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Setting: A referral centre in South Korea., Objective: To investigate trends in drug resistance, treatment modalities and outcomes, and adverse events of multidrug-resistant tuberculosis (MDR-TB) over two decades., Design: MDR-TB patients treated at Seoul National Hospital University between 1996 and 2015 were divided into four 5-year cohorts according to the date of initial diagnosis. Changes in demographic characteristics, drug resistance, drugs used, treatment outcomes and adverse events over time were elucidated., Results: Between 1996 and 2015, 418 patients were treated for MDR-TB: 86 patients between 1996 and 2000, 125 between 2001 and 2005, 123 between 2006 and 2010, and 84 between 2011 and 2015. The proportion of patients with positive acid-fast bacilli sputum (60.5-29.7%, P < 0.001) or cavities on chest radiographs (86.0-40.5%, P < 0.001) decreased over time. Resistance to pyrazinamide, fluoroquinolones, cycloserine and p-aminosalicylic acid decreased. Later-generation fluoroquinolones (77.9-90.5%) and linezolid (0-26.2%) became more frequently prescribed. The treatment success rate increased (45.3-88.1%, P < 0.001); neurological adverse events, including peripheral neuropathy also increased (4.7-13.1%, P = 0.027)., Conclusion: MDR-TB patients presented with less severe disease and better resistance profiles over time in South Korea, with treatment outcomes improving continuously.

Rationale: Current guidelines recommend that all patients undergoing treatment with a tumor necrosis factor-α antagonist should receive screening for latent tuberculosis and appropriate treatment before initiating the inhibitor. However, no well-designed study has shown the efficacy of treating these patients for latent tuberculosis., Objectives: To compare the risk of active tuberculosis between tumor necrosis factor antagonist users who have received treatment for latent tuberculosis with those who have not., Methods: We performed a national-level retrospective cohort study in South Korea, a country with an intermediate tuberculosis burden, by analyzing claims recorded between January 1, 2011, and December 31, 2013, in an obligatory national health insurance claims database. The primary outcome, the incidence of active tuberculosis, was measured as the occurrence of an International Statistical Classification of Diseases and Related Health Problems, 10th edition, diagnosis of tuberculosis and prescription of at least two antituberculosis drugs at least twice within 90 days., Results: Among 10,863 eligible new tumor necrosis factor antagonist users, 2,461 (22.7%) received treatment for latent tuberculosis. The incidence rate of tuberculosis per 1,000 person-years was lower for the treated group (4.07; 95% confidence interval [CI], 1.55-6.60) than for the untreated group (12.34; 95% CI, 9.96-14.72). The risk for tuberculosis was significantly reduced by preventive chemotherapy (incidence rate ratio, 0.33; 95% CI, 0.17-0.63)., Conclusions: Treatment for latent tuberculosis was highly effective in preventing the development of tuberculosis among tumor necrosis factor antagonist users.

