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

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

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

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.

Tuberculosis in the paediatric age group: a reflection on transmission.

INTRODUCTION: Paediatric tuberculosis (TB) disease continues to be a challenge. Difficulties in its diagnosis and limited experience on its treatment in children are some of the reasons to consider the need for specialized paediatric TB centres and to prioritize children in tuberculosis control programmes, particularly in low-incidence countries. We describe the paediatric tuberculosis cases managed in a specialized paediatric outpatient TB centre. PATIENTS AND METHODS: We conducted a retrospective analysis of epidemiological and clinical data on TB cases in patients aged less than 18 years in the period ranging from January 2007 to June 2017. RESULTS: We identified 46 cases of TB. The median age of the patients was 5 years (IQR, 1.75-13.25). Thirty cases (65.2%) were identified through screening following exposure to TB. Thirty-six children (78%) presented with a median duration of symptoms during 2 weeks, the most frequent being cough (54%) and fever (48%). The findings of the chest radiograph were abnormal in 73.9% of patients, and a CT scan was performed in 82.2%, the findings of which contributed significantly to the decision to treat in 85.3%. Despite collection of different microbiological specimens, diagnostic confirmation was possible in only 12 cases (26.1%). The results of culture and/or nucleic acid amplification tests were positive in 33.3% of samples of sputum, 28.1% of bronchoalveolar lavage and 12.9% of gastric aspirates. The most frequent diagnosis was pulmonary TB (n=31), followed by pleuropulmonary TB (n=6), lymph node disease (n=3), uveitis (n=2), bone tuberculosis, disseminated TB, cerebellar tuberculoma and erythema nodosum (each n=1). CONCLUSIONS: Tuberculosis in children is an epidemiological indicator of recent transmission of Mycobacterium tuberculosis in the community. Efforts must be made to collect microbiological specimens before initiating treatment whenever possible. Management by an experienced paediatrics team allows an accurate diagnosis even when microbiologic confirmation is not possible.

Tuberculosis en la edad pediátrica: una reflexión sobre la transmisión / Tuberculosis in the paediatric age group: A reflection on transmission

Introducción: La tuberculosis (TB) continúa siendo un reto en la edad pediátrica. Las dificultades en su diagnóstico y la escasa experiencia en su tratamiento en la infancia y adolescencia son algunas de las razones para considerar la necesidad de centros especializados en tuberculosis pediátrica y priorizar a la población pediátrica en los programas de control de tuberculosis, especialmente en países de baja incidencia. Descripción de casos de tuberculosis pediátrica tratados en un centro ambulatorio especializado en TB. Pacientes y métodos: Análisis retrospectivo de datos epidemiológicos y clínicos de casos de TB en pacientes menores de 18 años en el período de enero de 2007 a junio de 2017. Resultados: Se identificaron 46 casos de TB, con una edad media de 5 años (RIC: 1,75-13,25). Treinta casos (65,2%) se identificaron en contexto de cribado por exposición conocida a la TB. En 36 pacientes (78%), la duración mediana de los síntomas fue de 2 semanas, y los síntomas más frecuentes fueron tos (54%) y fiebre (48%). La radiografía de tórax fue anormal en el 73,9% de los pacientes, y se realizó TC en el 82,2%, cuyos hallazgos proporcionaron claves importantes para la decisión de tratar en el 85,3%. A pesar de recogerse distintas muestras microbiológicas, solo se confirmó el diagnóstico en 12 casos (26,1%). Las pruebas de cultivo y/o de amplificación de ácidos nucleicos fueron positivas en el 33,3% de las muestras de esputo, el 28,1% de las de lavado broncoalveolar y el 12,9% de las de aspirado gástrico. La TB pulmonar fue el diagnóstico más frecuente (n=31), seguida de la TB pleural (n=6), la linfadenitis tuberculosa (n=3), la uveítis (n=2), la TB ósea, la TB diseminada, la TB cerebelar y el eritema nudoso (cada uno, n=1). (AU)

