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Tuberculosis (TB) does not respect borders, and migration confounds global TB control and elimination. Systematic screening of immigrants from TB high burden settings and—to a lesser degree TB infection (TBI)—is recommended in most countries with a low incidence of TB. The aim of the study was to evaluate the views of a diverse group of international health professionals on TB management among migrants. Participants expressed their level of agreement using a six-point Likert scale with different statements in an online survey available in English, French, Mandarin, Spanish, Portuguese and Russian. The survey consisted of eight sections, covering TB and TBI screening and treatment in migrants. A total of 1055 respondents from 80 countries and territories participated between November 2019 and April 2020. The largest professional groups were pulmonologists (16.8%), other clinicians (30.4%), and nurses (11.8%). Participants generally supported infection control and TB surveillance established practices (administrative interventions, personal protection, etc.), while they disagreed on how to diagnose and manage both TB and TBI, particularly on which TBI regimens to use and when patients should be hospitalised. The results of this first knowledge, attitude and practice study on TB screening and treatment in migrants will inform public health policy and educational resources.

A tuberculose multidroga resistente (TB-MDR) é um dos grandes desafios para o controle da doença. Diante disso, o objetivo desse estudo é avaliar e comparar os desafios enfrentados na cascata de cuidados da TB-MDR, por meio da percepção de profissionais de saúde (PS) de um centro de referência em Lisboa e outro no Rio de Janeiro. Realizou-se um estudo transversal qualitativo com amostragem não probabilística. A produção dos dados empíricos deu-se por meio de entrevistas semiestruturadas com PS em Lisboa e no Rio de Janeiro, entre 2018 e 2019. Utilizou-se a análise de conteúdo temática, com o auxílio do Nvivo versão 12, para análise dos dados. A vulnerabilidade social dos pacientes, redução das equipes, problemas na busca de pacientes faltosos e sistema laboratorial não integrado ao sistema clínico foram desafios em comum. Lisboa destaca-se por ter um diagnóstico da resistência mais ágil, suporte aos grupos de risco e medicamentos mais modernos, enquanto o Rio de Janeiro tem melhor biossegurança e mais recursos humanos. Lisboa tem um tratamento mais centrado no paciente, enquanto a falta de um fluxo que agilize o diagnóstico da resistência e de políticas públicas que amparem o paciente compromete a evolução do tratamento na cidade brasileira. A tuberculose multidroga resistente (TB-MDR) é um dos grandes desafios para o controle da doença. Diante disso, o objetivo desse estudo é avaliar e comparar os desafios enfrentados na cascata de cuidados da TB-MDR, por meio da percepção de profissionais de saúde (PS) de um centro de referência em Lisboa e outro no Rio de Janeiro. Realizou-se um estudo transversal qualitativo com amostragem não probabilística. A produção dos dados empíricos deu-se por meio de entrevistas semiestruturadas com PS em Lisboa e no Rio de Janeiro, entre 2018 e 2019. Utilizou-se a análise de conteúdo temática, com o auxílio do Nvivo versão 12, para análise dos dados. A vulnerabilidade social dos pacientes, redução das equipes, problemas na busca de pacientes faltosos e sistema laboratorial não integrado ao sistema clínico foram desafios em comum. Lisboa destaca-se por ter um diagnóstico da resistência mais ágil, suporte aos grupos de risco e medicamentos mais modernos, enquanto o Rio de Janeiro tem melhor biossegurança e mais recursos humanos. Lisboa tem um tratamento mais centrado no paciente, enquanto a falta de um fluxo que agilize o diagnóstico da resistência e de políticas públicas que amparem o paciente compromete a evolução do tratamento na cidade brasileira. La tuberculosis multidrogorresistente (TB-MDR) es uno de los grandes retos para el control de la enfermedad. Por lo tanto, el objetivo de este estudio es evaluar y comparar los desafíos enfrentados en la cascada de atención de la TB-MDR, a través de la percepción de los profesionales de la salud (PS) de un centro de referencia en Lisboa y otro en Río de Janeiro. Se realizó un estudio transversal cualitativo con muestreo no probabilístico. La producción de datos empíricos se realizó a través de entrevistas semiestructuradas con PS en Lisboa y Río de Janeiro, entre 2018 y 2019. Se utilizó el análisis de contenido temático, con la ayuda de Nvivo versión 12, para el análisis de datos. La vulnerabilidad social de los pacientes, la reducción de equipos, los problemas para encontrar pacientes ausentes y el sistema de laboratorio no integrado con el sistema clínico fueron desafíos comunes. Lisboa se destaca por tener un diagnóstico de resistencias más ágil, apoyo a grupos de riesgo y medicamentos más modernos, mientras que Río de Janeiro tiene mejor bioseguridad y más recursos humanos. Lisboa tiene un tratamiento más centrado en el paciente, mientras que la falta de un flujo que acelere el diagnóstico de las resistencias y de políticas públicas que apoyen al paciente compromete la evolución del tratamiento en la ciudad brasileña.

