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Treatment of drug-resistant tuberculosis (TB), which is usually less successful than that of drug-susceptible TB, represents a challenge for TB control and elimination. We aimed to evaluate treatment outcomes and to identify the factors associated with death among patients with MDR and XDR-TB in Portugal. We assessed MDR-TB cases reported for the period 2000-2016, using the national TB Surveillance System. Treatment outcomes were defined according to WHO recommendations. We identified the factors associated with death using logistic regression. We evaluated treatment outcomes of 294 MDR- and 142 XDR-TB patients. The treatment success rate was 73.8% among MDR- and 62.7% among XDR-TB patients (p = 0.023). The case-fatality rate was 18.4% among MDR- and 23.9% among XDR-TB patients. HIV infection (OR 4.55; 95% CI 2.31-8.99; p < 0.001) and resistance to one or more second-line injectable drugs (OR 2.73; 95% CI 1.26-5.92; p = 0.011) were independently associated with death among MDR-TB patients. HIV infection, injectable drug use, past imprisonment, comorbidities, and alcohol abuse are conditions that were associated with death early on and during treatment. Early diagnosis of MDR-TB and further monitoring of these patients are necessary to improve treatment outcome., Competing Interests: The authors have declared that no competing interests exist.

Background: Tuberculosis and its resistance are a major global health problem in the world. The increased incidence and mortality of tuberculosis in Indonesia remain a big public health issue especially in Jakarta Province. No published studies have focused on assessing the outcome treatment of tuberculosis resistance both in success and death. We aimed this study to assess the survival of cured and death outcomes as well as the determinant factors which might influence drugs resistant tuberculosis in Jakarta between 2010 and 2015., Methods: this study analyzed the national electronic tuberculosis register (e-TB Manager) of Jakarta province in 2010 to 2015. All adult patients who lived in Jakarta province and were diagnosed with multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) were eligible for the study. Kaplan Meier survival curve was used, together with log-rank test and Chi-Square (X2) test for descriptive analysis. Cox regression analysis helped determine the potential risk factors. Several risk factors were analyzed in this study, including age, gender, residency, HIV status, resistance status, and history of previous treatment., Results: we analyzed 553 samples in this study. The drug-resistant tuberculosis cases increased gradually from 2010 to 2015. Of all cases, 248 and 67 patients were cured and death, respectively. There was a difference in survival rate between patients diagnosed with MDR-TB and XDR-TB with successful treatment. Poor treatment outcome (death) among patients was predicted by age greater than 60 years old (HR 3.48; 95% CI 1.48 - 8.38, p-value = 0.004)., Conclusion: there was a difference survival rates between success treatment (cured) and poor treatment outcome (death) during six years of observation. Age of patients is a single-predictor in survival of death. While, HIV status and resistance status were predictors in survival of cured.

Background: Extensively drug-resistant tuberculosis (XDR TB) is a very serious form of tuberculosis that is burdened with a heavy mortality toll, especially before the advent of new TB drugs. The Democratic Republic of the Congo (DRC) is among the countries most affected by this new epidemic., Methods: A retrospective analysis was performed of the records of all patients with pre- and extensively drug-resistant tuberculosis hospitalized from January 1, 2015 to December 31, 2017 and monitored for at least 6 months to one year after the end of their treatment in Kinshasa; an individualized therapeutic regimen with bedaquiline for 20 months was built for each patient. The adverse effects were systematically monitored., Results: Of the 40 laboratory-confirmed patients, 32 (80%) patients started treatment, including 29 preXRB and 3 XDR TB patients. In the eligible group, 3 patients (9.4%) had HIV-TB coinfections. The therapeutic success rate was 53.2%, and the mortality rate was 46.8% (15/32); there were no relapses, failures or losses to follow-up. All coinfected HIV-TB patients died during treatment. The cumulative patient survival rate was 62.5% at 3 months, 53.1% at 6 months and 53.1% at 20 months. The most common adverse events were vomiting, Skin rash, anemia and peripheral neuropathy., Conclusion: The new anti-tuberculosis drugs are a real hope for the management of Drug Resistant tuberculosis patient and other new therapeutic combinations may improve favorable outcomes., Competing Interests: No authors have competing interests.

Background: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes., Methods: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated., Results: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid., Conclusions: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.)., (Copyright © 2020 Massachusetts Medical Society.)

Setting: The State of Rio de Janeiro stands out as having the second highest incidence and the highest mortality rate due to TB in Brazil. This study aims at identifying the factors associated with the unfavourable treatment of MDR/XDR-TB patients in that State., Method: Data on 2269 MDR-TB cases reported in 2000-2016 in Rio de Janeiro State were collected from the Tuberculosis Surveillance System. Bivariate and multivariate logistic regressions were run to estimate the factors associated with unfavourable outcomes (failure, default, and death) and, specifically, default and death., Results: The proportion of unfavourable outcomes was 41.9% among MDR-TB and 81.5% among XDR-TB. Having less than 8 years of schooling, and being an Afro-Brazilian, under 40 years old and drug user were associated with unfavourable outcome and default. Bilateral disease, HIV positive, and comorbidities were associated with death. XDR-TB cases had a 4.7-fold higher odds of an unfavourable outcome, with 29.3% of such cases being not treated for multidrug resistance in the past., Conclusion: About 30% of XDR-TB cases may have occurred by primary transmission. The high rates of failure and death in this category reflect the limitation of treatment options. This highlights the urgency to incorporate new drugs in the treatment., Competing Interests: The authors have declared that no competing interests exist.

Background: The increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015., Methods: A retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15., Results: A total of 134 patients were selected. Median (IQR) age at admission was 33 (26-41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively)., Conclusions: Tailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

Background: Tuberculosis (TB) continues to be a public health challenge in Saudi Arabia, particularly for the elderly. This study was conducted to estimate mortality per 1000 person-year among TB and resistant TB cases and to identifying factors associated with mortality., Methods: This is a retrospective cohort study of 713 new TB cases at King Abdulaziz Medical City in Riyadh diagnosed between January 1, 2000, and December 31, 2016. Patient medical records and microbiology lab databases were used to identify TB cases. Through reviews were conducted of patients' medical records, including physician notes, physical examinations, radiology (scans and imaging), laboratory tests, and follow-up notes. Collected data include demographic information, clinical features, diagnoses, comorbidities, and death rates., Results: Of the 713 TB patients included in this study, 110 died, giving an average mortality rate of 22 per 1000 person-years (PY; 95% CI: 18.2-26.4). Elderly patients (≥ 60 years) had a higher mortality rate of 36.5 per 1000 PY (95% CI: 28.9-45.5). As age increases by one year, the hazard of mortality increase by 2.4% (aHR: 1.024 [95% CI: 1.009-1.039, P = 0.002]). Higher hazard of mortality was found among males (aHR: 2.014 [95% CI: 1.186-3.418, P = 0.010]). Patients with respiratory and other types of comorbidities and cancer had a higher mortality hazard (aHR: 1.898 [95% CI: 1.005-3.582, P = 0.048]; aHR: 2.346 [95% CI: 1.313-4.192, P = 0.004]; aHR: 3.292 [95% CI: 1.804-6.006, P = 0.001]), respectively. Multidrug-resistant TB (MDR-TB) was found in 2 cases (0.28%) (95% CI: 0.08-1.02), 1.68% were resistant to only one antibiotic, 0.14% had rifampicine-resistant TB (RR-TB), 0.28% had MDR-TB, and 0.14% had extensively drug-resistant TB (XDR-TB)., Conclusions: The mortality rate among TB patients was found to be 22 per 1000 person-year at our center. TB was associated with high mortality rates among males, the elderly, and patients with cancer, respiratory illness, and other comorbidities. Future clinical practice should include establishing an efficient TB diagnostic program and continued hazard assessment of TB treatment options.

