Strain structure analysis of Mycobacterium tuberculosis circulating among HIV negative, positive and drug resistant TB patients attending chest clinics in Western Kenya
Martin O. OgwangLameck DieroFlorence Ng’ong’aGabriel MagomaLucy M. MuthariaMabel ImbugaCaroline Ngugi
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Abstract Background Despite global tuberculosis (TB) interventions, the disease remains one of the major public health concerns. Kenya is ranked 15th among 22 high burden TB countries globally. Methods A cross-sectional study was conducted in Western Kenya, which comprises 10 counties. A multistage sampling method was used where a single sub-county was randomly selected followed by sampling two high volume health facility from each sub-county. Identification of spoligotype profiles and their family distribution and lineage level were achieved by comparison with SITVIT database. Results Lineage distribution pattern revealed that the most predominant lineage was CAS 220 (39.8%) followed by Beijing 128 (23.1%). The other lineages identified were T, LAM, H, X, S and MANU which were quantified as 87 (15.7%), 67 (12.1%), 16 (2.8%), 10 (1.8%), 8 (1.4%) and 5 (0.9%) respectively. CAS and Beijing strains were the most predominant lineage in both HIV negative and positive TB patients. The Beijing lineage was also the most predominant in resistant M. tuberculosis strains as compared to wild type. A total of 12 (2.0%) were orphaned M. tuberculosis strains which were spread across all the 10 counties of the study site. In multivariate logistic regression adjusting for potential cofounders three potential risk factors were significant. HIV status (OR = 1.52, CI = 0.29–3.68 and P value of 0.001), Alcohol use (OR = 0.59, CI = 0.43–3.12 and P -value =0.001) and cross border travel (OR = 0.61, CI = 0.49–3.87 and P value = 0.026). Most M. tuberculosis clinical isolates showed genetic clustering with multivariate logistic regression indicating three potential risk factors to clustering. HIV status (OR = 1.52, CI = 0.29–3.68 and P value of 0.001), Alcohol use (OR = 0.59, CI = 0.43–3.12 and P-value =0.001) and cross border travel (OR = 0.61, CI = 0.49–3.87 and P value = 0.026). Conclusion There exist diverse strains of M. tuberculosis across the 10 counties of Western Kenya. Predominant distribution of clustered genotype points to the fact that most TB cases in this region are as a result of resent transmission other than activation of latent TB.Keywords:
Lineage (genetic)
Cross-sectional study
Objective To observe the mutations of katG in Mycobacterium tuberculosis isoniazid-resident isolates,to research their l value in isoniazid resistanceMethods Analyzing the mutations of katG in 72 Mycobacterium tuberculosis with PCR-SSCP.32 isoniazid susceptible Mycobacterium tuberculosis clinical isolates and 40 isoniazid resistant isolates with Mycobacterium tuberculosis H37RV reference strains as control group.Results Amplification was abserved all of isoniazid susceptible Mycobacterium tuberculosis clinical isolates.Among 40 isoniazid resistant chinial isolates,15 isolates diaplayed the same patterns as H37RV and 25 isolates showed PCR-SSCP diffirent from that of H37RV.About 62.5 percent isoniazid-resident isolates showed mutation or deletion of katG gene.Conclusion The changes of katG gene are associated with isoniazid residenance.PCR-SSCP technique will be useful to rapidly screen gene mutation of isoniazid resistant Mycobacterium tuberculosis.
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The treatment of drug-susceptible tuberculosis (TB) is long and cumbersome. Mismanagement of TB treatment can lead to the emergence of drug resistance in patients, so shortening the treatment duration could significantly improve TB chemotherapy and prevent the development of drug resistance. We previously discovered that high concentrations of vitamin C sterilize cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis Here, we tested subinhibitory concentration of vitamin C in combination with TB drugs against M. tuberculosisin vitro and in a mouse model of M. tuberculosis infection. In vivo, we showed that the vitamin C level in mouse serum can be increased by intraperitoneal injection of vitamin C to reach vitamin C levels close to the concentrations required for activity in vitro Although vitamin C had no activity by itself in M. tuberculosis-infected mice, the combination of vitamin C with the first-line TB drugs isoniazid and rifampin reduced the bacterial burden in the lungs of M. tuberculosis-infected mice faster than isoniazid and rifampin combined in two independent experiments. These experiments suggest that the addition of vitamin C to first-line TB drugs could shorten TB treatment. Vitamin C, an inexpensive and nontoxic compound, could easily be added to the TB pharmacopeia to substantially improve chemotherapy outcome, which would have a significant impact on the worldwide TB community.
