Barriers faced by patients in the diagnosis of multidrug-resistant tuberculosis in Brazil

ABSTRACT OBJECTIVE To understand patients' narratives about the barriers they faced in the diagnosis and treatment of multidrug-resistant tuberculosis, and their consequences in Rio de Janeiro State, Brazil. METHODS This is a qualitative cross-sectional study with non-probabilistic sampling. A theoretical saturation criterion was considered for composing the number of interviewees. Semi-structured interviews were conducted from August to December 2019 with 31 patients undergoing treatment for multidrug-resistant tuberculosis at an outpatient referral center in Rio de Janeiro. Data were transcribed and processed with the aid of the NVIVO software. Interviews were evaluated by content analysis, and their themes, cross-referenced with participants' characterization data. RESULTS Our main findings were: a) participants show a high proportion of primary drug resistance, b) patients experience delays in the diagnosis and effective treatment of multidrug-resistant tuberculosis ; c) healthcare providers fail to value or seek the diagnosis of drug-resistant tuberculosis, thus beginning the inadequate treatment for drug-susceptible tuberculosis, d) primary health units show low report rates of active case-finding and contact monitoring, and e) patients show poor knowledge about the disease. CONCLUSIONS We need to improve referral systems, and access to the diagnosis and effective treatment of multidrug-resistant tuberculosis; conduct an active investigation of contacts; intensify the training of healthcare providers, in collaboration with medical and nursing schools, in both public and private systems; and promote campaigns to educate the population on tuberculosis signs and symptoms.

Tuberculosis farmacorresistente en provincia Guantánamo, 2010-2019 / Drug-resistant tuberculosis in Guantánamo province, 2010-2019 / Tuberculose resistente a medicamentos na província de Guantánamo, 2010-2019

RESUMEN Introducción: En los últimos 10 años en Cuba y, especialmente, en provincia Guantánamo se ha observado incremento del número de pacientes tuberculosos farmacorresistentes; esta es la provincia de mayor incidencia en el país. Objetivo: Identificar las características epidemiológicas y el patrón de resistencia de la tuberculosis farmacorresistente en provincia Guantánamo. Método: Se diseñó un estudio descriptivo y transversal que incluyó la totalidad de casos (n=6) con tuberculosis farmacorresistentes diagnosticados entre diciembre de 2010 y diciembre de 2019. Se estudiaron las variables: edad, sexo, régimen terapéutico, situación económica, categorías de casos, clasificación epidemiológica de la resistencia y resistencia de la cepa aislada según el grado y perfil. Resultados: Predominó el sexo masculino (66, 6 %) y el grupo de edades de menores de 45 años (83,3 %), la mayor cantidad de resistencia estuvo propiciada por violaciones en los tratamientos anteriores (66,6 %), categorizados mayormente como crónicos y reingresos por abandono. Predominó el nivel educacional de secundaria básica terminada (66,7 %), con situación económica regular (50,0 %) y alto nivel de alcoholismo (66,7 %). La multidrogorresistencia prevaleció en cepas de pacientes con tratamiento previo (66,6 %). Conclusiones: Existe coincidencia del patrón epidemiológico y el patrón de resistencia mostrado en la investigación actual con los resultados de estudios previos nacionales e internacionales, estos resultados sugieren fallas en la aplicación local del Programa Nacional de Control y Tratamiento de la tuberculosis. Se recomienda investigar y resolver estas fallas lo que produciría un impacto inmediato en la disminución de la incidencia de tuberculosis farmacorresistentes.

ABSTRACT Introduction: An increase in the number of drug-resistant tuberculosis patients has been observed in the last 10 years in Cuba and, especially, in Guantánamo province. This is the province with the highest incidence in the country. Objective: To identify the epidemiological characteristics and the resistance pattern of drug-resistant tuberculosis in Guantánamo province. Method: A descriptive, cross-sectional study was designed that included all cases (n=6) with drug-resistant tuberculosis, diagnosed between December 2010 and December 2019. The variables studied were: age, gender, therapeutic regimen, economic situation, categories of cases, epidemiological classification of resistance, and resistance of the isolated strain according to the grade and profile. Results: Males predominated (66.6%), and also the age group under 45 years (83.3%), the greatest resistance was caused by not abiding the previous treatments (66.6%), categorized mostly as chronic, and readmitted due to treatment abandonment. Highschool degree (66.7%) predominated, with a moderate economic situation (50.0%) and high levels of alcoholism (66.7%). Multi-drug resistance prevailed in the strains in patients with previous treatment (66.6%). Conclusions: There is a coincidence of the epidemiological pattern and the resistance pattern shown in the current research with the results of previous national and international studies; these results suggest flaws in the local application of the Programa Nacional de Control y Tratamiento de la tuberculosis. It is recommended to investigate and resolve these flaws, which would have an immediate impact on reducing the incidence of drug-resistant tuberculosis.