Background: Extensively drug-resistant tuberculosis (XDR-TB)/HIV coinfection has been associated with high mortality and poor TB outcomes. We performed a prospective study to comprehensively characterize a cohort of patients with XDR-TB., Methods: Adult patients with XDR-TB were enrolled at treatment initiation at a TB referral hospital in KwaZulu-Natal Province, South Africa, and followed through the end of treatment. Clinical data, questionnaires, adherence data, and sputum were collected monthly. Whole genome sequencing was performed on baseline Mycobacterium tuberculosis (MTB) isolates. Treatment outcomes were defined using standard definitions., Results: One hundred five patients with XDR-TB (76.1% HIV-infected) were enrolled from August 2009 to July 2011. Among HIV-coinfected patients, 82.5% were on antiretroviral therapy initially and 93.8% cumulatively over the study period. At 24 months, 31.4% had a successful outcome and 68.6% had an unsuccessful outcome with 41% mortality. Antiretroviral therapy was associated with improved mortality in HIV-coinfected patients (P = 0.05), as was TB culture conversion (P < 0.0001). On whole genome sequencing, most strains were LAM4/KZN lineage (68%), with few single nucleotide polymorphism differences., Conclusions: Despite improved HIV care, treatment outcomes and mortality were only modestly improved compared with previous South African XDR-TB/HIV treatment cohorts. Of note, this study was completed before the introduction of new antimycobacterial agents (eg, bedaquiline and delamanid). As new TB drugs and regimens become available, it is important to monitor treatment to ensure that benefits seen in clinical trials are reproduced in high-burden, low-resource settings.

Background: In Peru, a treatment approach for extensively drug-resistant tuberculosis (XDR-TB) incorporating World Health Organization Group 5 drugs and patient-centred care has achieved 65% success. To extend this approach to pre-XDR-TB patients, we evaluated this population separately., Objective: To assess programmatic management of pre-XDR-TB., Method: Retrospective study using the official national registry from 2011 to 2014. Cases were separately evaluated according to resistance to fluoroquinolones (FQs) (pre-XDR-F) or to second-line injectables (SLIs) (pre-XDR-I)., Results: Of 610 pre-XDR-TB patients, 120 (20%) had pre-XDR-F and 490 (80%) had pre-XDR-I. Pre-XDR-F cases were older (34 years vs. 28 years, P < 0.001) and a higher proportion had previously received two or more regimens (70% vs. 38%, P < 0.001). Among the 452 patients who started treatment in 2011-2013, treatment success was 43.3%, 26.5% were lost to follow-up, 12.1% died and 13.7% failed treatment. Success was higher in pre-XDR-I (48.5%) than pre-XDR-F (21.4%) patients. History of previous treatment (OR 2.23, 95%CI 1.52-3.38) and pre-XDR-F (OR 2.39, CI 1.18-4.83) were associated with unsuccessful outcomes., Conclusion: Programmatic management of pre-XDR-TB has not been successful, particularly in pre-XDR-F patients, with lower rates of success than those achieved in the same setting for XDR-TB. The strategy used for XDR-TB should be extended to pre-XDR-TB patients in Peru.

Background: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline., Methods: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment., Findings: 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens., Interpretation: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Limited treatment options of extensive drug-resistant tuberculosis (XDR-TB) have led to its high mortality worldwide. Relevant data about mortality of XDR-TB patients in literature are limited and likely underestimate the real situation in China, since the majority of patients with XDR-TB are lost to follow-up after discharge from TB hospitals. In this study, we sought to investigate the mortality and associated risk factors of Human Immunodeficiency Virus (HIV)-negative patients with XDR-TB in China., Methods: All patients who were diagnosed with XDR-TB for the first time in four TB care centers across China between March 2013 and February 2015 were consecutively enrolled. Active tracking through contacting patients or family members by phone or home visit was conducted to obtain patients' survival information by February 2017. Multivariable Cox regression models were used to evaluate factors associated with mortality., Results: Among 67 patients enrolled, the mean age was 48.7 (Standard Deviation [SD] = 16.7) years, and 51 (76%) were men. Fourteen patients (21%) were treatment naïve at diagnosis indicating primary transmission. 58 (86.8%) patients remained positive for sputum smear or culture when discharged. During a median follow-up period of 32 months, 20 deaths occurred, with an overall mortality of 128 per 1000 person-years. Among patients who were dead, the median survival was 5.4 months (interquartile range [IQR]: 2.2-17.8). Seventeen (85%) of them died at home, among whom the median interval from discharge to death was 8.4 months (IQR: 2.0-18.2). In Cox proportional hazards regression models, body mass index (BMI) < 18.5 kg/m 2 (adjusted hazard ratio [aHR] = 4.5, 95% confidence interval [CI]: 1.3-15.7), smoking (aHR = 4.7, 95%CI:1.7-13.2), or a clinically significant comorbidity including heart, lung, liver, or renal disorders or auto-immune diseases (aHR = 3.5, 95%CI: 1.3-9.4), were factors independently associated with increased mortality., Conclusion: Our study suggested an alarming situation of XDR-TB patients in China with a sizable proportion of newly transmitted cases, a high mortality rate, and a long period in community. This observation calls for urgent actions to improve XDR-TB case management in China, including providing regimens with high chances of cure and palliative care, and enhanced infection control measures.

