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 have 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 are being conducted in collaboration with Asan Medical Center, Samsung Medical Center, and the National Medical Center, all located in Seoul. Specific protocol-driven investigations underway 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 and has over 750 subjects enrolled. A substudy of this protocol is investigating biomarkers of disease response in collaboration with University of Stellenbosch and Rutgers Biomedical and Health Sciences. The Natural History study has allowed a number of basic biology questions about the differences in drug resistant and drug sensitive TB to be addressed by whole genome sequencing. We are also studying the mechanism of action of various TB drugs and how mutations in the Mtb genome confer resistance and affect fitness. As part of the TB Clinical Diagnostics Research Consortium (TB-CDRC), we used 200 isolates collected under this protocol to investigate the performance of a microtiter plate-based drug susceptibility assay called SENSITITREMYCOTB. This test gives minimum inhibitory concentration (MIC) results to both first and second line agents faster than traditional methods. Several new next generation GeneXpert tests are being developed. For rifampin resistance, more mutations using a unique sloppy beacon approach are being added. An XDR cartridge is under development to detect fluoroquinolone and kanamycin resistance. A new GeneXpert assay is being investigated to measure response to treatment by inhibiting DNA from dead bacteria from amplifying. Another promising test for the direct detection of pathogen-specific biomarkers is under development with Los Alamos National Laboratory. Traditional immunoassay platforms have poor sensitivity but our collaboration has demonstrated direct detection of three TB-specific biomarkers (LAM, ESAT6, Ag85) using a waveguide-based optical biosensor platform has improved sensitivity. These platforms and biomarkers from easily accessible human samples, such as urine and exhaled breath condensate, if confirmed to correlate with treatment outcomes, may be used to develop point of care tests. In an ongoing analysis, we are examining the risk factors associated with treatment outcomes among new TB cases (primarily drug sensitive) and retreatment cases (often MDR TB patients). Preliminary results show that factors associated with poor outcomes are similar between the two groups and include diabetes mellitus, smoking, low BMI, far advanced disease on CXR at presentation, and having MDR TB.(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 is under investigation 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. Although more subjects in the metronidazole arm converted their sputum smear (P=0.04) and liquid culture (P=0.04) to negative at one month compared to placebo, these differences were lost by two months. Overall, 81% showed clinical success six months after stopping therapy, with no differences by arm. However, subjects in the metronidazole arm were 4.3 fold (95% CI 1.1-17.1) more likely to develop peripheral neuropathies. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer tem. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens. Additional analyses are ongoing to determine whether or not PET/CT can serve as an early radiological biomarker (radiomarker) of treatment response. Preliminary results suggest that change in PET total glycolytic activity from baseline to two months and change in total abnormal lung volume on quantitative CT analysis from baseline to six months both are predictive of final treatment outcomes six months after the end of therapy.(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 is 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 has enrolled 39 evaluable subjects with XDR TB and closed to enrollment in 7/2010. By four months, 15/19 (79%) subjects in the immediate-start arm and 7/20 (35%) subjects in the delayed-start arm achieved culture conversion (P=0.001). 34/39 (87%) subjects achieved culture negative sputum within six months of adding LZD to their failing drug regimens. Among the 38 subjects exposed to LZD, 31 (82%) experienced clinically significant adverse events (AEs) possibly or probably related to LZD that resulted in 3 subjects discontinuing therapy. Subjects who de-escalated to 300 mg/day after the second randomization had fewer adverse events than subjects who continued taking 600 mg/day. 26 subjects successfully completed therapy and remain relapse-free. Four cases of acquired resistance to LZD have been observed thus far. LZD is highly effective at achieving culture conversion among subjects with treatment-refractory pulmonary XDR tuberculosis but adverse events must be monitored carefully. Due to these results, LZD is now an insurance reimbursable TB drug in Korea.(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 7 subjects have been enrolled at Asan Medical Center, 4 at Pusan National University Hospital, and 2 at National Medical Center. The study will further define the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up work we have conducted on lesion penetration in rabbits. Initial imaging mass spectrometry results show similar drug distribution results to those in the rabbit model, with concentration of moxifloxacin in the rim of lesions.(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 is 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 is a critically important issue as no biomarker currently can predict TB reactivation. Only about 10% of people latently infected with TB will develop active TB, thus 90% of exposed people are needlessly treated with a potentially hepatotoxic drug. The study has been open for almost one year now and 13 TB index cases have been enrolled but only 2 of their contacts eligible to or agreed to participate in the study for a number of different reasons.We are amending the protocol to allow for increased participation.

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Song, Taeksun; Park, Yumi; Shamputa, Isdore Chola et al. (2014) Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the ?' subunit of RNA polymerase. Mol Microbiol 91:1106-19
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