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Currently, tuberculosis (TB) and COVID-19 account for substantial morbidity and mortality worldwide, not only during their acute phase, but also because of their sequelae. This scoping review aims to describe the specific aspects of post-TB and post-COVID (long-COVID-19) sequelae, and the implications for post-disease follow-up and rehabilitation. In particular, evidence on how to identify patients affected by sequelae is presented and discussed. A section of the review is dedicated to identifying patients eligible for pulmonary rehabilitation (PR), as not all patients with sequelae are eligible for PR. Components of PR are presented and discussed, as well as their effectiveness. Other essential components to implement comprehensive rehabilitation programmes such as counselling and health education of enrolled patients, evaluation of cost-effectiveness of PR and its impact on health systems as well as research priorities for the future are included in this scoping review.

Background The study aimed to analyze frequency and severity of adverse events (AEs) and other reasons for interruption of treatment and loss to follow up (LTFU) during first six months of treatment among tuberculosis patients on bedaquiline containing regimens. Methods This pilot exploratory observational study included 275 patients enrolled consecutively over two years who received bedaquiline containing regimen under programmatic conditions in India. Results Among 275 patients with median age of 25 years, 86 (31.3%) patients had at least one interruption with 122 total episodes of interruption. Among these 70 were temporary, 35 were permanent interruptions and 17 were LTFU. The AEs due to drugs were the commonest reason for interruption observed in 81.4% of temporary interruption group and 97.1% of permanent interruption group. Among a total 192 adverse event episodes, (49.5%) were minor (grade 1–2) and (50.5%) were serious (grade 3–5). Personal factors were the commonest reason for interruption observed in LTFU (94.1%) group. The most common temporarily interrupted drug was bedaquiline in 8.7% and permanently stopped drug was linezolid in 5% of patients. Conclusions Our study observed that drug related AEs are important risk factors associated with treatment interruptions in bedaquiline containing regimens. Bedaquiline is the most common temporarily interrupted drug due to AEs.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

Background and objectives Mortality of patients with pulmonary tuberculosis (TB) admitted to emergency departments is high. This study was aimed at analysing the risk factors associated with early mortality and designing a risk score based on simple parameters. Methods This prospective case-control study enrolled patients admitted to the emergency department of a referral TB hospital. Clinical, radiological, biochemical and microbiological risk factors associated with death were compared among patients dying within one week from admission (cases) and those surviving (controls). Results Forty-nine of 250 patients (19.6%) experienced early mortality. Multiple logistic regression analysis showed that oxygen saturation (SaO2) ≤90%, severe malnutrition, tachypnoea, tachycardia, hypotension, advanced disease at chest radiography, severe anaemia, hyponatremia, hypoproteinemia and hypercapnia were independently and significantly associated with early mortality. A clinical scoring system was further designed to stratify the risk of death by selecting five simple parameters (SpO2 ≤ 90%, tachypnoea, hypotension, advanced disease at chest radiography and tachycardia). This model predicted early mortality with a positive predictive value of 94.88% and a negative predictive value of 19.90%. Conclusions The scoring system based on simple parameters may help to refer severely ill patients early to a higher level to reduce mortality, improve success rates, minimise the need for pulmonary rehabilitation and prevent post-treatment sequelae.

Resumen La evidencia acumulada en los 3 ultimos anos sobre el manejo clinico de la tuberculosis (TB) con resistencia a farmacos ha sido tan importante que hace necesario actualizar la normativa que SEPAR publico en 2017, sobre todo en lo referente a nuevos metodos diagnosticos, a la clasificacion racional de los farmacos con actividad frente a Mycobacterium tuberculosis y a los esquemas basicos a recomendar en los pacientes con TB con resistencia a isoniacida, con resistencia a rifampicina o con multifarmacorresistencia. En el diagnostico de la enfermedad recomendamos la utilizacion de metodos moleculares rapidos que son utiles ademas para la deteccion precoz de mutaciones asociadas a resistencias a farmacos. Para el tratamiento de los enfermos con TB con multifarmacorresistencia se hace necesario dar prioridad a esquemas orales acortados que incluyan bedaquilina, una fluoroquinolona (levofloxacino o moxifloxacino) y linezolid en lugar de los esquemas cortos previamente recomendados con aminoglucosidos y otros muchos farmacos de menor eficacia y mas toxicos. La recomendacion de la normativa es que el diseno de los tratamientos en estos pacientes, tanto el inicial como si se precisan cambios, sea consultado siempre con expertos en el manejo de TB con resistencia a farmacos y que se realicen por personal con experiencia en TB y en unidades que garanticen la supervision de los tratamientos y el abordaje de sus reacciones adversas.