Optimal treatment regimens for patients with extensively drug-resistant tuberculosis (XDR-TB) remain unclear. Long-term prospective outcome data comparing XDR-TB regimens with and without bedaquiline from an endemic setting are lacking.We prospectively followed-up 272 South African patients (49.3% HIV-infected; median CD4 count 169 cells·µL -1 ) with newly diagnosed XDR-TB between 2008 and 2017. Outcomes were compared between those who had not received bedaquiline (pre-2013; n=204) and those who had (post-2013; n=68; 80.9% received linezolid in addition).The 24-month favourable outcome rate was substantially better in the bedaquiline versus the non-bedaquiline group (66.2% (45 out of 68) versus 13.2% (27 out of 204); p<0.001). In addition, the bedaquiline group exhibited reduced 24-month rates of treatment failure (5.9% versus 26.0%; p<0.001) and default (1.5% versus 15.2%; p<0.001). However, linezolid was withdrawn in 32.7% (18 out of 55) of patients in the bedaquiline group because of adverse events. Admission weight >50 kg, an increasing number of anti-TB drugs and bedaquiline were independent predictors of survival (the bedaquiline survival effect remained significant in HIV-infected persons, irrespective of CD4 count).XDR-TB patients receiving a backbone of bedaquiline and linezolid had substantially better favourable outcomes compared to those not using these drugs. These data inform the selection of XDR-TB treatment regimens and roll-out of newer drugs in TB-endemic countries., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

Despite the low expensive and effective four-drug treatment regimen (isoniazid, rifampicin, pyrazinamide and ethambutol) was introduced 40 years ago, TB continues to cause considerable morbidity and mortality worldwide. In 2015, the WHO estimated a total of 10.4 million new tuberculosis (TB) cases worldwide. Currently, the increased number of multidrug-resistant (MDR-TB), extensively-drug resistant (XDR-TB) and in some recent reports, totally drug-resistant TB (TDR-TB) cases raises concerns about this disease. MDR-TB and XDR-TB have lower cure rates and higher mortality levels due to treatment problems. Novel drugs and regimens for all forms of TB have emerged in recent years. Moreover, scientific interest has recently increased in the field of host-directed therapies (HDTs) in order to identify new treatments for MDR-TB. In this review, we offer an update on the discovery of new drugs for TB therapy with a glance at molecular mechanisms leading to drug resistance in Mycobacterium tuberculosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Cavitary disease and bilateral lesions are among the risk factors for poor outcome of pulmonary tuberculosis (TB). Our aim was to explore the value and limits of surgery in patients with advanced TB., Methods: A retrospective study of 57 consecutive patients who underwent thoracic surgery for culture-positive bilateral cavitary pulmonary TB was performed. Forty-four (77.2%) patients were men and 13 (22.8%) patients were women; their ages were in the range of 18-61 years. Twenty-two (38.6%) patients had multidrug-resistant (MDR) TB and 35 (61.4%) patients had extensively drug-resistant (XDR) TB confirmed with cultures. On admission, 49 (86.0%) patients had sputum smear microscopy positive for acid-fast bacilli. The main indication for surgery was treatment failure manifested as contagious persisting cavities despite best available therapy. The surgical procedures included combinations of pulmonary resections of different levels, selective thoracoplasties and/or endobronchial valve treatment. The operations were performed consecutively, starting with the most affected side. TB therapy preceded the operation for a minimum of 6 months and was continued after the operation on the basis of the patient's susceptibility to drugs for Mycobacterium tuberculosis., Results: We performed 121 operations: 42 in 22 patients with MDR TB (1.9 operations per patient) and 79 procedures in 35 patients with XDR TB (2.3 operations per patient). No deaths occurred in the 1st year. Two late deaths followed, 1 unrelated to and 1 due to TB progression. Ten major complications (1 complication per patient) developed: main bronchus stump fistula (n = 4), prolonged air leak (n = 3), respiratory failure (n = 2) and wound seroma (n = 1). At the 1-month follow-up visit, sputum smear conversion was observed in 11 (68.8%) patients with MDR and in 15 (45.5%) patients with XDR TB. At the late (20-36 months) follow-up visit, culture negativity was achieved in 21 (95.5%) patients with MDR TB and in 23 (65.7%) patients with XDR TB (P = 0.015)., Conclusions: Thoracic surgery may significantly improve patients' outcomes and even result in a cure in a good portion of patients with bilateral cavitary MDR and XDR TB and should be considered as the essential element of multimodality treatment for MDR and XDR TB, even in patients with bilateral cavitary disease and borderline respiratory reserves., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The worldwide emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has posed additional challenges for global tuberculosis (TB) control efforts, as limited treatment options are available and treatment outcomes are often sub-optimal. This study determined treatment outcomes among a cohort of MDR-TB and XDR-TB patients in Hunan Province, China, and identified factors associated with poor treatment outcomes., Methods: We conducted a retrospective study using data obtained from medical records of TB patients in Hunan Chest Hospital, and from the internet-based TB management information system managed by the Tuberculosis Control Institute of Hunan Province, for the period 2011 to 2014. Treatment outcomes were assessed for patients diagnosed with MDR-TB (TB resistant to at least isoniazid and rifampicin) and XDR-TB (MDR-TB plus resistance to any fluoroquinolone and at least 1 second-line injectable drug). Cumulative incidence functions were used to estimate time to events (i.e. poor treatment outcomes, loss to follow-up, and unfavourable treatment outcomes); and a competing-risks survival regression model was used to identify predictors of treatment outcomes., Result: Of 481 bacteriologically-confirmed patients, with a mean age of 40 years (standard deviation SD ± 13 years), 10 (2%) had XDR-TB and the remainder (471; 98%) had MDR-TB. For the entire cohort, treatment success was 57% (n = 275); 58% (n = 272) for MDR-TB and 30% (n = 3) for XDR-TB. Overall, 27% were lost to follow-up (n = 130), 27% (n = 126) for MDR-TB and 40% (n = 4) for XDR-TB; and 16% had a poor treatment outcome (n = 76), 15% for MDR-TB and 30% (n = 3) for XDR-TB. Of the 10 XDR-TB patients, 3 (30%) completed treatment, 3 (30%) died and 4 (40%) were lost to follow-up. Of the 471 MDR-TB patients, 258 (57%) were cured, 16 (3%) completed treatment, 13 (3%) died, 60 (13%) experienced treatment failure, and 126 (27%) were lost to follow-up. Resistance to ofloxacin was an independent predictor of poor (AHR = 3.1; 95%CI = 1.5, 6.3), and unfavourable (AHR = 1.7; 95%CI = 1.07, 2.9) treatment outcomes. Patients who started treatment during 2011-2012 (AHR = 2.8; 95% CI = 1.5, 5.3) and 2013 (AHR = 2.1; 95% CI = 1.2, 3.9) had poorer treatment outcomes compared to patients who started treatment during 2014., Conclusion: Patients with MDR-TB and XDR-TB had low rates of treatment success in Hunan Province, especially among patients who started treatment during 2011 to 2013, with evidence of improved treatment outcomes in 2014. Resistance to ofloxacin was an independent predictor of poor treatment outcomes.

Background: Extensively Drug-Resistant (XDR) Tuberculosis (TB) has posed a great threat to global health and finance systems, especially for developing countries with high TB and Multidrug-Resistant (MDR) TB burden., Methods: We retrospectively analyzed HIV-uninfected TB case confirmed and treated in Shandong Provincial Chest Hospital (SPCH) between January 2008 and December 2015. Unique characteristics of XDR-TB were identified; its longitudinal changes and survival were analyzed., Results: Between January 2008 and December 2015, a total of 144 cases were confirmed to be XDR-TB (2.5% of 5663 culture-confirmed TB cases; 27.9% of 516 MDR-TB cases). The proportion of XDR TB cases among MDR-TB cases has increased from 26.5% in 2008 to 44.5% in 2014 (Chi-Square test for trends: P < 0.01). Among the 144 XDR-TB cases, 21 patients (14.6%) had treatment success, 123 (85.1%) had poor treatment outcomes. Mortality was higher among XDR-TB cases than among MDR TB cases (8.3% vs. 3.8%, P = 0.033) and drug-susceptible TB cases (8.3% vs. 2.1%, P < 0.01)., Conclusions: XDR-TB cases comprise a substantial and increasing fraction of MDR-TB cases, causing poor treatment outcomes and high mortalities. Early drug susceptibility testing, adequate TB treatment and efficient infection control must be in place in future TB control strategies.