RESUMO Introdução: Nos últimos 10 anos, em Cuba e, principalmente, na província de Guantánamo, observou-se um aumento no número de pacientes com tuberculose resistente aos medicamentos; esta é a província com maior incidência no país. Objetivo: Identificar as características epidemiológicas e o padrão de resistência da tuberculose resistente a medicamentos na província de Guantánamo. Método: Foi elaborado um estudo descritivo e transversal que incluiu todos os casos (n=6) com tuberculose resistente a medicamentos diagnosticados entre dezembro de 2010 e dezembro de 2019. Foram estudadas as variáveis: idade, sexo, regime terapêutico, situação econômica, categorias de casos, classificação epidemiológica de resistência e resistência da cepa isolada de acordo com o grau e perfil. Resultados: Houve predomínio do sexo masculino (66,6%) e na faixa etária abaixo de 45 anos (83,3%), a maior quantidade de resistência foi causada por violações nos tratamentos anteriores (66,6%), categorizados principalmente como crônicos e reinternações por abandono. Predominou situação econômica regular (50,0%) e alto nível de alcoolismo (66,7%). A multirresistência prevaleceu em cepas de pacientes com tratamento anterior (66,6%). Conclusões: Há coincidência do padrão epidemiológico e do padrão de resistência mostrado na pesquisa atual com os resultados de estudos nacionais e internacionais anteriores, esses resultados sugerem falhas na aplicação local do Programa Nacional de Controle e Tratamento da Tuberculose. Recomenda-se investigar e resolver essas falhas, que teriam um impacto imediato na redução da incidência de tuberculose resistente aos medicamentos.

Cost-effectiveness of Xpert®MTB/RIF in the diagnosis of tuberculosis: pragmatic study

Abstract INTRODUCTION: The intensification of research and innovation with the creation of networks of rapid and effective molecular tests as strategies for the end of tuberculosis are essential to avoid late diagnosis and for the eradication of the disease. We aimed to evaluate the cost-effectiveness of Xpert®MTB/RIF (Xpert) in the diagnosis of drug-resistant tuberculosis in reference units, in scenarios with and without subsidies, and the respective cost adjustment for today. METHODS: The analyses were performed considering as criterion of effectiveness, negative culture or clinical improvement in the sixth month of follow-up. The comparison was performed using two diagnostic strategies for the drug susceptibility test (DST), BactecTMMGITTM960 System, versus Xpert. The cost effectiveness and incremental cost-effectiveness ratio (ICER) were calculated and dollar-corrected for American inflation (US$ 1.00 = R$ 5,29). RESULTS: Subsidized Xpert had the lowest cost of US$ 33.48 (R$67,52) and the highest incremental average efficiency (13.57), thus being a dominated analysis. After the inflation was calculated, the mean cost was DST-MGIT=US$ 74.85 (R$ 396,73) and Xpert = US$ 37.33 (R$197,86) with subsidies. CONCLUSIONS: The Xpert in the diagnosis of TB-DR in these reference units was cost-effective with subsidies. In the absence of a subsidy, Xpert in TB-DR is not characterized as cost effective. This factor reveals the vulnerability of countries dependent on international organizations' subsidy policies.

Directrices unificadas de la OMS sobre el tratamiento de la tuberculosis farmacorresistente / WHO consolidated guidelines on drug-resistant tuberculosis treatment

Las cepas del bacilo tuberculoso con farmacorresistencia (TB-DR) son más difíciles de tratar que las farmacosensibles y amenazan el progreso mundial hacia los objetivos establecidos por la Estrategia Fin de la TB, de la Organización Mundial de la Salud (OMS). Por lo tanto, existe una necesidad imperiosa de contar con recomendaciones de política basadas en la evidencia sobre el tratamiento y la atención a los pacientes con TB-DR, de acuerdo con la evidencia más reciente y completa disponible. A este respecto, las Directrices unificadas de la OMS sobre el tratamiento de la tuberculosis farmacorresistente cumplen el mandato de la OMS de informar a los profesionales de la salud de los Estados Miembros sobre cómo mejorar el tratamiento y la atención de los pacientes con TB-DR.

Genotype®MTBDRplus and Xpert®MTB/RIF in the diagnosis of tuberculosis and resistant tuberculosis: cost analysis in a tertiary referral hospital

Abstract INTRODUCTION: The present study sought to assess the mean and activity based cost (ABC) of the laboratory diagnosis for tuberculosis through the application of conventional and molecular techniques-Xpert®MTB/RIF and Genotype®MTBDRplus-in a tertiary referral hospital in Brazil. METHODS: The mean cost and ABC formed the basis for the cost analysis of the TB laboratory diagnosis. RESULTS: The mean cost and ABC were US$ 4.00 and US$ 3.24, respectively, for a bacilloscopy; US$ 6.73 and US$ 5.27 for a Lowenstein-Jensen (LJ) culture; US$ 105.42 and US$ 76.56 for a drug sensitivity test (DST)-proportions method (PM) in LJ; US$ 148.45 and US$ 136.80 for a DST-BACTECTM MGITTM 960 system; US$ 11.53 and US$ 9.89 for an Xpert®MTB/RIF; and US$ 84.21 and US$ 48.38 for a Genotype®MTBDRplus. CONCLUSIONS: The mean cost and ABC proved to be good decision-making parameters in the diagnosis of TB and MDR-TB. The effective implementation of algorithms will depend on the conditions at each location.

Factors associated with tuberculosis and multidrug-resistant tuberculosis in patients treated at a tertiary referral hospital in the state of Minas Gerais, Brazil / Fatores associados à tuberculose e à tuberculose multirresistente em pacientes atendidos em um hospital de referência terciária em Minas Gerais, Brasil

ABSTRACT Objective: To evaluate the risk factors for the development of tuberculosis and multidrug-resistant tuberculosis (MDR-TB) in patients treated at a tertiary referral hospital. Methods: This was a cross-sectional study based on data obtained from patients treated at the Júlia Kubitschek Hospital, located in the city of Belo Horizonte, Brazil, between October of 2012 and October of 2014. We evaluated sociodemographic, behavioral, clinical, and radiological variables. The outcome considered to identify associations between tuberculosis and the explanatory variables was the treatment prescribed. To evaluate the associations between MDR-TB and the same explanatory variables, the change in MDR-TB treatment was considered. Results: The factors associated with tuberculosis were alcoholism, comorbidities, pulmonary cavitations, and a radiological pattern suggestive of tuberculosis. Cavitation and previous treatment for tuberculosis were associated with MDR-TB. Conclusions: Despite the significant progress made in the fight against tuberculosis, there is a need for coordinated actions that include social protection measures and patient support.

