Cheongju, South Korea
Cheongju, South Korea

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Dalton T.,Centers for Disease Control and Prevention | Cegielski P.,Centers for Disease Control and Prevention | Akksilp S.,Office of Disease Prevention and Control Region 7 | Asencios L.,National Tuberculosis Reference Laboratory | And 16 more authors.
The Lancet | Year: 2012

Background: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries. Methods: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis. Findings: Among 1278 patients, 43·7 showed resistance to at least one second-line drug, 20·0 to at least one second-line injectable drug, and 12·9 to at least one fluoroquinolone. 6·7 of patients had XDR tuberculosis (range across study sites 0·8-15·2). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries. Interpretation: Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies. Funding: US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare. © 2012 Elsevier Ltd.


Jnawali H.N.,Korean Institute of Tuberculosis | Hwang S.C.,Ajou University | Park Y.K.,Korean Institute of Tuberculosis | Kim H.,Korean Institute of Tuberculosis | And 4 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2013

In order to characterize molecular mechanisms of first- and second-line drug resistance in Mycobacterium tuberculosis and to evaluate the use of molecular markers of resistance, we analyzed 62 multidrug-resistant, 100 extensively drug-resistant, and 30 pan-susceptible isolates from Korean tuberculosis patients. Twelve genome regions associated with drug resistance, including katG, ahpC, and inhA promoter for isoniazid (INH); embB for ethambutol (EMB), rpoB for rifampin (RIF), pncA for pyrazinamide (PZA), gyrA for fluoroquinolones; rpsL, gidB, and rrs for streptomycin; rrs and eis for kanamycin (KM); rrs and tylA for capreomycin (CAP); and rrs for amikacin (AMK) were amplified simultaneously by polymerase chain reaction, and the DNA sequences were determined. We found mutations in 140 of 160 INH-resistant isolates (87.5%), 159 of 162 RIF-resistant isolates (98.15%), 127 of 143 EMB-resistant isolates (88.8%), 108 of 123 ofloxacin-resistant isolates (87.8%), and 107 of 122 PZA-resistant isolates (87.7%); 43 of 51 STM-resistant isolates (84.3%), 15 of 17 KM-resistant isolates (88.2%), and 14 of 15 (AMK and CAP)-resistant isolates (93.3%) had mutations related to specific drug resistance. In addition, the sequence analyses of the study revealed many novel mutations involving these loci. This result suggests that mutations in the rpoB531, katGSer315Thr, and C-15T in the inhA promoter region, and gyrA94, embB306, pncA159, rpsL43, and A1401G in the rrs gene could serve as useful markers for rapid detection of resistance profile in the clinical isolates of M. tuberculosis in Korea, with potentials for the new therapeutic benefits in actual clinical practice. © 2013 Elsevier Inc.


Kim J.-J.,Chungnam National University | Lee H.-M.,Chungnam National University | Shin D.-M.,Chungnam National University | Kim W.,Seoul National University | And 15 more authors.
Cell Host and Microbe | Year: 2012

The current standard of treatment against tuberculosis consists of a cocktail of first-line drugs, including isoniazid and pyrazinamide. Although these drugs are known to be bactericidal, contribution of host cell responses in the context of antimycobacterial chemotherapy, if any, remains unknown. We demonstrate that isoniazid and pyrazinamide promote autophagy activation and phagosomal maturation in Mycobacterium tuberculosis (Mtb)-infected host cells. Treatment of Mtb-infected macrophages with isoniazid or pyrazinamide caused significant activation of cellular and mitochondrial reactive oxygen species and autophagy, which was triggered by bacterial hydroxyl radical generation. Mycobacterium marinum-infected autophagy-defective, atg7 mutant Drosophila exhibited decreased survival rates, which could not be rescued by antimycobacterial treatment, indicating that autophagy is required for effective antimycobacterial drug action in vivo. Moreover, activation of autophagy by antibiotic treatment dampened Mtb-induced proinflammatory responses in macrophages. Together, these findings underscore the importance of host autophagy in orchestrating successful antimicrobial responses to mycobacteria during chemotherapy.


Koh W.-J.,Sungkyunkwan University | Jeon K.,Sungkyunkwan University | Lee N.Y.,Sungkyunkwan University | Kim B.-J.,Seoul National University | And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. Objectives: To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. Methods: We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. Measurements and Main Results: The clinical and radiographic manifestations of disease causedb yeach species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P< 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). Conclusions: Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M.massiliense lung disease than inthose with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.