Objective: To describe the characteristics and assess the factors of mortality in drug-resistant tuberculosis patients., Methods: This retrospective study was conducted at 11 programmatic management of drug-resistant tuberculosis centres located in different cities of the Punjab province of Pakistan, and comprised record of patients with drug-resistant tuberculosis from January 2010 to September 2015. Data was retrieved from patient medical records using electronic nominal review system of the provincial tuberculosis control programme. Cox's proportional hazards model was performed to identify the factors for death. SPSS 17 was used for data analysis., Results: Of the 1,136 patients, 472(41.5%) died during treatment and 664(58.5%) were declared cured or their treatment was completed. Of those who expired, 97(20.6%) expired within 3 months of the start of the treatment. Men had higher rates of death which was not significantly associated with the drug-resistant tuberculosis mortality (p>0.05)., Conclusions: The number of patients who died from drug-resistant tuberculosis treatment was relatively high.

Background: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies., Methods: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179)., Findings: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid., Interpretation: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing., Funding: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In July 2013, a passenger died of infectious extensively drug-resistant tuberculosis (XDR-TB) on board of an aircraft after a 3-hour flight from Turkey to Germany. Initial information indicated the patient had moved about the aircraft coughing blood. We thus aimed to contact and inform all persons exposed within the aircraft and to test them for newly acquired TB infection. Two-stage testing within 8 weeks from exposure and at least 8 weeks after exposure was suggested, using either interferon gamma release assays (IGRAs) or tuberculin skin test (TST). The TST cut-off was defined at a diameter > 10 mm; for differentiation between conversion and boosting, conversion was defined as increase of skin induration > 5 mm. Overall, 155 passengers and seven crew members were included in the investigation: the questionnaire response rate was 83%; 112 (69%) persons were tested at least once for TB infection. In one passenger, who sat next to the area where the patient died, a test conversion was registered. As of March 2017, no secondary active TB cases have been reported. We describe an unusual situation in which we applied contact tracing beyond existing European guidelines; we found one latent tuberculosis infection in a passenger, which we consider probably newly acquired., (This article is copyright of The Authors, 2017.)

Background: The quality of care for patients with TB in Eastern Europe has improved significantly; nevertheless drug resistance rates remain high. We analysed survival in a cohort of patients with multidrug-resistant and extensively drug-resistant (MDR-/XDR-) TB from Latvia, Lithuania, Estonia and Bucharest city., Methods: Consecutive adult new and retreatment patients with culture-confirmed pulmonary MDR-TB registered for treatment in 2009 (and in 2007 in Latvia) were enrolled; prospective survival information was collected., Results: A total of 737 patients were included into the cohort. Of all MDR-TB cases, 46% were newly diagnosed; 56% of all MDR-TB cases had no additional resistance to fluoroquinolones or injectable agents, 33% had pre-XDR-TB and 11% XDR-TB. Median survival was 5.9 years in patients with MDR-TB and XDR-TB; 1.9 years in patients coinfected with HIV. Older age, male gender, alcohol abuse, retirement, co-morbidities, extrapulmonary involvement and HIV coinfection independently worsened survival. Inclusion of fluoroquinolones and injectable agents improves survival in patients with MDR-TB. Pre-XDR and XDR status did not significantly shorten survival as long as fluoroquinolones and injectable agents were part of the regimen. Moxifloxacin seems to improve survival in ofloxacin-susceptible patients when compared with older generation fluoroquinolones., Conclusions: The burden of additional resistances in patients with MDR-TB is high likely due to primary transmission of resistant strains. Social and programmatic factors including management of alcohol dependency, expansion of HIV testing and antiretroviral treatment need to be addressed in order to achieve cure and to interrupt transmission. The role of last generation fluoroquinolones and injectable agents in treatment of patients with pre-XDR and XDR-TB needs to be further investigated., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa., Methods: Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays., Results: A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%)., Conclusions: Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.

Setting: Pediatric multidrug-resistant tuberculosis (MDR-TB) is complicated by difficult diagnosis, complex treatment, and high mortality. In South Africa, these challenges are amplified by human immunodeficiency virus (HIV) co-infection; however, evidence on treatment outcomes among co-infected children is limited., Objective: Using conventional and new pediatric definitions, to describe treatment outcomes and identify risk factors for unfavorable outcome and mortality in children aged <15 years with MDR-TB or extensively drug-resistant TB (XDR-TB) in KwaZulu-Natal, South Africa., Design: Retrospective cohort study in a regional TB referral hospital., Results: From January 2009 to June 2010, 84 children (median age 8 years, IQR 4-12) with MDR-TB (n = 78) or XDR-TB (n = 6) initiated treatment. Sixty-four (77%) were HIV-positive and 62 (97%) received antiretroviral therapy. Sixty-six (79%) achieved favorable treatment outcomes. Overall mortality was 11% (n = 9) at 18 months after initiation of treatment. Malnutrition (aOR 27.4, 95%CI 2.7-278.7) and severe radiographic findings (aOR 4.68, 95%CI 1.01-21.9) were associated with unfavorable outcome. New pediatric outcome definitions increased the proportion classified as cured., Conclusion: It is possible to successfully treat pediatric MDR-TB-HIV even in resource-poor settings. Malnutrition is a marker for severe TB-HIV disease, and is a potential target for future interventions in these patients.