Objective The objective of the study was to determine the trend of variables related to tuberculosis (TB) from the Integrated Tuberculosis Research Program (PII-TB) registry of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and to evaluate the PII-TB according to indicators related to its scientific objectives. Method Cross-sectional, population-based, multicenter study of new TB cases prospectively registered in the PII-TB between 2006 and 2016. The time trend of quantitative variables was calculated using a lineal regression model, and qualitative variables using the χy test for lineal trend. Results A total of 6,892 cases with an annual median of 531 were analyzed. Overall, a significant down-ward trend was observed in women, immigrants, prisoners, and patients initially treated with 3 drugs. Significant upward trends were observed in patients aged 40−50 and >50 years, first visit conducted by a specialist, hospitalization, diagnostic delay, disseminated disease and single extrapulmonary location, culture(+), drug susceptibility testing performed, drug resistance, directly observed treatment, prolonged treatment, and death from another cause. The scientific objectives of the PII-TB that showed a significant upward trend were publications, which reached a maximum of 8 in 2016 with a total impact factor of 49.664, numbers of projects initiated annually, presentations at conferences, and theses. Conclusions PII-TB provides relevant information on TB and its associated factors in Spain. A large team of researchers has been created; some scientific aspects of the registry were positive, while others could have been improved.

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities.

In the last 2 decades, drug-resistant tuberculosis has become a threat and a challenge to worldwide public health. The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies. Nevertheless, it is important to remember that with the appropriatesystematic clinical management, most of these patients can be cured. These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients, from those infected by strains that are sensitive to all drugs, to those who are extensively drug-resistant. Specific recommendations are given forall cases. The current and future role of new molecular methods for detecting resistance, shorter multi-drug-resistant tuberculosis regimens, and new drugs with activity against Mycobacterium tuberculosis are also addressed.

Resumen En las ultimas 2 decadas la tuberculosis con resistencia a farmacos se ha convertido en una amenaza y un reto para la salud publica mundial. El diagnostico y el tratamiento de estas formas de tuberculosis es mucho mas complejo, y el pronostico empeora claramente a medida que se incrementa el patron de las resistencias. Sin embargo, es necesario destacar como con el manejo clinico y programatico adecuado de estos enfermos se puede conseguir la curacion de una mayoria de ellos. En esta normativa se razonan las bases del diagnostico y tratamiento de todos los pacientes afectos de tuberculosis, desde aquellos que tienen formas de la enfermedad con sensibilidad a todos los farmacos hasta aquellos que son portadores de los patrones mas extensos de resistencia. Asimismo, se dan recomendaciones especificas para cada uno de estos supuestos. Tambien se aborda el papel que ya estan teniendo y pueden tener en un futuro inmediato los nuevos metodos moleculares de deteccion de resistencias, los esquemas acortados de tratamiento de la tuberculosis multi-farmacorresistente (TB-MDR) y los nuevos farmacos con actividad frente a Mycobacterium tuberculosis.

Tuberculosis (TB) continues to cause more deaths worldwide than any other single infectious disease. Even though tuberculosis appears to be decreasing in incidence globally for some time, the proportion of drug resistance is increasing, contributing to greater complexity, morbidity and mortality as well as cost. Since the advent of rifampicin in the 1960s, and the implementation of standard quadruple anti-tuberculosis regimen in the late 1970s, no new drugs have been changed the first line regimen. This regimen is effective however it is pill burden, and duration has not received investment and innovation. Drug-resistant regimens are long and frequently poorly tolerated due to significant toxicity. This review is an update on what is new in the treatment of drug-susceptible and drug-resistant tuberculosis, new TB drugs currently being used and studied in clinical trials are also mentioned. Fortunately, there have been many significant advances in this field in recent years. The horizon is changing with the new WHO shorter multidrug-resistant tuberculosis regimens and with the increasing availability of new or repurposed drugs like bedaquiline, delamanid, clofazimine and linezolid. These drugs pose new challenges relating to their rational use to prevent selection of resistant strains of Mycobacterium tuberculosis even before a new regimen has been studied. The availability of these new drugs is offering hope and new possibilities for saving patients who had few or no treatment options. Their use and combination into effective regimens need to be studied; trials are in progress. It is hoped that soon we will be able to treat sensitive and drug-resistant cases with a universal regimen, this would revolutionise treatment and take us another step closer towards elimination.

