Uso de N-acetilcisteína en pacientes que desarrollaron hepatitis por medicamentos antituberculosos: revisión sistemática / Use of N-acetylcysteine in patients with hepatitis by antitubercular agents: systematic review

RESUMEN El objetivo de esta revisión sistemática fue estimar la efectividad de la N-acetilcisteína en el tratamiento de hepatotoxicidad por antituberculosos; se incluyeron ensayos clínicos controlados aleatorizados, sin restricciones de idioma ni estado de publicación; se tuvieron en cuenta estudios publicados hasta diciembre de 2022. Búsqueda en bases de datos bibliográficas: CENTRAL, CINAHL, LILACS, MEDLINE, Pubmed, Scielo, Scopus y Web of Science; de 33 artículos encontrados, uno cumplió los criterios de inclusión con bajo riesgo de sesgos. El tiempo a mejoría bioquímica del grupo intervención fue 7,5 días (RIQ 5,5-11) y en el grupo placebo 8 (RIQ 5-13). El tiempo de estancia hospitalaria en el grupo intervención fue 9 días (RIQ 6-15) y en el grupo placebo 18 (RIQ 10-25). La mortalidad no difirió entre grupos y fue 14 %. No es posible concluir sobre el efecto terapéutico de la N-acetilcisteína en pacientes con DILI por antituberculosos, lo cual justifica realizar ensayos clínicos.

ABSTRACT The aim of this systematic review was to estimate the effectiveness of N-Acetylcysteine in the treatment of hepatotoxicity induced by antitubercular agents, we included randomized clinical trials, there was no language nor publication status restriction, published until December 2021. The searched databases were CENTRAL, CINAHL, LILACS, MEDLINE, Pubmed, Scielo, Scopus y Web of Science; out of 33 articles found, one of them met the inclusion criteria and had low bias risk. The time to biochemical resolution was 7,5 days (IQR 5,511) in the treatment arm, and 8 (IQR 5-13) in the placebo arm. Time of hospital stay was 9 days (IQR 6-15) in the treatment arm, and 18 (IQR 10-25) in the placebo arm. Mortality (14 %) didn't differ between groups. Further clinical trials may be needed to determine the therapeutic role of N-acetylcysteine in patients with drug-induced liver injury caused by antituberculous agents.

Incidence, Diagnosis and Treatment of Otorhinolaryngological, Head and Neck Tuberculosis: A Prospective Clinical Study.

Introduction Tuberculosis is a disease of diversified presentation. It affects almost all organs in the body, and otorhinolaryngological, head and neck involvement is not an exception. Objective To increase awareness about the different clinical presentations of otorhinolaryngological, head and neck tuberculosis, the techniques employed to diagnose it, and to assess the response to the treatment. Methods We conducted a prospective study of 114 patients who presented primarily with otorhinolaryngological, head and neck tuberculosis. Routine blood investigations, chest radiographs, the tuberculin test, and sputum examination for the presence of acid-fast bacilli were performed in all cases. Site-specific investigations were performed in relevant cases only. The patients were treated according to the antitubercular treatment (ATT) regimen recommended by the Indian Ministry of Health and Family Welfare's National Tuberculosis Elimination Program (NTEP), and they were followed up clinically two and six months after starting the ATT. Results Tubercular cervical lymphadenopathy was the most common clinical presentation (85.96%), followed by deep neck abscess (5.27%). Fine-needle aspiration cytology proved to be a reliable tool for the diagnosis of tubercular lymphadenopathy. Improvement at the end of 2 and 6 months of the ATT was observed in 90.35% and 96.50% of the cases respectively. Conclusion The diagnosis of otorhinolaryngological, head and neck tuberculosis requires a high index of clinical suspicion, and the ATT proved to be very effective in reducing the severity of the disease.

Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis.