RESUMO Objetivo: Avaliar os fatores de risco de pacientes atendidos em um hospital de referência terciária para o desenvolvimento de tuberculose e tuberculose multirresistente (TBMR). Métodos: Estudo transversal baseado em dados obtidos de pacientes atendidos no Hospital Júlia Kubitschek, na cidade de Belo Horizonte (MG), entre outubro de 2012 e outubro de 2014. As variáveis utilizadas foram agrupadas em características sociodemográficas, comportamentais, clínicas e radiológicas. O desfecho considerado para verificar associações entre tuberculose e variáveis explicativas foi o tratamento prescrito para tuberculose. Para avaliar a associação entre a tuberculose resistente e as mesmas variáveis explicativas considerou-se a mudança de tratamento para TBMR. Resultados: Alcoolismo, padrão radiológico sugestivo de tuberculose, presença de comorbidades e presença de cavitações pulmonares foram fatores associados à tuberculose. A TBMR foi associada a tratamento prévio para tuberculose e presença de cavitações. Conclusões: Apesar dos importantes progressos na luta contra a tuberculose, é necessário um conjunto de ações articuladas que incluam medidas de proteção social e suporte aos pacientes.

Avaliação do Sistema de Vigilância da Tuberculose Drogarresistente, Brasil, 2013-2017 / Evaluación del Sistema de Vigilancia de la Tuberculosis Drogorresistente, Brasil, 2013-2017 / Evaluation of the Drug-Resistant Tuberculosis Surveillance System, Brazil, 2013-2017

Objetivo: avaliar o Sistema de Vigilância da Tuberculose Drogarresistente (SV-TBDR)/Brasil. Métodos: estudo avaliativo, segundo diretrizes do Centro de Controle e Prevenção de Doenças, sobre dados nacionais do Sistema de Informação de Tratamentos Especiais de Tuberculose (SITETB) e do Sistema de Informação de Agravos de Notificação (Sinan) de 2013-2017. Resultados: a completitude média dos dados foi de 95% (escolaridade [89,1%; 5.417/6.078]; nacionalidade [94,7%; 5.754/6.078]; raça/cor da pele [99,1%; 6.023/6.078]; tipo de resistência [98,6%; 5.995/6.078]; forma clínica [100%; 6.078/6.078]; e teste para HIV [87%; 5.289/6.078]); a proporção média de casos com culturas realizadas foi de 65,7% (cultura 1 [94,8%; 5.764/6.078]; cultura 2 [69,8%; 4.241/6.078]; cultura 3 [54,7%; 3.324/6.078]; e cultura 4 [43,6%; 2.652/6.078]); em 2015, o SV-TBDR notificou 52% (1.197/2.300) dos casos multirresistentes estimados pela Organização Mundial da Saúde, 41,3% (990/2.400) em 2016 e 45,8% (1.100/2.400) em 2017. Conclusão: a baixa sensibilidade do SV-TBDR recomenda melhorias no acesso ao diagnóstico da TBDR.

Objetivo: evaluar el Sistema de Vigilancia de la Tuberculosis Drogorresistente (SV-TB -DR)/Brasil. Métodos: estudio evaluativo, según directrices del Centro de Control y Prevención de Enfermedades, sobre datos nacionales del Sistema de Información de Tratamientos Especiales de Tuberculosis (SITETB) y del Sistema Nacional de Agravamientos de Notificación (Sinan) entre 2013 y 2017. Resultados: la completitud promedio de los datos fue de 95% (escolaridad [89,1%; 5.417/6.078]; nacionalidad [94,7%; 5.754/6.078]; raza/color de la piel ­[99,1%; 6.023/6.078]; tipo de resistencia [98,6%; 5.995/6.078]; forma clínica [100%; 6.078/6.078]; y prueba de VIH [87%; 5.289/6.078]); la proporción promedio de los casos con cultivos realizados fue 65,7% (cultivo 1 [94,8%; 5.764/6.078]; cultivo 2 [69,8%; 4.241/6.078]; cultivo 3 [54,7%; 3.324/6.078]; y cultivo 4 [43,6%; 2.652/6.078]); el SV-TB-DR reportó en 2015 52% (1.197/2.300) de los casos multirresistentes estimados por la Organización Mundial de la Salud, 41,3% (990/2.400) en 2016 y 45,8% (1.100/2.400) en 2017. Conclusión: la baja sensibilidad del SV-TB-DR sugiere la necesidad de mejorar el acceso al diagnóstico de TB-DR.

Objective: to evaluate the Brazilian Drug-Resistant Tuberculosis Surveillance System (DRTB-SS). Methods: this was an evaluative study, following Centers for Disease Control and Prevention guidelines, using national data from the Special Tuberculosis Treatment Information System (SITETB), and the Notifiable Diseases Information System (SINAN), from 2013 to 2017. Results: average data completeness was 95% (schooling [89.1%; 5,417/6,078], nationality [94.7%; 5,754/6,078], race/skin color [99.1%; 6,023/6,078], type of resistance [98.6%; 5,995/6,078], clinical form [100%; 6,078/6,078], and HIV test [87%; 5,289/6,078]); average proportion of cases with sputum cultures performed was 65.7% (culture 1 [94.8%; 5,764/6,078], culture 2 [69.8%; 4,241/6,078], culture 3 [54.7%, 3,324/6,078], and culture 4 [43.6%; 2,652/6,078]); DRTB-SS reported 52% (1,197/2,300) of multi-resistant cases estimated by the World Health Organization in 2015, 41.3% (990/2,400) in 2016, and 45.8% (1,100/2,400) in 2017. Conclusion: low DRTB-SS sensitivity suggests the need for improved access to DRTB diagnosis.