Lee S.W.,Armed Forces Capital Hospital | Lee S.W.,University of Ulsan | Lee S.H.,Korean Institute of Tuberculosis | Yim J.-J.,Seoul National University
Infection | Year: 2012

Purpose: Interferon-gamma release assay (IGRA) results have been suggested as a surrogate marker of treatment response in latent tuberculosis infection (LTBI). However, data have not been consistent, and most previous studies focused on participants taking isoniazid prophylaxis. The aim of this study was to elucidate the changes in the IGRA results in patients who underwent chemoprophylaxis with isoniazid and rifampicin daily for 3 months. Methods: In a TB outbreak cohort, 26 asymptomatic close contacts with normal chest radiographs and positive QuantiFERON-TB Gold In-Tube assay (QFT-GIT) results were recruited. These patients were treated with isoniazid and rifampicin daily for 3 months. The QFT-GIT was repeated at 3 and 6 months following treatment initiation. Results: Compared with the initial QFT-GIT results (3.59 ± 3.39 IU/mL), the interferon-gamma (IFN-γ) levels had decreased significantly at 6 months (0.84 ± 1.14 IU/mL; P = 0.005), but not at 3 months (3.58 ± 3.64 IU/mL; P = 0.98). Reversions occurred in seven (26.9 %) patients at 3 months and in an additional two participants at 6 months; a total of nine participants (34.6 %) had reversions. Recent conversion was associated with reversion of the test results (odds ratio 26.3, 95 % confidence interval 3.04-226.6). Conclusion Chemoprophylaxis with isoniazid and rifam-picin generally decreased IFN-y levels among tuberculosis contacts. However, only a small portion of participants achieved reversion. © Springer-Verlag 2012.


Song Y.,Sungkyunkwan University | Seol J.-H.,Sungkyunkwan University | Yang J.-H.,Sungkyunkwan University | Kim H.-J.,Korean Institute of Tuberculosis | And 3 more authors.
Nucleic Acids Research | Year: 2013

The mammalian genome encodes multiple variants of histone H3 including H3.1/H3.2 and H3.3. In contrast to H3.1/H3.2, H3.3 is enriched in the actively transcribed euchromatin and the telomeric heterochromatins. However, the mechanism for H3.3 to incorporate into the different domains of chromatin is not known. Here, taking the advantage of well-defined transcription analysis system of yeast, we attempted to understand the molecular mechanism of selective deposition of human H3.3 into actively transcribed genes. We show that there are systemic H3 substrate-selection mechanisms operating even in yeasts, which encode a single type of H3. Yeast HIR complex mediated H3-specific recognition specificity for deposition of H3.3 in the transcribed genes. A critical component of this process was the H3 A-IG code composed of amino acids 87, 89 and 90. The preference toward H3.3 was completely lost when HIR subunits were absent and partially suppressed by human HIRA. Asf1 allows the influx of H3, regardless of H3 type. We propose that H3.3 is introduced into the active euchromatin by targeting the recycling pathway that is mediated by HIRA (or HIR), and this H3-selection mechanism is highly conserved through the evolution. These results also uncover an unexpected role of RI chaperones in evolution of variant H3s. © 2013 The Author(s) 2013.


Koh W.-J.,Sungkyunkwan University | Hong G.,Sungkyunkwan University | Kim S.-Y.,Sungkyunkwan University | Jeong B.-H.,Sungkyunkwan University | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Moxifloxacin (MXF) has in vitro and in vivo activity against Mycobacterium avium complex (MAC) in experimental models. However, no data are available concerning its treatment effect in patients with MAC lung disease. The aim of this study was to evaluate the clinical efficacy of an MXF-containing regimen for the treatment of refractory MAC lung disease. Patients with MAC lung disease who were diagnosed between January 2002 and December 2011 were identified from our hospital database. We identified 41 patients who received MXF for>4 weeks for the treatment of refractory MAC lung disease. A total of 41 patients were treated with an MXF-containing regimen because of a persistent positive culture after at least 6 months of clarithromycin- based standardized antibiotic therapy. The median duration of antibiotic therapy before MXF administration was 410 days (interquartile range [IQR], 324 to 683 days). All patients had culture-positive sputum when MXF treatment was initiated. The median duration of MXF administration was 332 days (IQR, 146 to 547 days). The overall treatment success rate was 29% (12/41), and the median time to sputum conversion was 91 days (IQR, 45 to 190 days). A positive sputum acid-fast-bacillus smear at the start of treatment with MXF-containing regimens was an independent predictor of an unfavorable microbiological response. Our results indicate that MXF may improve treatment outcomes in about one-third of patients with persistently culturepositive MAC lung disease who fail to respond to clarithromycin-based standardized antibiotic treatment. Prospective studies are required to assess the clinical efficacy of MXF treatment for refractory MAC lung disease. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Lee S.W.,Armed Forces Capital Hospital | Jang Y.S.,Three Armed Forces | Park C.M.,Seoul National University | Kang H.Y.,Korean Institute of Tuberculosis | And 3 more authors.
Chest | Year: 2010