Introduction: paediatric tuberculosis (TB) disease continues to be challenge. Difficulties in its diagnosis and limited experience on its treatment in children are some of the reasons to consider the need for specialized paediatric TB centres and to prioritize children in tuberculosis control programmes, particularly in low-incidence countries. We describe the paediatric tuberculosis cases managed in a specialized paediatric outpatient TB centre. Patients and methods: We conducted a retrospective analysis of epidemiological and clinical data on TB cases in patients aged less than 18 years in the period ranging from January 2007 to June 2017. Results: We identified 46 cases of TB. The median age of the patients was 5 years (IQR: 1.75-13.25). Thirty cases (65.2%) were identified through screening following exposure to TB. Thirty-six children (78%) presented with a median duration of symptoms was 2 weeks, the most frequent being cough (54%) and fever (48%). The findings of the chest radiograph were abnormal in 73.9% of patients, and a CT scan was performed in 82.2%, the findings of which contributed significantly to the decision to treat in 85.3%. Despite collection of different microbiological specimens, diagnostic confirmation was possible in only 12 cases (26.1%). The results of culture and/or nucleic acid amplification tests were positive in 33.3% of samples of sputum, 28.1% of bronchoalveolar lavage and 12.9% of gastric aspirates. The most frequent diagnosis was pulmonary TB (n=31), followed by pleuropulmonary TB (n=6), lymph node disease (n=3), uveitis (n=2), bone tuberculosis, disseminated TB, cerebellar tuberculoma and erythema nodosum (each n=1). (AU)

Treatment of pulmonary and extrapulmonary tuberculosis. / Tratamiento de la enfermedad tuberculosa pulmonar y extrapulmonar.

The purpose of tuberculosis treatment is twofold: to provide an individual benefit centred on healing the patient with TB, and to provide a collective benefit to the community in which the patient resides. The different treatment regimens for tuberculosis sensitive to first-line antituberculosis drugs as well as resistant tuberculosis are examined and the peculiarities in the management of pulmonary and extrapulmonary tuberculosis are discussed.

[Recommendations for the preparation and administration of antituberculosis drugs in children. Second phase of the Magistral Project of the Spanish Network for the Study of Paediatric Tuberculosis (pTBred)]. / Recomendaciones para la elaboración y administración de fármacos antituberculosos en niños. Segunda fase del Proyecto Magistral de la Red Española de Estudio de la Tuberculosis Pediátrica (pTBred).

The Spanish Network for the Study of Paediatric Tuberculosis has shown a lack of national consensus on the treatment of tuberculosis in children, partly due to the unavailability of paediatric presentations of antituberculosis drugs. The harmonisation of tuberculosis treatment in children is a priority in Spain. A joint action is proposed by a group of Spanish experts in childhood tuberculosis and in the area of Paediatric Pharmacology. To this end, a pTBred-led workgroup of members from five scientific bodies has been created. Drug pharmaceutical compounding in oral suspensions or oral solutions are recommended as follows: isoniazid 50mg/mL, pyrazinamide 100mg/mL, and ethambutol 50mg/mL. Raw materials, period of validity, and storage conditions are specified. Recommendations for the use of fixed-dose combination drugs are also established. If oral solutions/suspensions or fixed-dose combination drugs are not appropriate, the use of crushed tablets is recommended. Adherence to treatment and optimal dosing of antituberculosis drugs are critical in the control and eradication of TB. This multidisciplinary document provides an opportunity to promote the appropriate treatment of paediatric tuberculosis in Spain, and should become a useful tool for paediatricians and pharmacists.

[The challenge of administering anti-tuberculosis treatment in infants and pre-school children. pTBred Magistral Project]. / El reto de la administración de antituberculosos en lactantes y preescolares. Proyecto Magistral de pTBred.

INTRODUCTION: There are no paediatric formulations of anti-tuberculous drugs in Spain, with the only exception being rifampicin. Some paediatricians often prescribe composite formulations (CF), while others prefer to give crushed tablets. Nevertheless, there is no consensus in this regard, or any pharmacokinetic studies validating these procedures. In this situation, the Spanish Network for the Study of Paediatric Tuberculosis (pTBred) has launched the Magistral Project, which has as its first phase aims to analyse the desirability of developing child-friendly pharmaceutical formulations and other aspects regarding the anti-tuberculous drug prescription in children. MATERIAL AND METHODS: A cross-sectional, multicentre, nationwide study was conducted, based on an online questionnaire sent to members of pTBred between February and March 2015. RESULTS: Fifty-four responses from 67 consulted institutions were received. Most of the respondents reported prescribing crushed tablets. A significant number of those surveyed, although being fewer, prescribe CF, for which availability varies widely among institutions. Eighty-three percent replied that it would be essential to have fixed dose combinations of anti-tuberculous drugs, specifically adapted to paediatric doses and administered by CF or tablets. Among the surveyed institutions, differences were found in the management of latent tuberculosis infection, in the use of directly observed therapy, and in the monitoring of adverse events. CONCLUSIONS: Our survey reveals great diversity in anti-tuberculous drug prescription in children, due to the lack of suitable infant formulations, which could have an impact on treatment adherence and outcomes. pTBred intends to develop a pioneering and useful consensus document on the management of anti-tuberculous medication in children.

