The past, present and future of tuberculosis treatment / 浙江大学学报·医学版

Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.

Tuberculosis pulmonar y laríngea: una forma poco frecuente de presentación en la edad pediátrica / Pulmonary and laryngeal tuberculosis: a rare presentation in pediatrics / Tuberculose pulmonar e laríngica: uma apresentação pouco frequente na idade pediátrica

Introducción: la tuberculosis (TB) es una enfermedad infectocontagiosa granulomatosa crónica, producida por Mycobacterium tuberculosis. En Uruguay se ha notificado un aumento en el número de casos, con una incidencia reportada en 2017 de 28,6/100.000 habitantes, siendo de 6,67/100.000 en menores de 15 años. La tuberculosis laríngea es una forma poco frecuente y evolucionada de tuberculosis, que suele manifestarse con disfonía crónica. Su diagnóstico requiere un alto índice de sospecha. Objetivo: describir un caso clínico de presentación poco frecuente en la edad pediátrica. Caso clínico: adolescente de 13 años, sana, vacunas vigentes, con antecedentes de conductas sexuales activas y papilomatosis laríngea diagnosticada por laringoscopía directa como causa de disfonía crónica. Consulta en emergencia por dolor abdominal, constatándose al examen clínico adelgazamiento asociado a síntomas respiratorios y síndrome tóxico bacilar asociado a disfonía crónica de cuatro meses de evolución, por lo cual se plantea tuberculosis laríngea e ingresa para estudio. Niega contacto de tuberculosis. En la radiografía de tórax se constata lesión cavernosa en vértice pulmonar izquierdo. Las baciloscopías de esputo fueron positivas (directo y cultivo) confirmando el planteo de TB pulmonar y laríngea. Se realizó tratamiento antituberculoso supervisado con excelente evolución posterior. Conclusiones: la tuberculosis es una enfermedad reemergente en nuestro país, que requiere un alto índice de sospecha. Su diagnóstico sigue siendo un desafío para los pediatras ya que la confirmación diagnóstica no siempre es posible. En este caso clínico la sospecha clínica frente a una disfonía crónica asociada a síntomas respiratorios fue fundamental para establecer el diagnóstico, a pesar de no contar con nexo epidemiológico.

Introduction: tuberculosis (TB) is an infectious, chronic granulomatous disease caused by Mycobacterium tuberculosis. An increase in the number of cases has been reported in Uruguay, with an incidence reported in 2017 of 28.6/100,000 inhabitants, being 6.67/100,000 in children under 15 years of age. Laryngeal tuberculosis is a rare and evolved form of tuberculosis, which usually shows chronic dysphonia, which requires high levels of suspicion. Objective: to describe a clinical case with a rare presentation in pediatric age. Clinical case: 13-year-old female adolescent, healthy, fully vaccinated, with a history of active sexual behaviors and laryngeal papillomatosis diagnosed by direct laryngoscopy as a cause of chronic dysphonia. The emergency consultation was caused by abdominal pain, confirming the clinical examination weight loss associated with respiratory symptoms and bacillary toxic syndrome associated with chronic dysphonia of four months of evolution, for which laryngeal tuberculosis was considered and she was admitted for screening. She denies having been in contact with tuberculosis. The chest X-ray revealed a cavernous lesion in the left pulmonary apex and sputum smears were positive (direct and culture), confirming the suggestion of pulmonary and laryngeal TB. Supervised anti-tuberculosis treatment was performed with excellent subsequent evolution. Conclusions: tuberculosis is a re-emerging disease in our country, which requires a high level of suspicion. Its diagnosis remains a challenge for pediatricians since diagnostic confirmation is not always possible. In this clinical case, clinical suspicion of chronic dysphonia associated with respiratory symptoms were key factors to establish the diagnosis, despite not having a clear epidemiological link.

