The project is a collaboration between the TRS/LCID/NIAID, Korean Ministry of Health & Welfare, Korea CDC, and Yonsei University College of Medicine in the Republic of Korea. These collaborators worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities, including a fully functional BSL3 laboratory facility. In addition, studies were conducted in collaboration with Asan Medical Center, Samsung Medical Center, Pusan National University Hospital, and the National Medical Center, all located in Seoul. Studies completed include: (1) NIAID 05-I-N069: A Natural History Study of MDR-TB Strains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR TB isolates and their contribution to human disease. A total of 776 subjects enrolled and study follow-up is now complete. A substudy of this protocol has been investigating biomarkers of disease response in collaboration with Stellenbosch University and Rutgers New Jersey Medical School and analyses are ongoing. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Anti-TB Chemotherapy vs. Anti-TB Chemotherapy with Placebo in Subjects with Pulmonary MDR-TB. The importance of anaerobic activity in candidate TB drugs was investigated in this study. In 2009, the trial closed to enrollment after 35 subjects enrolled because of excessive peripheral neuropathies in the metronidazole arm. The study is now complete and the overall analysis has been published. Additional analyses showed that both PET and CT changes were more predictive of final treatment outcomes than 2-month sputum culture conversion was, although statistical significance was limited by the small sample size. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Anti-TB Therapy in Subjects with Pulmonary XDR-TB. The major aim of this study was to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). This trial opened in 12/2008 and enrolled 39 evaluable subjects with XDR TB and the study is now complete. 27/38 patients (71%) with chronic XDR-TB were cured of the infection at 1 year after the termination of the study. LZD is highly effective at achieving culture conversion among subjects with treatment-refractory pulmonary XDR tuberculosis but adverse events must be monitored carefully. Analyses of the PET/CT data collected during this study showed quantitative changes of a similar magnitude as those observed in macaques treated with oxazolidinones, demonstrating that the therapeutic effect of oxazolidinones in humans can be reproduced in the macaque model of experimental chemotherapy. Analyses of mitochondrial toxicity-related adverse events in this study demonstrated that mitochondrial toxicity risk increased with increasing linezolid trough concentrations. All subjects with a mean linezolid trough greater than 2 ug/ml developing an adverse event related to mitochondrial toxicity. (4) NIAID 09-I-N061: Pharmacokinetics of Standard First and Second Line Anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This is a multicenter study of the differential penetration of TB chemotherapeutics into pulmonary TB lesions. The study opened in 2010 and completed at the end of 2014 after 15 subjects were enrolled. The study further defined the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up work we conducted on lesion penetration in rabbits. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging, drug concentrations were measured in resected human TB lung lesions and different drugs were shown to differentially penetrate TB lesions. Rifampin and pyrazinamide, for example, penetrated necrotic caseum well whereas moxifloxacin did not. These findings may help explain why fluoroquinolones were unable to shorten TB therapy from 6 to 4 months. The lesion penetration properties of TB drugs may contribute to treatment outcomes and should therefore be taken into account when developing novel drugs and combination treatment regimens. (5) NIAID 12-I-N036: Risk Stratification in Latent Tuberculosis: PET/CT Findings in TB Contacts and the Effect of Preventive Treatment. The primary purpose of this study was to determine whether or not FDG uptake by PET scanning, as well as other biomarkers, can predict activation of latent TB infection in close contacts of active TB cases. This study was closed due to poor enrollment but the study concept has been transferred to Robert Wilkinson at the University of Cape Town, where a similar study is underway in collaboration with TRS investigators. (6) DMID Protocol Number 13-0029, DMID Funding Mechanism: Award Number N01AI90500C: Feasibility and accuracy of a novel Xpert cartridge for rapid molecular detection of drug resistant Mycobacterium tuberculosis in sputum. This prospective, cross-sectional study was conducted in conjunction with the Clinical Diagnostics Research Consortium (PI: Susan Dorman, Johns Hopkins University) and is now complete. The primary objective was to estimate the sensitivity and specificity of the investigational Xpert XDR cartridge to detect M. tuberculosis resistant to isoniazid, fluoroquinolones, and second-line injectable drugs. This highly multiplexed second-generation cartridge may provide significant advancement in determining multidrug and extensively drug resistant tuberculosis within 2 hours and with minimal technical expertise. The study was conducted in Zhengzhou, Henan Province and Seoul, South Korea. Data analyses showed that, compared with DNA sequencing, overall sensitivities and specificities of the investigational assay for detection of resistance, by drug, were 98.1% and 100% for isoniazid, 95.8% and 100% for fluoroquinolones, 92.7% and 99.6% for kanamycin, and 96.8% and 100% for amikacin.

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Manson, Abigail L; Cohen, Keira A; Abeel, Thomas et al. (2017) Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. Nat Genet 49:395-402
Choi, H; Chung, H; Muntaner, C et al. (2016) The impact of social conditions on patient adherence to pulmonary tuberculosis treatment. Int J Tuberc Lung Dis 20:948-54
Shenai, Shubhada; Ronacher, Katharina; Malherbe, Stefanus et al. (2016) Bacterial Loads Measured by the Xpert MTB/RIF Assay as Markers of Culture Conversion and Bacteriological Cure in Pulmonary TB. PLoS One 11:e0160062
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Chakravorty, Soumitesh; Lee, Jong Seok; Cho, Eun Jin et al. (2015) Genotypic susceptibility testing of Mycobacterium tuberculosis isolates for amikacin and kanamycin resistance by use of a rapid sloppy molecular beacon-based assay identifies more cases of low-level drug resistance than phenotypic Lowenstein-Jensen testin J Clin Microbiol 53:43-51
Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung et al. (2015) Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis. EBioMedicine 2:1627-33

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