Impact of Xpert MTB/RIF implementation in tuberculosis case detection and control in Brazil: a nationwide intervention time-series analysis (2011-2022).

Background: Since 2014, Brazil has gradually implemented the Xpert MTB/RIF (Xpert) test to enhance early tuberculosis (TB) and drug-resistant (DR-TB) detection and control, yet its nationwide impact remains underexplored. Our study conducts an intervention time-series analysis (ITSA) to evaluate how the Xpert's implementation has improved TB and DR-TB detection nationwide. Methods: 1,061,776 cases from Brazil's National TB Registry (2011-2022) were reviewed and ITSA (2011-2019) was used to gauge the impact of the Xpert's adoption on TB and DR-TB notification. Granger Causality and dynamic regression modelling determined if incorporating Xpert testing as an external regressor enhanced forecasting accuracy for Brazil's future TB trends. Findings: Xpert implementation resulted in a 9.7% increase in TB notification and substantial improvements in DR-TB (63.6%) and drug-susceptible TB (92.1%) detection compared to expected notifications if it had not been implemented. Xpert testing counts also presented a time-dependent relationship with DR-TB detection post-implementation, and improved predictions in forecasting models, which depicted a potential increase in TB and DR-TB detection in the next six years. Interpretation: This study underscores the critical role of Xpert's adoption in boosting TB and DR-TB detection in Brazil, reinforcing the case for its widespread use in disease control. Improvements in prediction accuracy resulting from integrating Xpert data are crucial for allocating resources and reducing the incidence of TB. By acknowledging Xpert's role in both disease control and improving predictions, we advocate for its expanded use and further research into advanced molecular diagnostics for effective TB and DR-TB control. Funding: FIOCRUZ.

A descriptive study on isoniazid resistance-associated mutations, clustering and treatment outcomes of drug-resistant tuberculosis in a high burden country.

PURPOSE: To describe katG and inhA mutations, clinical characteristics, treatment outcomes and clustering of drug-resistant tuberculosis (TB) in the State of São Paulo, southeast Brazil. METHODS: Mycobacterium tuberculosis isolates from patients diagnosed with drug-resistant TB were screened for mutations in katG and inhA genes by line probe assay and Sanger sequencing, and typed by IS6110-restriction fragment-length polymorphism for clustering assessment. Clinical, epidemiological and demographic data were obtained from surveillance information systems for TB. RESULTS: Among the 298 isolates studied, 127 (42.6%) were isoniazid-monoresistant, 36 (12.1%) polydrug-resistant, 93 (31.2%) MDR, 16 (5.4%) pre-extensively drug-resistant (pre-XDR), 9 (3%) extensively drug-resistant (XDR) and 17 (5.7%) susceptible after isoniazid retesting. The frequency of katG 315 mutations alone was higher in MDR isolates, while inhA promoter mutations alone were more common in isoniazid-monoresistant isolates. Twenty-six isolates phenotypically resistant to isoniazid had no mutations either in katG or inhA genes. The isolates with inhA mutations were found more frequently in clusters (75%) when compared to the isolates with katG 315 mutations (59.8%, p = 0.04). In our population, being 35-64 years old, presenting MDR-, pre-XDR- or XDR-TB and being a retreatment case were associated with unfavourable TB treatment outcomes. CONCLUSION: We found that katG and inhA mutations were not equally distributed between isoniazid-monoresistant and MDR isolates. In our population, clustering was higher for isolates with inhA mutations. Finally, unfavourable TB outcomes were associated with specific factors.

Obstacles in combating multidrug resistant tuberculosis in pediatric patients: a scope review / Obstáculos no combate à tuberculose multidroga resistente em pacientes pediátricos: uma revisão de escopo

Abstract Objectives: to identify the scientific evidence on excessively resistant and multidrug resistant tuberculosis in pediatric patients. Methods: this is a scope review of the literature, with a guiding question: "What is the scientific evidence on multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis in pediatric patients?". The research used the descriptors: "extensively drug-resistant tuberculosis" OR "multidrug-resistant tuberculosis" AND "pediatrics". The research was carried out in a double-blind manner in the following databases of the Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific's Institutional Repository for Information Sharing, Embase/Elsevier and International Clinical Trials Registry Platform, with a temporal cut-off from 2011 to 2021, sending a final synthesized sample of 18 articles, which evaluated the methodological content through the level of evidence. Results: the results show the lack of research with a high level of evidence related to MDR-TB in children, the lack of adequate dosage of second-line drugs for the pediatric population and the importance of drug sensitivity testing for the cases of treatment Conclusions: it was identified that the obstacles to MDR-TB treatment were concentrated in the lack of detailed protocols, safe drug dosages with a low side effect, and mainly in the social health determinants and disease process involving MDR-TB.

Resumo Objetivos: identificar as evidências científicas sobre tuberculose excessivamente resistente e multidroga resistente em pacientes pediátricos. Métodos: trata-se de uma revisão de escopo da literatura, tendo como questão norteadora: "Quais as evidências científicas sobre tuberculose multidroga-resistente (TB-MDR) e tuberculose extensivamente resistente em pacientes pediátricos?" A pesquisa usou os descritores: "tuberculose extensivamente resistente a medicamentos" OR "tuberculose resistente a múltiplos medicamentos" AND "pediatria". A pesquisa foi realizada de modo duplo-cego nas bases de dados Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific's Institutional Repository for Information Sharing, Embase/Elsevier e International Clinical Trials Registry Platform, com um corte temporal de 2011 a 2021, sendo a amostra final sintetizada de 18 artigos, nos quais avaliou-se o conteúdo metodológico por meio do nível de evidência. Resultados: os resultados mostraram a escassez de pesquisas de alto nível de evidência relacionadas à TB-MDR em crianças, ausência de posologia adequada das drogas de segunda linha para o público pediátrico e a importância do teste de sensibilidade a drogas para o tratamento dos casos. Conclusões: identificou-se que os obstáculos do tratamento TB-MDR se concentraram na ausência de protocolos detalhados, de dosagens medicamentosas seguras e com menor efeito colateral, e, principalmente, nos determinantes sociais do processo saúde e doença que envolvem a TB-MDR.