Introdução: a tuberculose (TB) é uma doença infecciosa granulomatosa crônica causada pelo Mycobacterium tuberculosis. No Uruguai, houve aumento do número de casos notificados, com uma incidência notificada em 2017 de 28,6/100.000 habitantes, sendo 6,67/100.000 casos de menores de 15 anos. A tuberculose laríngea é uma forma rara e evoluída de tuberculose, que geralmente se manifesta com disfonia crônica, exigindo alto índice de suspeita. Objetivo: descrever um caso clínico de apresentação pouco frequente em idade pediátrica. Caso clínico: menina adolescente de 13 anos, saudável, totalmente vacinada, com história de comportamentos sexuais ativos e papilomatose laríngea diagnosticada por laringoscopia direta como causa de disfonia crônica. Consulta de urgência por dor abdominal, comprovando emagrecimento associado a sintomas respiratórios e síndrome bacilar tóxica associada a disfonia crônica de quatro meses de evolução, para a qual foi considerada tuberculose laríngea e a paciente foi internada para estudo. Ele nega contato com tuberculose. A radiografia de tórax revelou lesão cavernosa em ápice pulmonar esquerdo e as baciloscopias de escarro foram positivas (direta e cultura) confirmando a sugestão de TB pulmonar e laríngea. O tratamento antituberculose supervisionado foi realizado com excelente evolução subsequente. Conclusões: a tuberculose é uma doença reemergente em Uruguai e requer alto índice de suspeita. Seu diagnóstico permanece um desafio para o pediatra, pois a confirmação diagnóstica nem sempre é possível. Neste caso clínico, a suspeita clínica de disfonia crônica associada a sintomas respiratórios foi fundamental para o estabelecimento do diagnóstico, apesar de não ter vínculo epidemiológico.

Disseminated tuberculosis associated with reactive arthritis of Poncet in an immunocompetent patient

Abstract Cutaneous tuberculosis is a rare extrapulmonary manifestation of tuberculosis which, like disseminated tuberculosis, commonly occurs in immunocompromised patients. Poncet reactive arthritis is a seronegative arthritis affecting patients with extrapulmonary tuberculosis, which is uncommon even in endemic countries. We report a previously healthy 23-year-old male patient with watery diarrhea associated with erythematous ulcers on the lower limbs and oligoarthritis of the hands. Histopathological examination of the skin showed epithelioid granulomatous process with palisade granulomas and central caseous necrosis. AFB screening by Ziehl-Neelsen staining showed intact bacilli, the culture was positive for Mycobacterium tuberculosis, and colonoscopy revealed multiple shallow ulcers. Disseminated tuberculosis associated with reactive Poncet arthritis was diagnosed, with an improvement of the clinical and skin condition after appropriate treatment.

The impact of ocular tuberculosis on vision after two months of intensive therapy

ABSTRACT Tuberculosis is an infectious disease of global importance with major economic and social burden accounting for 25% of all avoidable deaths in developing countries. Extrapulmonary involvement may occur either in association with clinically apparent pulmonary tuberculosis or in isolation. This cross-sectional descriptive study aimed to evaluate the impact of ocular tuberculosis in visual acuity at baseline and after two months of intensive anti-tuberculous therapy. A sample of 133 pulmonary tuberculosis patients, seven disseminated tuberculosis, and three pleural tuberculosis patients was evaluated. All patients underwent routine ophthalmic evaluation, including assessment of visual acuity, biomicroscopy, applanation tonometry, indirect ophthalmoscopy, and fluorescent angiography as appropriate. None of the patients had impaired visual acuity due to tuberculosis. A rate of 4.2% (6/143) of ocular involvement was found. None of the patients with ocular involvement were HIV-infected. Of the six patients with ocular involvement, five met the diagnostic criteria for probable and one for possible ocular lesions. As for the type of ocular lesions, two patients had bilateral findings: one had sclerouveitis and the second had choroidal nodules. The other four patients presented with unilateral lesions: peripheral retinal artery occlusion in the right eye (one case), choroidal nodules in the left eye (one case), and choroidal nodules in the right eye (two cases). Patients progressed favorably after two month of intensive therapy, with no significant reduction in vision.

Osteomielitis por Mycobacterium tuberculosis / Mycobacterium tuberculosis osteomyelitis

Resumen Introducción: en Uruguay se ha notificado un aumento en el número de casos de tuberculosis en niños con formas pulmonares y extrapulmonares. La infección osteoarticular representa 10%-15% de las formas extrapulmonares. Objetivo: alertar sobre una etiología poco habitual de osteomielitis cuya forma de presentación genera dificultades diagnósticas. Caso clínico: niña de 18 meses, previamente sana. Consulta por edema e impotencia funcional de tobillo derecho de tres meses de evolución, en apirexia. La radiografía muestra múltiples imágenes geódicas en el sector distal de la diáfisis con secuestro en peroné derecho. Se realiza punción ósea obteniéndose líquido serohemático. El cultivo de dicha muestra y el hemocultivo fueron negativos. Luego de recibir clindamicina 21 días más gentamicina 10 días por via intravenosa y dos limpiezas quirúrgicas, se otorga alta con cefuroxime acetil vía oral. El cultivo de la muestra ósea desarrolló Mycobacterium tuberculosis. Se inició tratamiento con isoniacida, rifampicina y piracinamida. No fue identificado el caso índice. Discusión: la presentación clínica de la tuberculosis ósea es generalmente insidiosa lo que generando dificultades y retraso en el diagnóstico. Sólo la biopsia permite confirmar el diagnóstico. La situación epidemiológica actual obliga a descartar posible etiología tuberculosa ante un proceso inflamatorio osteoarticular de evolución tórpida. El tratamiento oportuno y adecuado requiere alto índice de sospecha y realización sistemática de punción ósea y/o articular.

