Practical Pharmacological Aspects of Drugs Used for the Treatment of Drug-Resistant Tuberculosis in Adults and Children / Aspectos farmacológicos prácticos de las drogas para el tratamiento de la tuberculosis drogorresistente en adultos y pediatría

ABSTRACT The emergence of resistant strains of Mycobacterium tuberculosis to multiple drugs and the difficulties of their diagnosis and treatment constitute a challenge to global public health. To face this challenge, new anti-tuberculosis drugs, such as bedaquiline, pretomanid, and delamanid, as well as replacement drugs, such as fluoroquinolones, linezolid and clofazimine, are used. Based on the evidence provided by multicenter studies, drugs associated with a better prognosis of drug-resistant tuberculosis have been discovered and, recently, a new classification has been proposed, as well as new totally oral regimens. In this review, we describe current treatment regimens and practical pharmacological aspects required when prescribing new drug-resistant tuberculosis treatment regimens.

RESUMEN La emergencia de cepas resistentes de Mycobacterium tuberculosis a múltiples drogas, las dificultades de su diagnóstico y tratamiento constituyen un desafío a la salud pública mundial. Para afrontar esta situación, se emplean nuevas drogas antituberculosis, como bedaquilina, pretomanid y delamanid, así como drogas repropuestas, como fluoroquinolonas, linezolid y clofazimina. Con base en la evidencia brindada por estudios multicéntricos, se han descubierto fármacos asociados a un mejor pronóstico de la tuberculosis drogorresistente y, recientemente, se ha propuesto una nueva clasificación, así como nuevos esquemas totalmente orales. En esta revisión, describimos los esquemas de tratamiento actuales y los aspectos farmacológicos prácticos necesarios a la hora de la prescripción de los nuevos regímenes de tratamiento de la tuberculosis drogorresistente.

Aspectos farmacológicos prácticos de las drogas para el tratamiento de la tuberculosis drogorresistente en adultos y pediatría / Practical Pharmacological Aspects of Drugs Used for the Treatment of Drug-Resistant Tuberculosis in Adults and Children

La emergencia de cepas resistentes de Mycobacterium tuberculosis a múltiples drogas, las dificultades de su diagnóstico y tratamiento constituyen un desafío a la salud pública mundial. Para afrontar esta situación, se emplean nuevas drogas antituberculosis, como bedaquilina, pretomanid y delamanid, así como drogas repropuestas, como fluoroquinolonas, linezolid y clofazimina. Con base en la evidencia brindada por estudios multicéntricos, se han descubierto fármacos asociados a un mejor pronóstico de la tuberculosis drogorresistente y, recientemente, se ha propuesto una nueva clasificación, así como nuevos esquemas totalmente orales. En esta revisión, describimos los esquemas de tratamiento actuales y los aspectos farmacológicos prácticos necesarios a la hora de la prescripción de los nuevos regímenes de tratamiento de la tuberculosis drogorresistente.

The emergence of resistant strains of Mycobacterium tuberculosis to multiple drugs and the difficulties of their diagnosis and treatment constitute a challenge to global public health. To face this challenge, new anti-tuberculosis drugs, such as bedaquiline, pretomanid, and delamanid, as well as replacement drugs, such as fluoroquinolones, linezolid and clofazimine, are used. Based on the evidence provided by multicenter studies, drugs associated with a better prognosis of drug-resistant tuberculosis have been discovered and, recently, a new classification has been proposed, as well as new totally oral regimens. In this review, we describe current treatment regimens and practi cal pharmacological aspects required when prescribing new drug-resistant tuberculosis treatment regimens.

Evaluación de una prueba de biología molecular para la identificación de Mycobacterium tuberculosis y sensibilidad a medicamentos de primera y segunda línea en un hospital de alta complejidad / Assessment of a molecular biology test for identification of Mycobacterium tuberculosis and first and second line anti tuberculosis drug susceptibility in a tertiary referral hospital