Pathogenic mycobacteria species may subvert the innate immune mechanisms and can modulate the activation of cells that cause disease in the skin. Cutaneous mycobacterial infection may present different clinical presentations and it is associated with stigma, deformity, and disability. The understanding of the immunopathogenic mechanisms related to mycobacterial infection in human skin is of pivotal importance to identify targets for new therapeutic strategies. The occurrence of reactional episodes and relapse in leprosy patients, the emergence of resistant mycobacteria strains, and the absence of effective drugs to treat mycobacterial cutaneous infection increased the interest in the development of therapies based on repurposed drugs against mycobacteria. The mechanism of action of many of these therapies evaluated is linked to the activation of autophagy. Autophagy is an evolutionary conserved lysosomal degradation pathway that has been associated with the control of the mycobacterial bacillary load. Here, we review the role of autophagy in the pathogenesis of cutaneous mycobacterial infection and discuss the perspectives of autophagy as a target for drug development and repurposing against cutaneous mycobacterial infection.

Early, accurate diagnosis of tuberculosis is one of the major pillars of the control of the disease. The purpose of this consensus statement is to provide health professionals with the most current, useful evidence for the diagnosis of tuberculosis in Brazil. To that end, the Tuberculosis Committee of the Brazilian Thoracic Association brought together 14 members of the Association with recognized expertise in tuberculosis in Brazil to compose the statement. A nonsystematic review of the following topics was carried out: clinical diagnosis, bacteriological diagnosis, radiological diagnosis, histopathological diagnosis, diagnosis of tuberculosis in children, and diagnosis of latent tuberculosis infection. RESUMO O diagnóstico precoce e adequado da tuberculose é um dos pilares mais importantes no controle da doença. A proposta deste consenso brasileiro é apresentar aos profissionais da área de saúde um documento com as evidências mais atuais e úteis para o diagnóstico da tuberculose. Para tanto, a Comissão de Tuberculose da Sociedade Brasileira de Pneumologia e Tisiologia reuniu 14 membros da Sociedade com reconhecida experiência em tuberculose no Brasil. Foi realizada uma revisão não sistemática dos seguintes tópicos: diagnóstico clínico, diagnóstico bacteriológico, diagnóstico radiológico, diagnóstico histopatológico, diagnóstico da tuberculose na criança e diagnóstico da tuberculose latente.

Tuberculosis (TB) is the ninth cause of global death, more than any other infectious disease. With growing drug resistance the epidemic remains and will require significant attention and investment for the elimination of this disease to occur. With susceptible TB treatment not changing over the last four decades and the advent of drug resistance, new drugs and regimens are required.Recently, through greater collaboration and research networks some progress with significant advances has taken place, not withstanding the comparatively low amount of resources invested. Of late the availability of the new drugs bedaquiline, delamanid and repurposed drugs linezolid, clofazimine and carbapenems are being used more frequently in drug-resistant TB regimens.The WHO shorter multidrug-resistant tuberculosis regimen promises to reach more patients and treat them more quickly and more cheaply.With this new enthusiasm and hope we this review gives an update on the new drugs and perspectives for the treatment of drug-susceptible and drug-resistant tuberculosis. Keywords: Bedaquiline, Delamanid, Linezolid, MDR, XDR-TB, TB

In 2015, tuberculosis ranked as the leading cause of death from an infectious disease, surpassing HIV/AIDS.(1) In 2016, an estimated 10.4 million people developed tuberculosis and 1.7 million died from the disease, 5,000 people dying from it every day, including approximately 1,000 individuals with tuberculosis/HIV coinfection.(1) In the past decade, the global tuberculosis community has engaged in activities to successfully attain the Millennium Development Goal target and other international targets for halting and reversing increases in tuberculosis incidence and mortality.(1) However, despite the achievements made to date, the global incidence of tuberculosis is declining at a rate of only 1.5% per year, far from the 10% expected.