Summary Introduction: in Uruguay, an increase in the number of cases of TB with pulmonary and extra-pulmonary involvement in children has been reported. Osteoarticular infections represent 10%-15% of extra-pulmonary involvement. Objective: to warn about an uncommon etiology of osteomyelitis whose presentation results in diagnostic difficulties. Clinical case: 18 month-old girl, previously healthy. Consultation was due to edema and right ankle functional insuficiency with three-month evolution, under apyrexia. X-ray imaging revealed multiple geodesic images in the distal portion of diaphysis, as well as a small sequestrum in right fibula. Through a bone puncture, serohematic fluid was extracted. Culture and hemoculture were negative. Treatment consisted of 21 days of intravenous clindamycin and 10 days of gentamicin. Two surgical debridements were performed. Progressive recovery followed. The child was discharged under cefuroxime axetil oral suspension and later a bone culture showed positive results for Mycobacterium TB. Treatment with isoniazid, rifampin and pyrazinamide was started. Index case could not be identified. Discussion: clinical presentation of bone tuberculosis is generally insidious. This explains difficulties and delays in diagnosis. It is remarkable that only biopsy allows the confirmation of diagnosis. The present epimediologic condition forces us to rule out possible TB etiology in the presence of an inflammatory osteoarticular process of lethargic evolution. Timely and accurate treatment requires a high degree of suspicion, as well as the performance of systematic bone and/or joint puncture.

Estimated rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a ­four-drug fixed-dose combination regimen at a tertiary health care facility in the city of Rio de Janeiro, Brazil / Estimativas das taxas de recidiva, cura e abandono de tratamento em pacientes com tuberculose pulmonar tratados com esquema de dose fixa combinada de quatro drogas em uma unidade de saúde terciária na cidade do Rio de Janeiro

ABSTRACT Objective: To estimate the rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a four-drug fixed-dose combination (FDC) regimen, as well as to evaluate possible associated factors. Methods: This was a retrospective observational study involving 208 patients with a confirmed diagnosis of pulmonary tuberculosis enrolled in the Hospital Tuberculosis Control Program at the Institute for Thoracic Diseases, located in the city of Rio de Janeiro, Brazil. Between January of 2007 and October of 2010, the patients were treated with the rifampin-isoniazid-pyrazinamide (RHZ) regimen, whereas, between November of 2010 and June of 2013, the patients were treated with the rifampin-isoniazid-pyrazinamide-ethambutol FDC (RHZE/FDC) regimen. Data regarding tuberculosis recurrence and mortality in the patients studied were retrieved from the Brazilian Case Registry Database and the Brazilian Mortality Database, respectively. The follow-up period comprised two years after treatment completion. Results: The rates of cure, treatment abandonment, and death were 90.4%, 4.8%, and 4.8%, respectively. There were 7 cases of recurrence during the follow-up period. No significant differences in the recurrence rate were found between the RHZ and RHZE/FDC regimen groups (p = 0.13). We identified no factors associated with the occurrence of recurrence; nor were there any statistically significant differences between the treatment groups regarding adverse effects or rates of cure, treatment abandonment, or death. Conclusions: The adoption of the RHZE/FDC regimen produced no statistically significant differences in the rates of recurrence, cure, or treatment abandonment; nor did it have any effect on the occurrence of adverse effects, in comparison with the use of the RHZ regimen.