The performance of Xpert MTB/RIF and MTBDRplus within a Programmatic setting at TB Laboratory in Rio de Janeiro, Brazil

ABSTRACT Background: Few studies in routine settings have confirmed the high accuracy of the Xpert MTB/RIF assay for detecting rifampicin resistance (RR) and the first-line probe assay (FL-LPA) for detecting both RR and isoniazid resistance (INHR). Methods: The performance of Xpert MTB/RIF and MTBDRplus VER 2.0 LPA was evaluated in 180 Mycobacterium tuberculosis samples collected from January 2018 to December 2019 in Rio de Janeiro, Brazil. The results were compared with those from BACTEC MGIT 960 culture and drug susceptibility testing (DST). Whole-genome sequencing was performed on the samples with discordant results. Results: The Xpert MTB/RIF assay showed a sensitivity (Se) of 93.3% and a specificity (Sp) of 97.6%, detecting RR. The performance of FL-LPA to identify RIF and INH resistance was, respectively, (Se) 100% and 83.3% and (Sp) 98.8% and 100%. Among 18 clinical isolates with INHR detected by FL-LPA, mutations in the katG gene were observed in 100% of samples, of which only two (11.1%) had mutations in both katG and inhA genes. Overall, the discordant results were identified in 9 (5%) samples. Among the four Xpert RIF-resistant and DST-sensitive, two harbored mutations in rpoB Leu430Pro. Among the four FL-LPA-sensitive and DST-resistant, one had a mutation in inhA 17G>T. FL-LPA showed high accuracy in detecting RR and INHR. Conclusions: The MTBDRplus test demonstrated excellent performance in detecting RR, and INHR in clinical isolates under routine conditions at a reference laboratory in Rio de Janeiro, Brazil. Incorporating both tests can improve drug-resistant tuberculosis treatment outcomes and monitor the INHR incidence.

Discordancia entre pruebas de susceptibilidad genotípicas y fenotípicas para tuberculosis en Cali, Colombia: un reto en la práctica clínica / Discordance between genotypic and phenotypic susceptibility tests for tuberculosis in Cali, Colombia: a challenge in the clinical practice

INTRODUCCIÓN: La detección de patrones de resistencia de Mycobacterium tuberculosis se basa en pruebas de susceptibilidad fenotípicas y genotípicas. Los resultados discordantes entre ellas son un desafío clínico para el manejo de pacientes con tuberculosis resistente a fármacos. OBJETIVO: Evaluar la concordancia entre pruebas fenotípicas y moleculares en pacientes con tuberculosis resistente a fármacos atendidos en una institución de Cali, Colombia. MATERIALES Y MÉTODOS: Se realizó un estudio transversal en el que se obtuvo el perfil de sensibilidad fenotípico de cultivos de micobacterias y la susceptibilidad genotípica con las pruebas moleculares Xpert-MTB/ RIF® o Genotype-MDRTBplus ®. Se evaluó el porcentaje de resistencia y porcentaje de acuerdo entre los resultados de las pruebas fenotípicas y genotípicas. Se estimó un coeficiente de kappa de Cohen (κ) para cada tipo de resistencia según la prueba utilizada. RESULTADOS: Se incluyeron 30 casos con resultados de pruebas genotípicas y fenotípicas. Las pruebas fenotípicas detectaron resistencia a fármacos de primera línea en 29/30 casos, mientras que las moleculares detectaron la resistencia en todos los casos evaluados. El porcentaje de resistencia a rifampicina detectado entre la prueba fenotípica y Genotype-MDRTBplus ® &e 61,5% (acuerdo global 41,1%, κ = 0,40, p = 0,96), mientras que el porcentaje de resistencia detectado con Xpert-MTB/RIF® fue 100% (acuerdo global 81,82%, κ: 0,00, p < 0,001) para este mismo medicamento. El porcentaje de resistencia a isoniacida detectado entre la prueba fenotípica y Genotype-MDRTBplus ® fue 94,4% (acuerdo global 89,47%, κ: -0,055 p = 0,59). CONCLUSIONES: La discordancia entre los resultados de las pruebas genotípicas y fenotípicas es posible, por lo que es importante usar e interpretar ambos tipos de pruebas de manera complementaria en el diagnóstico de la resistencia a fármacos de primera línea en la infección por M. tuberculosis.

