Jose A. Caminero

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are generally thought to have high mortality rates. However, many cases can be treated with the right combination and rational use of available antituberculosis drugs. This Review describes the evidence available for each drug and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis. The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Among the first group (the oral first-line drugs) high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis. The second group is the fluoroquinolones, of which the first choice is high-dose levofloxacin. The third group are the injectable drugs, which should be used in the following order: capreomycin, kanamycin, then amikacin. The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid. The fifth group includes drugs that are not very effective or for which there are sparse clinical data. Drugs in group five should be used in the following order: clofazimine, amoxicillin with clavulanate, linezolid, carbapenems, thioacetazone, then clarithromycin.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB : systematic review and meta-analysis

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 versus >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.

European union standards for tuberculosis care.

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.

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

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

Diagnóstico y tratamiento de la tuberculosis

Lamentablemente, las novedades en tuberculosis (TB) se producen de forma lenta, demasiado lenta. No obstante, han pasado bastantes anos desde las ultimas Normativas de la Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) sobre el diagnostico y el tratamiento de la TB, y durante este periodo no solo se han producido avances en el diagnostico y el tratamiento, especialmente en el campo del diagnostico, sino que ademas hemos asistido a un importante cambio demografico en Espana motivado por el incremento de la inmigracion. En la actualidad el 10% del total de la poblacion espanola no ha nacido en el pais y el 30% de los casos de TB corresponden a pacientes inmigrantes. Por todo ello, nos ha parecido oportuno y necesario revisar nuestras guias para actualizarlas y adaptarlas a la presente configuracion social espanola. En un esfuerzo de simplificacion hemos decidido agrupar en una sola las normativas previas sobre diagnostico y tratamiento de la TB. Para la elaboracion de la presente guia hemos tenido en cuenta la evidencia cientifica disponible. El grado de recomendacion se clasifica como A, B, C y D. El grado A significa que la evidencia cientifica en que se basa es buena o muy buena (estudios de nivel 1); el B, que es razonablemente buena (estudios de nivel 2); el C, que es escasa (series y casos), y el D, que asienta en opiniones de expertos y consensos. Agradecemos al Comite Cientifico de la SEPAR la deferencia y la confianza que han otorgado al grupo de expertos para llevar a cabo la nueva Normativa y esperamos y deseamos que sea de utilidad para mejorar el control de la TB. DIAGNOSTICO DE LA INFECCION TUBERCULOSA

Tuberculosis treatment adherence and fatality in Spain.

BackgroundThe adherence to long tuberculosis (TB) treatment is a key factor in TB control programs. Always some patients abandon the treatment or die. The objective of this study is to identify factors associated with defaulting from or dying during antituberculosis treatment.MethodsProspective study of a large cohort of TB cases diagnosed during 2006-2007 by 61 members of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). Predictive factors of completion outcome (cured plus completed treatment vs. defaulters plus lost to follow-up) and fatality (died vs. the rest of patients) were based on logistic regression, calculating odds ratios (OR) and 95% confidence intervals (CI).ResultsOf the 1490 patients included, 29.7% were foreign-born. The treatment outcomes were: cured 792 (53.2%), completed treatment 540 (36.2%), failure 2 (0.1%), transfer-out 33 (2.2%), default 27 (1.8%), death 27 (1.8%), lost to follow-up 65 (4.4%), other 4 (0.3%). Completion outcome reached 93.5% and poor adherence was associated with: being an immigrant (OR = 2.03; CI:1.06-3.88), living alone (OR = 2.35; CI:1.05-5.26), residents of confined institutions (OR = 4.79; CI:1.74-13.14), previous treatment (OR = 2.93; CI:1.44-5.98), being an injecting drug user (IDU) (OR = 9.51; CI:2.70-33.47) and treatment comprehension difficulties (OR = 2.93; CI:1.44-5.98). Case fatality was 1.8% and it was associated with the following variables: age 50 or over (OR = 10.88; CI:1.12-105.01), retired (OR = 12.26;CI:1.74-86.04), HIV-infected (OR = 9.93; CI:1.48-66.34), comprehension difficulties (OR = 4.07; CI:1.24-13.29), IDU (OR = 23.59; CI:2.46-225.99) and Directly Observed Therapy (DOT) (OR = 3.54; CI:1.07-11.77).ConclusionImmigrants, those living alone, residents of confined institutions, patients treated previously, those with treatment comprehension difficulties, and IDU patients have poor adherence and should be targeted for DOT. To reduce fatality rates, stricter monitoring is required for patients who are retired, HIV-infected, IDU, and those with treatment comprehension difficulties.