RESUMO Objetivo: Estimar as taxas de recidiva, cura e abandono de tratamento em pacientes com tuberculose pulmonar tratados com o esquema de dose fixa combinada (DFC) de quatro drogas e avaliar possíveis fatores associados. Métodos: Estudo observacional retrospectivo com 208 pacientes com diagnóstico confirmado de tuberculose pulmonar registrados no Programa de Controle da Tuberculose Hospitalar do Instituto de Doenças do Tórax, localizado na cidade do Rio de Janeiro. Os pacientes tratados entre janeiro de 2007 e outubro de 2010 receberam o esquema rifampicina-isoniazida-pirazinamida (RHZ), e aqueles tratados entre novembro de 2010 e junho de 2013 receberam o esquema rifampicina-isoniazida-pirazinamida-etambutol em DFC (RHZE/DFC). Os dados dos pacientes sobre recidiva e óbito foram obtidos no Sistema de Informação de Agravos de Notificação e no Sistema de Informação de Mortalidade, respectivamente. O período de acompanhamento foi de dois anos após o encerramento do tratamento. Resultados: As taxas de cura, abandono e óbito foram de 90,4%, 4,8% e 4,8%, respectivamente. Houve 7 casos de recidivas durante o período de acompanhamento. Não houve diferenças significativas na taxa de recidiva entre os grupos de tratamento RHZ e RHZE/DFC (p = 0,13). Não foram identificados fatores associados com a ocorrência de recidiva, nem houve diferenças estatisticamente significativas na ocorrência dos efeitos adversos ou nas taxas de cura, abandono e óbito entre os grupos de tratamento. Conclusões: A adoção do esquema de tratamento RHZE/DFC não produziu diferenças estatisticamente significativas nas taxas de recidiva, cura e abandono nem na ocorrência de efeitos adversos em comparação com o esquema RHZ.

Cutaneous tuberculosis: diagnosis, histopathology and treatment - Part II

The evolution in the knowledge of tuberculosis' physiopathology allowed not only a better understanding of the immunological factors involved in the disease process, but also the development of new laboratory tests, as well as the establishment of a histological classification that reflects the host's ability to contain the infectious agent. At the same time, the increasing bacilli resistance led to alterations in the basic tuberculosis treatment scheme in 2009. This article critically examines laboratory and histological investigations, treatment regimens for tuberculosis and possible adverse reactions to the most frequently used drugs.

Polaciúria incapacitante para a vida usual. Relato de tuberculose da bexiga. A tuberculose permanece no rol do diagnóstico diferencial da maioria das doenças / Incapacitating pollakiuria affecting daily life. A case report of tuberculosis of the bladder. Tuberculosis remains on the list of the differential diagnoses for most diseases

A tuberculose (TB) é dos mais graves problemas de saúde humano e associa-se a pobreza, incipiência do sistema de saúde, deficiência de gestão que dificulta a diminuição de doenças de determinismo social, epidemia do vírus da imunodeficiência humana e imunodeficiência adquirida e multirresistência do M. tuberculosis. O acometimento extrapulmonar ocorre em 15% dos casos de TB e pode evoluir com amesma sintomatologia geral do acometimento pulmonar, com variações na dependência de sua localização e gravidade. Este relato apresenta paciente com hematúria e polaciúria incapacitante para a vida social, associada inicialmente à neoplasia, e determinada pela TB geniturinária, com diagnóstico após histopatologia de espécime clínico obtido da bexiga, em que o tempo longo para o diagnóstico foi determinante para grave sequela. Objetiva alertar para a TB como doença permanente no Brasil ea necessidade de ser considerada sempre como diagnóstico diferencial de doenças pulmonares ou extrapulmonares.

Tuberculosis (TB) is among the most serious human health concerns and is associated with poverty, limited availability of health care services and bad management, all of which negatively affect the possibility of reducing socially-determined diseases, such as HIV/AIDS epidemics and multidrug resistant M. tuberculosis. Extrapulmonary involvement occurs in 15% of TB cases and can develop with the same overall symptomatology of exclusively pulmonary involvement, with smaller variations depending on location and severity. This report presents a patient with hematuria and pollakiuria with incapacitating effects on social life, initially thought of as a malignancy and later identified as genitourinary TB. Diagnosis was based on histopathology of clinical specimens from the bladder. Time elapsed between onset and diagnosis led to considerable sequelae. This report aims at raising awareness of TB as a permanent concern in Brazil and of the need to always considered it as a differential diagnosis of pulmonary or extrapulmonary disease.

Mastitis tuberculosa / Tuberculosis of the breast

Se informa un caso de mastitis granulomatosa causada por Mycobacterium tuberculosis en una paciente inmunocompetente con lesiones inflamatorias crónicas de la mama, diagnosticada por la detección de ADN de la micobacteria mediante la técnica de reacción en cadena de la polimerasa de la secuencia de inserción IS6110 presente en el complejo M. tuberculosis , en una biopsia de mama embebida en parafina. La tuberculosis primaria de la mama es rara, incluso en países con alta prevalencia de tuberculosis, y debe sospecharse en pacientes con mastitis granulomatosa crónica de causa no clara. El pilar del tratamiento es la quimioterapia antituberculosa y, ocasionalmente, la cirugía.