BACKGROUND: The detection of Mycobacterium tuberculosis resistance patterns is based on phenotypic and genotypic susceptibility tests. The discordant results between them are a clinical challenge for the management of patients with drug-resistant tuberculosis. Aim: To evaluate the concordance between phenotypic and molecular tests in patients with drug-resistant tuberculosis treated in an institution in Cali, Colombia. METHODS: A cross-sectional study was conducted. A phenotypic sensitivity profile was obtained from mycobacterial cultures. The genotypic susceptibility was obtained with Xpert-MTB/ RIF® or Genotype-MDRTBplus ®. The percentage of resistance and percentage of agreement between the results of the phenotypic and genotypic tests were evaluated. A Cohen's kappa coefficient (κ) was estimated for each type of resistance according to the test used. RESULTS: A total of 30 cases with both genotypic and phenotypic testing were included. The phenotypic tests detected resistance to first-line drugs in 29/30 cases, while the molecular tests detected resistance in all the cases evaluated. The percentage of resistance detected between Genotype-MDRTBplus® and the phenotypic test for rifampicin was 61.5% (overall agreement 41.1%, κ = 0.40, p = 0.96), while the percentage of resistance detected with XpertMTB/RIF® was 100% (overall agreement 81.82%, κ: 0.00, p < 0.001) for this same drug. Resistance to isoniazid detected by both types of tests was 94.4% (overall agreement 89.47%, κ: -0.055 p = 0.59). CONCLUSIONS: Discordance between the results of genotypic and phenotypic tests is possible, so it is important to use and interpret both types of tests in a complementary way in the diagnosis of resistance to first-line drugs in M. tuberculosis infection.

Factores asociados a tuberculosis pre extensamente resistente en pacientes del Hospital Nacional Dos de Mayo, Lima, Perú / Factors associated with pre-extensively drug-resistant tuberculosis in patients at Dos de Mayo National Hospital, Lima - Perú

INTRODUCCIÓN: La resistencia a fármacos antituberculosos está influenciada por las características personales y las condiciones de salud de países en vías de desarrollo. OBJETIVO: Determinar los factores asociados a TB-pre extensamente resistente (TB-PRE XDR) en pacientes del Hospital Nacional Dos de Mayo (HNDM) entre 2017 y 2019. PACIENTES Y MÉTODO: Se desarrolló un estudio caso control no pareado, definiendo como caso al paciente con TB- PRE XDR y como control al paciente con TB-S. Se recolectaron variables epidemiológicas, clínicas y radiológicas. RESULTADOS: Se analizaron 51 casos y 102 controles. El análisis bivariado determinó como factores con p 51 años (OR: 0,17, IC95%: 0,05-0,51), uso de drogas (OR:2,5, IC95%: 1,1-5,4), antecedente de TB (OR: 20, IC95%: 8,4-47), reclusión previa (OR: 8, IC95%: 2,7-23,8), infección por VIH (OR: 0,2, IC95%: 0,08-1) y uso previo de fármacos antituberculosos (OR: 21, IC95%: 8,8-50). El análisis de regresión logística identificó como factores asociados a TB-PRE XDR al contacto de TB, antecedente de TB, tiempo de enfermedad y uso previo de fármacos antituberculosos. CONCLUSIÓN: Las medidas para limitar el desarrollo de TB-PRE XDR en pacientes con TB-S deben incidir sobre el antecedente de TB, contacto con TB, tiempo de enfermedad y uso previo de anti-TB no controlados; sin embargo, existen resultados no concluyentes sobre el hábito nocivo y la comorbilidad, siendo necesario más estudios para determinar su influencia como factores asociados identificables.

BACKGROUND: Resistance to anti-TB drugs is influenced by personal characteristics and health conditions in developing countries. AIM: To determine the factors associated with pre-extensively drug-resistant tuberculosis (PRE XDR-TB) at Hospital Nacional Dos de Mayo (HNDM) in patients between the 2017 and 2019. METHODS: An unpaired case control study was developed; defining as case PRE XDR-TB patient and as control S-TB patient. Epidemiological, clinical and radiological variables were collected. RESULTS: We analyzed 51 cases and 102 controls. The bivariate analysis showed as factors with p 51 years (OR: 0.17, 95% CI: 0.05-0.51), drug use (OR: 2.5, 95% CI: 1.1-5.4), previous history of TB (OR: 20, 95% CI: 8.4-47), previous confinement (OR: 8, 95% CI: 2.7-23.8), HIV infection (OR: 0.2, 95% CI: 0.08-1) and previous use of antiTB drugs (OR: 21, 95% CI: 8.8-50). The logistic regression analysis identified as associated factors with PRE XDR-TB the previous contact with TB, a history of TB, length of illness and previous use of tuberculosis antibiotics. CONCLUSION: The measures to limit the development of TB-PRE XDR in patients with TB-S must include the previous history of TB, TB contact, length of illness and previous use of uncontrolled antibiotics against TB; however, there are inconclusive results about the harmful habits and comorbidity, requiring more studies to determine their influence as identifiable associated factors.

Factores de riesgo asociados a la farmacorresistencia y al tratamiento no exitoso de la tuberculosis en Chile 2014-2018 / Risk factors and predictors of drug resistance in tuberculosis: A comprehensive analysis of cases in Chile (2014-2018)