Objectivo: Evaluar la utilidad de Anyplex™II_MTB/MDR/XDR para la detección de Mycobacterium tuberculosis y sensibilidad a medicamentos de primera y segunda línea, además del impacto en la conducta terapéutica en pacientes con sospecha de tuberculosis pulmonar atendidos en una institución de alta complejidad de Medellín, 2014-2015. Material y Metodos: Estudio descriptivo de corte trasversal retrospectivo, de pacientes en cuyo proceso de atención se les realizó: baciloscopia, cultivo Ogawa- Kudoh, prueba molecular Anyplex™II_MTB/MDR/XDR y registro adecuado de historia clínica. Se realizaron medidas estadísticas descriptivas univariadas y de validez diagnóstica. Resultados: Se incluyeron 156 muestras de 154 pacientes, de los cuales el 65,6% fueron hombres. El diagnóstico de ingreso más frecuente fue el Virus de la Inmunodeficiencia Humana (VIH) (46,1%). La sensibilidad y especificidad global fue del 96,36% (IC 95%. 90,51 - 100) y 90,51% (IC 95%: 83,62 - 96,38) respectivamente. Se detectó algún tipo de resistencia en el 12,6%. El 57% de los resultados fueron tomados en cuenta por el médico tratante para definir conductas terapéuticas. Discusión: Se obtuvo una sensibilidad mayor respecto a otros estudios previos. Entre las limitaciones a destacar están: el diseño retrospectivo y la no disponibilidad de medios de cultivo líquido (MIGIT). Conclusión: Anyplex™II_MTB/MDR/XDR fue útil en la identificación del complejo M. tuberculosis y sensibilidad a medicamentos en muestra directa. El resultado de la prueba influyó en la toma de conductas terapéuticas en más de la mitad de los pacientes con resultados positivos. La implementación de nuevas ayudas diagnósticas, deben estar en concordancia con las necesidades en la atención del paciente.

Objective: To evaluate the utility of Anyplex™II_MTB/MDR/XDR for detection of Mycobacterium tuberculosis and drug susceptibility testing to first and second line, and the impact on the therapeutic approach, in patients with suspected pulmonary tuberculosis at a reference hospital. Medellin, 2014-2015. Material and Methods: This is a retrospective, descriptive, observational study in patients that during its hospitalization were studied by: ZN-smear, Ogawa-Kudoh culture, Anyplex™II_MTB/MDR/XDR assay and had an adequate record of medical history. Univariate descriptive statistics was performed and accuracy of the test was analyzed. Results: 156 samples of 154 patients were included, 65.6% were men. The most frequent diagnosis of admission was the Human Immunodeficiency Virus (46.1%). Sensitivity and specificity was 96.36% (95% CI 90.51 to 100) and 90.51% (95% CI 83.62 to 96.38) respectively. Some type of resistance was found in 12.6% of cases. 57% of the results were taken into account to make treatment decisions. Discussions: The sensitivity was higher than regarding in previous studies were obtained, comparing with cultures available at institution. Among limitations, this study was retrospective and the unavailability liquid culture medium (MIGIT). Conclusions: Anyplex™II_MTB/MDR/XDR was useful in the identification of mycobacteria and drug susceptibility in direct sample. The result influenced therapeutic decisions in more than half of patients with positive result. The implementation of new diagnostic aids must be in accordance with the needs in patient care.

Frecuencia de infecciones por Mycobacterium tuberculosis en el Hospital Luis Vernaza / Frequency of Mycobacterium tuberculosis infections in the Luis Vernaza Hospital

La tuberculosis (TB) es una enfermedad que representa un gran problema de salud pública en países en vías de desarrollo, como lo es el Ecuador, en el que, pese a una incidencia cada vez menor de casos reportados, sigue presente dentro de los grupos vulnerables de la población, como son los pacientes inmunodeprimidos, e incluso existen formas de difícil tratamiento como las multidrogorresistentes (TB-MDR). En este estudio presentamos la frecuencia de casos diagnosticados positivos a través del uso del kit Xpert MTB/RIF (GeneXpert®, Cepheid Innovation) y la frecuencia de casos resistentes a la rifampicina (Rifr). De este estudio, evidenciamos la aplicabilidad y utilidad del ensayo molecular para la detección de TB en muestras pulmonares y extrapulmonares, consiguiendo resultados de positividad del 13 %, y de ellos 7 % Rifr, resultados que superan los obtenidos con técnicas tradicionales de laboratorio.