We report a case of granulomatous mastitis caused by Mycobacterium tuberculosis in an immunocompetent woman with chronic inflammatory lesions of the breast. It was diagnosed by detection of mycobacteria DNA using polymerase chain reaction technique targeting IS6110 insertion element of M. tuberculosis complex in a paraffin-embedded histological specimen. The primary breast tuberculosis is rare, even in countries where the incidence and prevalence of pulmonary and extra pulmonary tuberculosis are high. It should be suspected in female patients with chronic granulomatous mastitis with no apparent cause. The cornerstone of treatment is antituberculous chemotherapy, and surgery is rarely required.

Desfechos clínicos do tratamento de tuberculose utilizando o esquema básico recomendado pelo Ministério da Saúde do Brasil com comprimidos em dose fixa combinada na região metropolitana de Goiânia / Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil

OBJETIVO: Descrever as taxas de cura, falência e abandono do tratamento da tuberculose com o esquema básico preconizado pelo Ministério da Saúde (tratamento com rifampicina, isoniazida, pirazinamida e etambutol por dois meses seguido de isoniazida e rifampicina por quatro meses) utilizando comprimidos em dose fixa combinada em regime autoadministrado e descrever os eventos adversos e seus possíveis impactos nos desfechos do tratamento. MÉTODOS: Estudo descritivo utilizando dados coletados prospectivamente dos prontuários médicos de pacientes com tuberculose (idade > 18 anos) tratados com o esquema básico em duas unidades básicas de saúde da região metropolitana de Goiânia, GO. RESULTADOS: A amostra foi composta por 40 pacientes com tuberculose. A taxa de cura foi de 67,5%, a taxa de abandono foi de 17,5%, e não ocorreram casos de falência. Nessa amostra, 19 pacientes (47%) relataram reações adversas aos medicamentos. Essas foram leves e moderadas, respectivamente, em 87% e 13% dos casos. Em nenhum caso houve necessidade de mudança do esquema ou suspensão do tratamento. CONCLUSÕES: A taxa de cura do esquema básico com o uso de comprimidos em dose fixa combinada sob regime autoadministrado foi semelhante às taxas históricas do esquema anterior. A taxa de abandono, na amostra estudada, foi muito acima da taxa preconizada como adequada (até 5%).

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

Protocolo 6: manejo de la tuberculosis en atención primaria de la salud / Protocol 6: management of tuberculosis in primary health care

La Tuberculosis es una enfermedad infectocontagiosa, producida por el Mycobacterium tuberculosis, o Bacilo de Koch, que se transmite por vía aérea, cuando una persona enferma expulsa bacilos al hablar, toser, estornudar, reír o cantar. La tuberculosis afecta principalmente los pulmones (TuberculosisPulmonar), pero también puede afectar cualquier órgano del cuerpo (Tuberculosi sextra-pulmonar). La tuberculosis afecta principalmente los pulmones (TuberculosisPulmonar), pero también puede afectar cualquier órgano del cuerpo (Tuberculosis extra-pulmonar La tuberculosis (TB) sigue siendo un gran problema de salud en la mayoría de los países del mundo, a pesar de los esfuerzos realizados para combatirla, apoyados por la existencia del conocimiento de la cadena de transmisión y de contar con medicamentos muy activos para prevenir y curar la enfermedad.

Resistência primária e adquirida à pirazinamida em pacientes com tuberculose pulmonar atendidos em um hospital de referência no Recife / Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

OBJETIVO: Verificar a resistência primária e adquirida à pirazinamida em cepas de Mycobacterium tuberculosis provenientes de amostras de escarro de pacientes com tuberculose pulmonar. MÉTODOS: Estudo prospectivo e descritivo realizado no período entre abril e novembro de 2011 em um hospital de referência para o tratamento de tuberculose em Recife (PE). Culturas, testes de sensibilidade a fármacos e testes da pirazinamidase foram realizados em um laboratório particular na mesma cidade. RESULTADOS: Dos 71 pacientes incluídos no estudo, 37 eram virgens de tratamento e 34 eram casos de retratamento. Desses, 0 (0,0%) e 14 (41,2%), respectivamente, apresentaram cepas resistentes à pirazinamida. Desses 14 isolados, 10 (90,9%) apresentaram resultados negativos no teste da pirazinamidase. Dos 60 isolados que apresentaram resultados positivos para o teste da pirazinamidase, 56 (93,3%) eram sensíveis à pirazinamida. CONCLUSÕES: A elevada frequência de cepas resistentes à pirazinamida em pacientes em retratamento da tuberculose destaca a necessidade da realização de testes de sensibilidade à pirazinamida antes de se escolher um novo esquema de tratamento.