Speeding up the diagnosis of multidrug-resistant tuberculosis in a high-burden region with the use of a commercial line probe assay / Agilizando o diagnóstico da tuberculose multirresistente em uma região endêmica com o uso de um teste comercial de sondas em linha

ABSTRACT Objective: To evaluate the rapid diagnosis of multidrug-resistant tuberculosis, by using a commercial line probe assay for rifampicin and isoniazid detection (LPA-plus), in the routine workflow of a tuberculosis reference laboratory. Methods: The LPA-plus was prospectively evaluated on 341 isolates concurrently submitted to the automated liquid drug susceptibility testing system. Results: Among 303 phenotypically valid results, none was genotypically rifampicin false-susceptible (13/13; 100% sensitivity). Two rifampicin-susceptible isolates harboured rpoB mutations (288/290; 99.3% specificity) which, however, were non-resistance-conferring mutations. LPA-plus missed three isoniazid-resistant isolates (23/26; 88.5% sensitivity) and detected all isoniazid-susceptible isolates (277/277; 100% specificity). Among the 38 (11%) invalid phenotypic results, LPA-plus identified 31 rifampicin- and isoniazid-susceptible isolates, one isoniazid-resistant and six as non-Mycobacterium tuberculosis complex. Conclusions: LPA-plus showed excellent agreement (≥91%) and accuracy (≥99%). Implementing LPA-plus in our setting can speed up the diagnosis of multidrug-resistant tuberculosis, yield a significantly higher number of valid results than phenotypic drug susceptibility testing and provide further information on the drug-resistance level.

RESUMO Objetivo: Avaliar o diagnóstico rápido de tuberculose multirresistente, utilizando um teste comercial de sondas em linha (LPA-plus), na rotina de um laboratório de referência de tuberculose. Métodos: O teste LPA-plus foi avaliado prospectivamente em 341 isolados simultaneamente submetidos ao teste de suscetibilidade aos antimicrobianos em meio líquido, pelo sistema automatizado. Resultados: Entre os 303 resultados fenotipicamente válidos, nenhum foi genotipicamente falso suscetível à rifampicina (13/13; 100% de sensibilidade). Dois isolados sensíveis à rifampicina apresentavam mutações no gene rpoB (288/290; especificidade de 99,3%), as quais, no entanto, não são associadas à resistência a rifampicina. O LPA-plus não identificou resistência à isoniazida em três isolados fenotipicamente resistentes (23/26; 88,5% de sensibilidade) e detectou todos os isolados sensíveis à isoniazida (277/277; especificidade de 100%). Entre os 38 (11%) resultados fenotípicos inválidos, o LPA-plus identificou 31 isolados sensíveis à rifampicina e à isoniazida, um resistente à isoniazida e seis como micobactérias não tuberculosas. Conclusões: O LPA-plus mostrou excelente concordância (≥91%) e acurácia (≥99%). Sua implementação pode acelerar o diagnóstico da tuberculose multirresistente, produzir número significativamente maior de resultados válidos do que o teste fenotípico de suscetibilidade aos antimicrobianos e fornecer informações adicionais sobre o nível de resistência aos fármacos.

Toxicité hématologique sévère du linezolide au cours du traitement de la tuberculose pharmacorésistante : A propos de deux(2) cas au service de Pneumo-Phtisiologie du CHU de Conakry

Introduction : Le linezolide est un médicament potentiellement efficace pour le traitement des patients atteints de tuberculose pharmaco-résistante. En dépit de son efficacité et sa bonne biodisponibilité, il présente des toxicités, dont celle hématologique demeure l'une des plus graves. Nous rapportons deux cas de toxicité hématologique du linézolide au cours du traitement de la tuberculose pharmacorésistante. Le premier cas concernait un patient de 65 ans traité pour une tuberculose multi-résistante avec un schéma thérapeutique contenant du linézolide. L'évolution fut marquée par la survenue d'une pancytopénie avec anémie sévère à 5,4 g et un tableau d'insuffisance rénale. L'issue fut favorable après arrêt du médicament et transfusion sanguine. Le second cas concernait un patient de 33 ans, pré XDR qui lutte contre la tuberculose depuis 10 ans avec cinq cures de chimiothérapie antituberculeuse qui se sont soldées par des échecs et résistances. Au cours de son suivi, il a présenté une bonne évolution clinique et bactériologique initiale mais rapidement était survenue une anémie sévère à 5g/dl, à cette anémie était associées des neuropathies périphériques. Le Linezolide avait été retiré du schéma thérapeutique, suivi de transfusions sanguines. La suite avait été favorable sous traitement antituberculeux et le patient fut guéri de sa tuberculose. Conclusion Le linézolide est efficace dans le traitement de la tuberculose pharmacorésistante mais présente une toxicité hématologique

Diagnóstico molecular de tuberculosis multidrogorresistente en muestras de esputo mediante el análisis de curvas de melting / Molecular diagnosis of multidrug-resistant tuberculosis in sputum samples by melting curve analysis

