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The aim of this study was to analyse temporal changes in treatments for and outcomes of multidrug-resistant (MDR)/rifampin-resistant (RR)-tuberculosis (TB) in the context of national economic status.We analysed data collected by the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment on MDR/RR-TB patients from 37 countries. The data were stratified by three national income levels (low-/lower-middle, upper-middle and high) and grouped by time of treatment initiation (2001-2003, 2004-2006, 2007-2009, 2010-2012 and 2013-2015). Temporal trends over the study period were analysed. The probability of treatment success in different income groups over time was calculated using generalised linear mixed models with random effects.In total, 9036 patients were included in the analysis. Over the study period, use of group A drugs (levofloxacin/moxifloxacin, bedaquiline and linezolid) recommended by the World Health Organization increased and treatment outcomes improved in all income groups. Between 2001-2003 and 2013-2015, treatment success rates increased from 60% to 78% in low-/lower-middle-income countries, from 40% to 67% in upper-middle-income countries, and from 73% to 81% in high-income countries. In earlier years, the probability of treatment success in upper-middle-income countries was lower than that in low-/lower-middle-income countries, but no difference was observed after 2010. However, high-income countries had persistently higher probability of treatment success compared to upper-middle income countries.Improved treatment outcomes and greater uptake of group A drugs were observed over time for patients with MDR/RR-TB at all income levels. However, treatment outcomes are still unsatisfactory, especially in upper-middle-income countries., Competing Interests: Conflict of interest: N. Kwak has nothing to disclose. Conflict of interest: N. Winters has nothing to disclose. Conflict of interest: J.R. Campbell has nothing to disclose. Conflict of interest: E.D. Chan has nothing to disclose. Conflict of interest: M. Gegia has nothing to disclose. Conflict of interest: C. Lange reports personal fees for lectures from Chiesi, Gilead, Janssen, Lucane, Novartis, Oxoid, Berlin Chemie and Thermofisher, personal fees for advisory board work from Oxford Immunotec, outside the submitted work. Conflict of interest: M. Lee has nothing to disclose. Conflict of interest: V. Milanov has nothing to disclose. Conflict of interest: D. Menzies has nothing to disclose. Conflict of interest: J-J. Yim received donations of linezolid (Zyvox) from Pfizer Inc. and Delamanid (Deltyba) from Otsuka Pharmaceutical Co. and served as principal investigator on clinical trials., (Copyright ©ERS 2020.)

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) poses a threat to public health as a result of high treatment costs and unsatisfactory outcomes. OBJECTIVE: To elucidate trend, demographic and clinical characteristics and treatment outcomes of patients with MDR-TB between 2011 and 2015 in South Korea. METHOD: Data of patients with MDR-TB diagnosed between 1 January 2011 and 31 December 2015 were retrieved from the nationwide Internet-based TB notification system and analysed retrospectively. RESULTS: During the study period, 5192 MDR-TB patients were notified. We identified an increasing number of MDR-TB patients among foreign populations (from 1.3% to 7.7%), decreasing resistance rates to other anti-TB drugs (e.g., resistance to pyrazinamide, from 40.9% to 28.2%), a decreasing interval from treatment initiation to negative conversion of sputum culture (from 165.7 to 103.7 days) and shortening of treatment duration (719.7 to 613.2 days). However, treatment success rates did not change, and had an average of 65.7%. CONCLUSION: Despite decreasing resistance rates to other drugs and faster treatment responses, treatment outcomes did not improve during the study period. Strict management of MDR-TB patients on treatment should be adopted to improve treatment outcomes.

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.

Background: Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis., Methods: We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460., Findings: Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient., Interpretation: Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis., Funding: Ministry of Health and Welfare, South Korea., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis., Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration., Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses., Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition., Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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: 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.