Setting Mozambique, one of the world's high tuberculosis (TB) burden countries, has conducted only one national-level drug resistance survey, in 2007-2008. Objective To determine the drug resistance patterns of laboratory-confirmed TB cases. Design This was a population-level survey conducted over a 1-year period in the district of Manhica. All laboratory-confirmed cases were evaluated for first-line anti-tuberculosis drug susceptibility testing using liquid culture. Results Resistance to at least one first-line drug was observed in 44 of 276 isolates (15.9%). Prevalence of drug resistance to each of the five anti-tuberculosis drugs tested was 4.0% for streptomycin, 10.1% for isoniazid (INH), 6.2% for rifampicin, 3.6% for ethambutol and 1.1% for pyrazinamide. The overall prevalence of multidrug-resistant TB (MDR-TB) was 5.1%: 3.8% (95%CI 2.0-7.0) in new and 13.2% (95%CI 5.8-27.3) in retreatment cases. Respectively 4.6% and 2.6% of new and retreatment cases were INH-monoresistant. Previous history of anti-tuberculosis treatment was associated with having MDR-TB (OR 4.3, 95%CI 1.3-14.1). Conclusion The prevalence of drug resistance in the district of Manhica is slightly higher than, but still compatible with, previous national estimates. INH monoresistance was high, posing the risk of hidden monotherapy in the continuation phase.

BACKGROUND Depending on the presence of mutations that determine isoniazid (INH) susceptibility (katG and inhA), Mycobacterium tuberculosis may be susceptible to high doses of INH or ethionamide (ETH). OBJECTIVE To describe the INH resistance profile and association of katG mutation with previous INH treatment and level of drug resistance based on rapid molecular drug susceptibility testing (DST) in southern Brazil and central Mozambique. DESIGN Descriptive study of 311 isolates from Ribeirao Preto, Sao Paulo, Brazil (2011-2014) and 155 isolates from Beira, Mozambique (2014-2015). Drug resistance patterns and specific gene mutations were determined using GenoType(®) MTBDRplus. RESULTS katG gene mutations were detected in 12/22 (54.5%) Brazilian and 32/38 (84.2%) Mozambican isolates. inhA mutations were observed in 9/22 (40.9%) isolates in Brazil and in 4/38 (10.5%) in Mozambique. Both katG and inhA mutations were detected in respectively 1/22 (5%) and 2/38 (5.2%). The difference in the frequency of katG mutations in Brazil and Mozambique was statistically significant (P = 0.04). katG mutations were present in 68.8% (33/48) of patients previously treated with INH and 31.2% (15/48) of patients without previous INH. This difference was not statistically significant (P = 0.223). CONCLUSION INH mutations varied geographically; molecular DST can be used to guide and accelerate decision making in the use of ETH or high doses of INH.

Prothionamide is slightly better than ethionamide in treating MDR-TB patients http://ow.ly/bSwY300i061

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanateversusmeropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanateversusmeropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8versus8) but more fluoroquinolone resistance (79.0%versus48.9%, pversus49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60–428)versus85 (49–156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7%versus94.8%, p=0.02 and 71.9%versus94.8%, pversus77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients.

Despite being considered one of the major infectious diseases in terms of mortality and morbidity, tuberculosis (TB) has not been among the priorities of the scientific community and pharmaceutical...