RESUMEN Objetivos. Analizar curvas de melting para el diagnóstico de tuberculosis multidrogorresistente a partir de muestras de esputo. Materiales y métodos. Se colectaron muestras de esputo (n = 250) de pacientes con sospecha clínica de tuberculosis pulmonar según resultado de baciloscopia y cultivados en medio sólido Lowenstein Jensen. Según el método de referencia se trabajó con 124 muestras sensibles a rifampicina e isoniacida, 24 resistentes a rifampicina, 33 resistentes a isoniacida y 69 multidrogorresistentes. Se evaluó por PCR en tiempo real y luego por las curvas de melting, se utilizó el gen rpoB como biomarcador de resistencia a rifampicina, y el gen katG y región promotora inhA como biomarcadores de resistencia a isoniacida. La cepa H37Rv fue considerada como control sensible a drogas. Se compararon los resultados del método de referencia y los resultados del análisis de curvas de melting para evaluar los parámetros de sensibilidad, especificidad, valor predictivo positivo y valor predictivo negativo. Resultados. La resistencia a rifampicina mostró una sensibilidad de 90,3 %, especificidad de 90,4 %, valor predictivo positivo de 84,8 % y valor predictivo negativo de 94,0 %. La resistencia a isoniacida mostró una sensibilidad de 90,2 %, especificidad de 93,9 %, valor predictivo positivo de 91,1 % y valor predictivo negativo de 93,3 %. La detección de tuberculosis multidrogorresistente mostró valores de 89,9 %, 90,6 %, 78,5 % y 95,9 % para sensibilidad, especificidad, valor predictivo positivo y valor predictivo negativo, respectivamente. Conclusiones. El análisis de curvas de melting mostró ser seguro y confiable para ser utilizado en el diagnóstico rápido de tuberculosis multidrogorresistente en muestras de esputo.

ABSTRACT Objectives. To analyze melting curves for the diagnosis of multidrug-resistant tuberculosis from sputum samples. Materials and Methods. Sputum samples (n = 250) were collected from patients with clinical suspicion of pulmonary tuberculosis as a result of bacilloscopy and cultured in solid medium Lowenstein Jensen. According to the reference method, 124 samples sensitive to rifampicin and isoniazid, 24 resistant to rifampicin, 33 resistant to isoniazid, and 69 multidrug-resistant were used. It was evaluated by real-time PCR and then by melting curves, the rpoB gene was used as a biomarker of rifampicin resistance, and the katG gene and inhA promoter region were used as biomarkers of isoniazid resistance. The H37Rv strain was considered a drug-sensitive control. The results of the reference method and the results of the melting curve analysis were compared to evaluate the parameters of sensitivity, specificity, positive predictive value and negative predictive value. Results. Rifampicin resistance showed a sensitivity of 90.3%, specificity of 90.4%, positive predictive value of 84.8% and negative predictive value of 94.0%. Isoniazid resistance showed a sensitivity of 90.2%, specificity of 93.9%, positive predictive value of 91.1% and negative predictive value of 93.3%. The detection of multidrug-resistant tuberculosis showed values of 89.9%, 90.6%, 78.5% and 95.9% for sensitivity, specificity, positive predictive value and negative predictive value, respectively. Conclusions. The melting curve analysis showed to be safe and reliable to be used in the rapid diagnosis of multidrug-resistant tuberculosis in sputum samples.

Manejo clínico y programático de la tuberculosis con resistencia a fármacos / Clinical and programatic management of multidrug resistant tuberculosis

Resumen Se presenta parte de la información entregada durante un curso de capacitación en tuberculosis con resistencia a fármacos para referentes clínicos del PROCET de Chile, con la colaboración del Dr. José Antonio Caminero Luna. Se enfatizó el uso de métodos de diagnóstico rápidos de resistencia a fármacos basados en la biología molecular, técnicas más sensibles y específicas, con el análisis de algunos algoritmos de diagnóstico factibles de implementar en nuestro país. Se detallaron las nuevas propuestas de terapia de tuberculosis con resistencia a fármacos, especialmente TBC-MDR (multidrogo resistente), y las ventajas de nuevos esquemas terapéuticos de mayor eficacia como los que son recomendados actualmente por la Organización Mundial de la Salud (OMS).

This publication summarizes part of the information provided during a training in multidrug resistant tuberculosis (MDR-TB) for clinical specialists in all health services of Chile with the collaboration of Dr. Jose Antonio Caminero Luna and the Chilean Program of Control and Eradication of Tuberculosis (PROCET). Emphasis was placed on early, sensitive and specific diagnostic methods of resistance to drugs based on molecular biology, showing some diagnostic algorithms feasible to implement in our country. Some proposals were made for changes in the treatment of tuberculosis with resistance to drugs, especially MDR-TB, with more effective therapeutic regimens recommended by the World Health Organization (WHO).

Tuberculosis por Mycobacterium africanum multirresistente: Caso clinico pediatrico / Tuberculosis by multiresistant Mycobacterium africanum: Pediatric clinical case

La tuberculosis, considerada desde 2003 por la Organización Mundial de la Salud una emergencia global de salud, provoca una mortalidad anual de alrededor de 2 millones de personas, fundamentalmente, en países en vías de desarrollo. En la población pediátrica española, la incidencia es de 5 casos/100 000 niños de entre 5 y 14 años y 13 casos/100 000 niños de entre 0 y 4 años. La infección se transmite por vía respiratoria por enfermos bacilíferos. Los niños eliminan escasos bacilos en secreciones respiratorias y no suelen transmitir la infección. En España, el porcentaje de resistencias a isoniazida en la población general es de 5% y es superior en la población inmigrante, lo cual es importante tener en cuenta para el tratamiento de los casos. Se presenta un caso de tuberculosis por Mycobacterium africanum multirresistente al tratamiento, con evolución satisfactoria posterior a la terapia múltiple.