Objective: To describe the clinical manifestations of patients with pulmonary infection caused by mycobacteria of the Mycobacterium abscessus complex (MABSC), and to compare these manifestations with those of patients infected with other nontuberculous mycobacteria (NTM). Methods: This was a retrospective cohort study involving 43 patients divided into two groups: the MABSC group, consisting of patients with pulmonary infection caused by MABSC (n = 17); and the NTM group, consisting of patients with pulmonary infection caused by NTM other than MABSC (n = 26). Patients were previously treated with a regimen of rifampin, isoniazid, pyrazinamide, and ethambutol before the diagnosis of NTM was confirmed by two culture-positive sputum samples. The nucleotide sequences of the hsp65, 16S rRNA, and/or rpoB genes were analyzed to identify the mycobacteria. Data were collected on demographic, clinical, and radiological characteristics, as well as on treatment responses and outcomes. Results: Loss of appetite was the only clinical manifestation that was significantly more common in the MABSC group than in the NTM group (p = 0.0306). The chance of having to use a second treatment regimen was almost 12 times higher in the MABSC group than in the NTM group. Treatment success was significantly higher in the NTM group than in the MABSC group (83.2% vs. 17.6%; p < 0.0001). The chance of recurrence was approximately 37 times higher in the MABSC group than in the NTM group. Conclusions: In the study sample, treatment response of pulmonary disease caused by MABSC was less favorable than that of pulmonary disease caused by other NTM. RESUMO Objetivo: Descrever as manifestações clínicas de pacientes com infecção pulmonar por micobactérias do complexo Mycobacterium abscessus (CMA) e compará-las com as daqueles infectados com outras micobactérias não tuberculosas (MNT). Métodos: Estudo de coorte retrospectivo envolvendo 43 pacientes divididos em dois grupos: grupo CMA, com pacientes com infecção pulmonar por CMA (n = 17); e grupo MNT, com pacientes com infecção pulmonar por MNT que não CMA (n = 26). Os pacientes foram previamente tratados com o esquema rifampicina, isoniazida, pirazinamida e etambutol antes de o diagnóstico de MNT ser confirmado com culturas positivas em duas amostras de escarro diferentes. As sequências nucleotídicas dos genes hsp65, RNAr 16S e/ou rpoB foram analisadas para a identificação das micobactérias. Foram coletadas características demográficas, clínicas e radiológicas, assim como respostas terapêuticas e desfechos. Resultados: A única manifestação clínica significativamente mais frequente no grupo CMA que no grupo MNT foi hiporexia (p = 0,0306). A chance de haver a necessidade de utilização de um segundo esquema terapêutico foi quase 12 vezes maior no grupo CMA que no grupo MNT. O sucesso terapêutico foi significativamente maior no grupo MNT que no grupo CMA (83,2% vs. 17,6%; p < 0,0001). A chance de recidiva no grupo CMA foi aproximadamente 37 vezes maior que no grupo MNT. Conclusões: Na amostra estudada, a resposta terapêutica da doença pulmonar causada por CMA evoluiu de forma menos favorável do que naquela causada pelas demais MNT.

The new drugs delamanid and bedaquiline are increasingly used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children ≥6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB. We used PubMed and Embase to identify any relevant manuscripts in English until 31 December 2016, excluding editorials and reviews. Three out of 96 manuscripts retrieved satisfied the inclusion criteria, while 93 were excluded because dealing exclusively with adults (12: 4 on delamanid and 8 on bedaquiline), being recommendations or guidelines (8 manuscripts), reviews (17 papers) or other studies (56 papers). One of the studies retrieved reported evidence on 19 M/XDR-TB children, 16 of them treated under compassionate use with delamanid (13 achieving consistent bacteriological conversion) and 3 candidates for the drug. Two studies reported details on the first paediatric case treated (and cured) with a delamanid-containing regimen. Eight trials including children were also retrieved (clinicaltrials.gov). Although the methodology used in the study was rigorous, the results are limited by the paucity of the studies available in the literature on the use of new anti-TB drugs in children. In conclusion, more evidence is needed on the use of delamanid and bedaquiline in paediatric patients.