Background: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases., Objective: To evaluate the potential cost-effectiveness of rapid DST for SLDs., Design: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST., Results: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries., Conclusion: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Background: Long-term treatment-related outcomes in patients with extensively drug-resistant (XDR) tuberculosis are unknown. We followed up a cohort of patients to address knowledge gaps., Methods: Between March, 2008, and August, 2012, we prospectively followed up a cohort of 107 patients from three provinces in South Africa, who had been diagnosed with XDR tuberculosis between August 2002, and February, 2008. Available isolates from 56 patients were genotyped to establish strain type and used for extended susceptibility testing., Findings: All patients were treated empirically as inpatients with a median of eight drugs (IQR six to ten). 44 patients (41%) had HIV. 36 (64%) of 56 isolates were resistant to at least eight drugs, and resistance to an increasing number of drugs was associated with the Beijing genotype (p=0·01). After 24 months of follow-up, 17 patients (16%) had a favourable outcome (ie, treatment cure or completion), 49 (46%) had died, seven (7%) had defaulted (interruption of treatment for at least 2 consecutive months), and 25 (23%) had failed treatment. At 60 months, 12 patients (11%) had a favourable outcome, 78 (73%) had died, four (4%) had defaulted, and 11 (10%) had failed treatment. 45 patients were discharged from hospital, of whom 26 (58%) had achieved sputum culture conversion and 19 (42%) had failed treatment. Median survival of patients who had failed treatment from time of discharge was 19·84 months (IQR 4·16-26·04). Clustering of cases and transmission within families containing a patient who had failed treatment and been discharged were shown with genotypic methods. Net sputum culture conversion occurred in 22 patients (21%) and median time to net culture conversion was 8·7 months (IQR 5·6-26·4). Independent predictors of probability of net culture conversion were no history of multidrug-resistant tuberculosis (p=0·0007) and use of clofazamine (p=0·0069). Independent overall predictors of survival were net culture conversion (p<0·0001) and treatment with clofazamine (p=0·021). Antiretroviral therapy was also a predictor of survival in patients with HIV (p=0·003)., Interpretation: In South Africa, long-term outcomes in patients with XDR tuberculosis are poor, irrespective of HIV status. Because appropriate long-stay or palliative care facilities are scarce, substantial numbers of patients with XDR tuberculosis who have failed treatment and have positive sputum cultures are being discharged from hospital and are likely to transmit disease into the wider community. Testing of new combined regimens is needed urgently and policy makers should implement interventions to minimise disease spread by patients who fail treatment., Funding: European and Developing Countries Clinical Trials Partnership, South African National Research Foundation (SARChI), and the South African Medical Research Council., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Without better vaccines it is unlikely that tuberculosis (TB) will ever be eliminated. An investment of ∼ €560 million is considered necessary to develop a new, effective vaccine in the European Union (EU). However, less is known about the costs of TB disease in the EU. We performed a systematic review of literature and institutional websites addressing the 27 EU members to summarise cost data. We searched MEDLINE, EMBASE and Cochrane bibliographies for relevant articles. Combining direct and indirect costs, we arrived at an average per-TB case costs in the original EU-15 states plus Cyprus, Malta and Slovenia of €10 282 for drug-susceptible TB, €57 213 for multidrug resistant (MDR)-TB and €170 744 for extensively drug resistant (XDR)-TB. In the remaining new EU states, costs amounted to €3427 for drug-susceptible TB and €24 166 for MDR-TB/XDR-TB. For the 70 340 susceptible TB cases, 1488 MDR-TB and 136 XDR-TB cases notified in 2011 costs of €536 890 315 accumulated in 2012. In the same year, the 103 104 disability-adjusted life years caused by these cases, when stated in monetary terms, amounted to a total of €5 361 408 000. Thus, the resulting economic burden of TB in the EU clearly outweighs the cost of investing in more efficient vaccines against TB.

Background: The Médecins Sans Frontières project of Uzbekistan has provided multidrug-resistant tuberculosis treatment in the Karakalpakstan region since 2003. Rates of default from treatment have been high, despite psychosocial support, increasing particularly since programme scale-up in 2007. We aimed to determine factors associated with default in multi- and extensively drug-resistant tuberculosis patients who started treatment between 2003 and 2008 and thus had finished approximately 2 years of treatment by the end of 2010., Methods: A retrospective cohort analysis of multi- and extensively drug-resistant tuberculosis patients enrolled in treatment between 2003 and 2008 compared baseline demographic characteristics and possible risk factors for default. Default was defined as missing ≥60 consecutive days of treatment (all drugs). Data were routinely collected during treatment and entered in a database. Potential risk factors for default were assessed in univariate analysis using chi-square test and in multivariate analysis with logistic regression., Results: 20% (142/710) of patients defaulted after a median of 6 months treatment (IQR 2.6-9.9). Factors associated with default included severity of resistance patterns (pre-extensively drug-resistant/extensively drug-resistant tuberculosis adjusted odds ratio 0.52, 95%CI: 0.31-0.86), previous default (2.38, 1.09-5.24) and age >45 years (1.77, 1.10-2.87). The default rate was 14% (42/294) for patients enrolled 2003-2006 and 24% (100/416) for 2007-2008 enrolments (p = 0.001)., Conclusions: Default from treatment was high and increased with programme scale-up. It is essential to ensure scale-up of treatment is accompanied with scale-up of staff and patient support. A successful first course of tuberculosis treatment is important; patients who had previously defaulted were at increased risk of default and death. The protective effect of severe resistance profiles suggests that understanding disease severity or fear may motivate against default. Targeted health education and support for at-risk patients after 5 months of treatment when many begin to feel better may decrease default.

Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo-controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Treatment outcomes, as assessed by clinicians and defined by the World Health Organization, were categorised as favourable and unfavourable. Delamanid treatment groups were combined for analysis, based on their duration of treatment. In total, for 421 (87.5%) out of 481 patients from the original randomised controlled trial, consent was granted for follow-up assessments. Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB. This analysis suggests that treatment with delamanid for 6 months in combination with an optimised background regimen can improve outcomes and reduce mortality among patients with both multidrug-resistant and extensively drug-resistant TB.

Background: New approaches are needed in the treatment of multidrug-resistant and extensively drug-resistant pulmonary tuberculosis (M/XDR-PTB). We evaluated the role of adjunctive surgical therapy in the treatment of M/XDR-PTB in the setting of directly observed treatment strategy (DOTS)-Plus implementation., Methods: We conducted an observational cohort study consisting of M/XDR-PTB patients who underwent thoracic surgery at the National Tuberculosis Center in Tbilisi, Georgia between October 2008 and February 2011. Indications for surgery included presence of M/XDR-PTB, localized pulmonary disease, fit to undergo surgery, and either medical treatment failure or such extensive drug resistance that failure was likely. Second-line anti-tuberculosis medical therapy was administered per World Health Organization (WHO) recommendations., Results: Seventy-five patients (51 MDR, 24 XDR) with PTB underwent adjunctive thoracic surgery. Median age was 30 years and average duration of preoperative M/XDR-PTB medical therapy was 342 days. The following surgical procedures were performed: pneumonectomy (11%), lobectomy (54%), and segmentectomy (35%). Mean postoperative follow-up time was 372 days. Of 72 patients with evaluable outcomes, 59 (82%) had favorable outcomes including 90% of MDR and 67% of XDR-TB patients. There was no postoperative mortality; postoperative complications occurred in 7 patients (9%). Risk factors for poor treatment outcomes in univariate analysis included bilateral disease, XDR, increasing effective drugs received, positive preoperative sputum culture, and major postoperative surgical complication., Conclusions: Patients with M/XDR-PTB undergoing adjunctive thoracic surgery had high rates of favorable outcomes, no surgical-related mortality, and low rates of complications. Adjunctive surgery appears to play an important role in the treatment of select patients with M/XDR-PTB., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Treatment-related outcomes in patients with extensively drug-resistant tuberculosis (XDR-TB) are poor. However, data about the type, frequency and severity of presumed drug-associated adverse events (AEs) and their association with treatment-related outcomes in patients with XDR-TB are scarce., Methods: Case records of 115 South-African XDR-TB patients were retrospectively reviewed by a trained researcher. AEs were estimated and graded according to severity [grade 0 = none; grade 1-2 = mild to moderate; and grade 3-5 = severe (drug stopped, life-threatening or death)]., Findings: 161 AEs were experienced by 67/115(58%) patients: 23/67(34%) required modification of treatment, the offending drug was discontinued in 19/67(28%), reactions were life-threatening in 2/67(3.0%), and 6/67(9.0%) died. ∼50% of the patients were still on treatment at the time of data capture. Sputum culture-conversion was less likely in those with severe (grade 3-5) vs. grade 0-2 AEs [2/27(7%) vs. 24/88(27%); p = 0.02]. The type, frequency and severity of AEs was similar in HIV-infected and uninfected patients. Capreomycin, which was empirically administered in most cases, was withdrawn in 14/104(14%) patients, implicated in (14/34) 41% of the total drug withdrawals, and was associated with all 6 deaths in the severe AE group (renal failure in five patients and hypokalemia in one patient)., Conclusion: Drug-associated AEs occur commonly with XDR-TB treatment, are often severe, frequently interrupt therapy, and negatively impact on culture conversion outcomes. These preliminary data inform on the need for standardised strategies (including pre-treatment counselling, early detection, monitoring, and follow-up) and less toxic drugs to optimally manage patients with XDR-TB.

