total, 105 (25.2%) of the 417 enrolled patients with MDR-TB were grouped into 40 genome clusters, suggesting recent transmission of MDR strains. The adjusted risk for student to have a clustered strain was 4.05 (95% confidence interval, 1.06–17.0) times greater than other patients. The majority (70%, 28/40) of the genomic clusters involved patients who lived in different districts, with residences separated by an average of 8.76 kilometers. Other than household members, confirmed epidemiological links were also identified among classmates and workplace colleagues. Conclusions These findings demonstrate that local transmission of MDR-TB is a serious problem in Shenzhen. While most transmission occurred between people who lived distant from each other, there was clear evidence that transmission occurred in schools and workplaces, which should be included as targeted sites for active case finding. The average residential distance between genomic-clustered cases was more than 8 kilometers, while schools and workplaces, identified as sites of transmission in this study, deserve increased vigilance for targeted case finding of multidrug-resistant tuberculosis.

scholarly journals Sources of Multidrug Resistance in Patients With Previous Isoniazid-Resistant Tuberculosis Identified Using Whole Genome Sequencing: A Longitudinal Cohort Study

2020 ◽  
Vol 71 (10) ◽  
pp. e532-e539 ◽  
Author(s):  
Vijay Srinivasan ◽  
Vu T N Ha ◽  
Dao N Vinh ◽  
Phan V K Thai ◽  
Dang T M Ha ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
De Novo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Genomic Distance ◽  
First Line ◽  
Pulmonary Tb ◽  
Resistant Tuberculosis ◽  
Mdr Tb

Abstract Background Meta-analysis of patients with isoniazid-resistant tuberculosis (TB) given standard first-line anti-TB treatment indicated an increased risk of multidrug-resistant TB (MDR-TB) emerging (8%), compared to drug-sensitive TB (0.3%). Here we use whole genome sequencing (WGS) to investigate whether treatment of patients with preexisting isoniazid-resistant disease with first-line anti-TB therapy risks selecting for rifampicin resistance, and hence MDR-TB. Methods Patients with isoniazid-resistant pulmonary TB were recruited and followed up for 24 months. Drug susceptibility testing was performed by microscopic observation drug susceptibility assay, mycobacterial growth indicator tube, and by WGS on isolates at first presentation and in the case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine the genomic relatedness between initial and subsequent isolates. De novo emergence of MDR-TB was assumed where the genomic distance was 5 or fewer single-nucleotide polymorphisms (SNPs), whereas reinfection with a different MDR-TB strain was assumed where the distance was 10 or more SNPs. Results Two hundred thirty-nine patients with isoniazid-resistant pulmonary TB were recruited. Fourteen (14/239 [5.9%]) patients were diagnosed with a second episode of TB that was multidrug resistant. Six (6/239 [2.5%]) were identified as having evolved MDR-TB de novo and 6 as having been reinfected with a different strain. In 2 cases, the genomic distance was between 5 and 10 SNPs and therefore indeterminate. Conclusions In isoniazid-resistant TB, de novo emergence and reinfection of MDR-TB strains equally contributed to MDR development. Early diagnosis and optimal treatment of isoniazid-resistant TB are urgently needed to avert the de novo emergence of MDR-TB during treatment.

scholarly journals INSERSI GEN pncA KE DALAM PLASMID pGEM-T

2016 ◽  
Vol 1 (2) ◽  
pp. 135
Author(s):  
Eli Hendrik Sanjaya
Keyword(s):  
3D Structure ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Genetic Level ◽  
Line Drug ◽  
Research Show ◽  
Selection Of

Abstract. Multidrug-resistant tuberculosis (MDR-TB) is among the most worrisome elements of the pandemic of  antibiotic resistance. As the first line drug, pyrazinamide is often used to treat TB desease so there are many case of TB resistant to pyrazinamide. The previous research show that pncA gene of isolate L20 MDR-TB have mutated T539C. That mutation propose as the cause of resistance M. tuberculosis to pyrazimanide at the genetic level. For make sure the resistance mechanism, we have to get the pure PZAse and crystalization so the 3D structure can be determined by X-ray defraction. The first step to get the pure PZAse is cloning the pncA gene to the plasmid. The aim of this research is to know that is the pncA gene can be cloned to pGEM-T plasmid. The prosedure for cloning the pncA gene to the pGEM-T plasmid is amplification, followed by insert the pncA gene to the pGEM-T plasmid, and transformation by a selection of blue and white colony. The last step are isolation plasmid recombinant (pGEM-T-pncA) followed by electrophoresis. The result of the research showed that pncA gene from isolate L20 was successfully cloned to pGEM-T plasmid. That was showed on blue and white colony and the result of isolation and electrophoresis pGEM-T-pncA. The electrophoregram showed that the length of pGEM-T-pncA from white colony is different with pGEM-T standart abaut 0,7 kb. It is similar with the length of pncA gene (0,72 kb). Keywords: kloning, pGEM-T, pncA gene, pyrazinamide (PZA).