Objective To evaluate clinical, tomographic, and microbiological characteristics of pulmonary disease caused by M. kansasii (MKPD) in patients treated at an outpatient unit from 2006-2016. Methods We studied thirty eight patients, and analyzed socio-demographic, clinical-radiological, laboratory, and therapeutic characteristics. Results The mean age was 64 years (SD = 10.6; IIQ = 57-72; median = 65.0), and 22 (57.9%) male patients. Pulmonary comorbidity was present in 89.5% of the patients. The most frequent comorbidity was bronchiectasis (78.9%). Previous treatment for pulmonary tuberculosis (PTB) was found in 65.9%. The most used therapeutic regimen was rifampicin, isoniazid and ethambutol (44.7%). Chest tomography (CT) showed bronchiectasis (94.1%), architectural distortion (76.5%), septum thickening (67.6%), and cavities (64.7%). Disease was bilateral in 85.2%. We observed 10.7% resistance to rifampicin, 67.9% resistance to ethambutol, and sensitivity to clarithromycin. Conclusion In patients with structural lung disease, it is important to search for NTM, the main differential diagnosis with PTB. Chest CT showed different patterns that overlapped with structural disease caused by PTB or other lung diseases. We observed resistance to ethambutol, a drug component of the recommended regimen.

The Epistem Genedrive assay rapidly detects the Mycobacterium tuberculosis complex from sputum and is currently available for clinical use. However, the analytical and clinical performance of this test has not been fully evaluated. The analytical limit of detection (LOD) of the Genedrive PCR amplification was tested with genomic DNA; the performance of the complete (sample processing plus amplification) system was tested by spiking M. tuberculosis mc 2 6030 cells into distilled water and M. tuberculosis -negative sputum. Specificity was tested using common respiratory pathogens and nontuberculosis mycobacteria. A clinical evaluation enrolled adults with suspected pulmonary tuberculosis, obtained three sputum samples from each participant, and compared the accuracy of the Genedrive to that of the Xpert MTB/RIF assay using M. tuberculosis cultures as the reference standard. The Genedrive assay had an LOD of 1 pg/μl (100 genomic DNA copies/reaction). The LODs of the system were 2.5 × 10 4 CFU/ml and 2.5 × 10 5 CFU/ml for cells spiked into water and sputum, respectively. False-positive rpoB probe signals were observed in 3/32 (9.4%) of the negative controls and also in few samples containing Mycobacterium abscessus , Mycobacterium gordonae , or Mycobacterium thermoresistibile . In the clinical study, among 336 analyzed participants, the overall sensitivities for the tuberculosis case detection of Genedrive, Xpert, and smear microscopy were 45.4% (95% confidence interval [CI], 35.2% to 55.8%), 91.8% (95% CI, 84.4% to 96.4%), and 77.3% (95% CI, 67.7% to 85.2%), respectively. The sensitivities of Genedrive and Xpert for the detection of smear-microscopy-negative tuberculosis were 0% (95% CI, 0% to 15.4%) and 68.2% (95% CI, 45.1% to 86.1%), respectively. The Genedrive assay did not meet performance standards recommended by the World Health Organization for a smear microscopy replacement tuberculosis test. Epistem is working on modifications to improve the assay.

Pharmacokinetic, pharmacodynamic and therapeutic drug monitoring data are useful in optimising treatment for Mycobacteriuam abscessus pulmonary disease, but such data are not routinely collected and analysis for clinical practice is difficulthttp://bit.ly/2pcTIUn

