A Survival Analysis of Successful and Poor Treatment Outcome Among Patients with Drug-Resistant Tuberculosis and the Associated Factors: A Retrospective Cohort Study.

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.

Evaluation of drug-resistant tuberculosis treatment outcome in Portugal, 2000-2016.

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.

Outcomes and adverse events of pre- and extensively drug-resistant tuberculosis patients in Kinshasa, Democratique Republic of the Congo: A retrospective cohort study.

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.

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

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.).

Predictive factors for unfavourable treatment in MDR-TB and XDR-TB patients in Rio de Janeiro State, Brazil, 2000-2016.

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.

Towards tailored regimens in the treatment of drug-resistant tuberculosis: a retrospective study in two Italian reference Centres.

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.

Tuberculosis mortality and associated factors at King Abdulaziz Medical City Hospital.

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.

Programmatic management of patients with pre-extensively drug-resistant tuberculosis in Peru, 2011-2014.

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.

Effect of Antiretroviral Therapy on Treatment Outcomes in a Prospective Study of Extensively Drug-Resistant Tuberculosis (XDR-TB) HIV Coinfection Treatment in KwaZulu-Natal, South Africa.

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.

Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.

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.

Mortality and associated factors of patients with extensive drug-resistant tuberculosis: an emerging public health crisis in China.

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/m2 (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.

Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa.

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.

Trends in the discovery of new drugs for Mycobacterium tuberculosis therapy with a glance at resistance.

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.

Bilateral cavitary multidrug- or extensively drug-resistant tuberculosis: role of surgery.

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.

Epidemiological trends and outcomes of extensively drug-resistant tuberculosis in Shandong, China.

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.

Treatment outcomes of patients with multidrug-resistant and extensively drug resistant tuberculosis in Hunan Province, China.

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.

Factors associated with mortality to drug-resistant tuberculosis and their programmatic management in treatment centres of Punjab, Pakistan.

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.

Contact investigation after a fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an aircraft, Germany, July 2013.

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.

Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study.

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.

Survival of patients with multidrug-resistant TB in Eastern Europe: what makes a difference?

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.