We present the first fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an injecting drug user (IDU) in Athens, Greece, co-infected with human immunodeficiency virus and hepatitis C virus and discuss the implications for public health. Despite immediate initiation of treatment, the patient's condition gradually deteriorated and he died 16 days after hospital admission because of multiple organ failure. The contact tracing investigation revealed no further infections among the patient's contacts.

High mortality rates have been reported for patients co-infected with extensively drug-resistant tuberculosis (XDR-TB) and HIV, but treatment outcomes have not been reported. We report treatment outcomes for adult XDR TB patients in KwaZulu-Natal Province, South Africa. Initial data were obtained retrospectively, and outcomes were obtained prospectively during 24 months of treatment. A total of 114 XDR TB patients were treated (median 6 drugs, range 3-9 drugs); 82 (73%) were HIV positive and 50 (61%) were receiving antiretroviral therapy. After receiving treatment for 24 months, 48 (42%) of 114 patients died, 25 (22%) were cured or successfully completed treatment, 19 (17%) withdrew from the study, and 22 (19%) showed treatment failure. A higher number of deaths occurred among HIV-positive patients not receiving antiretroviral therapy and among patients who did not show sputum culture conversion. Culture conversion was a major predictor of survival but was poorly predictive (51%) of successful treatment outcome.

Objective: To assess the treatment outcome of the first Green Light Committee (GLC) approved countrywide management of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) in Estonia and to evaluate risk factors contributing to TB recurrence over 8 years of follow-up., Design: Prospective assessment of MDR- and XDR-TB patients starting second-line anti-tuberculosis drug treatment between 1 August 2001 and 31 July 2003, with follow-up until 31 December 2010., Results: In 211 MDR- and XDR-TB patients, treatment success was 61.1%; 22.3% defaulted, 8.5% failed and 8.1% died. TB recurrence among successfully treated patients was 8.5%, with no significant difference between XDR-TB and MDR-TB. TB recurrence was associated with resistance to all injectables (HR 2.27, 95%CI 1.16-5.06, P = 0.046), resistance to a greater number of drugs (HR 1.35, 95%CI 1.11-1.64, P = 0.003), and sputum smear positivity (HR 2.16, 95%CI 1.16-4.00, P = 0.016). A history of previous TB treatment was associated with TB recurrence among successfully treated patients (HR 4.28, 95%CI 1.13-16.15, P = 0.032)., Conclusions: The internationally recommended Category IV treatment regimens are sufficiently effective to cure 75% of adherent MDR- and XDR-TB patients. A history of previous treatment, resistance to all injectable agents and resistance to a greater number of drugs increase the recurrence of MDR- and XDR-TB.

Multidrug-resistant tuberculosis (MDRTB) infections that continue to increase in frequency globally have progressed to become extremely drug-resistant tuberculosis (XDRTB). The therapeutic problems associated with MDRTB pale in comparison to those for XDRTB where mortality is high. This mini-review highlights the evidence that supports the use of the phenothiazine neuroleptic thioridazine for the therapy of XDRTB. Although thioridazine does produce some serious side-effects, the poor prognosis associated with an XDRTB infection of a patient that presents with AIDS merits that the use of thioridazine for therapy of XDRTB is seriously considered. A recommended protocol is presented.

Background: Drug-resistant tuberculosis (TB) is a major threat to global public health. Patients with extensively drug-resistant TB (XDR-TB), particularly those with HIV-coinfection, experience high and accelerated mortality with limited available interventions. To determine modifiable factors associated with survival, we evaluated XDR-TB patients from a community-based hospital in rural South Africa where a large number of XDR-TB cases were first detected., Methodology/principal Findings: A retrospective case control study was conducted of XDR-TB patients diagnosed from 2005-2008. Survivors, those alive at 180 days from diagnostic sputum collection date, were compared with controls who died within 180 days. Clinical, laboratory and microbiological correlates of survival were assessed in 69 survivors (median survival 565 days [IQR 384-774] and 73 non-survivors (median survival 34 days [IQR 18-90]). Among 129 HIV+ patients, multivariate analyses of modifiable factors demonstrated that negative AFB smear (AOR 8.4, CI 1.84-38.21), a lower laboratory index of routine laboratory findings (AOR 0.48, CI 0.22-1.02), CD4>200 cells/mm(3) (AOR 11.53, 1.1-119.32), and receipt of antiretroviral therapy (AOR 20.9, CI 1.16-376.83) were independently associated with survival from XDR-TB., Conclusions/significance: Survival from XDR-TB with HIV-coinfection is associated with less advanced stages of both diseases at time of diagnosis, absence of laboratory markers indicative of multiorgan dysfunction, and provision of antiretroviral therapy. Survival can be increased by addressing these modifiable risk factors through policy changes and improved clinical management. Health planners and clinicians should develop programmes focusing on earlier case finding and integration of HIV and drug-resistant TB diagnostic, therapeutic, and preventive activities.

Setting: Recent studies suggest that the prevalence of drug-resistant tuberculosis (TB) in sub-Saharan Africa may be rising. This is of concern, as human immunodeficiency virus (HIV) co-infection in multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has been associated with exceedingly high mortality rates., Objective: To identify risk factors associated with mortality in MDR- and XDR-TB patients co-infected with HIV in South Africa., Design: Case-control study of patients who died of all causes within 2 years of diagnosis with MDR- or XDR-TB., Results: Among 123 MDR-TB patients, 78 (63%) died following diagnosis. CD4 count ≤ 50 (HR 4.64, P = 0.01) and 51-200 cells/mm(3) (HR 4.17, P = 0.008) were the strongest independent risk factors for mortality. Among 139 XDR-TB patients, 111 (80%) died. CD4 count ≤ 50 cells/mm(3) (HR 4.46, P = 0.01) and resistance to all six drugs tested (HR 2.54, P = 0.04) were the principal risk factors. Use of antiretroviral therapy (ART) was protective (HR 0.34, P = 0.009)., Conclusions: Mortality due to MDR- and XDR-TB was associated with greater degree of immunosuppression and drug resistance. Efforts to reduce mortality must focus on preventing the amplification of resistance by strengthening TB treatment programs, as well as reducing the pool of immunosuppressed HIV-infected patients through aggressive HIV testing and ART initiation.

