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Gauthier M.,Fondation Merieux Center International Of Recherche En Infectiologie Ciri | Bidault F.,Fondation Merieux Center International Of Recherche En Infectiologie Ciri | Mosnier A.,Fondation Merieux Center International Of Recherche En Infectiologie Ciri | Bablishvili N.,National Center for Tuberculosis and Lung Disease | And 7 more authors.
Journal of Clinical Microbiology | Year: 2015

The emergence of drug-resistant forms of tuberculosis (TB) represents a major public health concern. Understanding the transmission routes of the disease is a key factor for its control and for the implementation of efficient interventions. Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) marker typing is a well-described method for lineage identification and transmission tracking. However, the conventional manual genotyping technique is cumbersome and time-consuming and entails many risks for errors, thus hindering its implementation and dissemination. We describe here a new approach using the QIAxcel system, an automated high-throughput capillary electrophoresis system that also carries out allele calling. This automated method was assessed on 1,824 amplicons from 82 TB isolates and tested with sets of markers of 15 or 24 loci. Overall allele-calling concordance between the methods from 140 to 1,317 bp was 98.9%. DNA concentrations and repeatability and reproducibility performances showed no biases in allele calling. Furthermore, turnaround time using this automated system was reduced by 81% compared to the conventional manual agarose gel method. In sum, this new automated method facilitates MIRU-VNTR genotyping and provides reliable results. Therefore, it is well suited for field genotyping. The implementation of this method will help to achieve accurate and cost-effective epidemiological studies, especially in countries with a high prevalence of TB, where the high number of strains complicates the surveillance of circulating lineages and requires efficient interventions to be carried out in an urgent manner. © 2015, American Society for Microbiology. All Rights Reserved. Source

Furin J.,Case Western Reserve University | Gegia M.,National Center for Tuberculosis and Lung Disease | Mitnick C.,Harvard University | Rich M.,Partners in Health | And 8 more authors.
Bulletin of the World Health Organization | Year: 2012

Problem The category II retreatment regimen for management of tuberculosis in previously treated patients was first introduced in the early 1990s. It consists of 8 months of total therapy with the addition of streptomycin to standard first-line medications. A review of 6500 patients on category II therapy in Georgia showed poor outcomes and high rates of streptomycin resistance. Approach The National Tuberculosis Program used an evidence-based analysis of national data to convince policy-makers that category II therapy should be eliminated from national guidelines in Georgia. Local setting The World Health Organization tuberculosis case-notification rate in Georgia is 102 per 100 000 population. All patients receive culture and drug susceptibility testing as a standard part of tuberculosis diagnosis. In 2009, routine surveillance found multidrug-resistant tuberculosis in 10.6% of newly diagnosed patients and 32.5% of previously treated cases. Relevant changes Category II retreatment regimen is no longer used in Georgia. Treatment is guided by results of drug susceptibility testing - using rapid, molecular tests where possible - for all previously treated tuberculosis patients. Lessons learnt There was little resistance to policy change because the review was initiated and led by the National Tuberculosis Program. This experience can serve as a successful model for other countries to make informed decisions about the use of category II therapy. Source

Tukvadze N.,National Center for Tuberculosis and Lung Disease | Sanikidze E.,National Center for Tuberculosis and Lung Disease | Kipiani M.,National Center for Tuberculosis and Lung Disease | Hebbar G.,Emory University | And 15 more authors.
American Journal of Clinical Nutrition | Year: 2015

Background: Tuberculosis, including multidrug-resistant tuberculosis (MDR-TB), is a major global health problem. Individuals with tuberculosis disease commonly exhibit Vitamin D deficiency, which may adversely affect immunity and the response to therapy. Objective: We determined whether adjunctive high-dose Vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease. Design: The study was a double-blind, randomized, placebocontrolled, intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi, Georgia. Subjects were randomly assigned to receive oral Vitamin D3 [50,000 IUs (1.25 mg) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk] or a placebo concomitant with standard first-line antituberculosis drugs. The primary outcome was the time for the conversion of a Mycobacterium tuberculosis (Mtb) sputum culture to negative. Results: Baseline characteristics between groups were similar. Most subjects (74%) were Vitamin D deficient (plasma 25-hydroxyVitamin D [25(OH)D] concentration <50 nmol/L). With Vitamin D3, plasma 25(OH)D concentrations peaked at ∼250 nmol/L by 8 wk and decreased to ∼125 nmol/L at week 16. Adverse events and plasma calcium concentrations were similar between groups. In 192 subjects with culture-confirmed tuberculosis, an adjusted efficacy analysis showed similar median culture-conversion times between Vitamin D3 and placebo groups [29 and 27 d, respectively; HR: 0.86; 95% CI: 0.63, 1.18; P = 0.33). Eight-week culture-conversion rates were also similar (84.0% and 82.1% for Vitamin D3 and placebo, respectively; P = 0.99). Conclusion: A high-dose Vitamin D3 regimen safely corrected Vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort. This trial was registered at clinicaltrials.gov at NCT00918086. © 2015 American Society for Nutrition. Source

Frediani J.K.,Emory University | Jones D.P.,Emory University | Tukvadze N.,National Center for Tuberculosis and Lung Disease | Uppal K.,Emory University | And 16 more authors.
PLoS ONE | Year: 2014

We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution. Copyright: © 2014 Frediani et al. Source

Chakhaia T.,The University of Georgia | Magee M.J.,Georgia State University | Magee M.J.,Emory University | Kempker R.R.,Emory University | And 4 more authors.
PLoS ONE | Year: 2014

Setting: The study was conducted at the National Center for Tuberculosis and Lung Diseases (NCTBLD) in Tbilisi, Georgia.Objective: To assess the utility of contact investigation for tuberculosis (TB) case detection. We also assessed the prevalence and risk factors for active TB disease and latent TB infection (LTBI) among contacts of active pulmonary TB cases.Design: A retrospective cohort study was conducted among the contacts of active pulmonary TB cases registered in 2010-2011 at the NCTBLD in Tbilisi, Georgia. Contacts of active TB patients were investigated according to an "invitation model": they were referred to the NCTBLD by the index case; were queried about clinical symptoms suggestive of active TB disease; tuberculin skin testing and chest radiographs were performed. Demographic, laboratory, and clinical data of TB patients and their contacts were abstracted from existing records up to February 2013.Results: 869 contacts of 396 index cases were enrolled in the study; a median of 2 contacts were referred per index case. Among the 869 contacts, 47 (5.4%) were found to have or developed active TB disease: 30 (63.8%) were diagnosed with TB during the baseline period (co-prevalent cases) and 17 (36.2%) developed active TB disease during the follow-up period (mean follow up of 21 months) (incident TB cases). The incidence rate of active TB disease among contacts was 1126.0 per 100 000 person years (95% CI 655.7-1802.0 per 100,000 person-years). Among the 402 contacts who had a tuberculin skin test (TST) performed, 52.7% (95% CI 47.7-57.7%) had LTBI.Conclusions: A high prevalence of LTBI and active TB disease was found among the contacts of TB cases in Tbilisi, Georgia. Our findings demonstrated that an "invitation" model of contact investigation was an effective method of case detection. Therefore, contact investigation should be scaled up in Georgia. © 2014 PLOS ONE. Source

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