Survival times of 219 patients diagnosed with multidrug-resistant tuberculosis were calculated and treatment outcomes compared. Mean survival of 20 patients who failed to be cured was 109.8 months (95% confidence interval [CI], 87.4-132.1), shorter than that of 150 patients who were cured (140.4 months; 95% CI, 136.1-144.7; P < .01) and that of 28 patients classified as treatment completed (138.5 months; 95% CI, 131.0-146.1; P = .02). The results demonstrate that patients with multidrug-resistant tuberculosis with poor treatment outcomes live 9 years, on average., (Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Negative conversion of sputum culture is a useful marker for predicting treatment outcome and relapse of pulmonary tuberculosis (TB). The effect of drug resistance on negative conversion of sputum culture with treatment was evaluated in this study., Methods: A total of 535 patients with culture-proven pulmonary TB were classified into three groups: drug-susceptible (DS), other drug-resistant (ODR), and multidrug-resistant/extensively drug-resistant (MDR/XDR). Rates of conversion of sputum culture at 4, 8, and 12 weeks were compared., Results: At 4 weeks of treatment, the conversion rate in the DS group (52.7%) was higher than that in the ODR group (30.8%, p=0.003), but was not different compared with the MDR group (45.7%, p=0.427). At 8 weeks, the conversion rate in the DS group (76.3%) was higher than that in the ODR (63.5%, p=0.042) and MDR groups (60.0%, p=0.031). At 12 weeks, the conversion rate in the DS group (85.9%) tended to be higher than that in the MDR group (74.3%, p=0.062), but was not different from that in the ODR group (84.6%, p=0.796)., Conclusion: The pattern of resistance to anti-TB drugs affects culture conversion rates in the early phase of treatment and also prolongs the time to culture conversion., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Setting: The Xpert(®) MTB/RIF assay is endorsed by the World Health Organization for the detection of rifampicin (RMP) resistant tuberculosis (TB)., Objective: To evaluate Xpert for its diagnostic accuracy in detecting RMP-resistant TB and its impact on treatment outcomes., Design: Patients with available phenotypic drug susceptibility testing (DST) results and those in whom RMP-resistant pulmonary TB was diagnosed using Xpert were evaluated. The accuracy and turnaround time (TAT) of Xpert for determining RMP-resistant TB was calculated. The TATs for treatment between patients diagnosed with RMP-resistant TB using Xpert and those diagnosed without the assay (phenotypic DST group) were compared., Results: In 321 patients, when phenotypic DST was used as the gold standard, Xpert sensitivity and specificity for RMP resistance diagnosis was respectively 100% and 98.7%; the positive and negative predictive values were respectively 86.2% and 100%. The Xpert group had a much shorter interval from initial evaluation to commencing second-line anti-tuberculosis treatment (64 vs. 2 days, P < 0.001), and negative conversion of mycobacterial cultures (197 vs. 62.5 days, P < 0.001) than the phenotypic DST group., Conclusion: Xpert was accurate at diagnosing RMP resistance in this setting with an intermediate TB burden and a low level of RMP resistance. Xpert might reduce disease transmission by reducing the sputum culture conversion times for patients with RMP-resistant TB.

Setting: After several changes in treatment modalities, it is time to re-evaluate treatment outcomes of multidrug-resistant tuberculosis (MDR-TB)., Objective: To evaluate treatment outcomes, elucidate changes in outcomes over time and identify predictors of treatment success for MDR-TB., Design: Patients diagnosed with MDR-TB at a tertiary referral centre in South Korea between January 2006 and December 2010 were included. Treatment modalities and outcomes were assessed. Predictors of treatment success were analysed using multiple logistic regression. The treatment modalities and outcomes of these patients were compared with those of MDR-TB patients between January 1996 and December 2005., Results: Of the 123 MDR-TB patients diagnosed during the later study period, treatment was successful in 103 (83.7%). Extensive drug resistance (OR 0.31, P = 0.044) and additional resistance to fluoroquinolones (OR 0.23, P = 0.039) were inversely associated with treatment success. The treatment success rate improved from 53.5% in 1996-2000 to 68.8% in 2001-2005 and 83.7% in 2006-2010 (P < 0.001). Improved outcomes were accompanied with more frequent use of later-generation fluoroquinolones and linezolid and less frequent surgical resection., Conclusion: Treatment outcomes for MDR-TB improved at a tertiary referral centre in South Korea. The improvement was associated with more frequent use of later-generation fluoroquinolones and linezolid.

The Xpert MTB/RIF assay was introduced for timely and accurate detection of tuberculosis (TB). The aim of this study was to determine the diagnostic accuracy and turnaround time (TAT) of Xpert MTB/RIF assay in clinical practice in South Korea. We retrospectively reviewed the medical records of patients in whom Xpert MTB/RIF assay using sputum were requested. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of pulmonary tuberculosis (PTB) and detection of rifampicin resistance were calculated. In addition, TAT of Xpert MTB/RIF assay was compared with those of other tests. Total 681 patients in whom Xpert MTB/RIF assay was requested were included in the analysis. The sensitivity, specificity, PPV and NPV of Xpert MTB/RIF assay for diagnosis of PTB were 79.5% (124/156), 100.0% (505/505), 100.0% (124/124) and 94.0% (505/537), respectively. Those for the detection of rifampicin resistance were 57.1% (8/14), 100.0% (113/113), 100.0% (8/8) and 94.9% (113/119), respectively. The median TAT of Xpert MTB/RIF assay to the report of results and results confirmed by physicians in outpatient settings were 0 (0-1) and 6 (3-7) days, respectively. Median time to treatment after initial evaluation was 7 (4-9) days in patients with Xpert MTB/RIF assay, but was 21 (7-33.5) days in patients without Xpert MTB/RIF assay. Xpert MTB/RIF assay showed acceptable sensitivity and excellent specificity for the diagnosis of PTB and detection of rifampicin resistance in areas with intermediate TB burden. Additionally, the assay decreased time to the initiation of anti-TB drugs through shorter TAT.