Item does not contain fulltext BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Objectives: To determine the main predictors of death in multidrug-resistant (MDRTB) patients from Brazil. Design: Retrospective cohort study, a survival analysis of patients treated between 2005 and 2012. Results: Of 3802 individuals included in study, 64.7% were men, mean age was 39 (1–93) years, and 70.3% had bilateral pulmonary disease. Prevalence of human immunodeficiency virus (HIV) was 8.3%. There were 479 (12.6%) deaths. Median survival time was 1452 days (4 years). Factors associated with increased risk of death were age greater than or equal to 60 years (hazard rate [HR] = 1.6, confidence interval [CI] = 1.15–2.2), HIV co-infection (HR = 1.46; CI = 1.05–1.96), XDR resistance pattern (HR = 1.74, CI = 1.05–2.9), beginning of treatment after failure (HR = 1.72, CI = 1.27–2.32), drug abuse (HR = 1.64, CI = 1.22–2.2), resistance to ethambutol (HR = 1.30, CI = 1.06–1.6) or streptomycin (HR = 1.24, CI = 1.01–1.51). Mainly protective factors were presence of only pulmonary disease (HR = 0.57, CI = 0.35–0.92), moxifloxacin use (HR = 0.44, CI = 0.25–0.80), and levofloxacin use (HR = 0.75; CI = 0.60–0.94). Conclusion: A more comprehensive approach is needed to manage MDRTB, addressing early diagnostic, improving adhesion, and comorbidities, mainly HIV infection and drug abuse. The latest generation quinolones have an important effect in improving survival in MDRTB. Keywords: Survival, Tuberculosis multidrug-resistant, Tuberculosis, Death

Systemic endemic mycoses cause high rates of morbidity and mortality in certain regions of the world and the real impact on global health is not well understood. Diagnosis and management remain challenging, especially in low-prevalence settings, where disease awareness is lacking. The main challenges include the variability of clinical presentation, the fastidious and slow-growing nature of the fungal pathogens, the paucity of diagnostic tests, and the lack of options and toxicity of antifungal drugs. Coccidioidomycosis and paracoccidioidomycosis are restricted to the Americas only, and while histoplasmosis and blastomycosis also occur predominantly in the Americas, these mycoses have also been reported on other continents, especially in sub-Saharan Africa. Talaromycosis is endemic in tropical and subtropical regions in South-East Asia and southern China. Systemic endemic mycoses causing pulmonary disease are usually acquired via the airborne route by inhalation of fungal spores. Infections can range from asymptomatic or mild with flu-like illnesses to severe pulmonary or disseminated diseases. Skin involvement is frequent in patients with paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis and manifests as localized lesions or diffuse nodules in disseminated disease, but can also occur with other endemic mycoses. Culture and/or characteristic histopathology from clinical samples is the diagnostic standard for endemic mycoses. Immunological assays are often not available for the diagnosis of most endemic mycoses and molecular amplification methods for the detection of fungal nucleic acids are not standardized at present. The first-line treatment for mild to moderate histoplasmosis, paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis is itraconazole. Severe illness is treated with amphotericin B. Patients with severe coccidioidomycosis should receive fluconazole. Treatment duration depends on the specific endemic mycosis, the severity of disease, and the immune status of the patient, ranging between 6 weeks and lifelong treatment.

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the “white plague”, and promising results are being reported. RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a “praga branca”, e resultados promissores estão sendo relatados.

Introduction: Well designed studies on BQ used programmatically to treat M/XDR tuberculosis (TB) are lacking. The aim of this study is to evaluate effectiveness and safety of BQ in a large retrospective, observational study conducted in 25 centres in 15 countries on 5 continents. Methods: Bacteriological conversion rates, treatment outcomes (WHO definitions) and adverse events observed in confirmed MDR-TB BQ-treated patients were analysed. Results: 428 MDR-TB cases (representing 10-100% of all national cases treated from January 2007 to March 2015) were enrolled: median age (IQR): 35 years (27-44); 61.3% males; 22.1% HIV-positive; 45.6% XDR-TB. The median (IQR) number of hospital admission days was 179 (92-280) and exposure to BQ 168 days (86-180). 5 cases received both BQ and delamanid. Treatment regimens included linezolid (82.0% of cases), moxifloxacin (53.7%) and carbapenems (15.7%). Sputum smear (SS) and culture (C) conversion rates were at 30 days 63.6 and 30.1%; at 60 days 81.1 and 56.7%; at 90 days 85.5 and 80.5% and the end of treatment 90.0 and 91.8%, respectively. The time to SS and C conversion was 34 (30-60) and 60 (33-90) days. Out of 246 cases completing treatment, 71.1% achieved success (62.2% cured; 8.9% treatment completed), 13.4% died, 8.1% failed and 7.3% were lost to follow-up. 51/428 (11.2%) cases interrupted BQ for any reason, 23/428 permanently (5.4%; 16/428 -1.4% - because of cardiologic disorders). Conclusions: The results of this study, the largest ever done, indicate that BQ-containing regimens used at the programmatic level achieve satisfactory outcomes and bacteriological conversion rates even with a significant proportion of XDR-TB cases.