Both tuberculosis and COVID-19 being communicable and prevalent diseases in India, the co-existence can lead to worse outcomes, as seen in this study, where there was high mortality among active as well as treated TB patients with COVID-19 co-infection https://bit.ly/3jHcGbQ

The treatment of TB, both drug-susceptible and drug-resistant forms, should be based on two principles: 1) the combination of drugs (at least four) to avoid selection pressure resulting in the emergence of DR-TB strains and 2) the need for prolonged treatment in order to sterilise all infectious sites and thus cure the patient and prevent relapses. The selection of drugs should be based on their bactericidal and sterilising properties, their ability to prevent drug resistance and their safety profile. Based on these principles, and on the mode of action of the different drugs, this chapter describes in detail anti-TB treatment, the most appropriate choice of drugs based on in vitro susceptibility testing, starting with drug-susceptible TB (DS-TB), and a proposal to standardise as much as possible the difficult-to-manage patients with DR-TB. The chapter delineates the recommended treatment for DS-TB, mono- and polyresistant TB, MDR-TB, XDR-TB and forms of TB beyond XDR-TB. Special attention is given to the 2018 WHO guidelines regarding the revised grouping of second-line TB drugs recommended for use in longer MDR-TB regimens, the shorter MDR-TB regimens, the possibility of designing a standardised pre-XDR and XDR-TB regimen adapted to the country, and some relevant management issues.

Drug-resistant strains of Mycobacterium tuberculosis pose a major threat to global tuberculosis control. Despite the availability of curative antituberculosis therapy for nearly half a century, inappropriate and inadequate treatment of tuberculosis, as well as unchecked transmission of M. tuberculosis, has resulted in alarming levels of drug-resistant tuberculosis. The World Health Organization (WHO) estimates that there were 600,000 cases of multidrug-resistant tuberculosis (MDR-TB)/rifampin-resistant (RR) tuberculosis in 2016, defined as strains that are resistant to at least isoniazid and rifampicin. Globally, WHO estimates that 4.1% of new tuberculosis cases and 19% of retreatment cases have MDR-TB. By the end of 2016, 123 countries had reported at least one case of extensively drug-resistant strains, which are MDR-TB strains that have acquired additional resistance to fluoroquinolones and at least one second-line injectable. It is estimated that only 22% of all MDR-TB cases are currently receiving therapy. This article reviews the management of MDR/RR-TB and updates recommendations regarding the use of shorter course regimens and new drugs.

The classification of the anti-TB drugs should probably be modified to optimise the use old and new compounds http://ow.ly/QbDSP

Resistance to anti-tuberculosis drugs is a formidable obstacle to effective tuberculosis (TB) care. A case of Pre-XDR (Pre-Extensive Drug Resistant) pulmonary TB was reported with limited therapeutic options, where low dose amoxicillin-clavulanic acid was used as an integral component of a successful regime for the first time in medical literature. World health organisation recommends giving amoxicillin-clavulanate along with meropenem as one of the therapeutic options in drug resistant tuberculosis, where clavulanate and not amoxicillin is being relied upon for anti TB activity. However, across the spectrum of dosage of amoxicillin-clavulanate combination, the dose of clavulanate is constant at 125 mg, whereas the dose of amoxicillin varies at 250 mg, 500 mg and 875 mg. This explains the rationale behind the use of low dose amoxicillin-clavulanate in combination with meropenem as a part of treatment regime for drug resistant TB.

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated.A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention.The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB.

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.

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.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking., TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

The emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (M. tuberculosis) have become tremendous challenges for clinical and programmatic tuberculosis (TB) management. Until recently, TB diagnosis was largely based on 120-year-old smear microscopy, and treatment was based on a limited number of drugs developed prior to 1970. During the past few years, we have witnessed a revolution in the ability of laboratories to detect TB and anti-TB drug resistance. Furthermore, after several years of silence, several new anti-TB drugs have recently appeared on the scene, offering hope for patients with very limited therapeutic options. There is also new evidence supporting the appropriate use of existing drugs in the treatment of MDR-TB and a better understanding of the relevance of additional resistance beyond extensive drug resistance patterns. In this article, we review the management of drug-resistant TB and highlight recent developments concerning its diagnosis and treatment.