Purpose: The aim of this study was to elucidate the effects of immunocompromising comorbidities on treatment response and adverse reactions in older tuberculosis (TB) patients., Materials and Methods: The medical records of 182 patients older than 65 years with proven TB by positive culture of Mycobacterium tuberculosis and with available drug susceptibility tests were reviewed retrospectively. These patients were subsequently assigned to either the comorbidity group (n=78) or non-comorbidity group (n=104) depending on whether they had immunocompromising comorbidities., Results: The mean durations of treatment were 9.9 ± 3.3 months in the comorbidity group and 9.3 ± 3.2 months in the non-comorbidity group (p=0.21). M. tuberculosis culture results converted to negative in most patients with available follow-up cultures at two months after treatment. The successful treatment rates were 94.9% and 98.9% in the comorbidity and non-comorbidity groups, respectively (p=0.30). The most common side effects of anti-TB treatment were skin rash/pruritus (13% in the comorbidity group vs. 11% in the non-comorbidity group, p=0.79), gastro-intestinal problems (14% vs. 9%, p=0.25) and hepatotoxicity (14% vs. 7%, p=0.09)., Conclusion: The present study shows that the successful treatment rate for TB is high and that immunocompromising comorbidities have no effect on the response to treatment and adverse effects in older TB patients.

Background and Objective: Vitamin D deficiency has been reported to be associated with the development of active tuberculosis (TB), but many discrepancies exist among studies. The aims of this study were to compare the frequency of vitamin D deficiency in a Korean population of TB patients and control subjects, and to monitor the changes in vitamin D levels during TB treatment., Methods: Patients with newly diagnosed TB were prospectively enrolled. In addition, healthy volunteers or patients with diseases other than TB were enrolled as controls. Baseline serum 25-hydroxyvitamin D (25-OHD) levels were measured in both groups and compared. In the TB patients, measurements of serum 25-OHD were repeated 1 month after the initiation of treatment and again after completion of treatment., Results: In total, 116 patients with TB and 86 control subjects were recruited. The median 25-OHD concentration was not different in TB patients at diagnosis (13.9 ng/mL; interquartile range (IQR) 8.80-21.8) compared with control subjects (13.2 ng/mL; IQR 9.6-19.3) (P = 0.97). The frequency of vitamin D deficiency (≤ 10 ng/mL) was also not different in TB patients (36.2%) compared with controls (27.3%) (P = 0.21). In TB patients, the median 25-OHD concentration decreased significantly during treatment, to 12.5 ng/mL at 1 month and 11.0 ng/mL on completion of treatment (P = 0.01)., Conclusions: Vitamin D levels do not appear to be associated with the development of TB in the Korean population. The median 25-OHD concentration decreased after treatment for TB., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

A retrospective review was conducted of patients with multidrug-resistant tuberculosis (MDR-TB) to elucidate the rate of recurrence after successful treatment. Of 123 MDR-TB patients, 90 were declared as 'cured' or 'treatment completed' after individualised treatment; four (4.4%) experienced recurrence. All patients with recur- rent MDR-TB were documented as 'treatment completed' after treatment. Recurrence of MDR-TB is possible after successful treatment, particularly among those documented as 'treatment completed'.