The tuberculosis (TB),is a major Public Health Issue in the Developing Countries, like Ecuador, in which, in spite of the low incidence of reported infections, TB still exist among the vulnerable population groups, like the immune compromised patients, and also as the multidrug-resistant TB (MDR-TB). In this study, we present the frequency of positive diagnosed cases, using the Xpert MTB/RIF Assay kit (GeneXpert®, Cepheid Innovation) and the frequency of Rifampicin-resistant cases (Rifr). From this study, we evidenced the applicability and utility of this assay in the TB detection in pulmonary and extra-pulmonary samples: 13% were TB positive and 7 % of them were Rifr. These results surpass those obtained through traditional laboratory techniques.

Nuevas perspectivas terapéuticas en tuberculosis / New perspectives in tuberculosis treatment

To advance in the control and elimination of tuberculosis (TB) we must achieve a high level of effectiveness in the prevention of TB in populations infected by Mycobacterium tuberculosis. Latent TB prevention success with current therapies (single isoniazid or in combination with rifampicin) is close to 60%. We also must offer a high level of treatment success in first-line drugs sensitive TB patients. With currently available drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) treatment success should reach at least 95%. Drug side reactions together with the lengthen treatment of infection and disease (6 months) decrease the compliance to these therapies. In Multi-Drug-Resistant TB (MDR-TB), therapies are even longer (20 months according to WHO's recommendation) and much less tolerated, with rates of success under 50%. New trials for latent TB using rifapentin and isoniacid; combined fixed-dose offirst-line drugs in sensible TB, and the addition of new drugs (fluorquinolones, bedaquiline, delamanid and linezolid) in multi-drug resistant TB, together with shorter regimens of 12 months duration which include Clofazimine (experience in Cameroon with modification of a 9 months trial previously used in Bangladesh showing 89% cure) are discussed in this article.

Para el control y eliminación de la tuberculosis se debe lograr un alto grado de eficacia en la prevención del desarrollo de tuberculosis en la población infectada por Mycobacterium tuberculosis. Esta prevención, con las terapias actuales de la tuberculosis latente (isoniazida sola o combinada con rifampicina), es cercana al 60%. También debemos alcanzar una alta tasa de curación para los enfermos con tuberculosis sensible a los fármacos de primera línea (vírgenes a tratamiento). Con los fármacos actualmente disponibles (isoniazida, rifampicina, etambutol y pirazinamida) esta curación debería alcanzar a no menos del 95%. La regular tolerancia y reacciones colaterales de los fármacos y el largo tiempo que demandan las terapias de la infección y de la enfermedad (6 meses) atenta contra su adherencia. En el caso de la Tuberculosis Multi-Drogo-Resistente (TB-MDR), los tratamientos son aún más prolongados (20 meses según recomienda la OMS actualmente) y menos tolerados, siendo sus tasas de curación inferiores a 50%. Se analizan nuevos esquemas para el tratamiento de la tuberculosis latente usando rifapentina asociada a isoniacida; dosis fijas combinadas de fármacos de primera línea para tuberculosis sensibles, y asociación de fármacos antiguos y nuevos (fluoroquinolonas, bedaquilina, delamanid y linezolid) para el tratamiento de las tuberculosis multirresistentes. También se presentan nuevos esquemas acortados, de 12 meses de duración, que incluyen clofazimina (experiencia en Camerún con modificación del esquema de 9 meses usado previamente en Bangladesh, con tasas de curación de 89%).

Detección de la mutación S315T en el gen katg como estrategia para identificación de Mycobacterium tuberculosis resistente a isoniacida en un laboratorio de referencia / Detection of S315T mutation in the katg gene as a strategy for identification of isoniazid-resistant Mycobacterium tuberculosis in a reference laboratory