Tuberculosis, considered since 2003 by the World Health Organization a global health emergency, causes annual mortality of approximately 2 million people, mainly in developing countries. In the Spanish pediatric population, the incidence is 5 cases/100 000 children between 5 and 14 years and 13 cases/100 000 children between 0 and 4 years. The infection is transmitted through the respiratory tract by baciliferous patients. Children eliminate few bacilli in respiratory secretions and do not usually transmit the infection. In Spain, the resistance to isoniazid in the general population is 5%, being higher in the immigrant population, which is important to take into account for the treatment of cases. A case of tuberculosis due to Mycobacterium africanum multiresistant to treatment is presented, with satisfactory evolution after multiple therapy.

A diagnosis of pulmonary tuberculosis and drug resistance among inmates in Mato Grosso do Sul, Brazil

Abstract INTRODUCTION: High endemic levels of pulmonary tuberculosis in prisons result from overcrowding, limited access to healthcare, delayed diagnosis, sustained transmission owing to poor control measures, and multidrug resistance. This study evaluated locally implemented measures for early pulmonary tuberculosis diagnosis and evaluated resistance to anti-tuberculosis drugs. METHODS: This transversal study employed data from the Mato Grosso do Sul State Tuberculosis Control Program obtained from 35 correctional facilities in 16 counties for 2 periods (2007-2010 and 2011-2014). RESULTS: Statewide prevalence (per 100,000) was 480.0 in 2007 and 972.9 in 2014. The following indicators showed improvement: alcohol-acid-fast bacillus testing (from 82.7% to 92.9%); cultures performed (55.0% to 81.8%); drug susceptibility testing of positive cultures (71.6% to 62.4%); and overall drug susceptibility testing coverage (36.6% to 47.4%). Primary and acquired resistance rates for 2007-2014 were 21.1% and 30.0%, respectively. Primary and acquired multidrug resistance rates were 0.3% and 1.3%, respectively. CONCLUSIONS: Prevalence rates increased, and laboratory indicators improved as a result of capacity building and coordination of technical teams and other individuals providing healthcare to inmates. Resistance rates were high, thereby negatively affecting disease control.

The role of the Xpert MTB/RIF assay among adolescents suspected of pulmonary tuberculosis in Rio de Janeiro, Brazil

Abstract INTRODUCTION The teste rápido molecular para tuberculose (TRM-TB) was introduced in 2014 in Brazil for tuberculosis screening. However, its role in adolescents in Brazil has not been studied. METHODS A descriptive study of adolescents with suspected tuberculosis using National Laboratory software. RESULTS Of 852 (15.4%) suspected cases, 131 were positive by TRM-TB and 2% were resistant to rifampicin. Among TRM-TB-positive cases, 105 (91.4%) were culture-positive. Sixty-four of 96 samples were sensitive to rifampicin by TRM-TB; 11 were resistant to other drugs by drug sensitivity test (DST). CONCLUSIONS Among suspected cases, 16% were diagnosed by TRM-TB, of which 17% were drug-resistant by DST.

Tuberculosis Multidrogo resistente en la era final de la Tuberculosis / Multidrug-Resistant Tuberculosis in the End Tuberculosis Era / Multidrug-Resistant Tuberculosis in the End Tuberculosis Era

RESUMEN La tuberculosis multidrogo resistente (TB-MDR) surgió poco después de la introducción de rifampicina en la década de 1960, cuando la resistencia a la isoniazida ya había emergido a mediados de la década de 1950. Sin estos dos medicamentos, la tuberculosis es muy difícil y costosa de tratar, con tasas inaceptablemente altas de fracaso del tratamiento, muertes, pérdidas durante el seguimiento y ningún tratamiento preventivo conocido. La atención global se centró por primera vez en la TB-MDR en la década de 1990 cuando se reportaron brotes hospitalarios con altas tasas de letalidad en muchos países. Los datos de prevalencia para TB-MDR a escala global estaban por primera vez disponibles en 1997. En 2016, 4,1% de aproximadamente 10,4 millones de pacientes nuevos más el 19% de un millón de pacientes tratados previamente, hacían un aproximado de 600 000 personas que desarrollaron TB-MDR o resistencia a la rifampicina; y 250 000 murieron dicho año. Hace diez años, menos del 5% de ellos fueron diagnosticados e iniciaron el tratamiento, aumentando a aproximadamente en 21,6% en 2016, dejando un amplio margen para mejorar. Durante ese mismo período de tiempo, se han fomentado avances para combatir la TB-MDR, incluidos los avances en diagnóstico, terapéutica y atención; descentralizando la atención en el paciente junto con el apoyo social; crecientes mejoras en la prevención de la transmisión; uso cada vez mayor de tratamientos antirretrovirales de alta efectividad; comunicación, abogacía y movilización social; liderazgo y actualización del enfoque de las políticas. Teniendo en cuenta las tendencias epidemiológicas a largo plazo, todos estos factores junto con el financiamiento del Fondo Mundial y otros donantes importantes, sugieren que podemos estar a punto de acelerar la disminución de la morbilidad y mortalidad por TB-MDR. La pobreza extrema, que permite el incremento de la tuberculosis ha disminuido en aproximadamente mil millones de personas en los últimos 25 años. Lo que se necesita ahora es voluntad política por parte de los gobiernos nacionales para aplicar estos avances con diligencia y buscar una mayor reducción de pobreza, empujando las tendencias epidemiológicas más allá del punto de inflexión hacia una pendiente descendente. Todo esto se puede acelerar con un mayor apoyo para la ciencia que conduzca a un mejor diagnóstico, tratamiento y una vacuna efectiva para sostener y acelerar las reducciones reportadas hasta el momento.