Ten extensively drug-resistant tuberculosis (XDR-TB) patients were identified among 104 human immunodeficiency virus negative multidrug-resistant tuberculosis (MDR-TB) patients treated at the Tuberculosis Research Centre, Chennai, India, in two different cohorts between 1999-2003 and 2006-2007. They were managed with individualised treatment regimens. At the time of diagnosis of MDR-TB, one patient had XDR-TB and three had initial ofloxacin resistance. One patient who had had a lobectomy in addition to chemotherapy became bacteriologically negative, three died, three defaulted and the remaining three, who are bacteriologically positive, are still continuing treatment. Although based on a small number of patients, our results have not been encouraging.

There are limited data on the temporal relationship between the regional introduction of multidrug-resistant tuberculosis (MDR-TB) treatment and the subsequent development of extensively drug-resistant TB (XDR-TB). The first XDR-TB case in the Western Cape province of South Africa was recorded in 1992, approximately 5 - 7 years after the regional introduction of MDR-TB-like treatment. Between 1990 and 2002 we identified 48 patients with XDR-TB in the Cape Metropole region of the Western Cape province. Patients were predominantly HIV-uninfected and median survival was 10.8 months. XDR-TB has therefore been present in the Western Cape at least since 1992. These data inform public health policy relevant to the introduction of new anti-TB drug regimens.

Tuberculosis is the second most common cause of death from an infectious disease after HIV/AIDS and the leading cause of death from an infectious disease in HIV-co-infected patients. Currently, drug susceptible TB is treated with a four drug regimen given over a period of two months followed by two drugs for four months. Drug resistant tuberculosis requires more complex and longer treatment with alternative substances. New antituberculosis drugs are currently being developed and investigated and are urgently needed to treat drug susceptible and drug resistant TB.

Background: Tuberculosis is a leading cause of morbidity and mortality worldwide. Patients with extensively drug-resistant tuberculosis (XDR-TB) have had high mortality rates, especially when coinfected with HIV., Methods: A retrospective cohort study of the first 206 patients treated for XDR-TB in Eastern Cape Province, South Africa, October 2006 to January 2008, a province that has treated multidrug-resistant tuberculosis since 2000. All 206 patients were hospitalized for treatment until monthly sputum specimens were culture negative., Results: Sixty-five patients diagnosed with XDR-TB died before XDR-TB treatment start. Among 195 patients starting treatment with a known HIV status, 108 (55.4%) were HIV positive, and 86 patients (44.1%) died during the first year of treatment. HIV-positive patients receiving antiretroviral treatment (ARVs) fared and HIV-negative patients, and more of both these groups survived than HIV-positive patients not on ARVs. However, HIV-negative patients experienced more serious adverse events requiring the withdrawal of medications than did HIV-positive patients, regardless of the use of ARVs., Conclusions: Experience in Eastern Cape Province, South Africa, suggests that patients can be treated for both XDR-TB and HIV. We have also shown that such combination therapy can be well tolerated by patients.

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.

Background: Extensively drug-resistant tuberculosis (XDR-TB) has recently emerged as a global public health problem. The objective of this study was to investigate the clinical characteristics, management and outcomes of human immunodeficiency virus-negative patients with XDR-TB at a specialist TB hospital in Shanghai, China., Methods: From July 2007 to June 2009 we analyzed TB patients with culture-proven XDR-TB at a specialist TB hospital in Shanghai., Results: Among 1156 TB cases, all culture-positive for Mycobacterium tuberculosis complex, 494 cases (42.7%) were classified as MDR-TB; 126 cases (10.9%) were XDR-TB. At least 3 lung fields were involved in 90.5% of XDR-TB patients and in 80.7% of other MDR-TB patients (p = 0.008). Of the XDR-TB cases, 40.5% were complicated by diabetes and other diseases, significantly higher compared with the other MDR-TB cases (p = 0.002). The rates of resistance to all drugs except isoniazid and rifampicin were significantly higher in patients with XDR-TB than in patients with other MDR-TB (p < 0.001). Treatment failure was more common in patients with XDR-TB than in those with other MDR-TB (p < 0.001), whereas the mortality and default rates did not differ significantly., Conclusions: The prevalence of XDR-TB is high in some areas of China. The clinical treatment outcome for XDR-TB is usually very poor.

Rationale: Few large-scale studies have investigated multidrug-resistant tuberculosis (MDR-TB) treatment outcomes relative to drug-resistance patterns., Objectives: To assess the impact of additional drug resistances on treatment outcomes and long-term survival in a large HIV-negative MDR-TB cohort., Methods: Treatment outcomes and long-term survival of patients with MDR-TB newly diagnosed or retreated in 2000 to 2002 were retrospectively analyzed based on drug-resistance patterns after 5-8 years of follow-up., Measurements and Main Results: Of 1,407 patients with MDR-TB, 75 (5.3%) had extensively drug-resistant TB (XDR-TB(re)) by the revised definition; 159 (11.3%) had ofloxacin-resistant pre-XDR-TB (pre-XDR-TB(o)); and 117 (8.3%) had second-line injectable drug (SLID)-resistant pre-XDR-TB (pre-XDR-TB(s)). Patients with XDR-TB(re) showed the lowest treatment success rate (29.3%) and the poorest long-term survival, and XDR-TB(re) was more strongly associated with long-term mortality than XDR-TB as originally defined (hazards ratio [HR], 3.15; 95% confidence interval [CI], 2.06-4.83; P < 0.001 vs. HR, 2.15; 95% CI, 1.49-3.09; P < 0.001). Patients with either form of pre-XDR-TB showed poorer cumulative survival than those with ofloxacin-susceptible/SLID-susceptible MDR-TB (P < 0.05 for each comparison). Although streptomycin susceptibility did not affect the treatment outcomes of patients with pre-XDR-TB, streptomycin-resistant pre-XDR-TB was more strongly associated with long-term mortality than ofloxacin-susceptible/SLID-susceptible MDR-TB (HR, 2.17; 95% CI, 1.22-3.84; P < 0.008 for pre-XDR-TB(o); and HR, 2.69; 95% CI, 1.40-5.16; P = 0.003 for pre-XDR-TB(s))., Conclusions: The revised XDR-TB definition is appropriate for defining patients with MDR-TB with the poorest outcomes. Both pre-XDR-TB(o) and pre-XDR-TB(s) were independently associated with poor long-term survival in patients with MDR-TB. SM susceptibility was linked to better survival in patients with pre-XDR-TB.