Background\ud \ud The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR-TB) evaluated under field conditions in high burden countries.\ud \ud Methods\ud \ud Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes.\ud \ud Results\ud \ud Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7–111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0–41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%–34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07).\ud \ud Conclusions\ud \ud This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized.

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Treatment of Mycobacterium abscessus pulmonary disease (MAB-PD), caused by M. abscessus subsp. abscessus, M. abscessus subsp. massiliense or M. abscessus subsp. bolletii, is challenging.We conducted an individual patient data meta-analysis based on studies reporting treatment outcomes for MAB-PD to clarify treatment outcomes for MAB-PD and the impact of each drug on treatment outcomes. Treatment success was defined as culture conversion for ≥12 months while on treatment or sustained culture conversion without relapse until the end of treatment.Among 14 eligible studies, datasets from eight studies were provided and a total of 303 patients with MAB-PD were included in the analysis. The treatment success rate across all patients with MAB-PD was 45.6%. The specific treatment success rates were 33.0% for M. abscessus subsp. abscessus and 56.7% for M. abscessus subsp. massiliense. For MAB-PD overall, the use of imipenem was associated with treatment success (adjusted odds ratio (aOR) 2.65, 95% CI 1.36–5.10). For patients with M. abscessus subsp. abscessus, the use of azithromycin (aOR 3.29, 95% CI 1.26–8.62), parenteral amikacin (aOR 1.44, 95% CI 1.05–1.99) or imipenem (aOR 7.96, 95% CI 1.52–41.6) was related to treatment success. For patients with M. abscessus subsp. massiliense, the choice among these drugs was not associated with treatment outcomes.Treatment outcomes for MAB-PD are unsatisfactory. The use of azithromycin, amikacin or imipenem was associated with better outcomes for patients with M. abscessus subsp. abscessus.

Foundation for Research Support of the State of SaoPaulo (FAPESP ? 06/1533-9) and the National Council for Scientific and Technological Development (CNPq ? Universal 470594/2006-3 and 475238/2008-7). Universidade Federal de S?o Paulo. Departamento de Microbiologia, Imunologia e Parasitologia. S?o Paulo, SP, Brazil. Universidade Federal de S?o Paulo. Departamento de Microbiologia, Imunologia e Parasitologia. S?o Paulo, SP, Brazil. Universidade Federal de S?o Paulo. Departamento de Microbiologia, Imunologia e Parasitologia. S?o Paulo, SP, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Universidade Federal do Esp?rito Santo. N?cleo de Doen?as Infecciosas. Vit?ria, ES, Brazil. Universidade Federal do Esp?rito Santo. N?cleo de Doen?as Infecciosas. Vit?ria, ES, Brazil. Universidade Federal do Esp?rito Santo. N?cleo de Doen?as Infecciosas. Vit?ria, ES, Brazil. Universidade Federal do Rio de Janeiro. Instituto de Microbiologia. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Instituto de Pesquisa Evandro Chagas. Rio de Janeiro, RJ, Brazil. Universidade Federal de Goi?s. Departamento de Microbiologia, Imunologia, Parasitologia e Patologia. Goi?nia, GO, Brazil. Secretaria Municipal de Sa?de de Goi?nia. Goi?nia, GO, Brazil. Secretaria Estadual da Sa?de do Paran?. Curitiba, PR, Brazil. Laborat?rio Central de Sa?de P?blica. Porto Alegre, RS, Brazil. Laborat?rio Central de Sa?de P?blica. Porto Alegre, RS, Brazil. Centro de Vigil?ncia Epidemiol?gica Professor Alexandre Vranjac. S?o Paulo, SP, Brazil. Centro de Vigil?ncia Epidemiol?gica Professor Alexandre Vranjac. S?o Paulo, SP, Brazil. Instituto Adolfo Lutz. Setor de Micobact?rias. S?o Paulo, SP, Brazil. Centro de Referencia Professor H?lio Fraga. Rio de Janeiro, RJ, Brazil. Aim: Our aim is to investigate if the clusters of postsurgical mycobacterial infections, reported between 2004 and 2008 in seven geographically distant states in Brazil, were caused by a single mycobacterial strain. Materials & methods: Available information from 929 surgical patients was obtained from local health authorities. A total of 152 isolates from surgical patients were identified by PCR restriction enzyme analysis of the hsp65 gene (PRA-hsp65) and sequencing of the rpoB gene. Isolates were typed by pulsed-field gel electrophoresis (PFGE) using two restriction enzymes, DraI and AseI. A total of 15 isolates not related to surgical cases were analyzed for comparison. Results: All isolates were identified as Mycobacterium abscessus ssp. massiliense. Isolates from surgical patients and one sputum isolate grouped in a single PFGE cluster, composed of two closely related patterns, with one band difference. A total of 14 other isolates unrelated to surgical cases showed distinctive PFGE patterns. Conclusion: A particular strain of M. abscessus ssp. massiliense was associated with a prolonged epidemic of postsurgical infections in seven Brazilian states, suggesting that this strain may be distributed in Brazilian territory and better adapted to cause surgical-site infections.