BACKGROUND: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. METHODS: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. RESULTS: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. CONCLUSIONS: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Factors affecting successful antituberculosis treatment: a single-center experience

SUMMARY OBJECTIVE: The identification of factors that influence a favorable antituberculosis treatment outcome could be of great use for the promotion of specific health actions to increase the success rate. Thus, the objective of this study was to investigate the factors affecting successful antituberculosis treatment in patients seen at a reference service in the Western region of São Paulo State/Brazil. METHODS: A retrospective study was carried out from 2010 to 2016 based on the data obtained from the Notification Disease Information System of TB patients treated at a reference service in Brazil. The study included patients with treatment outcomes and excluded those from the penitentiary system or with resistant or multidrug-resistant TB. Patients were categorized as having a successful (cured) or unsuccessful (treatment default and death) treatment outcome. The association between TB treatment outcomes and social and clinical factors was analyzed. RESULTS: A total of 356 cases of TB were treated between 2010 and 2016. Among the cases, the majority were cured and the overall treatment success rate was 85.96%, with a range between 80.33% (2010) and 97.65% (2016). After the exclusion of resistant/multidrug-resistant TB, 348 patients were analyzed. In the final logistic regression model analysis, education less than 8 years (OR 1.66; p<0.0001) and people living with human immunodeficiency virus/acquired immunodeficiency syndrome (OR 0.23; p<0.0046) were found to be significantly related to an unfavorable treatment outcome. CONCLUSION: Low education and being a person living with human immunodeficiency virus/acquired immunodeficiency syndrome are vulnerability factors that can affect the successful outcome of antituberculosis treatment.

Tuberculose: principais fatores associados ao abandono do tratamento / Tuberculosis: main factors associated with treatment abandonment / Tuberculosis: principales factores asociados al abandono del tratamiento

O abandono do tratamento de tuberculose é uma questão relevante e preocu- pante na saúde pública mundial. Mediante uma revisão integrativa, esse estudo busca identificar os possíveis fatores que levam ao abandono do tratamento. Foi realizada pes- quisa em estudos indexados nas bases de dados: Biblioteca Virtual em Saúde (BVS) e Scientific Eletronic Library Online (SciELO), no período de 2017 a 2021, utilizando-se os seguintes descritores (DeCS): tuberculose, agente antituberculose e tuberculose pul- monar. Ao fim, foram selecionados onze estudos, publicados nos idiomas português, es- panhol e inglês. Os resultados mostraram que o abandono está relacionado a fatores de diversas esferas, com destaque para as esferas social, da saúde e a do próprio tratamento. Como perfil das pessoas dos casos de abandono, em geral, observou-se que elas são eco- nomicamente ativas, com faixa etária entre 15 e 49 anos, possuem baixa escolaridade, baixa renda e é comum que os usos abusivos de álcool e drogas sejam apresentados como comorbidades relevantes. Portanto, o trabalho evidenciou os principais fatores associados ao abandono do tratamento de tuberculose e a importância da participação de diferentes atores como forças que somarão para diminuir a ocorrência do problema em questão.

The abandonment of tuberculosis treatment is a relevant and worrisome issue in public health worldwide. Through an integrative review, this study seeks to iden- tify the possible factors that lead to treatment dropout. A search was carried out in studies indexed in the databases: Virtual Health Library (BVS) and Scientific Electronic Library Online (SciELO), from 2017 to 2021, using the following descriptors (DeCS): tuberculo- sis, antitubercular agentes and pulmonary tuberculosis. Finally, eleven studies, published in Portuguese, Spanish and English, were selected. The results showed that abandonment is related to factors from different spheres, with emphasis on the social, health and treat- ment spheres. As for the profile of people in cases of abandonment, in general, it was observed that they are economically active, aged between 15 and 49 years old, have low education, low income and it is common for alcohol and drug abuse to be presented as relevant comorbidities. Therefore, the work highlighted the main factors associated with the abandonment of tuberculosis treatment and the importance of the participation of dif- ferent actors as forces that will add to reduce the occurrence of the problem in question. KEYWORDS: Tuberculosis; Antitubercular Agents; Pulmonary Tuberculosis.

El abandono del tratamiento de la tuberculosis es un tema relevante y pre- ocupante en la salud pública mundial. A través de una revisión integradora, este estudio busca identificar los posibles factores que conducen al abandono del tratamiento. Se rea- lizó una búsqueda en estudios indexados en las bases de datos: Biblioteca Virtual en Salud (BVS) y Scientific Electronic Library Online (SciELO), de 2017 a 2021, utilizando los siguientes descriptores (DeCS): tuberculosis, agente antituberculoso y tuberculosis pul- monar. Al final, fueron seleccionados once estudios, publicados en portugués, español e inglés. Los resultados mostraron que el abandono está relacionado con factores en dife- rentes esferas, con énfasis en las esferas social, de salud y de tratamiento. Como perfil de las personas en casos de abandono, en general, se observó que son económicamente acti- vas, con edades entre 15 y 49 años, baja escolaridad, bajos ingresos y es común que el abuso de alcohol y drogas se presenten como comorbilidades relevantes. Por lo tanto, el trabajo destacó los principales factores asociados al abandono del tratamiento de la tuber- culosis y la importancia de la participación de diferentes actores como fuerzas que se sumarán para disminuir la ocurrencia del problema en cuestión.