OBJECTIVE: To determine primary and acquired resistance to pyrazinamide in Mycobacterium tuberculosis strains isolated in sputum samples from patients with pulmonary tuberculosis. METHODS: This was a prospective, descriptive study conducted between April and November of 2011 at a referral hospital for tuberculosis in the city of Recife, Brazil. Cultures, drug sensitivity tests, and tests of pyrazinamidase activity were conducted in a private laboratory in Recife. RESULTS: Of the 71 patients included in the study, 37 were treatment-naïve and 34 represented cases of retreatment. Pyrazinamide-resistant strains were isolated in 14 (41.2%) of the 34 patients who had previously been treated for tuberculosis and in none of the 37 treatment-naïve patients. Of the 14 isolates, 10 (90.9%) tested negative for pyrazinamidase activity. A total of 60 isolates tested positive for pyrazinamidase activity. Of those, 56 (93.3%) were found to be sensitive to pyrazinamide. CONCLUSIONS: The high frequency of pyrazinamide-resistant strains (41.2%) in patients previously treated for tuberculosis highlights the need for drug susceptibility testing prior to the adoption of a new treatment regimen.

Efficacy of the 6-month thrice-weekly regimen in the treatment of new sputum smear-positive pulmonary tuberculosis under clinical trial conditions.

Background. Under the Revised National Tuberculosis Control Programme of India, patients with new smear-positive pulmonary tuberculosis are treated with a thrice-weekly regimen of antitubercular drugs (2H3R3Z3E3/4H3R3 [H isoniazid, R rifampicin, Z pyrazinamide and E ethambutol]) for 6 months. We conducted a retrospective analysis of the efficacy and tolerability of this regimen under clinical trial conditions in HIV-negative patients with newly diagnosed smear-positive pulmonary tuberculosis. Methods. We retrospectively analysed the data on patients assigned to the control regimen (2H3R3Z3E3/4H3R3) in two clinical trials during 2001–06 at the National Institute for Research in Tuberculosis, Chennai, India. Results. Of the 268 patients treated with this regimen, data for efficacy analysis were available for 249. At the end of treatment, of 249 patients, 238 (96%) had a favourable status. Treatment failure occurred in the remaining 11: 7 in whom the organisms were initially drug-susceptible and 4 with initial drug resistance. Of the 238 patients who had a favourable status at the end of treatment, 14 (6%) had recurrence of tuberculosis during the following 24 months. In the intention-to-treat analysis, 245 (94%) of 262 patients had a favourable status at the end of treatment. Of the 28 patients with initial drug resistance, 24 (86%) had a favourable outcome. Only 4 of these 24 patients were found to have recurrence of tuberculosis in 2 years of follow-up. Among the 221 patients initially infected with drug-susceptible organisms, drug resistance did not develop in any of the 7 patients in whom the treatment failed or the 10 who had recurrence of tuberculosis. Further, 5 of the 7 patients in whom the treatment failed continued to excrete drug-susceptible bacilli at 6 months. Adverse drug reactions were observed in 38 (14%) of the 262 patients. Only 3 (1.1%) needed a modification in the treatment. Conclusion. This thrice-weekly 6-month regimen of antitubercular drugs, when administered under full supervision, is associated with a high rate of favourable treatment outcomes in HIV-negative patients with newly diagnosed sputum smearpositive pulmonary tuberculosis. There are few adverse drug reactions in these patients.

Lupus vulgar: caso infrecuente de tuberculosis extrapulmonar / Cutaneous tuberculosis: Report of one case

Background: Tuberculosis is uncommonly located in the skin, corresponding to 1 to 2% of extrapulmonary forms. We report a 61-year-old woman, referred due to a two months history of erythematous plaques covered with honey-colored crusts in the left preauricular region and below the chin. The lesions were previously treated as pyoderma with poor response. She was otherwise healthy, without any other symptom. Skin biopsy showed exudative tuberculoid granulomas with caseation necrosis. Koch culture was positive for Mycobacterium tuberculosis. Complementary studies ruled out other foci. Lupus vulgaris was diagnosed and antituberculous therapy started, achieving regression of cutaneous lesions.