Background: Data from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes., Methods: In a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes-mortality and culture conversion., Findings: 195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0.13). Treatment with moxifloxacin (hazard ratio 0.11, 95% CI 0.01-0.82; p=0.03), previous culture-proven multidrug-resistant tuberculosis (5.21, 1.93-14.1; p=0.001), and number of drugs used in a regimen (0.59, 0.45-0.78, p<0.0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0.38, 0.18-0.80; p=0.01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment., Interpretation: In South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity., Funding: South African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Rationale: The multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) epidemics are rapidly expanding in South Africa. Our initial report of HIV-associated XDR TB in South Africa revealed rapid and near complete mortality. Lower mortality has been described in the literature, but few of these patients have been HIV coinfected., Objectives: To characterize mortality from MDR and XDR TB in a setting with high HIV-coinfection rates., Methods: We conducted a retrospective observational study among 654 MDR and XDR TB cases diagnosed in Tugela Ferry, South Africa, from 2005 to 2007. Demographics and HIV status were abstracted from available medical records., Measurements and Main Results: Survival was determined from the date of sputum collection until October 2008 and correlated with year of diagnosis and drug-susceptibility test results. From 2005 to 2007, 272 MDR TB and 382 XDR TB cases were diagnosed; HIV-coinfection rates were 90 and 98%, respectively. One-year mortality was 71% for MDR and 83% for XDR TB patients; 40% of MDR TB and 51% of XDR TB cases died within 30 days of sputum collection. One-year mortality among both MDR and XDR TB patients improved from 2005 to 2007; however, the majority of deaths still occurred within the first 30 days. One-year and 30-day mortality rates were worse with greater degree of drug resistance (P < 0.001)., Conclusions: Mortality from MDR and XDR TB in this high HIV-prevalence region is extraordinarily high, particularly within the first 30 days. Efforts to reduce mortality must focus on earlier diagnosis and early initiation of second-line TB and antiretroviral therapy.

Setting: A tuberculosis (TB) referral hospital in South Korea., Objective: To evaluate predictors of treatment outcomes and survival among non-human immunodeficiency virus (HIV) infected patients with extensively drug-resistant TB (XDR-TB)., Design: Patients who were diagnosed with XDR-TB at the National Masan Tuberculosis Hospital from January 2001 to December 2005 were included in this study. We conducted a retrospective review of their medical records and mortality data., Results: A total of 176 non-HIV-infected patients with XDR-TB were included. TB-related mortality was 48% (84/176), and the median survival time from the diagnosis date of XDR-TB was 51 months (range 0-127, 95%CI 32.53-69.47). Cure and treatment completion were classified as favourable outcome and treatment failure, death during treatment and default as poor outcome. Previous TB treatment with second-line drugs (aOR 2.76, 95%CI 1.02-7.44) and cavitary disease (aOR 3.01, 95%CI 1.12-8.08) were independent risk factors for poor outcome. Use of linezolid (aOR 0.10, 95%CI 0.01-0.69) and surgical resection (aOR 0.18, 95%CI 0.04-0.78) were associated with favourable outcome., Conclusion: There was high mortality in non-HIV-infected patients with XDR-TB at a TB referral hospital in South Korea. Adjunctive surgical treatment and linezolid improved the outcome for selected patients with XDR-TB.

Purpose of Review: Physicians, researchers and policy makers must understand the myriad consequences of multidrug and extensively drug-resistant tuberculosis (TB) within the HIV community in order to guide clinical care, research and resource allocation., Recent Findings: Extensively drug-resistant TB can no longer be considered as occurring in isolated outbreaks as it has been reported in 45 countries from all regions of the world. HIV has been associated as an independent risk factor for infection with drug-resistant TB. HIV patients appear more likely to suffer from primary, transmitted resistance as opposed to developing acquired resistance during the course of treatment for TB. New rapid diagnostics offer promise of providing clinically useful first-line drug susceptibility information but require validation in HIV patients and smear negative individuals. Demonstration projects of community-based treatment of drug-resistant TB and integration of TB and HIV care provide opportunities to decentralize management of drug-resistant TB., Summary: Multidrug-resistant and extensively drug-resistant TB disproportionately affect HIV patients and result in increased morbidity and mortality. In this study, we address these challenging issues and offer some short-term and longer term strategies for their alleviation.

Purpose of Review: The spread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) is a major medical and public health concern for the world. These two forms of highly drug-resistant TB threaten to make TB into an untreatable and highly fatal disease, particularly in resource-poor countries with a high prevalence of AIDS. The focus of this review is to highlight the current extent of the problem., Recent Findings: There is a great variability in clinical outcomes for MDR-TB, in part due to differences in the definitions of outcome measures and retrospective nature of the studies. Outcomes for XDR-TB are uniformly worse than those for MDR-TB., Summary: A multifaceted approach is needed to prevent a more widespread epidemic of MDR-TB and XDR-TB. Rapid diagnostic assays to detect highly drug-resistant TB are essential in preventing delays in treatment of MDR-TB and XDR-TB and curbing their spread. Development of new drugs to effectively treat all forms of TB in a shorter period of time is urgently needed.

Context: Worldwide emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised global public health concern, given the limited therapy options and high mortality., Objectives: To describe the epidemiology of XDR-TB in the United States and to identify unique characteristics of XDR-TB cases compared with multidrug-resistant TB (MDR-TB) and drug-susceptible TB cases., Design, Setting, and Patients: Descriptive analysis of US TB cases reported from 1993 to 2007. Extensively drug-resistant TB was defined as resistance to isoniazid, a rifamycin, a fluoroquinolone, and at least 1 of amikacin, kanamycin, or capreomycin based on drug susceptibility test results from initial and follow-up specimens., Main Outcome Measures: Extensively drug-resistant TB case counts and trends, risk factors for XDR-TB, and overall survival., Results: A total of 83 cases of XDR-TB were reported in the United States from 1993 to 2007. The number of XDR-TB cases declined from 18 (0.07% of 25 107 TB cases) in 1993 to 2 (0.02% of 13 293 TB cases) in 2007, reported to date. Among those with known human immunodeficiency virus (HIV) test results, 31 (53%) were HIV-positive. Compared with MDR-TB cases, XDR-TB cases were more likely to have disseminated TB disease (prevalence ratio [PR], 2.06; 95% confidence interval [CI], 1.19-3.58), less likely to convert to a negative sputum culture (PR, 0.55; 95% CI, 0.33-0.94), and had a prolonged infectious period (median time to culture conversion, 183 days vs 93 days for MDR-TB; P < .001). Twenty-six XDR-TB cases (35%) died during treatment, of whom 21 (81%) were known to be HIV-infected. Mortality was higher among XDR-TB cases than among MDR-TB cases (PR, 1.82; 95% CI, 1.10-3.02) and drug-susceptible TB cases (PR, 6.10; 95% CI, 3.65-10.20)., Conclusion: Although the number of US XDR-TB cases has declined since 1993, coinciding with improved TB and HIV/AIDS control, cases continue to be reported each year.