Factors of abandonment of tuberculosis treatment in the public health network / Factores de abandono al tratamiento de la tuberculosis en la red pública de salud

ABSTRACT This study determines the factors of abandonment of tuberculosis treatment in the public health network of Cali, Colombia, during years 2016 to 2018. We conducted an operational case-control investigation including 224 patients with tuberculosis (112 abandoned treatment and 112 completed it). We found that treatment abandonment for tuberculosis is driven by factors related to the individuals and health services that facilitate non-adherence and drive them away from the care provided in medical institutions.

RESUMEN Este estudio determina los factores de abandono al tratamiento de la tuberculosis en la red pública de salud de Cali, Colombia, durante los años 2016 a 2018. Se realizó una investigación operativa de casos y controles en la que se incluyeron 224 pacientes con tuberculosis (112 abandonaron el tratamiento y 112 lograron completarlo). Se encuentra que el abandono del tratamiento para la tuberculosis está impulsado por factores relacionados con el individuo y los servicios de salud que facilitan la no adherencia y los alejan de la atención brindada en las instituciones médicas.

Incidence, Diagnosis and Treatment of Otorhinolaryngologicl, Head and Neck Tuberculosis: A Prospective Clinical Study

Abstract Introduction Tuberculosis is a disease of diversified presentation. It affects almost all organs in the body, and otorhinolaryngological, head and neck involvement is not an exception. Objective To increase awareness about the different clinical presentations of otorhinolaryngological, head and neck tuberculosis, the techniques employed to diagnose it, and to assess the response to the treatment. Methods We conducted a prospective study of 114 patients who presented primarily with otorhinolaryngological, head and neck tuberculosis. Routine blood investigations, chest radiographs, the tuberculin test, and sputum examination for the presence of acid-fast bacilli were performed in all cases. Site-specific investigations were performed in relevant cases only. The patients were treated according to the antitubercular treatment (ATT) regimen recommended by the Indian Ministry of Health and Family Welfare's National Tuberculosis Elimination Program (NTEP), and they were followed up clinically two and six months after starting the ATT. Results Tubercular cervical lymphadenopathy was the most common clinical presentation (85.96%), followed by deep neck abscess (5.27%). Fine-needle aspiration cytology proved to be a reliable tool for the diagnosis of tubercular lymphadenopathy. Improvement at the end of 2 and 6 months of the ATT was observed in 90.35% and 96.50% of the cases respectively. Conclusion The diagnosis of otorhinolaryngological, head and neck tuberculosis requires a high index of clinical suspicion, and the ATT proved to be very effective in reducing the severity of the disease.

Efficacy and safety of daily treatments for drug-susceptible pulmonary tuberculosis: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB). METHODS: A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals. KEY FINDINGS: Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists. CONCLUSION: The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.

Hepatotoxicidad por antituberculosos en pacientes con tuberculosis multidrogorresistente / Hepatotoxicity due to antitubercular drugs in multidrug-resistant tuberculosis patients