Setting The Dominican Republic is a high-incidence area for multidrug-resistant tuberculosis (MDR-TB; 6.6% of initial cases). Standardised treatment regimens for MDR-TB may be a potential solution. Objective To present the effectiveness of standard regimens under routine national conditions. Design We reviewed all MDR-TB patients treated under routine conditions from 29 August 2006 to 30 June 2010, showing interim and final outcomes. Patients were treated with regimens that were standardised or individualised based on previously received second-line anti-tuberculosis drugs. Results Population description and culture conversion data are reported for the 289 MDR-TB patients. The median patient age was 31 years. Most had failed first-line treatment (72.6%). Culture negativity was obtained within 4 months (median 2 months) in 78.6%. Among the 150 patients treated between 2006 and 2008, 74% had favourable results on standardised and 66% on individualised regimens (P = 0.211). The efficacy of the standardised and individualised regimens was respectively 92.8% and 81% (P = 0.056). The relapse rate was approximately 1%. A median of five drug side effects occurred per patient. More than 2 months to culture conversion and bilateral cavitation on chest X-ray were found to be unfavourable outcome risk factors. Conclusions Standardised MDR-TB regimens may be effective at the national level, even in resource-poor settings.

Multidrug-resistant (MDR) tuberculosis (TB) (defined as resistance to at least isoniazid and rifampicin), has a relevant epidemiological impact, with 480, 000 cases and 190,000 deaths notified in 2014; 10% of them meet the criteria for extensively drug-resistant (XDR)-TB [MDR-TB with additional resistance to any fluoroquinolone, and to at least one injectable second-line drugs (SLDs)] (capreomycin, kanamycin or amikacin) (1,2).

Background: Meropenem/clavulanate (MC) has been prescribed to treat MDR/XDR-TB cases, although limited scientific evidence exists. Aim: To retrospectively evaluate the effectiveness, safety, and tolerability of MC added to build an optimal regimen when treating MDR/XDR-TB patients. Methods: An observational, retrospective, cohort study was performed in 5 countries across Europe and South America, where consecutive patients with bacteriologically proven MDR-TB were recruited and divided by MC exposure. Information on demographic, epidemiological, microbiological, and clinical variables were collected from the clinical files using standardized e-forms. Results: A cohort of 264 MDR-TB patients was established: 96 patients were treated with MC-containing regimens and 168 without. Only thirteen (5.2%) were HIV-infected. The proportion of XDR-TB was higher in those exposed to MC-containing regimens (49.0% vs. 6.0%), as was the median (IQR) number of antibiotic resistances (8[6-9] vs 5[4-6]). Sputum smear and culture conversion rates were not statistically different in MDR-TB cases exposed and not exposed to MC-containing regimens, including the XDR-TB subgroup (88.0% vs. 100.0%, P=1.00, and 88.0% vs. 100.0%, P=1.00, respectively). Only 6 MC-related adverse events were reported. In 4 cases, MC was re-started after interruption Conclusion: MC-containing regimens can help achieve sputum culture conversion in MDR/XDR-TB cases with no significant toxicity. This study suggests a potential added value of MC in severe forms of drug-resistant TB when an optimal regimen can not be built with available drugs.

Background: Carbapenems are used to treat MDR/XDR-TB cases in order to build a robust regimen, however limited evidence of their effectiveness exists. Aim: To compare the therapeutic contribution of imipenem and amoxicillin/clavulanate (IC) vs. meropenem and amoxicillin/clavulanate (MC) added to background regimens to treat MDR/XDR-TB cases. Methods: An observational, retrospective, cohort study was performed in 5 centres in Europe and South America, consecutive adult patients with bacteriologically proven MDR-TB were recruited and divided by MC and IC exposure. Demographic, epidemiological, microbiological, and clinical variables were collected using standardized e-forms. Results: A cohort of 180 MDR-TB patients were enrolled: 84 and 96 were treated with IC and MC respectively. Both groups had similar median number of antibiotic resistances (8 vs. 8) but more fluoroquinolone resistance (79.0% vs. 48.9% ; p-value: Conclusion: Our study suggests that MC is safe and more effective than IC in treating M/XDR-TB patients.