OBJETIVOS: Determinar los factores de riesgos asociados a la farmacorresistencia y al tratamiento no exitoso de tuberculosis en Chile durante el 20142018. METODOLOGÍA: Estudio transversal observacional analítico que incluye los pacientes notificados con tuberculosis (TB) que ingresaron a tratamiento durante el 2014-2018 en Chile, contenidos en el registro nacional TB. Se determinaron variables demográficas, clínicas y grupos de riesgos asociados a la farmacorresistencia y al tratamiento no exitoso en pacientes con TB mediante regresión logística. RESULTADOS: Entre los años 2014-2018 se notificaron 13.1761 pacientes con TB en Chile, de los cuales 3,4% (n = 445) son farmacorresistentes. El 43,1% de estos son TB resistente a rifampicina (TB-RR), multidrogorresistente (TB-MDR) y extensamente resistente (TB-XDR). Los factores de riesgo que generaron mayor probabilidad de presentar farmacorresistencia fueron la recaída (OR: 4,27; IC 95% 2,94; 6,20), extranjero (OR: 3,97; IC 95% 2,86; 5,52), TB pulmonar (OR: 2,92; IC 95% 1,71; 4,99) y VIH (OR: 1,97; IC 95% 1,33; 2,90). Frente a la probabilidad de generar un tratamiento no exitoso, las variables que presentaron mayor probabilidad fueron situación de calle (OR: 3,33; IC 95% 2,45; 4,52), drogadicción (OR: 1,91; IC 95% 1,52; 2,41), extranjero (OR: 1,51; IC: 95% 1,25; 1,83), farmacorresistencia (OR: 2,81; IC 95% 1,87; 4,20), VIH (OR: 3,24; IC: 95% 2,61; 4,02), no pertenecer a un pueblo indígena (OR: 1,43; IC: 95% 1,00; 2,06) alcoholismo (OR: 1,25; IC 95% 1,01; 1,54), TB pulmonar (OR: 1,43; IC 95% 1,20; 1,70) y sexo masculino (OR: 1,44; IC 95% 1,25; 1,65). CONCLUSIONES: Los factores de riesgo identificados como la recaída y la coinfección con VIH como predictores de farmacorresistencia destaca la complejidad del manejo de la enfermedad. Asimismo, la presencia de situaciones de calle, drogadicción y alcoholismo resalta la necesidad de enfoques específicos y personalizados para abordar la tuberculosis en distintos grupos poblacionales. Estos resultados subrayan la importancia de abordar estos factores de riesgo en la gestión y tratamiento de la tuberculosis en Chile, sugiriendo la necesidad de estrategias específicas y personalizadas.

OBJECTIVE: Determine the risk factors associated with drug resistance and unsuccessful treatment of tuberculosis in Chile between 2014 and 2018. METHODOLOGY: Analytical observational cross-sectional study including patients diagnosed with Tuberculosis (TB) who entered treatment during 2014-2018, contained in the national TB records. Demographic, clinical variables, and risk groups associated with drug resistance and unsuccessful treatment in TB patients were determined using logistic regression. RESULTS: Between 2014 and 2018, 13,1761 TB patients were reported in Chile, of whom 3.4% (n = 445) were drug-resistant. From this, 43.1% are rifampicin-resistant TB (RR-TB), multidrug-resistant (MDR-TB), and extensively drug-resistant (XDR-TB). The risk factors that generated the highest probability of drug resistance were relapse (OR: 4.27; CI95% 2.94; 6.20), foreigner (OR: 3.97; CI95% 2.86; 5.52), pulmonary TB (OR: 2.92; CI95% 1.71; 4.99) and HIV (OR: 1.97; CI: 95% 1.33; 2.90). Regarding the probability of unsuccessful treatment against TB, the highest probability were street situation (OR: 3.33; CI: 95% 2.45; 4.52), drug addiction (OR: 1.91; CI 95% 1.52; 2.41), foreigner (OR: 1.51; CI 95% 1.25; 1.83), drug resistance (OR: 2.81; CI 95% 1.87; 4.20), HIV (OR: 3.24; CI: 95% 2.61; 4.02), not belonging to an indigenous people (OR: 1.43; CI 95% 1.00; 2.06) alcoholism (OR: 1.25; CI 95% 1.01; 1.54), pulmonary TB (OR: 1.43; CI 95% 1.20; 1.70) and male sex (OR: 1.44; CI 95% 1.25; 1.65). CONCLUSIONS: The risk factors identified as relapse and coinfection with HIV as predictors of drug resistance highlight the complexity of disease management. Likewise, the presence of street situations, drug addiction, and alcoholism highlights the need for specific approaches to address tuberculosis in different population groups, suggesting the need for personalized strategies.

Comparación de regímenes de linezolid, en adición a bedaquilina y pretomanida, para el manejo de tuberculosis farmacorresistente (estudio ZeNix): Lectura crítica / Comparison of linezolid regimens, in addition to bedaquiline and pretomanid, for the management of drug-resistant tuberculosis (the ZeNix study): Critical reading

RESUMEN Presentación: En el presente artículo exponemos nuestra valoración crítica de un ensayo clínico aleatorizado publicado en la revista New England Journal of Medicine el año 2022. Conclusiones del estudio: El estudio compara cuatro regímenes de linezolid (en adición a bedaquilina y pretomanid) para el manejo de tuberculosis farmacorresistente. Finalmente, se demuestra que el régimen de 600 mg de linezolid durante 26 semanas tuvo menos frecuencia de falla terapéutica y eventos adversos (en comparación con darlo por menos semanas o a más dosis). Comentario crítico: El artículo es relevante porque aún no es clara la dosis adecuada de linezolid y la duración del tratamiento con este agente para minimizar los efectos adversos y mantener la eficacia contra la tuberculosis altamente resistente. A pesar de algunas limitaciones como el bajo número de participantes, la alta pérdida al seguimiento, y el no realizar comparaciones estadísticas entre grupos; los resultados son relativamente confiables para la toma de decisiones.

ABSTRACT Presentation: In this article we present our critical appraisal of a randomized clinical trial published in the New England Journal of Medicine in 2022. Study conclusions: The study compares four linezolid regimens (in addition to bedaquiline and pretomanid) for the management of drug-resistant tuberculosis. Finally, it shows that the regimen of 600 mg of linezolid for 26 weeks had less frequency of therapeutic failure and adverse events (compared to giving it for fewer weeks or at higher doses). Critical comment: The article is relevant because the appropriate dose of linezolid and duration of treatment with this agent to minimize adverse effects and maintain efficacy against highly resistant tuberculosis is still unclear. Despite some limitations such as low number of participants, high loss to follow-up, and no statistical comparisons between groups, the results are relatively reliable for decision making.