RESUMEN Objetivo: Describir las características clínicas de la injuria hepática inducida por antituberculosos (IHIA) en pacientes con tuberculosis multirresistente (MDR-TB). Materiales y métodos: Estudio retrospectivo de pacientes hospitalizados con TB-MDR e IHIA. Se utilizó los criterios de la DILI-Expert Working Group, y el instrumento de análisis de causalidad fue el RUCAM (Roussel Uclaf Causality Assessment Method). La asociación específica de la IHIA con un antituberculoso fue por un proceso de reexposición o suspensión y recuperación. Resultados: Reportamos 7 casos de MDR-TB e IHIA; la edad media (desviación estándar) fue de 39,1 (3,3) años. La media de la IHIA apareció después de 30,4 (27,70) días de iniciar el tratamiento. Tres (43,00 %) pacientes presentaron ictericia. En cuanto al patrón, en 4 (57,00 %) fue hepatocelular y en 3 (43,00 %), colestásico. En 4 pacientes, la IHIA fue leve, y moderada en 3. En todos los casos estuvo involucrada la pirazinamida (pirazinamida sola, 4; pirazinamida y etionamida, 1; pirazinamida, rifampicina e isoniazida, 1; pirazinamida y rifampicina, 1). La estancia hospitalaria media fue de 48,10 (48,70) días. Los promedios de fosfatasa alcalina (FA), alanina aminotransferasa (ALT) y gamma-glutamiltranspeptidasa (GGT) sérica fueron 2,40 (1,10), 7,9 (7,10) y 5,60 (3,70) veces el límite superior normal (NUL), respectivamente. La bilirrubina total media fue 2,30 (2,10), rango de 0,50 a 6,40 mg/dl. Como parte del esquema de alta del paciente, se administraron quinolonas a 7 pacientes (levofloxacino, 6; ofloxacino, 1), y en un paciente se agregó ácido amoxicilina/ácido clavulánico. Conclusiones: La IHIA en pacientes con TB-MDR puede aparecer después del primer mes de tratamiento. El patrón de lesión común fue hepatocelular, y la pirazinamida fue el antimicobacteriano involucrado con mayor frecuencia.

ABSTRACT Objective: To describe the clinical characteristics of drug-induced liver injury (DILI) in multidrug-resistant tuberculosis (MDR-TB) patients. Materials and methods: A retrospective study conducted in hospitalized patients with MDR-TB and DILI. The criteria of the DILI Expert Working Group were used for the diagnosis of DILI, and the RUCAM (Roussel Uclaf Causality Assessment Method) for the causality analysis. The specific association between DILI and antitubercular drugs was established by drug rechallenge or discontinuation and recovery. Results: Seven cases of MDR-TB and DILI are described in this research. The mean age (standard deviation) was 39.10 (3.30) years. Mean DILI occurred 30.40 (27.70) days after starting the treatment. Three (43.00 %) patients presented jaundice. Regarding the type of injury, four (57.00 %) had hepatocellular injury and three (43.00 %) cholestatic injury. Four patients showed mild DILI and three moderate DILI. All the patients had taken pyrazinamide (pyrazinamide alone: four patients; pyrazinamide and ethionamide: one patient; pyrazinamide, rifampin and isoniazid: one patient; pyrazinamide and rifampicin: one patient). The mean hospital stay was 48.10 (48.70) days. The mean serum alkaline phosphatase (AP), alanine aminotransferase (ALT) and gamma-glutamyl- transpeptidase (GGT) were 2.40 (1.10), 7.90 (7.10) and 5.60 (3.70) times the upper limit of normal (ULN), respectively. The mean total bilirubin was 2.30 (2.00), with a range of 0.50 to 6.40 mg/dl. As part of the discharge plan, quinolones were given to seven patients (levofloxacin: six patients; ofloxacin: one patient) and amoxicillin/clavulanic acid was added to one patient. Conclusions: MDR-TB patients may develop DILI after the first month of treatment. Hepatocellular injury was the most common type of liver injury, and pyrazinamide was the most frequently used antimycobacterial.

Increased diversity, fungal burden, and virulence of oral Candida spp. in patients undergoing anti-tuberculosis treatment.

Some studies have demonstrated a high prevalence of Candida species in patients with tuberculosis (TB). This is most likely due to long-term antimicrobial therapy. To date, no longitudinal studies addressed the effects of anti-TB treatment on the fungal burden and virulence of Candida spp. This study investigated the prevalence and virulence of Candida spp. in the oral cavity of 30 TB patients at different stages of treatment through a cohort study. These results were compared with those of 60 systemically healthy individuals in a cross-sectional study. Oral rinse samples from TB patients were collected before 45 and after 120 days of treatment. In the control group, the biological samples were collected only once. Candida spp. were identified by restriction fragment length polymorphism (RFLP) assays, and the following virulence factors were studied: phospholipase C and proteinase production, as well as Candida spp. biofilm and hyphae formation. The clinical diagnosis of TB and its treatment time were associated with the greater fungal burden (p < 0.0001), presence of non-albicans Candida (NAC) species (p = 0.0003), and increased virulence factors when compared with the Candida spp. isolated from systemically healthy individuals. The results showed that anti-TB treatment time was responsible for the increased fungal burden and isolation of NAC in TB patients (p = 0.0233). The increased prevalence, quantification, and virulence of Candida spp. isolated from the oral cavity of TB patients highlight the greater risk of oral lesions and cases of systemic dissemination in these patients.

Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis.

Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide (5 b) was particularly remarkable in this regard as it demonstrated MIC90 values below 0.28 µM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b, with excellent potency against the replicating and drug-resistant strains of M. tuberculosis.

Assessment of factors associated with potential drug-drug interactions in patients with tuberculosis and HIV/AIDS

Abstract INTRODUCTION: The concomitant use of antituberculosis and antiretroviral drugs, as well as drugs to treat other diseases, can cause drug-drug interactions. This study aimed to describe potential drug-drug interactions (pDDI) in patients with TB and HIV/AIDS co-infection, as well as to analyze possible associated factors. METHODS: This study was performed in a reference hospital for infectious and contagious diseases in the southeastern region of Brazil and evaluated adult patients co-infected with tuberculosis and HIV/AIDS. A cross-sectional study was conducted in which sociodemographic, clinical, and pharmacotherapeutic characteristics were assessed. The pDDI were identified using the Drug-Reax software. Association analysis was performed using either a chi-squared test or a Fisher's exact test. Correlation analysis was performed using the Spearman's coefficient. RESULTS: The study included 81 patients, of whom 77 (95.1%) were exposed to pDDI. The most frequent interactions were between antituberculosis and antiretroviral drugs, which can cause therapeutic ineffectiveness and major adverse reactions. A positive correlation was established between the number of associated diseases, the number of drugs used, and the number of pDDI. An association was identified between contraindicated and moderate pDDI with excessive polypharmacy and hospitalization. CONCLUSIONS: We found a high frequency of pDDI, especially among those hospitalized and those with excessive polypharmacy. These findings highlight the importance of pharmacists in the pharmacotherapeutic monitoring in these patients.

Efeitos adversos às drogas antituberculose: hepatotoxicidade / Adverse effects to antituberculosis drugs: hepatotoxicity

Objetivo: Verificar a frequência de efeitos adversos em pacientes em uso de drogas antituberculose de primeira linha, além dos fatores de risco associados aos efeitos adversos e à hepatotoxicidade. Métodos: Estudo transversal, envolvendo 196 pacientes portadores de tuberculose em Maceió (AL), de agosto de 2017 a junho de 2018. Os efeitos adversos foram classificados de acordo com o Manual de Recomendações para Controle da Tuberculose de 2011, do Ministério da Saúde, em efeitos menores (queixas gastrintestinais, cutâneos, articulares e neurológicos) e maiores (psicose e hepatotoxicidade). Os fatores de risco avaliados foram: idade superior a 40 anos, etilismo, sexo feminino, anemia, doença hepática anterior, diabetes e infecção por HIV. Resultados: Foram observados efeitos adversos às drogas antituberculose em 85 pacientes (43,4%); destes, 40,8% eram menores e 8,2%, maiores. Os mais frequentes foram distúrbios gastrintestinais (25,5%) e cutâneos (15,3%). Identificaram-se como fatores de risco anemia, diabetes e doença hepática anterior. Hepatotoxicidade foi diagnosticada em 15 pacientes (10,6%), dos quais 80% eram sintomáticos, sendo fatores de risco doença hepática anterior e diabetes. Houve suspensão da terapia em todos os casos de hepatotoxicidade com modificação do esquema em 80% dos casos. Conclusão: Demonstrou-se frequência elevada de efeitos adversos às drogas antituberculose, associada à doença hepática anterior e ao diabetes. A hepatotoxicidade representou o efeito adverso mais grave, responsável pela suspensão e pela adequação do esquema terapêutico.