Towards elimination of tuberculosis in a low income country: the experience of Cuba, 1962-97.

BACKGROUND This study describes the epidemiological trends of tuberculosis in Cuba and the performance of the tuberculosis control programme. The circumstances that caused an increase in the incidence of new cases of tuberculosis between 1991 and 1994 had been analysed and were corrected in 1995–7. METHODS A descriptive study of the incidence rates of new cases of tuberculosis notified from 1962 to 1997 was made, with special emphasis on the total change between 1965 and 1991 and the increase thereafter. RESULTS The case notification rate of 14.7 per 100 000 in 1994 was almost three times the rate found in 1991 (4.8 per 100 000) and reversed the mean annual decrease of 5% observed since 1965. This increase was almost twofold in the rate of smear positive new cases (4.4 per 100 000 in 1991 and 8.3 in 1994). From 1971 onwards the programme had achieved a cure rate of 90% throughout the country with only 2% absconding by applying directly observed treatment. The main factors associated with the increasing trends were: (1) a probable underdetection of cases for the 1988–92 period that generated contagious sources in the community; (2) improved case finding from 1993 onwards and the introduction of an expanded case definition in 1994; (3) a considerable increase in the diagnostic delay from initial medical consultation to beginning of antituberculosis treatment (56.9 days in 1993); and (4) operational changes in the tuberculosis control programme due to the economic crisis in Cuba. In 1995, 1996 and 1997 it has been possible to reverse this trend, achieving rates of 14.1, 13.5, and 12.2 per 100 000, respectively (7.6, 7.6, and 6.9 for smear positive cases) as a result of effective intervention correcting the problems identified. Reducing the diagnostic delay attributable to shortcomings in the health care system and the study of contacts were of particular importance for re-establishing the tuberculosis programme as a priority. CONCLUSIONS Cuba represents a good example of how it is possible to fight against tuberculosis effectively, even in a low income country, by applying control strategies advocated by the World Health Organisation and the International Union Against Tuberculosis and Lung Disease and by giving adequate support to the programme through political commitment.

Evaluation of a directly observed six months fully intermittent treatment regimen for tuberculosis in patients suspected of poor compliance.

BACKGROUND: Although a priority for tuberculosis control is to achieve the maximum cure rate, compliance with chemotherapy in specific high risk groups (homeless, intravenous drug abusers, chronic alcoholics) is usually poor. METHODS: From January 1990 to December 1994 102 patients with tuberculosis (96 pulmonary, six extrapulmonary) who were poorly compliant with treatment were treated with a six month fully intermittent (twice weekly) directly observed regimen. They comprised 71 homeless subjects, 50 chronic alcoholics, 23 intravenous drug abusers, nine infected with HIV, and 11 who had previously abandoned a daily antituberculosis regimen; 53 had more than one of these risk factors. Treatment included isoniazid and rifampicin for six months and pyrazinamide during the first two months. Patients who failed to take their medication on two consecutive occasions were actively sought by telephone or by personal search. RESULTS: After two months of treatment 95 of the 102 patients had taken their medication regularly and 90 of them had negative cultures. Four of the remaining patients had negative cultures after three months. At the end of the six months 87 patients had completed treatment and were considered cured. Only 15 patients abandoned the treatment (13 of whom had more than one risk factor). Only three relapses occurred in the 102 patients at one year follow up and in the 88 patients followed for two years. Two patients required a change of treatment due to major side effects. Although intravenous drug abuse was the only predictor of non-compliance in the multivariate analysis, if the available variables in the second month of treatment were analysed, current poor compliance and abandonment of treatment in the past were found to be significantly associated with non-compliance. CONCLUSIONS: This study shows the efficacy of this intermittent regimen and the effectiveness of a directly observed treatment programme.

Effectiveness and safety of meropenem/ clavulanate-containing regimens in the treatment of MDR- and XDR-TB

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases. Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6–9) versus 5 (4–6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49–156) days. No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment). The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases. Meropenem/clavulanate is effective and safe to treat MDR- and XDR-TB in comparison with controls http://ow.ly/XG75j