Drug-Resistant Tuberculosis and COVID-19: A Scoping Review on a New Threat to Antimicrobial Resistance / Tuberculosis Resistente a Medicamentos y COVID-19: Una Revisión de Alcance de una Nueva Amenaza a la Resistencia Antimicrobiana / Tuberculose droga-resistente e COVID-19: revisão de escopo de uma nova ameaça à resistência microbiana a medicamentos

ABSTRACT Objective: To assess the impact of COVID-19 on the morbidity and mortality associated with drug-resistant tuberculosis (DR-TB). Methods: A comprehensive review of articles published in international databases since December 2019 was conducted. The findings are presented in a narrative format, supplemented with tables, diagrams, and a map created using ArcGIS software. Results: Thirty-five studies were selected, highlighting the significant consequences of COVID-19 on TB and DR-TB treatment progress. Four main thematic areas were identified: Clinical and epidemiological aspects of the interaction between COVID-19 and DR-TB; Management of physical resources and the team; Challenges and circumstances; Perspectives and possibilities. Conclusions: This study revealed that the COVID-19 pandemic significantly negatively impacted the control of long-standing diseases like TB, particularly in the context of morbidity and mortality related to DR-TB.

RESUMEN Objetivo: Evaluar el impacto de COVID-19 en la morbilidad y mortalidad asociada con la tuberculosis resistente a medicamentos (DR-TB). Métodos: Se realizó una revisión integral de artículos publicados en bases de datos internacionales desde diciembre de 2019. Los hallazgos se presentaron de forma narrativa, complementados con tablas, diagramas y un mapa creado con el software ArcGIS. Resultados: Se seleccionaron 35 estudios que destacaron las consecuencias significativas de COVID-19 en el progreso del tratamiento de la TB y la DR-TB. Se identificaron cuatro áreas temáticas principales: "Aspectos clínicos y epidemiológicos de la interacción entre COVID-19 y DR-TB", "Gestión de recursos físicos y del equipo", "Desafíos y circunstancias" y "Perspectivas y posibilidades". Conclusiones: Este estudio reveló que la pandemia de COVID-19 tuvo un impacto negativo significativo en el progreso del control de enfermedades antiguas como la TB, especialmente en el contexto de la morbilidad y mortalidad relacionada con la DR-TB.

RESUMO Objetivo: Avaliar o impacto da COVID-19 na morbimortalidade associada à tuberculose resistente a medicamentos (DR-TB). Métodos: Realizou-se uma revisão abrangente de artigos publicados em bases de dados internacionais a partir de dezembro de 2019. As evidências foram apresentadas de maneira narrativa, com o suporte de tabelas, diagramas e um mapa elaborado no software ArcGIS. Resultados: Foram selecionados 35 estudos que destacaram as consequências significativas da COVID-19 nos avanços no tratamento da TB e da DR-TB. Quatro áreas temáticas foram identificadas: "Aspectos clínicos e epidemiológicos da interação entre COVID-19 e DR-TB", "Gestão de recursos físicos e da equipe", "Desafios e circunstâncias" e "Perspectivas e potencialidades". Conclusões: Este estudo evidenciou que a pandemia de COVID-19 teve um impacto negativo significativo na progressão do controle de uma doença ancestral como a TB, especialmente no contexto da morbimortalidade por DR-TB.

New insights on tuberculosis transmission dynamics and drug susceptibility profiles among the prison population in Southern Brazil based on whole-genome sequencing

ABSTRACT Background: The rate of tuberculosis (TB) infection among the prison population (PP) in Brazil is 28 times higher than that in the general population, and prison environment favors the spread of TB. Objective: To describe TB transmission dynamics and drug resistance profiles in PP using whole-genome sequencing (WGS). Methods: This was a retrospective study of Mycobacterium tuberculosis cultivated from people incarcerated in 55 prisons between 2016 and 2019; only one isolate per prisoner was included. Information about movement from one prison to another was tracked. Clinical information was collected, and WGS was performed on isolates obtained at the time of TB diagnosis. Results: Among 134 prisoners included in the study, we detected 16 clusters with a total of 58 (43%) cases of M. tuberculosis. Clusters ranged from two to seven isolates with five or fewer single nucleotide polymorphism (SNP) differences, suggesting a recent transmission. Six (4.4%) isolates were resistant to at least one anti-TB drug. Two of these clustered together and showed resistance to rifampicin, isoniazid, and fluoroquinolones, with 100% concordance between WGS and phenotypic drug-susceptibility testing. Prisoners with clustered isolates had a high amount of movement between prisons (two to eight moves) during the study period. Conclusions: WGS demonstrated the recent transmission of TB within prisons in Brazil. The high movement among prisoners seems to be related to the transmission of the same M. tuberculosis strain within the prison system. Screening for TB before and after the movement of prisoners using rapid molecular tests could play a role in reducing transmission.

The first successful cochlear implant in Latin America after severe aminoglycoside-induced ototoxicity in a Peruvian patient cured of extensively drug-resistant tuberculosis

Introduction: Multidrug-resistant tuberculosis is a significant public health problem for which drugs are used with many adverse effects. Among the devastating consequences of these diseases, there is a wide variation in the incidence of ototoxicity and hearing loss in patients with multidrug-resistant and extremely resistant tuberculosis. Cochlear implants may be indicated in patients with unilateral/severe bilateral hearing loss with no benefit from conventional hearing aids, but their use in patients with tuberculosis is rare. Case report: We present the first case of a right unilateral cochlear implant performed on a 34-year-old Peruvian patient who presented profound sensorineural hearing loss of cochlear origin. Conclusion: Cochlear implant surgery is an essential milestone in the treatment of patients with auditory sequelae of tuberculosis treatment. Close monitoring of possible complications of tuberculosis treatment should be strengthened in countries with a high incidence of multidrug-resistant and extremely resistant tuberculosis.