ABSTRACT Multidrug-resistant (MDR) tuberculosis (TB) emerged shortly after introduction of rifamycins in the 1960s; isoniazid resistance had already emerged by the mid-1950s. Without these two drugs, tuberculosis is very difficult and costly to treat, with unacceptably high rates of treatment failure, death, loss to follow-up, and no known preventive treatment. Global attention first focused on MDR TB in the early 1990s when nosocomial outbreaks with high case fatality rates were reported in many countries. Prevalence data for MDR TB on a global scale first became available in 1997. In 2016, about 4.1% of estimated ~10.4 million new TB patients plus 19% of ~1 million previously treated patients, that is ~600,000 people develop MDR TB or rifampicin resistant TB; 250,000 die annually. Ten years ago, <5% of them were diagnosed and enrolled on treatment, increasing to about 21.6% in 2016, leaving much room for improvement. Over that same period of time, momentum has been building to combat MDR TB, including advances in diagnostics, therapeutics, and care; decentralizing patient-centered care coupled with social support; growing improvements in prevention of transmission; increasing use of highly effective antiretroviral treatment; communications, advocacy, and social mobilization; leadership and updated policy guidance. Taking into account long-term epidemiological trends, all of these factors coupled with funding from the Global Fund and other major donors, suggest we may be on the verge of accelerating declines in MDR TB morbidity and mortality. Extreme poverty, which allows tuberculosis to flourish, has actually decreased by about one billion people over the past 25 years. What is needed now is political will on the part of national governments to apply these advances diligently and further reductions in poverty, pushing epidemiological trends past the inflection point to the downward slope. All these can be accelerated with increased support for science leading to better diagnosis, treatment and an effective vaccine to sustain and accelerate the meager declines reported thus far.

ABSTRACT Multidrug-resistant (MDR) tuberculosis (TB) emerged shortly after introduction of rifamycins in the 1960s; isoniazid resistance had already emerged by the mid-1950s. Without these two drugs, tuberculosis is very difficult and costly to treat, with unacceptably high rates of treatment failure, death, loss to follow-up, and no known preventive treatment. Global attention first focused on MDR TB in the early 1990s when nosocomial outbreaks with high case fatality rates were reported in many countries. Prevalence data for MDR TB on a global scale first became available in 1997. In 2016, about 4.1% of estimated ~10.4 million new TB patients plus 19% of ~1 million previously treated patients, that is ~600,000 people develop MDR TB or rifampicin resistant TB; 250,000 die annually. Ten years ago, <5% of them were diagnosed and enrolled on treatment, increasing to about 21.6% in 2016, leaving much room for improvement. Over that same period of time, momentum has been building to combat MDR TB, including advances in diagnostics, therapeutics, and care; decentralizing patient-centered care coupled with social support; growing improvements in prevention of transmission; increasing use of highly effective antiretroviral treatment; communications, advocacy, and social mobilization; leadership and updated policy guidance. Taking into account long-term epidemiological trends, all of these factors coupled with funding from the Global Fund and other major donors, suggest we may be on the verge of accelerating declines in MDR TB morbidity and mortality. Extreme poverty, which allows tuberculosis to flourish, has actually decreased by about one billion people over the past 25 years. What is needed now is political will on the part of national governments to apply these advances diligently and further reductions in poverty, pushing epidemiological trends past the inflection point to the downward slope. All these can be accelerated with increased support for science leading to better diagnosis, treatment and an effective vaccine to sustain and accelerate the meager declines reported thus far.

Molecular characterization and spoligotyping analysis of multi drug resistant mycobacterium tuberculosis from a high TB endemic area of Pakistan

Background: Multidrug resistant tuberculosis caused by Mycobacterium tuberculosis is an infection that is resistant to rifampicin and isoniazid. Management of Multidrug resistant tuberculosis is a serious challenge worldwide

Objectives: To investigate hotspot mutations in rpoB, katG and inhA genes and its possible co-relation with predominant genotypes in Khyber Pakhtunkhwa, Pakistan

Study design, settings and duration: This cross sectional study was conducted after approval from research and ethics committee of Provincial TB Control Program, Khyber Pakhtunkhwa in March 2015

Materials and Methods: A total of 166 clinical isolates were analysed which were collected from programmatic management of drug-resistant tuberculosis units. All samples were characterized by phonotypical drug susceptibility test, genotypic drug resistant test [line probe assay] and spoligotyping analysis using ''TB-SPRINT' micro bead assay

Results: Out of the total 166 samples, 97 strains were resistant to rifampicin [RIF] and 106 strains were resistant to isoniazid [INH]. Most common mutation in rpoB was S531L in 75 [77%] isolates followed by D516V in 10 [10%] and H526Y in 6 [6%] samples respectively. A rare mutation in rpoB gene at codon 522 and deletion of codon 518 was also reported. In 106 INH resistant strains, 97[91%] were associated with mutation in katG gene while resistance in 9 [8.4%] strain was due to mutation in the inhA promoter region. Spoligotyping analysis revealed 55 distinct types of different patterns. Spoligotyping patterns of 146 samples matched with 15 different linage of M.tuberculosis in which 101 [60%] were identified as the predominant CAS1-Delhi linage. The pattern of 20 strains [12%] did not matched to any other pattern in the SITVIT database and were named orphan KP