Diariamente novos artigos científicos sobre tuberculose (TB) são publicados em todo mundo. No entanto, é difícil para o profissional sobrecarregado na rotina de trabalho acompanhar a literatura e discernir o que pode e deve ser aplicado na prática diária juntos aos pacientes com TB. A proposta das "III Diretrizes para TB da Sociedade Brasileira de Pneumologia e Tisiologia (SBPT)" é revisar de forma crítica o que existe de mais recente na literatura científica nacional e internacional sobre TB e apresentar aos profissionais da área de saúde as ferramentas mais atuais e úteis para o enfrentamento da TB no nosso país. As atuais "III Diretrizes para TB da SBPT" foram desenvolvidas pela Comissão de TB da SBPT e pelo Grupo de Trabalho para TB a partir do texto das "II Diretrizes para TB da SBPT" (2004). As bases de dados consultadas foram LILACS (SciELO) e PubMed (Medline). Os artigos citados foram avaliados para determinação do nível de evidência científica, e 24 recomendações sobre TB foram avaliadas, discutidas por todo grupo e colocadas em destaque. A primeira versão das "III Diretrizes para TB da SBPT" foi colocada no website da SBPT para consulta pública durante três semanas, e as sugestões, críticas e o nível de evidência da referência científica que as embasavam foram avaliados e discutidos antes de serem incorporadas ou não ao texto final.

An epidemic of infections after video-assisted surgery (1,051 possible cases) caused by rapidly growing mycobacteria (RGM) and involving 63 hospitals in the state of Rio de Janeiro, Brazil, occurred between August 2006 and July 2007. One hundred ninety-seven cases were confirmed by positive acid-fast staining and/or culture techniques. Thirty-eight hospitals had cases confirmed by mycobacterial culture, with a total of 148 available isolates recovered from 146 patients. Most ( n = 144; 97.2%) isolates presented a PRA- hsp65 restriction pattern suggestive of Mycobacterium bolletii or Mycobacterium massiliense . Seventy-four of these isolates were further identified by hsp65 or rpoB partial sequencing, confirming the species identification as M. massiliense . Epidemic isolates showed susceptibility to amikacin (MIC at which 90% of the tested isolates are inhibited [MIC 90 ], 8 μg/ml) and clarithromycin (MIC 90 , 0.25 μg/ml) but resistance to ciprofloxacin (MIC 90 , ≥32 μg/ml), cefoxitin (MIC 90 , 128 μg/ml), and doxycycline (MIC 90 , ≥64 μg/ml). Representative epidemic M. massiliense isolates that were randomly selected, including at least one isolate from each hospital where confirmed cases were detected, belonged to a single clone, as indicated by the analysis of pulsed-field gel electrophoresis (PFGE) patterns. They also had the same PFGE pattern as that previously observed in two outbreaks that occurred in other Brazilian cities; we designated this clone BRA100. All five BRA100 M. massiliense isolates tested presented consistent tolerance to 2% glutaraldehyde. This is the largest epidemic of postsurgical infections caused by RGM reported in the literature to date in Brazil.