Introducción: La tuberculosis multidrogorresistente es un importante problema de salud pública para el que se utilizan fármacos con múltiples efectos adversos. Entre las devastadoras consecuencias de estas enfermedades, existe una amplia variación en la incidencia de ototoxicidad y pérdida auditiva en pacientes con tuberculosis multirresistente y extremadamente resistente. Los implantes cocleares pueden estar indicados en pacientes con pérdida auditiva unilateral/bilateral severa sin beneficio de los audífonos convencionales, pero su uso en pacientes con tuberculosis es raro. Reporte de un caso: Presentamos el primer caso de implante coclear unilateral derecho realizado a un paciente peruano de 34 años que presentaba hipoacusia neurosensorial profunda de origen coclear. Conclusión: La cirugía de implante coclear es un hito fundamental en el tratamiento de los pacientes con secuelas auditivas del tratamiento de la tuberculosis. Se debe fortalecer la vigilancia estrecha de las posibles complicaciones del tratamiento de la tuberculosis en los países con una alta incidencia de tuberculosis multirresistente y extremadamente resistente.

Fatores associados à tuberculose drogarresistente na população privada de liberdade, distribuição espacial e tendência temporal no estado do Paraná / Factors associated with drug-resistant tuberculosis in the privacy of the freedom population in the state of Paraná

Introdução: A tuberculose é um grave problema de saúde pública no mundo. Associada às condições de vida, a ocorrência e transmissão da doença são mais elevadas no sistema penitenciário, o que torna o risco de adoecimento por tuberculose na população privada de liberdade maior em comparação à população em geral. Além desse cenário, observa-se a presença da drogaresistência. Objetivo: analisar os fatores associados à tuberculose drogarresistente na população privada de liberdade do estado do Paraná, a distribuição espacial e tendência temporal da ocorrência da doença. Métodos: Estudo ecológico de casos de tuberculose resistente a medicamentos registrados no Sistema de Informação do Paraná, Brasil (2008 a 2018). Realizou-se estatística descritiva dos parâmetros quantitativos calculados com frequências absolutas. Adicionalmente, utilizou-se a regressão logística binária, no qual, foi calculado o Odds Ratio com seu respectivo intervalo de confiança. Para identificar a tendência temporal, utilizou-se o método Prais-Winsten e para verificar a associação espacial, bem como, a presença de clusters, recorreu-se a técnica Getis-Ord Gi*. Resultados: Dos 653 casos registrados como casos de tuberculose na população privada de liberdade, 98 apresentaram a tuberculose na sua forma resistente. Observou-se que ter até 8 e 11 anos de estudo, não fazer uso de tabaco e cultura de escarro apresentaram menos chances para o desenvolvimento de TBDR enquanto que, a forma clínica pulmonar e baciloscopia positiva no quarto mês de seguimento apresentaram-se favoráveis para o desenvolvimento de TBDR. A autoregressão de Prais-Winsten identificou uma tendência crescente, com APC = 15,08% (IC 95%: 0,02-0,09) de 2008 a 2018; quando analisada de 2012 a 2018, a tendência aumentou ainda mais, com APC = 23,31% (IC95%: 0,01-0,16). Foram observados hotspots nas macrorregiões norte, leste e oeste do Estado. A tuberculose pulmonar clinicamente confirmada e baciloscopia positiva no quarto mês de seguimento mostraram-se associados ao desenvolvimento de resistência aos medicamentos. Conclusão: O estudo evidenciou os fatores associados à TB resistente. Observou-se tendência crescente dos casos de TB resistente. A análise espacial revelou padrão heterogêneo da distribuição da tuberculose resistente, e sua concentração principalmente nas regiões com unidades prisionais

Introduction: Tuberculosis is a serious public health problem in the world. Associated with living conditions, the occurrence and transmission of the disease are higher in the penitentiary system, which makes the risk of becoming ill from tuberculosis in the population deprived of liberty greater compared to the general population. In addition to this scenario, the presence of drug resistance is observed. Objective: to analyze the factors associated with drug-resistant tuberculosis in the population deprived of liberty in the state of Paraná, the spatial distribution and temporal trend of the disease's occurrence. Methods: Ecological study of cases of drug-resistant tuberculosis registered in the Information System of Paraná, Brazil (2008 to 2018). Descriptive statistics were performed on the quantitative parameters calculated with absolute frequencies. Additionally, binary logistic regression was used, where the Odds Ratio with its respective confidence interval was calculated. To identify the temporal trend, the Prais-Winsten method was used and to verify the spatial association, as well as the presence of clusters, the Getis-Ord Gi* technique was used. Results: Of the 653 cases registered as cases of tuberculosis in the prison population, 98 had tuberculosis in its resistant form. It was observed that having up to 8 and 11 years of study, not using tobacco and sputum culture were less likely to develop TBDR, while the pulmonary clinical form and positive bacilloscopy in the fourth month of follow-up were favorable for the development of TBDR. Prais-Winsten autoregression identified an increasing trend, with APC = 15.08% (95% CI: 0.02-0.09) from 2008 to 2018; when analyzed from 2012 to 2018, the trend increased even more, with APC = 23.31% (95% CI: 0.01-0.16). Hotspots were observed in the North, East and West macro-regions of the State. Clinically confirmed pulmonary tuberculosis and positive bacilloscopy in the fourth month of follow-up were associated with the development of drug resistance. Conclusion: The study highlighted the factors associated with resistant TB. There was a growing trend in resistant TB cases. Spatial analysis revealed a heterogeneous pattern of distribution of resistant tuberculosis, and its concentration mainly in regions with prison units

Risk factors associated with drug-resistant tuberculosis in prisons in Sao Paulo State, Brazil (2006-2016).