[The Spanish AIDS Study Group and Spanish National AIDS Plan (GESIDA/Secretaría del Plan Nacional sobre el Sida) recommendations for the treatment of tuberculosis in HIV-infected individuals (Updated January 2013)]. / Recomendaciones de GESIDA/Secretaría del Plan Nacional sobre el Sida para el tratamiento de la tuberculosis en adultos infectados por el virus de la inmunodeficiencia humana (actualización enero de 2013).

This consensus document was prepared by an expert panel of the Grupo de Estudio de Sida (GESIDA [Spanish AIDS Study Group]) and the Plan Nacional sobre el Sida (PNS [Spanish National AIDS Plan]). The document updates current guidelines on the treatment of tuberculosis (TB) in HIV-infected individuals contained in the guidelines on the treatment of opportunistic infections published by GESIDA and PNS in 2008. The document aims to facilitate the management and treatment of HIV-infected patients with TB in Spain, and includes specific sections and recommendations on the treatment of drug-sensitive TB, multidrug-resistant TB, and extensively drug-resistant TB, in this population. The consensus guidelines also make recommendations on the treatment of HIV-infected patients with TB in special situations, such as chronic liver disease, pregnancy, kidney failure, and transplantation. Recommendations are made on the timing and initial regimens of antiretroviral therapy in patients with TB, and on immune reconstitution syndrome in HIV-infected patients with TB who are receiving antiretroviral therapy. The document does not cover the diagnosis of TB, diagnosis/treatment of latent TB, or treatment of TB in children. The quality of the evidence was evaluated and the recommendations graded using the approach of the Grading of Recommendations Assessment, Development and Evaluation Working Group.

Características clínicas y sociodemográficas de los casos con tuberculosis resistente en el municipio de Armenia, Quindío (Colombia) / Clinical and socio-demographic characteristics of tuberculosis with antimicrobial resistance in Armenia, Quindio (Colombia)

Objetivo: Analizar los factores sociodemográficos y clínicos de los pacientes con diagnóstico de tuberculosis resistente en el municipio de Armenia durante el período 2006-2009. Métodos: Se realizó un estudio descriptivo y retrospectivo con base en la notificación de pacientes con tuberculosis resistentes durante el período de estudio. Los datos fueron tomados de los registros consignados en las fichas de notificación y las tarjetas individuales de tratamiento categoría IV. Resultados: Entre 2006 y 2009, 678 pacientes ingresaron en el programa de control de la tuberculosis. De ellos, 14 casos (2,0%) fueron resistentes al menos a un medicamento, y entre estos, 7 (50%) fueron multirresistentes. El 21% estuvo asociado a infección por virus de la inmunodeficiencia humana. La tasa de fallecimientos en pacientes con tuberculosis con farmacorresistencia múltiple fue del 71%. Se encontró amplificación de la resistencia en 2 casos, quienes presentaron deterioro en el estado de salud y deceso. Conclusión: La situación en Armenia de resistencia a antituberculosos es de proporción similar a la del resto del país. Se encontraron factores de riesgo conocidos en los casos de resistencia (coinfección con virus de la inmunodeficiencia humana, farmacodependencia, abandono social) en la mayoría de casos, pero también de resistencia primaria y sin factores de riesgo con farmacorresistencia múltiple y una alta mortalidad, lo que llama la atención para mejorar la vigilancia y el control de los casos en tratamiento en la ciudad.

Objective: To analyze the socio-demographic and clinical diagnosis of patients with resistant tuberculosis in the municipality of Armenia in the period 2006-2009. Methods: We performed a retrospective descriptive study based on the notification of patients with resistant tuberculosis during the study period, data were taken from registrations under notification forms and individual treatment cards category IV. Results: 678 patients were admitted to the program of tuberculosis control between 2006 and 2009, 14 cases (2,0%) were resistant to at least one drug and from these cases 7 were multidrug resistant (MDR). In 21% of cases there was co-infection with HIV. The death rate in patients with MDR-TB was 71%. Amplification in resistance was observed in two cases which lead to further deterioration in the health status and death. Conclusion: Armenia has levels of resistance to anti tuberculosis drugs similar to the reported in the rest of Colombia. We found factors already know to be associated with resistance (drug addiction, social abandon, HIV co infection) but there were also cases without these factors and with primary MDR and high mortality, therefore is urgent to improve the public health measures for cases under treatment in this city.