Background/aims: To compare the effect of levofloxacin and moxifloxacin on treatment outcomes among patients with multidrug-resistant tuberculosis (MDR-TB)., Methods: A retrospective analysis of 171 patients with MDR-TB receiving either levofloxacin or moxifloxacin was performed. Treatment responses were categorized into treatment success (cured and treatment completed) or adverse treatment outcome (death, failure, and relapsed)., Results: The median age of the patients was 42.0 years. Approximately 56% of the patients were male. Seventeen patients had extensively drug-resistant tuberculosis, and 20 had a surgical resection. A total of 123 patients (71.9%) received levofloxacin for a median 594 days, and 48 patients (28.1%) received moxifloxacin for a median 673 days. Other baseline demographic, clinical, and radiographic characteristics were similar between the two groups. The moxifloxacin group had a significantly higher number of resistant drugs (p < 0.001) and a higher incidence of resistance to ofloxacin (p = 0.005) in the drug sensitivity test. The treatment success rate was 78.9% in the levofloxacin group and 83.3% in the moxifloxacin group (p = 0.42). Adverse reactions occurred at similar rates in the groups (p = 0.44). Patients in the moxifloxacin group were not more likely to have treatment success than those in the levofloxacin group (adjusted odds ratio, 0.76; 95% confidence interval, 0.24 to 2.43; p = 0.65)., Conclusions: Both levofloxacin and moxifloxacin showed equivalent efficacy for treating MDR-TB.

Objectives: The aim of this study was to analyze changes in the extent of radiographic lesions with treatment in patients with pulmonary tuberculosis (TB) and, further, to identify clinical and radiographic factors related to radiographic response., Methods: A prospective cohort study including patients with culture-proven pulmonary TB was performed. The posterior-anterior view films of the chest that had been taken at the time of diagnosis and at 6 months after the initiation of treatment were compared. We expressed the extents of the lesions as percentages involving the parenchyma compared with the remaining normal parenchyma., Results: Among 135 patients enrolled, three failed to achieve smear conversion of sputa after 6 months of treatment. The extent of radiographic lesions decreased from 22.8% at the time of diagnosis to 10.5% after 6 months of treatment. Through the multiple regression model, we found that increasing age (p=0.034), previous history of TB (p=0.016), presence of cavity (p=0.016) or fibrotic lesion (p=0.009), and multidrug-resistant TB (p=0.002) were significantly associated with a poor radiographic response., Conclusion: Patients with less-prominent radiographic improvement and sustained negative tuberculous cultures of the sputa could be closely observed without ordering unnecessary chest radiographs or mycobacterial cultures as well as prolonging treatment.

Recently, resistance to additional first-line and injectable drugs was reported to be an independent risk factor for adverse outcomes in multidrug-resistant (MDR) tuberculosis (TB) patients. The aim of the present study was to confirm these observations in MDR-TB patients without HIV infection. MDR-TB patients treated at a tertiary referral hospital in South Korea between January 1996 and December 2005 were included. The unadjusted and adjusted odds ratios of adverse treatment outcome were calculated for resistance to each drug and combination of drugs using simple or multiple logistic regressions. None of the resistance to additional first-line or injectable drugs was associated with higher odds for adverse treatment outcome in 155 MDR but nonextensively drug-resistant (non-XDR) TB patients. However, streptomycin resistance was associated with 12 times the odds for adverse treatment outcome in 42 extensively drug-resistant (XDR) TB patients. Neither combinations of first-line drugs nor those of injectable drugs were associated with increased odds for adverse treatment outcomes in non-XDR MDR-TB patients or XDR-TB patients. Only streptomycin resistance among the first-line or injectable drugs was associated with adverse treatment outcomes in extensively drug-resistant tuberculosis patients without HIV infection.