Clinical response of newly diagnosed HIV seropositive & seronegative pulmonary tuberculosis patients with the RNTCP Short Course regimen in Pune, India.

Background & objectives In the Revised National Tuberculosis Control Programme (RNTCP) in India prior to 2005, TB patients were offered standard DOTS regimens without knowledge of HIV status. Consequently such patients did not receive anti-retroviral therapy (ART) and the influence of concomitant HIV infection on the outcome of anti-tuberculosis treatment remained undetermined. This study was conducted to determine the results of treatment of HIV seropositive pulmonary tuberculosis patients with the RNTCP (DOTS) regimens under the programme in comparison with HIV negative patients prior to the availability of free ART in India. Methods Between September 2000 and July 2006, 283 newly diagnosed pulmonary TB patients were enrolled in the study at the TB Outpatient Department at the Talera Hospital in the Pimpri Chinchwad Municipal Corporation area at Pune (Maharashtra): they included 121 HIV seropositive and 162 HIV seronegative patients. They were treated for tuberculosis as per the RNTCP in India. This study was predominantly conducted in the period before the free ART become available in Pune. Results At the end of 6 months of anti-TB treatment, 62 per cent of the HIV seropositive and 92 per cent of the HIV negative smear negative patients completed treatment and were asymptomatic; among smear positive patients, 70 per cent of the HIV-seropositive and 81 per cent of HIV seronegative pulmonary TB patients were cured. Considering the results in the smear positive and smear negative cases together, treatment success rates were substantially lower in HIV positive patients than in HIV negative patients, (66% vs 85%). Further, 29 per cent of HIV seropositive and 1 per cent of the HIV seronegative patients expired during treatment. During the entire period of 30 months, including 6 months of treatment and 24 months of follow up, 61 (51%) of 121 HIV positive patients died; correspondingly there were 6 (4%) deaths among HIV negative patients. Interpretation & conclusions The HIV seropositive TB patients responded poorly to the RNTCP regimens as evidenced by lower success rates with chemotherapy and high mortality rates during treatment and follow up. There is a need to streamline the identification and management of HIV associated TB patients in the programme with provision of ART to achieve high cure rates for TB, reducing mortality rates and ensuring a better quality of life.

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide in patients with pulmonary tuberculosis

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide were studied in healthy controls and patients with active pulmonary tuberculosis. A case-control study of 29 controls and 30 cases attending at the Health Center, July, 2004 to December, 2005 was conducted. The body mass index was significantly reduced in cases compared to controls (p < 0.001). The intestinal paracellular transport of lactulose was significantly (p = 0.019) reduced in cases compared to controls. The transcellular transport of mannitol and the lactulose:mannitol ratio were not significantly (p = 0.0698) reduced in cases compared to controls. Low serum concentrations of rifampin, isoniazid and pyrazinamide were observed in 81 percent (48/59), 92 percent (54/59) and 28 percent (12/59), respectively, in all individuals. The results demonstrated a marked decrease on intestinal paracellular transport in patients with active pulmonary tuberculosis and reduced serum concentrations of rifampin and isoniazid in both groups.

Incomplete immunological recovery following anti-tuberculosis.

Background & objectives: Mycobacterium tuberculosis infection has been shown to result in increased HIV replication and disease progression in HIV-infected individuals through increased immune activation. The objective of this study was to correlate plasma levels of immune activation markers with the presence of tuberculosis (TB) in HIV-infected and uninfected individuals, and to study the changes following anti-tuberculosis treatment. Methods: Plasma markers of immune activation - neopterin, beta-2-microglobulin (β2M) and soluble tumour necrosis factor alpha receptor type I (sTNFα-RI) were measured by ELISA in 42 HIV positive TB patients (HIV+TB+) undergoing a six-month course of TB chemotherapy. Thirty seven HIV+ persons without active TB, 38 TB patients without HIV infection, and 62 healthy volunteers served as controls. Results: Plasma levels of all three markers were elevated in HIV+ individuals, more so in those with active TB. When HIV+ individuals were further categorized based on CD4+ T cell counts, HIV+TB+ patients with CD4+ T cells counts < 200 cells/μl were found to have the highest levels at baseline with a steep fall in neopterin and sTNFα-RI during treatment, but in most instances the levels did not drop to normal. β2M levels remained persistently high despite completing TB treatment. Interpretation & conclusions: The fi ndings of the study suggest that both HIV and TB act synergistically to activate the host immune system. Although ATT was effective in clearing M. tuberculosis infection, a high proportion of HIV+ TB patients continued to have levels well above the normal range, indicating that underlying immune activation persists despite TB treatment. None of the markers were specific enough to be used to assess cure of TB.