Background: In TB outbreaks, detecting active cases is the key step in stopping transmission of the disease. The aim of this study was to evaluate the role of high-resolution CT (HRCT) scanning of the chest in the investigation of a TB outbreak that developed in a cohort of 92 soldiers in the South Korean army. Methods: Outbreak investigation, including tuberculin skin test (TST), QuantiFERON TB Gold In-Tube (QFT) test, and simple chest radiograph (CXR), was performed. For participants with any abnormal findings in these tests, HRCT scanning was done. Active pulmonary TB was diagnosed based on sputum studies or HRCT scan findings. In addition, participants with positive results in both TST and QFT were treated as having a latent TB infection (LTBI). TST and QFT were repeated in participants with a positive result in one of these tests. CXR was repeated in all participants at 3 and 6 months of follow-up. Results: Eighty-seven participants completed the study protocol. Among them, 18 active TB cases were diagnosed. Nine of these had normal CXR, but had lesions that were suggestive of active TB on HRCT scan. Twenty-two participants with normal HRCT scans and positive results with TST and QFT at initial investigation were treated as LTBI. Among 13 participants with normal CXR and positive results in either TST or QFT, nine completed a 3-month investigation. All but one of nine participants revealed positive results in both tests. Conclusion: Inclusion of HRCT scanning in the outbreak investigation of TB may be helpful in differentiating active TB from LTBI more reliably. Trial registration: clinicaltrials.gov; Identifier: NCT00889759. © 2010 American College of Chest Physicians.


Lee S.W.,University of Ulsan | Oh S.Y.,Korean Institute of Tuberculosis | Lee J.B.,Korean Institute of Tuberculosis | Choi C.M.,University of Ulsan | Kim H.J.,Korean Institute of Tuberculosis
PLoS ONE | Year: 2014

Background: Epidemiologic data regarding tuberculin skin test (TST) responses are an important basis for TB control strategies. This study analyzed TST responses in Korea, which experienced a rapid change in BCG vaccination status. Methods: TST responses in young adults were examined over 5 years. Participants with active TB lesions were excluded. Results: A total of 5,552 participants were enrolled with median age of 21 years. When an induration diameter ≥10 mm was used as the criterion for a positive test, TST positivity fell (from 28.0% in 2005 to 15.3% in 2009); however, they remained steady when the criterion was ≥15-20 mm. A positive TST was associated with a personal or family of TB, the presence of a Bacille Calmette-Guérin (BCG) scar, and age (odds ratio [95% confidence interval] = 4.03 [2.61-6.22], 2.91 [1.80-4.71], 1.50 [1.31-1.72], and 1.15 [1.09-1.20], respectively). Among these factors, the decrease of participants with BCG scars was the most prominent change, which appeared to be associated with the change of TST positivity rate. Conclusion: Overall, the rate of TST positivity in Korea decreased. However, this trend seems associated with the change of BCG vaccination strategy rather than successful control of LTBI. This study showed that change in BCG vaccination strategy can have great impact on TB epidemiologic survey based on TST. © 2014 Lee et al.


Lee Y.,Yonsei University | Kim C.-K.,Korean Institute of Tuberculosis | Lee H.,Catholic Kwandong University | Jeong S.H.,Yonsei University | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

We investigated an outbreak caused by carbapenem-resistant Acinetobacter baumannii carrying the blaOXA-23 gene. A novel insertion sequence (IS), named ISAba10, was found to be inserted into the ISAba1 element preceding the blaOXA-23 gene in a group of isolates showing higher carbapenem MICs. The presence of ISAba10 was associated with increased OXA-23 expression, likely by providing additional promoter sequences. ISAba10 was also inserted into the carO outer membrane protein gene in most of these isolates. Copyright © 2011 American Society for Microbiology. All Rights Reserved.

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