The role of tuberculosis as a public health care priority and the availability of diagnostic tools to evaluate functional status (spirometry, plethysmography, and DLCO determination), arterial blood gases, capacity to perform exercise, lesions (chest X-ray and CT), and quality of life justify the effort to consider what needs to be done when patients have completed their treatment. To our knowledge, no review has ever evaluated this topic in a comprehensive manner. Our objective was to review the available evidence on this topic and draw conclusions regarding the future role of the "post-tuberculosis treatment" phase, which will potentially affect several million cases every year. We carried out a non-systematic literature review based on a PubMed search using specific keywords (various combinations of the terms "tuberculosis", "rehabilitation", "multidrug-resistant tuberculosis", "pulmonary disease", "obstructive lung disease", and "lung volume measurements"). The reference lists of the most important studies were retrieved in order to improve the sensitivity of the search. Manuscripts written in English, Spanish, and Russian were selected. The main areas of interest were tuberculosis sequelae following tuberculosis diagnosis and treatment; "destroyed lung"; functional evaluation of sequelae; pulmonary rehabilitation interventions (physiotherapy, long-term oxygen therapy, and ventilation); and multidrug-resistant tuberculosis.The evidence found suggests that tuberculosis is definitively responsible for functional sequelae, primarily causing an obstructive pattern on spirometry (but also restrictive and mixed patterns), and that there is a rationale for pulmonary rehabilitation. We also provide a list of variables that should be discussed in future studies on pulmonary rehabilitation in patients with post-tuberculosis sequelae. RESUMO O papel da tuberculose como uma prioridade de saúde pública e a disponibilidade de ferramentas diagnósticas para avaliar o estado funcional (espirometria, pletismografia e DLCO), a gasometria arterial, a capacidade de realizar exercícios, as lesões (radiografia de tórax e TC) e a qualidade de vida justificam o esforço de se considerar o que deve ser feito quando os pacientes completam seu tratamento. Até onde sabemos, nenhuma revisão avaliou esse tópico de forma abrangente. Nosso objetivo foi revisar as evidências disponíveis e obter algumas conclusões sobre o futuro papel da fase de "tratamento pós-tuberculose", que irá potencialmente impactar milhões de casos todos os anos. Realizou-se uma revisão não sistemática da literatura tendo como base uma pesquisa no PubMed usando palavras-chave específicas (várias combinações dos termos "tuberculose", "reabilitação", "tuberculose multirresistente", "doença pulmonar", "doença pulmonar obstrutiva", e "medidas de volume pulmonar"). As listas de referências dos artigos principais foram recuperadas para melhorar a sensibilidade da busca. Foram selecionados manuscritos escritos em inglês, espanhol e russo. As principais áreas de interesse foram sequelas de tuberculose após diagnóstico e tratamento; "pulmão destruído"; avaliação funcional das sequelas; intervenções de reabilitação pulmonar (fisioterapia, oxigenoterapia de longo prazo e ventilação); e tuberculose multirresistente. As evidências encontradas sugerem que a tuberculose é definitivamente responsável por sequelas funcionais, principalmente causando um padrão obstrutivo na espirometria (mas também padrões restritivos e mistos) e que há razão para a reabilitação pulmonar. Fornecemos também uma lista de variáveis a serem discutidas em futuros estudos sobre reabilitação pulmonar em pacientes com sequelas pós-tuberculose.

BACKGROUND:The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment. METHODS:Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment. RESULTS:121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm). CONCLUSION:For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin. TRIAL REGISTRATION:www.ClinicalTrials.gov NCT00728507.

SummaryMultidrug-resistant tuberculosis (MDR-TB) is known as having a poor prognosis with a weak response to therapy and very high death rates. The aim of this work was to assess the immune response to the RD1-encoded antigen ESAT-6 of Mycobacterium tuberculosis in MDR-TB patients and compare to non-resistant (NR) TB patients and healthy controls (HC). Evaluation of interferon (IFN)-γ production showed that, although 55% of the MDR patients were responsive to ESAT-6, they produced lower IFN-γ levels (553 ± 11 pg/ml) when compared to NR-TB (1179 ± 163 pg/ml; P

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30–60) days and 60 (33–90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

The difficulties in managing multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant (XDR) TB are well known. The regimens are very expensive, often toxic, and require up to 24 months to achieve an acceptable probability of success [1–3]. The first nationwide report on the drug resistance profile of the drugs composing the WHO “shorter” regimen in Brazil