INTRODUCTION: Prisons are high-risk settings for drug-resistant tuberculosis because the prevalence of the tuberculosis (TB) is much higher than in the general population. This study to investigated the factors associated with drug-resistant tuberculosis in prisons in the state of São Paulo, Brazil. METHODOLOGY: Retrospective cohort of drug-resistant TB cases for incarcerated people in São Paulo state, reported in the Tuberculosis Patient Control System between 2006 and 2016. To analyze the factors associated with drug-resistant TB, the backward method (likelihood ratio) was used, determining the adjusted odds ratio and respective 95%CI coefficients. Multiple models were proposed to adjust for potential confusion and interaction. The best fit model was selected based on the lowest Akaike information criterion coefficient. RESULTS: In total, 473 drug-resistant tuberculosis cases were reported in the prison population of Sao Paulo state, the majority were male. The cases that presented negative results for sputum smear and sputum culture had, respectively, an aOR=0.6 and aOR=0.16 for drug-resistant tuberculosis in relation to the cases with positive results. The cases where the patient had AIDS and reported alcoholism, respectively, an aOR=1.47 and aOR=1.60 for drug-resistant TB. Individuals with a background treatment history for TB presented a stronger association with drug-resistant tuberculosis, aOR=35.08. CONCLUSIONS: Sputum spear, sputum culture, chest X-ray, AIDS, alcoholism and background treatment history for TB were factors associated with resistance to antituberculosis drugs among prisoners. This is useful for the implementation of disease control measures related to the detection and monitoring of cases in the prison system.

Revisiting the methods for detecting Mycobacterium tuberculosis: what has the new millennium brought thus far?

Tuberculosis (TB) affects around 10 million people worldwide in 2019. Approximately 3.4 % of new TB cases are multidrug-resistant. The gold standard method for detecting Mycobacterium tuberculosis, which is the aetiological agent of TB, is still based on microbiological culture procedures, followed by species identification and drug sensitivity testing. Sputum is the most commonly obtained clinical specimen from patients with pulmonary TB. Although smear microscopy is a low-cost and widely used method, its sensitivity is 50-60 %. Thus, owing to the need to improve the performance of current microbiological tests to provide prompt treatment, different methods with varied sensitivity and specificity for TB diagnosis have been developed. Here we discuss the existing methods developed over the past 20 years, including their strengths and weaknesses. In-house and commercial methods have been shown to be promising to achieve rapid diagnosis. Combining methods for mycobacterial detection systems demonstrates a correlation of 100 %. Other assays are useful for the simultaneous detection of M. tuberculosis species and drug-related mutations. Novel approaches have also been employed to rapidly identify and quantify total mycobacteria RNA, including assessments of global gene expression measured in whole blood to identify the risk of TB. Spoligotyping, mass spectrometry and next-generation sequencing are also promising technologies; however, their cost needs to be reduced so that low- and middle-income countries can access them. Because of the large impact of M. tuberculosis infection on public health, the development of new methods in the context of well-designed and -controlled clinical trials might contribute to the improvement of TB infection control.

Resistencia de Mycobacterium tuberculosis a quinolonas y fármacos inyectables en el departamento del Atlántico, 2013-2016 / Resistance of Mycobacterium tuberculosis to quinolone and injectable drugs in Atlántico department, 2013-2016

Introducción: En el departamento del Atlántico los estudios de resistencia del Mycobacterium tuberculosis se han limitado a drogas de segunda línea. Objetivo: Determinar prevalencia de resistencia a amikacina, kanamicina, capreomicina y ofloxacina en casos de tuberculosis resistente a isoniacida, rifampicina o a ambas drogas, en el periodo 2013 a 2016 en el departamento del Atlántico. Métodos: Estudio transversal de 194 aislamientos resistentes a isoniacida, rifampicina o ambas, por metodología Genotype MTBDR plus versión 2, enviados al Instituto Nacional de Salud en el periodo 2013 al 2016 para ser confirmados y procesados para drogas de segunda línea. La proporción de resistencia, se hizo según variables sociodemográficas, clínica y de vigilancia en salud pública. Resultados: Las comorbilidades frecuentes encontradas fueron desnutrición con el 18,56 por ciento, seguido de infección concomitante VIH-tuberculosis con el 13,40 por ciento. La ofloxacina en casos no tratados obtuvo la mayor resistencia global con el 1,50 por ciento (IC 95 por ciento 0,18-5,33). En los que fueron previamente tratados la resistencia global a capreomicina fue del 8,10 por ciento (IC 95 por ciento 2,7-17,8). En los resistentes a rifampicina, un caso fue extensivamente resistente y dos casos resistentes en los multidrogorresistente. Conclusiones: Se encontró baja resistencia a fluoroquinolonas y fármacos inyectables en pacientes no tratados resistentes a isoniacida, rifampicina o ambas, que muestra que todavía no constituye un problema mayor en el departamento del Atlántico. Se debe complementar su seguimiento con buen manejo tanto físico como psicológico y un equipo de salud fortalecido que actúe prontamente y ayude a la adherencia del paciente a los tratamientos(AU)