Objective: To determine the adverse effects frequency in patients on first-line antituberculosis drugs, as well as the risk factors associated with adverse effects and hepatotoxicity. Methods: Cross-sectional study, involving 196 tuberculosis patients in Maceió (AL), from August 2017 to June 2018. Adverse effects were classified according to the Manual de Recomendações para Controle da Tuberculose, of the Brazilian Health Ministry, in minor effects (gastrointestinal, cutaneous, articular, neurologic complaints) and major effects (psychosis and hepatotoxicity). The risk factors evaluated were age over 40 years, alcoholism, female sex, anemia, previous hepatic disease, diabetes, and infection by HIV. Results: Adverse effects to the antituberculosis drugs were observed in 85 patients (43.4%) and, among those, 40.8% were minor and 8.2% were major effects. The most frequent were gastrointestinal (25.5%) and skin (15.3%) disorders. Risk factors were identified as anemia, diabetes, and previous hepatic disease. Hepatotoxicity was diagnosed in 15 patients (10.6%), from which 80% were symptomatic, with previous hepatic disease and diabetes being the risk factors. Therapy was discontinued in all cases of hepatotoxicity with regimen modification in 80% of cases. Conclusion: An elevated frequency of adverse effects to antituberculosis drugs was demonstrated. Hepatotoxicity represented the most severe adverse effect, being responsible for the discontinuation and adaptation of the therapeutic regimen.

Tuberculosis multidrogorresistente / Multidrug-resistant tuberculosis / Tuberculose multirresistente

La tuberculosis (TB) es la enfermedad bacteriana infecciosa que más muertes causa en el mundo, panorama que puede empeorar debido a la drogorresistencia. La tuberculosis multidrogoresistente (TB-MDR), es decir la que presenta resistencia simultánea a isoniazida y rifampicina (principales fármacos antituberculosos), tiene una relevancia particular: de los 10 millones de personas que desarrollan TB anualmente, 458.000 presentan TB-MDR con un pronóstico mucho peor que el de los infectados por cepas sensibles. En el presente artículo se exploran los principales aspectos de la TB-MDR, haciendo énfasis en su tratamiento

Tuberculosis (TB) is the worldwide leading infectious cause of death and, the emergence of drug-resistant tuberculosis can only worsen the scenario. Multidrug-Resistant Tuberculosis (TB-MDR) has proven resistant to both isoniazid and rifampin, the main antituberculous drugs. Out of 10 million people developing TB annually, 458 000 exhibit TB-MDR, having worse prognosis than those infected by sensitive strains. Recently, new drug-resistant TB treatment guidelines were issued both by the World Health Organization and health authorities in Colombia. The present paper explores the main aspects of TB-MDR emphasizing s sanitary authorities also, new guidelines were published by Colombian minister of health and social protection. In this paper, the main aspects of TB-MDR are explored, especially those related to its treatment.

Resistant tuberculosis in children under 15 years of age, Colombia 2010-2015 / Vigilancia por el laboratorio de la tuberculosis resistente en menores de 15 años, Colombia, 2010 a 2015.

Introduction: Tuberculosis in children is a recent transmission reflection in the community. It is estimated that every year one million children get sick in the world because of this. In Colombia, 291 cases were notified in 2015. Objective: To update the information obtained from the surveillance activities of the drugresistance laboratory in children younger than 15 years of age in Colombia between 2010 and 2015. Materials and methods: This was a cross-sectional retrospective study. We studied the variables of origin, gender, age, type of tuberculosis, and HIV status in sensitive and resistant cases. We classified them according to their treatment background between new and previously treated to analyze their first and second line drug resistance profile. Results: From the notified cases, 16.4 % had a sensitivity test. 50.6 % were women, the pulmonary form was present in 70.6% cases, and 1.4 % presented with tuberculosis/HIV coinfection. We studied 565 cases, from which 503 (89.1 %) were new, presenting with multidrug-resistant tuberculosis, and a global resistance of 3.9 % and 9.5 %, respectively. From them, 62 had been previously treated (10.9 %), with 4.8 % and 19.3 % multidrug resistance and global resistance, respectively. There was no evidence of statistically significant differences during the studied years. Extremely resistant tuberculosis in new cases was 9.0 %. Conclusions: It is necessary for the Ministerio de Salud y Protección Social and the Instituto Nacional de Salud to promote the use of faster and more sensitive diagnostic tests such as the molecular ones recommended by the World Health Organization.