Conclusion: Molecular characterization of M.tuberculosis is very helpful in the early identification of MDR-TB. As CAS1-Delhi is the predominant type in this region, its association with drug resistance, treatment failure and patient demographic profiles should be investigated

Combination of commercially available molecular assays and culture based methods in diagnosis of tuberculosis and drug resistant tuberculosis

ABSTRACT Early diagnosis of tuberculosis is of major clinical importance. Among 4733 clinical specimens collected from 3363 patients and subjected to Ziehl-Neelsen microscopy, 4109 were inoculated onto Löwenstein-Jensen slants and 3139 in Bactec/9000MB. Polymerase Chain Reaction (PCR) was performed in 3139 specimens, whereas, a genotypic assay was directly applied in 93 Mycobacterium tuberculosis complex PCR-positive for isoniazid and rifampicin resistance detection specimens (GenoType MTBDRplus). Recovered M. tuberculosis isolates (64) as well as, 21 more sent from Regional Hospitals were tested for antimycobacterial resistance with a phenotypic (manual MGIT-SIRE) and a genotypic assay (GenoType MTBDRplus). PCR in the clinical specimens showed excellent specificity (97.4%) and accuracy (96.8%), good sensitivity (70.4%), but low positive predictive value (40.3%). MGIT-SIRE performed to M. tuberculosis did not confer a reliable result in 16 isolates. Of the remaining 69 isolates, 15 were resistant to streptomycin, seven to isoniazid, seven to ethambutol and five to rifampicin. GenoType MTBDRplus correctly detected isoniazid (seven) and rifampicin-resistant M. tuberculosis strains (five), showing an excellent performance overall (100%). Susceptibility results by the molecular assay applied directly to clinical specimens were identical to those obtained from recovered isolates of the corresponding patients. Combining molecular and conventional methods greatly contribute to early diagnosis and accurate susceptibility testing of tuberculosis.

An evaluation of false-positive rifampicin resistance on the Xpert MTB/RIF

BACKGROUND Mycobacterium tuberculosis (MTB) is one of the most significant causes of mortality and morbidity. Early diagnose is important especially in multiple drug resistant tuberculosis to avoid transmission. Traditional techniques requires at least one to three weeks for diagnosis of tuberculosis. Diagnostic delays with multiple drug resistant tuberculosis are associated with worse clinical outcomes and increased transmission The Xpert MTB/RIF assay is one of the new diagnostic device for the diagnosis of tuberculosis and rapid detection of rifampicin resistance. OBJECTIVE We assessed the performance of Xpert MTB/RIF assay for detecting rifampicin resistance using phenotypic drug susceptibility tests as automated BD MGIT 960. METHODS Total of 2136 specimens were included in the study. Xpert MTB/RIF testing was performed on samples, using version 4 cartridges, according to the manufacturer's recommendations. The MTBC culture and first-line phenotypic DST were performed in automated BD MGIT 960 (Becton & Dickinson, USA) according to the recommendations of the manufacturer. Agar proportion was used in the case of inconsistency for rifampicin resistance. FINDINGS Thirty-four samples (19 respiratory and 15 nonrespiratory samples) were determined as positive for M. tuberculosis complex by Xpert MTB/RIF (Cepheid GeneXpert® System, USA). Xpert MTB/RIF assay detected 4/34 (11.7%) specimens as rifampicin resistant. One of the rifampicin resistant isolates was determined susceptible in MGIT 960 automated system. This isolate was also tested with agar proportion method and found susceptible to rifampicin. MAIN CONCLUSION The Xpert MTB/RIF assay can be used as first-line assay for the detection of M. tuberculosis. However, microbiologists must be aware of the limitations of the assay.

Correlation between the BACTEC MGIT 960 culture system with Genotype MTBDRplus and TB-SPRINT in multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

BACKGROUND The accurate detection of multidrug-resistant tuberculosis (MDR-TB) is critical for the application of appropriate patient treatment and prevention of transmission of drug-resistant Mycobacterium tuberculosis isolates. The goal of this study was to evaluate the correlation between phenotypic and molecular techniques for drug-resistant tuberculosis diagnostics. Molecular techniques used were the line probe assay genotype MTBDRplus and the recently described tuberculosis-spoligo-rifampin-isoniazid typing (TB-SPRINT) bead-based assay. Conventional drug susceptibility testing (DST) was done on a BACTECTM MGIT 960 TB. METHOD We studied 80 M. tuberculosis complex (MTC) clinical isolates from Minas Gerais state, of which conventional DST had classified 60 isolates as MDR and 20 as drug susceptible. FINDINGS Among the 60 MDR-TB isolates with MGIT as a reference, sensitivity, specificity, accuracy, and kappa for rifampicin (RIF) resistance using TB-SPRINT and MTBDRplus, were 96.7% versus 93.3%, 100.0% versus 100.0%, 97.5% versus 95.0% and 0.94 versus 0.88, respectively. Similarly, the sensitivity, specificity, accuracy, and kappa for isoniazid (INH) resistance were 85.0% and 83.3%, 100.0% and 100.0%, 88.8% and 87.5% and 0.74 and 0.71 for both tests, respectively. Finally, the sensitivity, specificity, accuracy, and kappa for MDR-TB were 85.0% and 83.3%, 100.0% and 100.0%, 88.8% and 87.5% and 0.74 and 0.71 for both tests, respectively. MAIN CONCLUSIONS Both methods exhibited a good correlation with the conventional DST. We suggest estimating the cost-effectiveness of MTBDRplus and TB-SPRINT in Brazil.