Setting: The university and municipal hospitals in Seoul, Korea., Objective: To evaluate the predictors of persistent airway stenosis following anti-tuberculosis chemotherapy in patients with endobronchial tuberculosis (TB)., Design: Diagnosis of TB was confirmed by microbiology or histopathology. Bronchoscopic examinations revealed that patients had endobronchial lesions compatible with endobronchial TB. Study subjects had at least one follow-up bronchoscopy to evaluate their treatment response. Treatment response was determined by changes in the degree or extent of airway stenosis between the first and last bronchoscopic examinations., Results: Sixty-seven subjects were recruited retrospectively from Seoul National University Hospital and Seoul National University Boramae Hospital. Persistent bronchostenosis occurred in 41.8% of the patients. In multivariate regression analysis, age >45 years (OR 3.65), pure or combined fibrostenotic subtype (OR 5.54) and duration from onset of chief complaint to the initiation of anti-tuberculosis chemotherapy >90 days (OR 5.98) were identified as independent predictors of persistent airway stenosis. Oral corticosteroids (prednisolone equivalent >or=30 mg/d) did not reduce the frequency of persistent airway stenosis., Conclusion: Early diagnosis and early administration of anti-tuberculosis chemotherapy before involvement of the deeper airways is important to prevent the development of unwanted sequelae of bronchostenosis.

Background: Recently, serious concerns about extensively drug-resistant tuberculosis (XDR-TB), which shows resistance to second-line anti-TB drugs in addition to isoniazid and rifampicin, have been raised. The aim of this study was to elucidate the impact of extensive drug resistance on treatment outcomes in non-human immunodeficiency virus (HIV)-infected patients with multidrug-resistant tuberculosis (MDR-TB)., Methods: Patients who received the diagnosis of and treatment as having MDR-TB at Seoul National University Hospital (Seoul, Republic of Korea) between January 1996 and December 2005 were included. The definition of XDR-TB was TB caused by bacilli showing resistance to both isoniazid and rifampicin and also showing resistance to any fluoroquinolone and to at least 1 of the following 3 injectable anti-TB drugs: capreomycin, kanamycin, and amikacin. To identify the impact of extensive drug resistance on treatment outcomes, univariate comparison and multiple logistic regression were performed., Results: A total of 211 non-HIV-infected patients with MDR-TB were included in the final analysis. Among them, 43 patients (20.4%) had XDR-TB. Treatment failure was observed in 19 patients (44.2%) with XDR-TB, whereas treatment of 46 patients (27.4%) with non-XDR-TB failed (P=.057). The presence of extensive drug resistance (adjusted odds ratio [OR], 4.46; 95% confidence interval [CI], 1.35-14.74) and underlying comorbidity (adjusted OR, 2.62; 95% CI, 1.00-6.87) were independent risk factors for treatment failure. However, a higher level of albumin was inversely associated with treatment failure (adjusted OR, 0.87; 95% CI, 0.77-0.97)., Conclusion: The presence of extensive drug resistance, the presence of comorbidity, and hypoalbuminemia were independent poor prognostic factors in non-HIV-infected patients with MDR-TB.

Although mycobacterial culture and the subsequent drug-susceptibility test (DST) for anti-tuberculosis (TB) drugs take several months to complete using solid media, there are no reports on the turnaround times of these tests under clinical conditions. The aim of this study was to determine the interval between initiation of anti-TB treatment and receipt of DST requested at an outpatient clinic. We prospectively enrolled patients with culture-positive pulmonary TB at Seoul National University Hospital from September 2002 to December 2004. Patients were followed up monthly. Mycobacterial cultures were done using Ogawa media at Seoul National University Hospital. DST were performed at the Korean Institute of Tuberculosis. Of the 104 patients enrolled, 54 were male. The median age was 41 yr. The median interval from initiation of anti-TB treatment to receipt of mycobacterial culture results by clinicians was 37 days (range, 0-89 days). The median interval from initiation of treatment to confirmation of DST by requesting clinicians was 80.5 days (range, 28-145 days). Clinicians only received the results of DST more than two months after initiation of treatment when they followed up patients monthly and mycobacterial culture was performed using solid media.