scholarly journals Follow-Up of Patients with Multidrug Resistant Tuberculosis Four Years after Standardized First-Line Drug Treatment

PLoS ONE ◽  
2010 ◽  
Vol 5 (5) ◽  
pp. e10799 ◽  
Author(s):  
Guang Xue He ◽  
Yan Guang Xie ◽  
Li Xia Wang ◽  
Martien W. Borgdorff ◽  
Marieke J. van der Werf ◽  
...  
Keyword(s):  
Drug Treatment ◽  
Multidrug Resistant ◽  
First Line ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Line Drug

scholarly journals Risk factors for acquired multidrug-resistant tuberculosis

2003 ◽  
Vol 29 (2) ◽  
pp. 89-97 ◽  
Author(s):  
Elizabeth Clara Barroso ◽  
Rosa Maria Salani Mota ◽  
Raimunda Oliveira Santos ◽  
Ana Lúcia Oliveira Sousa ◽  
Joana Brasileiro Barroso ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Control Program ◽  
Multidrug Resistant ◽  
Population Based ◽  
Central Public Health ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Five Factors ◽  
Mdr Tb

Multidrug-resistant tuberculosis (MDR-TB) is a severe and feared problem, that is difficult to control and has shown a tendency to increase worldwide. OBJECTIVE: To analyze the risk factors for acquired MDR-TB. CASUISTIC AND METHODS: A retrospective population-based case-control study was conducted. A bacillus was considered multidrug-resistant whenever it was resistant at least to rifampin (RFP) + isoniazid (INH), and a case was considered as sensitive tuberculosis (TB) if it had undergone the first treatment during a similar period as the first treatment of an MDR-TB case, but was cured at the time of the interview. Case selection was made based on the list of Sensitivity Tests (ST) performed at the Central Public Health Laboratory of the State of Ceará, from 1990 through 1999. The Proportion Method was used to investigate resistance to the six antituberculosis drugs (isoniazid, rifampin, pyrazinamide, ethambutol, ethionamide, streptomycin) used as the standard treatment in Brazil. Controls were selected from the registry of the TB Control Program. Univariate and multivariate analysis were performed, with p < 0.05 considered significant. RESULTS: Out of the 1,500 STs performed during the studied period, 266 strains were multidrug-resistant; 153 patients were identified, 19 of which were excluded. The Group of Cases comprised 134 patients, and the Group of Controls comprised 185. Multivariate analysis helped to detect the following risk factors: lack of home sewer system, alcoholism + smoking, number of previous treatments, irregular treatment, and lung cavities. CONCLUSION: These five factors are important for the development of acquired MDR-TB, and an attempt to neutralize them might contribute to control TB.

scholarly journals Molecular characterization of multidrug-resistant tuberculosis against levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, and delamanid in southwest of China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huiwen Zheng ◽  
Wencong He ◽  
Weiwei Jiao ◽  
Hui Xia ◽  
Lin Sun ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Southwest China ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Resistance Rate ◽  
Cross Resistance ◽  
Genetic Characteristics ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Abstract Objectives To explore the drug susceptibility of levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ) and delamanid (DLM) against multidrug resistant tuberculosis (MDR-TB) isolates from drug resistance survey of southwest China, and to illustrate the genetic characteristics of MDR-TB isolates with acquired drug resistance. Methods A total of 339 strains were collected from smear-positive TB patients in the drug resistance survey of southwest China between January 2014 and December 2016. The MICs for the above mentioned drugs were determined for MDR-TB by conventional drug susceptibility testing. Genes related to drug resistance were amplified with their corresponding pairs of primers. Results MDR was observed in 88 (26.0%; 88/339) isolates. LFX had the highest resistance rate (50.0%; 44/88), followed by MFX (38.6%; 34/88). The resistance rate to LZD, CFZ, and DLM was 4.5% (4/88), 3.4% (3/88), and 4.5% (4/88), respectively, and the lowest resistance rate was observed in BDQ (2.3%; 2/88). Of the 45 isolates resistant to LFX and MFX, the most prevalent resistance mutation was found in gyrA with the substitution of codon 94 (34/45, 75.6%). Two strains with CFZ - BDQ cross resistance had a mutation in the Rv0678 gene. Of the four LZD resistant isolates, two carried mutations in rplC gene. For the four isolates resistant to DLM, one isolate had mutations in codon 318 of fbiC gene, and two isolates were with mutations in codon 81 of ddn gene. Conclusion This study provided evidence of the usefulness of new anti-TB drugs in the treatment of MDR-TB in China.

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