Objective To analyze the direct and indirect costs of diagnosis and management of tuberculosis (TB) and associated factors. Patients and methods Prospective study of patients diagnosed with TB between September 2014 and September 2015. We calculated direct (hospital stays, visits, diagnostic tests, and treatment) and indirect (sick leave and loss of productivity, contact tracing, and rehabilitation) costs. The following cost-related variables were compared: age, gender, country of origin, hospital stays, diagnostic testing, sensitivity testing, treatment, resistance, directed observed therapy (DOT), and days of sick leave. Proportions were compared using the chi-squared test and significant variables were included in a logistic regression analysis to calculate odds ratio (OR) and corresponding 95% confidence intervals. Results 319 patients were included with a mean age of 56.72±20.79 years. The average cost was €10,262.62±14,961.66, which increased significantly when associated with hospital admission, polymerase chain reaction, sputum smears and cultures, sensitivity testing, chest computed tomography, pleural biopsy, drug treatment longer than nine months, DOT and sick leave. In the multivariate analysis, hospitalization (OR=96.8; CI 29–472), sensitivity testing (OR=4.34; CI 1.71–12.1), chest CT (OR=2.25; CI 1.08–4.77), DOT (OR=20.76; CI 4.11–148) and sick leave (OR=26.9; CI 8.51–122) showed an independent association with cost. Conclusion Tuberculosis gives rise to significant health spending. In order to reduce these costs, more control of transmission, and fewer hospital admissions would be required.

To determine the prevalence of nontuberculous mycobacteria (NTM) colonization and disease in cystic fibrosis (CF) patients.All the CF patients followed-up from 2002 to 2012 with three acid-fast bacilli (AFB) cultures were included. The American Thoracic Society (ATS) criteria for NTM lung disease were applied.Forty-four of the 53 patients being followed-up were included. The mean time of follow-up was 7.0 years. A total of 18 patients (40.9%) were NTM positive. The NTN mean annual prevalence was 14.1%. The risk of Mycobacterium abscessus complex was higher in the group of 10-14 years-old (p 0.001). Ten patients (22.7% of the entire cohort) met the ATS microbiological criteria. The mean annual prevalence of NTM disease was 10.4%. Seven patients (four with Mycobacterium simiae and three with M. abscessus complex) with multiple positive cultures, positive AFB smears and clinical worsening were treated. Three patients with M. simiae and none of those with M. abscessus were cured.Overall NTM prevalence of colonization and disease were high in our CF patients. Patients15 years old had a higher risk of M. abscessus complex colonization. Multiple positive cultures or positive AFB smears were associated with disease.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis.12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure).Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage 600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg.The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

The capacity of infection and the ability of Mycobacterium tuberculosis strains belonging to the Beijing family to spread rapidly probably result from genetic advantages and unidentified mechanisms of virulence not yet thoroughly investigated. Among the mechanisms proposed to be responsible for the varying virulence phenotypes of M. tuberculosis strains we find IS6110 insertions, genetic reorganizations and deletions, which have strong influences on fitness. Beijing family is one of the lineages with the highest number of copies of IS6110. By studying genetic markers characteristic for this lineage, here we have characterized the clinical isolate M. tuberculosis GC1237 strain responsible for important epidemic outbreaks in the Gran Canary Island. We have identified and analyzed each point of insertion of IS6110 using a bacterial artificial chromosome (BAC) library of this strain, in addition to the use of other approximations. Nineteen copies of IS6110 have been localized in GC1237 genome of which, four copies of IS6110 can act as a promoter and we have focused in the characterization of one copy located 31 bp upstream of the essential gene Rv2179c and compared to the reference strain H37Rv.

We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875–2950) and 500 (200–1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.

Though spontaneous pneumothorax (SP) is a well-known complication of pulmonary tuberculosis (TB), there are very few reports addressing this topic. For this reason, we retrospectively analysed the experience of SP in patients diagnosed with TB in our hospital between 1989 and 2010. Out of 872 patients treated for SP during this period, 47 (5.4%) had TB antecedents, 21 with active TB (0.95% of the 2,089 TB cases diagnosed during this period) and 26 with residual inactive TB. 46 cases were treated with pleural drainage (PD): 40 (85%) with only one PD, two with two, and four with three. The mean ± SD length of PD treatment was 12.9 ± 11.3 days. In 11 (23%) cases, a relapse of SP occurred, with no statistical relationship between the different studied variables. In 13 (28%) cases, it became necessary to carry out a resection (atypical segmentectomy in all cases) for persistent air leaks with PD. Survival statistics were unfavourable only in elderly patients and those infected with HIV. We conclude that the treatment of SP secondary to TB with PD is usually a sound response, with a good general prognosis and a low percentage of cases that require another PD and surgical treatment.