Introducción. La tuberculosis en los niños es un reflejo de transmisión reciente en la comunidad. Se estima que en el mundo cada año un millón de niños enferma por esta causa; en Colombia se notificaron 291 casos en el 2015. Objetivo. Actualizar la información obtenida de las actividades de vigilancia por el laboratorio de la farmacorresistencia del bacilo Mycobacterium tuberculosis en menores de 15 años en Colombia entre el 2010 y el 2015. Materiales y métodos. Se llevó a cabo un estudio retrospectivo de corte transversal. Se estudiaron las variables de procedencia, sexo, edad, tipo de tuberculosis y estado de HIV en los casos sensibles y resistentes. Estos se clasificaron como caso nuevo sin tratamiento o caso previamente tratado para analizar el perfil de resistencia a fármacos de primera y segunda línea. Resultados. De los 3.440 casos notificados, en el 16,4 % se practicó la prueba de sensibilidad. El 50,6 % eran mujeres, la forma pulmonar se presentó en el 70,6 % y el 1,4 % presentó coinfección de tuberculosis y HIV. Se estudiaron 565 casos, de los cuales 503 (89,0 %) eran nuevos: el 3,9 % con tuberculosis multirresistente y el 9,5 % con resistencia global. Los previamente tratados fueron 62 (10,9 %), 4,8 % con multirresistencia y 19,3 % con resistencia global. No se evidenciaron diferencias estadísticamente significativas en los años estudiados. La proporción de tuberculosis extremadamente resistente en los casos nuevos evaluados fue de 9,0 %. Conclusiones. Es necesario que el Ministerio de Salud y Protección Social y el Instituto Nacional de Salud promuevan el uso de pruebas diagnósticas rápidas y muy sensibles, como las moleculares recomendadas por la Organización Mundial de la Salud.

Vigilancia por el laboratorio de la tuberculosis resistente en menores de 15 años, Colombia, 2010 a 2015 / Resistant tuberculosis in children under 15 years of age, Colombia 2010-2015

Resumen Introducción. La tuberculosis en los niños es un reflejo de transmisión reciente en la comunidad. Se estima que en el mundo cada año un millón de niños enferma por esta causa; en Colombia se notificaron 291 casos en el 2015. Objetivo. Actualizar la información obtenida de las actividades de vigilancia por el laboratorio de la farmacorresistencia del bacilo Mycobacterium tuberculosis en menores de 15 años en Colombia entre el 2010 y el 2015. Materiales y métodos. Se llevó a cabo un estudio retrospectivo de corte transversal. Se estudiaron las variables de procedencia, sexo, edad, tipo de tuberculosis y estado de HIV en los casos sensibles y resistentes. Estos se clasificaron como caso nuevo sin tratamiento o caso previamente tratado para analizar el perfil de resistencia a fármacos de primera y segunda línea. Resultados. De los 3.440 casos notificados, en el 16,4 % se practicó la prueba de sensibilidad. El 50,6 % eran mujeres, la forma pulmonar se presentó en el 70,6 % y el 1,4 % presentó coinfección de tuberculosis y HIV. Se estudiaron 565 casos, de los cuales 503 (89,0 %) eran nuevos: el 3,9 % con tuberculosis multirresistente y el 9,5 % con resistencia global. Los previamente tratados fueron 62 (10,9 %), 4,8 % con multirresistencia y 19,3 % con resistencia global. No se evidenciaron diferencias estadísticamente significativas en los años estudiados. La proporción de tuberculosis extremadamente resistente en los casos nuevos evaluados fue de 9,0 %. Conclusiones. Es necesario que el Ministerio de Salud y Protección Social y el Instituto Nacional de Salud promuevan el uso de pruebas diagnósticas rápidas y muy sensibles, como las moleculares recomendadas por la Organización Mundial de la Salud.

Abstract Introduction: Tuberculosis in children is a recent transmission reflection in the community. It is estimated that every year one million children get sick in the world because of this. In Colombia, 291 cases were notified in 2015. Objective: To update the information obtained from the surveillance activities of the drug-resistance laboratory in children younger than 15 years of age in Colombia between 2010 and 2015. Materials and methods: This was a cross-sectional retrospective study. We studied the variables of origin, gender, age, type of tuberculosis, and HIV status in sensitive and resistant cases. We classified them according to their treatment background between new and previously treated to analyze their first and second line drug resistance profile. Results: From the notified cases, 16.4 % had a sensitivity test. 50.6 % were women, the pulmonary form was present in 70.6% cases, and 1.4 % presented with tuberculosis/HIV coinfection. We studied 565 cases, from which 503 (89.1 %) were new, presenting with multidrug-resistant tuberculosis, and a global resistance of 3.9 % and 9.5 %, respectively. From them, 62 had been previously treated (10.9 %), with 4.8 % and 19.3 % multidrug resistance and global resistance, respectively. There was no evidence of statistically significant differences during the studied years. Extremely resistant tuberculosis in new cases was 9.0 %. Conclusions: It is necessary for the Ministerio de Salud y Protección Social and the Instituto Nacional de Salud to promote the use of faster and more sensitive diagnostic tests such as the molecular ones recommended by the World Health Organization.