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The BACTEC radiometric method of drug susceptibility testing of Mycobacterium tuberculosis is a reliable and rapid diagnostic tool in clinical mycobacteriology. However, large scale comparative studies have also shown that the level of agreement with standard methodology was less satisfactory with strains resistant to ethambutol and streptomycin than with strains resistant to rifampin and to isoniazid. Since disagreement with drug resistance strains is far more frequent than with drug susceptible strains, it was felt that only the comparison of a large number of resistant strains would be needed to further refine this new technique. The analysis of BACTEC-derived data for isoniazid and rifampin shows that the level of agreement with conventional methodology falls well within accepted limits. Statistical analysis of the radiometric versus conventional comparisons shows no significant differences between the two methods in the case of isoniazid, rifampin, and ethambutol (3 mg/L). Streptomycin and two other ethambutol concentrations tested showed lower levels of agreement and significant statistical differences with conventional methodology.
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Isoniazid,the first line drug of anti-Mycobacterium tuberculosis,is one of the most extensively used anti-tuberculosis drugs.Since its application in clinical practice in 1952,isoniazid had become a basic drug for treatment of tuberculosis and potential infections.Some reports considered that the resistance to isoniazid has become the top problem in China.The molecule mechanisms of Mycobacterium tuberculosis resistance to isoniazid are very complicated,involving multiple genes including katG,inhA,kasA,ndh and axyR.The article reviewed some researches on this issue.
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Abstract We modified the micro-scale spectrophotofluorometric method of Miceli et al. [Biochem. Med. 12, 348 (1975)] for the assay of "apparent" isoniazid (isoniazid plus acid-labile hydrazones) to improve its clinical application. We also adapted the method for determination of acetyl isoniazid. Data are presented showing how long plasma containing isoniazid may validly be stored. The applicability of the method was demonstrated in studies on children and small animals.
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Isoniazid resistance in Mycobacterium tuberculosis is associated with lack of catalase-peroxidase activity. A recent study showed that some isoniazid-resistant M. tuberculosis strains have a complete deletion of the gene (katG) encoding this enzyme. To examine what proportion of clinical isolates of M. tuberculosis have katG deletion, katG sequences in 80 randomly selected isolates from New York City were analyzed. Polymerase chain reaction was used to amplify a 282-bp segment of M. tuberculosis katG and showed that 35 (90%) of 39 isoniazid-sensitive and 31 (76%) of 41 isoniazid-resistant strains contained katG sequences (P > .1). Ten multidrug and high-level isoniazid-resistant strains with identical restriction fragment length polymorphism patterns were also analyzed. All were found to have katG sequences. These findings suggest that mechanisms other than complete deletion of katG are involved in isoniazid resistance among most clinical isolates of M. tuberculosis from New York City.
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ObjectivesDespite having potent activity against actively replicating Mycobacterium tuberculosis, isoniazid has very limited activity against dormant bacilli. In order to investigate the lack of bactericidal activity of this drug under conditions leading to mycobacterial dormancy, we studied the transcriptional pattern of M. tuberculosis in different physiological states following exposure to isoniazid.
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SUMMARY Exposure of growing Mycobacterium tuberculosis bcg to 1 µ g. isoniazid/ml. inhibited the incorporation of 14C from [U-14C] and [2-14C]glycerol and [1-14C]- glutamate into its walls by about 50 % over 12 h. because 14C incorporation into the mycolic acids of the walls was prevented. Isoniazid, 0·5 µ g. / ml. with M. tuberculosis bcg or 0·1 µ g./ml. with M. tuberculosis H37 Ra, inhibited incorporation of 14C from [U-14C] glycerol into total mycolic acids by about 90 % over 6 h., indicating that inhibition began within 1 h. of the addition of the drug. There was no effect on mycolic acid synthesis in an isoniazid- resistant strain of M. tuberculosis bcg. The primary inhibitory action of isoniazid in sensitive mycobacteria is probably on mycolic acid synthesis, and this leads to formation of defective boundary layers of the bacteria.
Mycolic acid
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It has been reported recently that isoniazid resistant strains of Mycobacterium tuberculosis have lost the katG gene which encodes the catalase-peroxidase enzyme. A 35 mer oligonucleotide probe specific for the katG gene of M tuberculosis, 39 end-labelled with digoxigenin, was constructed and hybridised with DNA extracted from 26 clinical isolates of M tuberculosis under high stringency conditions. Twenty two of these isolates were resistant to 0.2 microgram/ml isoniazid and 20 to 1.0 microgram/ml isoniazid. Semiquantitative detection of catalase did not show any discrimination between isoniazid sensitive and resistant strains. The katG gene was present in all clinical strains of M tuberculosis. Therefore, complete deletion of the katG gene does not seem to be the mechanism of isoniazid resistance in M tuberculosis strains isolated from patients in India.
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Isoniazid is one of the most important first-line drugs of anti-tuberculosis strategy. In the past 50 years, isoniazid played a very important role in anti-tuberculosis treatment. However, with the emergence of isoniazid-resistant Myeobacterium tuberculosis, the efficacy is decreasing. Herein, this article discusses the mechanism of isoniazid action against Mycobacterium tuberculosis, and reviews the molecular mechanism of isoniazid resistance in Myeobacterium tuberculosis.
Key words:
Isoniazid; Mycobacterium tuberculosis; Drug-resistant
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