Pulmonary tuberculomas are well-circumscribed masses caused by Mycobacterium tuberculosis. However, the response of tuberculomas to anti-tuberculous (TB) treatment has not been well defined as yet. The response of pulmonary tuberculomas to anti-TB treatment was retrospectively reviewed in 45 patients diagnosed between January 1997 and December 2001. The areas of pulmonary tuberculomas were estimated by calculating products of the longest and their perpendicular short diameters on chest radiographs. The response to anti-TB treatment was categorised as "decreased" (> 25% reduction in area versus its initial area), "increased" (> 251% increase) and "no change" (the remainder). The mean of treatment duration was 11.5 +/- 3.6 months. Three months after treatment, 18 patients (40.0%) were categorised as decreased, 25 (55.6%) as no change and two (4.4%) as increased. Twelve months after treatment, out of 42 patients available for chest radiographs, 32 patients (76.2%) were categorised as decreased, nine (21.4%) as no change and one patient (2.4%) as increased. At the last follow-up (mean follow-up 27.0 +/- 10.2 months), 37 patients (82.2%) were categorised as decreased. The majority of pulmonary tuberculomas were decreased by anti-tuberculosis treatment during and even after treatment, although a transient enlargement during the early period of treatment was observed infrequently.

Background: Medical treatment of multiple drug resistant (MDR) pulmonary tuberculosis is generally quite unsuccessful. Recently, surgical management is increasing and shows promise. We analyzed our experience to identify the benefits and complications of pulmonary resection in MDR pulmonary tuberculosis., Methods: A retrospective review was performed in 27 patients undergoing pulmonary resection for MDR pulmonary tuberculosis between January 1994 and March 1998. Their average ages were 40 years and were diagnosed a median of 15 months before surgery. All patients had resistance to an average of 4.4 drugs including isoniazid and rifampin, and had received second line drugs selected according to drug sensitivity test preoperatively. Most patients (92.6%) had cavitary lesions. Bilateral lesions were also identified in 19 patients (70.4%), but the main focus was recognized in one side of the lung. Most patients were indicated to operation for those who could not achieve negative sputum despite adequate medical treatment (n = 16, 59.3%); or for negative patients who had significant pulmonary parenchymal lesion (n = 11, 40.7%) which would have had a high probability of recurrence. Pneumonectomy was done in nine patients, lobectomy in 16 and segmentectomy in two., Results: There was no operative mortality. Morbidity occurred in seven patients (25.9%); prolonged air leakage in three patients, reoperation due to bleeding in two, bronchopleural fistula in one, and reversible blindness in one. The median follow up period was 15 months (range 3-45). Sputum negative conversion was achieved in 22 patients (81.5%) initially. However, continued postoperative chemotherapy could convert to negative in another four patients (14.8%). Only one pneumonectomy patient (3.7%) failed because of considerable contralateral cavity., Conclusion: For patients with MDR pulmonary tuberculosis which is localized, and with adequate pulmonary reserve function, surgical pulmonary resection combined with appropriate pre and postoperative anti-tuberculosis chemotherapy can achieve high success rate with acceptable morbidity.

It has long been known that almost all isoniazid (INH) resistant mycobacteria lose the catalase and peroxidase activities along with reduced or no virulence for guinea pigs. Recently resistance to INH has become known to be associated with mutations of katG gene encoding the HPI (Hydroperoxidase I) type catalase and peroxidase. Among these mutations, the point mutation of codon 463 of katG gene is found frequently, and is suggested as being associated with INH resistance. Therefore we performed this study in order to confirm the correlation between the point mutation of codon 463 of the katG gene and INH resistance of M. tuberculosis in Korea. Fifty isolates, 32 of which were resistant to INH, and 18 of which were sensitive to INH, were selected for this study. We used PCR-SSCP and RFLP analysis to detect the point mutation of the codon 463 of katG gene and confirmed the CGG (arginine) to CTG (leucine) mutation by direct sequencing analysis. Among 32 resistant isolates, 7 isolates (22%) had the same restriction pattern compared with that of the reference strain (H37Rv), and 25 isolates (78%) showed a different restriction pattern. Among 18 sensitive isolates, 7 isolates (39%) had the same restriction pattern compared with that of H37Rv, and 11 isolates (61%) showed a different restriction pattern. These results suggest that the CGG to CTG change of codon 463 of katG gene of M. tuberculosis may be a polymorphism not related with INH resistance.