Tuberculose: como eu trato / Tuberculosis: how I deal

Historicamente, o Brasil teve papel pioneiro na organização das ações de controle da tuberculose. Desde os primeiros anos do século XX, por meio de estratégias diagnósticas e terapêuticas padronizadas simples e efetivas, baseadas na patobiologia da doença e nas características do agente etiológico, o Programa de Controle da Tuberculose vem contribuindo para o controle da doença e para a organização do sistema público de saúde. A padronização terapêutica em todo o território nacional, associada à garantia de fornecimento gratuito dos medicamentos a todos os doentes identificados, são instrumentos fundamentais para a redução do impacto da tuberculose na população. Os esquemas medicamentosos padronizados para cada situação, previamente testados e validados, possibilitam a cura da maior parte dos doentes. Atualmente, os maiores obstáculos ao controle desejado da doença incluem a infecção pelo HIV e o desenvolvimento de bacilos resistentes aos principais agentes quimioterápicos.

Historically, Brazil has had a major role in the organization of tuberculosis control activities. Since the beginning of the XX Century, using simple and effective standardized diagnostic and therapeutic strategies, based on an understanding of the pathophysiology of the disease and on the characteristics of the etiologic agent, the Tuberculosis Control Program has contributed to the control of the disease and to the organization of the public health system. Nationwide standardization of the treatment, along with the quarantee of free medicines to all patients, are fundamental tools for reducing the impact of the disease. A structured approach to care lead to the cure of the majority of the patients. At present, the major obstacles to the desired level of tuberculosis control include HIV infection and the development of Mycobacterium tuberculosis strains resistant to the most important anti tubercular drugs.

Tuberculose e silicose: epidemiologia, diagnóstico e quimioprofilaxia / Tuberculosis and silicosis: epidemiology, diagnosis and chemoprophylaxis

A silicose, a mais prevalente das pneumoconioses, é provocada pela inalação de partículas de sílica cristalina. Indivíduos expostos à sílica, com ou sem silicose, apresentam risco aumentado de tuberculose e de micobacterioses não-tuberculosas. O risco de silicóticos desenvolverem tuberculose em relação a controles sadios varia de 2,8 a 39 vezes, em conformidade com a gravidade da doença de base. Têm sido estudados diferentes esquemas de quimioprofilaxia para tuberculose em silicóticos, todos com eficácia semelhante e com redução final de risco para cerca da metade em relação ao uso de placebo. São, no entanto, esquemas de longa duração, o que, acrescido dos possíveis efeitos colaterais (particularmente hepatotoxicidade), podem prejudicar a aderência. As diretrizes atuais recomendam a realização de prova tuberculínica e, se positiva, a instituição de quimioprofilaxia. São vários os esquemas possíveis, tanto em termos de drogas quanto de duração. Nossa recomendação é de que se use isoniazida na dose de 300 mg/dia (ou 10 mg/kg/dia) por seis meses para os indivíduos com silicose ou sadios com exposição superior a 10 anos, se forem reatores fortes à prova tuberculínica (induração > 10 mm). São necessários, no entanto, novos estudos para que indicações, drogas, doses e duração da profilaxia sejam definidas mais apropriadamente.

Silicosis, the most prevalent of the pneumoconioses, is caused by inhalation of crystalline silica particles. Silica-exposed workers, with or without silicosis, are at increased risk for tuberculosis and nontuberculous mycobacteria-related diseases. The risk of a patient with silicosis developing tuberculosis is higher (2.8 to 39 times higher, depending on the severity of the silicosis) than that found for healthy controls. Various regimens for tuberculosis chemoprophylaxis in patients with silicosis have been studied, all of which present similar efficacy and overall risk reduction to about one half of that obtained with placebo. Long-term regimens have potential side effects (particularly hepatotoxicity). In addition, the use of such regimens can jeopardize adherence to treatment. The current guidelines recommend that tuberculin skin tests be performed, and, if positive, that chemoprophylaxis be instituted. There are several possible regimens, varying in terms of the drugs prescribed, as well as in terms of treatment duration. We recommend the use of isoniazid at 300 mg/day (or 10 mg/kg/day) for six months for patients with silicosis, as well as for healthy patients with periods of exposure to silica longer than 10 years and strongly positive tuberculin skin test results (induration > 10 mm). Nevertheless, further studies are necessary so that indications, drugs, doses and duration of chemoprophylaxis regimens can be more properly defined.