Abdominal tuberculosis in renal transplant recipient. Presentation of a case and literature review / Tuberculosis abdominal en receptor de trasplante renal. Presentación de un caso y revisión de literatura

Background: Kidney transplantation presents a susceptible point, and is related to infections; tuberculosis is a common and endemic etiology in a country like Mexico, where the most frequent presentation is the respiratory condition, the extrapulmonary is extremely rare and it is derived from immunosuppression conditions. Case report: 33-year-old man with kidney disease of undetermined etiology, kidney transplant in 2003 (donor mother) with adequate evolution; presented with chronic graft nephropathy, with baseline creatinine of 1.8 mg / dL, immunosuppression with prednisone 10 mg every 24 hours, mycophenolate mofetil 500 mg every 8 hours and ciclosporin 100 mg every 12 hours; surgical intervention was performed due to acute abdomen, appendectomy and omentectomy with histopathological finding of tuberculosis, Dotbal, antiproliferative in suspension was started and decrease of calcineurin inhibitor. Adequate kidney function was recovered and maintained as well as control of the infectious disease during the maintenance period. Conclusions: The management of immunosuppression is vital to find the right dose to avoid rejection and allow an immune response to infection, together with antimicrobial treatment.

Introducción: el trasplante renal presenta un punto susceptible y está relacionado con las infecciones; siendo la tuberculosis una etiología común y más en un país endémico como lo es México, siendo la forma de presentación más frecuente la afección respiratoria, lo extrapulmonar es sumamente raro derivado de condiciones de inmunosupresión. Caso clínico: hombre de 33 años de edad, con enfermedad renal de etiología no determinada, trasplantado renal en el año 2003 (madre donadora) con adecuada evolución; se presentó con nefropatía crónica del injerto, con creatinina basal de 1.8 mg/dL, inmunosupresión con prednisona 10 mg cada 24 horas, micofenolato de mofetilo 500 mg cada 8 horas y ciclosporina 100 mg cada 12 horas; se intervino quirúrgicamente por cuadro de abdomen agudo, se realizó apendicetomía y omentectomía con hallazgo histopatológico de tuberculosis, se inició Dotbal, antiproliferativo en suspensión y disminución del inhibidor de calcineurina. Se recuperó y mantuvo adecuada función renal y control del cuadro infeccioso, en periodo de mantenimiento. Conclusiones: el manejo de la inmunosupresión es vital para encontrar la dosis adecuada evitando rechazo, así como permitir una respuesta inmunológica ante la infección, junto con el tratamiento antimicrobiano.

Reação em cadeia da polimerase como determinante para o diagnóstico de tuberculose cutânea / Polymerase chain reaction as a cutaneous tuberculosis diagnostic determinant

Relatamos um caso de tuberculose cutânea do tipo eritema indurado de Bazin em paciente do sexo feminino, 26 anos de idade, com presença de úlceras e nódulos infiltrados, eritêmato- ferruginosos, com áreas de supuração e de aspecto endurecido em região de membro inferior esquerdo. O diagnóstico foi feito por meio da detecção de DNA micobacteriano nas lesões cutâneas por meio do método de reação em cadeia da polimerase. Realizou-se tratamento com pirazinamida, rifampicina, isoniazida e etambutol, obtendo-se melhora clínica e resolução das lesões cutâneas da paciente.(AU)

We report a clinical case of Erythema Induratum of Bazin cutaneous tuberculosis on a 26-year-old female patient that presented with ulcers and erythematous-ferruginous infiltrated nodules, with hardened suppuration areas on left lower limb. Diagnosis was made through mycobacterian DNA detection on cutaneous lesions using the chain polymerase reaction method. The treatment was carried out with Pyrazinamide, Rifampicin, Isoniazid and ethambutol, which provided clinical improvement and resolution of the patient's cutaneous lesions.(AU)

New and repurposed drugs to treat multidrug- and extensively drug-resistant tuberculosis / Novos fármacos e fármacos repropostos para o tratamento da tuberculose multirresistente e extensivamente resistente

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.

RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a "praga branca", e resultados promissores estão sendo relatados.

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

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

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

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