Introduction: In Atlántico department, resistance studies of Mycobacterium tuberculosis have been limited to second-line drugs. Objective: Determine prevalence of resistance to amikacin, kanamycin, capreomycin and ofloxacin in cases of tuberculosis resistant to isoniazid, rifampicin or both, in the period 2013 to 2016 in Atlántico department. Methods: Cross-sectional study of 194 isolations resistant to isoniazid, rifampicin or both, by Genotype MTBDR plus version 2 methodology, that were sent to the National Institute of Health from 2013 to 2016 to be confirmed and processed for second-line drugs. The resistance ratio was made according to sociodemographic, clinical and public health surveillance variables. Results: The common comorbilities found were malnutrition with 18.56 percent, followed by concomitant HIV-tuberculosis infection with 13.40 percent. Ofloxacin in non-treated cases achieved the highest overall resistance with 1.50 percent (95 percent CI 0.18-5.33). In those previously treated, global resistance to capreomycin was 8.10 percent (95 percent CI 2.7-17.8). In the ones resistant to rifampicin, one case was extensively resistant and two cases were resistant in multi-drugs resistant. Conclusions: Low resistance to fluoroquinolones and injectable drugs was found in non-treated patients who were resistant to isoniazid, rifampicin or both, showing that it is not yet a major problem in Atlántico department. Its follow-up should be complemented with good physical and psychological management and a strengthened health team that acts promptly and helps the patient adherence to treatments(AU)

Five-year microevolution of a multidrug-resistant Mycobacterium tuberculosis strain within a patient with inadequate compliance to treatment.

BACKGROUND: Whole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution -the genetic variability of M. tuberculosis at short time scales- of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported. CASE PRESENTATION: In this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5' untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy. CONCLUSIONS: This report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

Clinical outcomes and molecular characterization of drug-resistant tuberculosis in pre- and extensively drug-resistant disease based on line probe assays.

Multidrug-resistant tuberculosis (MDR-TB) represents a significant impact in transmission, outcome, and health costs. The World Health Organization recommends implementation of rapid diagnostic methods for multidrug-resistance detection. This study was performed to evaluate the frequency of pre- and extensively drug resistant tuberculosis (pre-XDR-TB and XDR-TB) among MDR-TB patients, the pattern of resistance mutations for fluoroquinolones and the clinical outcome. Adult patients followed at a Brazilian regional reference center for TB, from January 2013 to June 2019 were included. Stored Mycobacterium tuberculosis (Mtb) cultures were recovered, the DNA was extracted, and the susceptibility test was performed using the line probe assay for second line antimycobacterial drugs, Genotype MTBDRsl version 2.0 (Hain Lifescience, CmbH, Germany). Among 33 MDR-TB included patients, we diagnosed XDR-TB or pre-XDR in five (15%) cases. Of these, mutations related to fluoroquinolones resistance were observed in four Mtb isolates, including one who had no phenotypic resistance profile. In two other patients with phenotypic resistance to ofloxacin, genotypic resistance was not found. Case fatality rate was 60% in pre/XDR-TB group, compared to 3.6% in the remaining of patients. This study observed few cases of pre-XDR and XDR-TB among a MDR-TB cohort. Phenotypic and genotypic assays presented good agreement. Clinical outcome was more favorable for patients with susceptibility to fluoroquinolones and injectable drugs.

Clinical outcomes and molecular characterization of drug-resistant tuberculosis in pre- and extensively drug-resistant disease based on line probe assays

ABSTRACT Multidrug-resistant tuberculosis (MDR-TB) represents a significant impact in transmission, outcome, and health costs. The World Health Organization recommends implementation of rapid diagnostic methods for multidrug-resistance detection. This study was performed to evaluate the frequency of pre- and extensively drug resistant tuberculosis (pre-XDR-TB and XDR-TB) among MDR-TB patients, the pattern of resistance mutations for fluoroquinolones and the clinical outcome. Adult patients followed at a Brazilian regional reference center for TB, from January 2013 to June 2019 were included. Stored Mycobacterium tuberculosis (Mtb) cultures were recovered, the DNA was extracted, and the susceptibility test was performed using the line probe assay for second line antimycobacterial drugs, Genotype MTBDRsl version 2.0 (Hain Lifescience, CmbH, Germany). Among 33 MDR-TB included patients, we diagnosed XDR-TB or pre-XDR in five (15%) cases. Of these, mutations related to fluoroquinolones resistance were observed in four Mtb isolates, including one who had no phenotypic resistance profile. In two other patients with phenotypic resistance to ofloxacin, genotypic resistance was not found. Case fatality rate was 60% in pre/XDR-TB group, compared to 3.6% in the remaining of patients. This study observed few cases of pre-XDR and XDR-TB among a MDR-TB cohort. Phenotypic and genotypic assays presented good agreement. Clinical outcome was more favorable for patients with susceptibility to fluoroquinolones and injectable drugs.

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates.

Tuberculosis (TB) is one of the most fatal diseases and is responsible for the infection of millions of people around the world. Most recently, scientific frontiers have been engaged to develop new drugs that can overcome drug-resistant TB. Following this direction, using a designed scaffold based on the combination of two separate pharmacophoric groups, a series of menadione-derived selenoesters was developed with good yields. All products were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and attractive results were observed, especially for the compounds 8a, 8c and 8f (MICs 2.1, 8.0 and 8.1 µM, respectively). In addition, 8a, 8c and 8f demonstrated potent in vitro activity against multidrug-resistant clinical isolates (CDCT-16 and CDCT-27) with promising MIC values ranging from 0.8 to 3.1 µM. Importantly, compounds 8a and 8c were found to be non-toxic against the Vero cell line. The SI value of 8a (>23.8) was found to be comparable to that of isoniazid (>22.7), which suggests the possibility of carrying out advanced studies on this derivative. Therefore, these menadione-derived selenoesters obtained as hybrid compounds represent promising new anti-tubercular agents to overcome TB multidrug resistance.