Introduction: The emergence of strains of Mycobacterium tuberculosis resistant to drugs is a public health problem. Aim: To characterize the resistance to isoniazid (INH) in M. tuberculosis. Methods: Phenotypic and genotypic methods were used to determine the contribution of mutations at 315 codon of katG gene to the phe-notypic expression of resistance. The analysis of susceptibility to antibiotics was performed by the proportional method of Canetti and nitrate reductase method.Genotypic analysis of INH resistance was performed by PCR-RFLP. Results: 193 strains of M. tuberculosis from patients with respiratory symptoms were analyzed. Nineteen (9.8%) strains resistant to INH were identified, of which 12 (63.2%) showed resistance to other drugs. Genotypic analysis allowed to detect the mutation S315T in the katG gene in 15 of 17 strains phenotypically resistant to INH, showing a sensitivity of 88.24%, 100% specificity, 100% positive predictive value, 92% negative predictive value and high concordance with phenotypic methods (kappa = 0.85 (p < 0.01). Conclusion: The S315T mutation in the katG gene is the predominant mechanism of INH resistance in our circulating strains. This feature could be used as a rapid diagnostic tool with potential to detect at least 88% of isoniazid resistant strains, with great impact on the therapeutic management of patients.

Introducción: La emergencia de cepas de Mycobacterium tuberculosis multi-resistentes a antimicrobianos constituye un problema de salud pública. Objetivo: Caracterizar la resistencia a isoniacida (HIN) en cepas de M. tuberculosis. Métodos: Se aplicaron métodos fenotí-picos y genotípicos para determinar la contribución de mutaciones en el codón 315 del gen katG a la expresión fenotípica de resistencia. El análisis fenotípico de susceptibilidad a antimicrobianos se realizó por métodos de las proporciones de Canetti y nitrato reductasa. El análisis genotípico se realizó por RPC-PLFR. Resultados: Se analizaron 193 cepas de M. tuberculosis aisladas de pacientes sintomáticos respiratorios. Se identificaron 19 (9,8%) cepas resistentes a HIN, de las cuales, 12 (63,2%) exhibieron resistencia a otros antimicrobianos. El análisis genotípico permitió detectar la mutación katG S315T en 15/17 cepas fenotípicamente resistentes a HIN, exhibiendo una sensibilidad de 88,24%, especificidad de 100%, valor predictor positivo de 100%, valor predictor negativo de 92% y alta concordancia al comparar con los métodos fenotípicos (kappa = 0,85 (p < 0,01). Conclusión: La mutación S315T en el gen katG representa un mecanismo de desarrollo de resistencia a HIN predominante en las cepas circulantes en nuestro medio, característica que podría ser utilizada como herramienta diagnóstica rápida para detectar al menos 88% de las cepas resistentes a isoniacida, con gran impacto en el manejo terapéutico de los pacientes.

Resistencia a fármacos antituberculosis en pacientes coinfectados con tuberculosis y virus de la inmunodeficiencia humana, en un hospital de referencia de 2007 a 2010 en Cali (Colombia) / Resistance to anti-tuberculosis drugs in patients co-infected with tuberculosis and human immunodeficiency virus from 2007 to 2010 in a reference hospital in Cali (Colombia)

Objetivo: La resistencia a los fármacos antituberculosis es de gran interés en salud pública. La coinfección con virus de la inmunodeficiencia humana (VIH) ha cambiado el comportamiento de dicha enfermedad. El objetivo de nuestro estudio es determinar la prevalencia de la resistencia a fármacos antituberculosis en pacientes coinfectados con tuberculosis (TB)/VIH. Método: Se realizó un estudio retrospectivo a partir de la revisión de los registros clínicos de casos nuevos y fracasos de TB coinfectados con VIH que consultaron a un centro de atención de nivel IV desde 2007 a 2010 y que contaban con pruebas de susceptibilidad. Resultados: Un 52% de los pacientes procedían de Santiago de Cali, y un 8%, de Buenaventura. La TB se presentó de forma extrapulmonar en el 80% de los pacientes. Del 48% de los sujetos que conocían su estado VIH previo al diagnóstico de la TB, el 40% estaban en terapia antirretroviral. El 16% de los casos eran fracasos, entre los cuales se detectó un caso multidrogorresistente. De los casos nuevos, se encontró monorresistencia a la isoniazida del 14%, y una resistencia total del 28%. Conclusiones: Se encontró una mayor prevalencia de resistencia a la esperada en población coinfectada TB/VIH; por lo que es necesario fortalecer el trabajo en equipo entre las entidades públicas y privadas para controlar dicha situación y fomentar el diagnóstico temprano y la realización de pruebas de susceptibilidad a fármacos antituberculosis.

Background: Resistance to anti-tuberculosis treatment is a matter of great interest in terms of public health. TB/HIV coinfection changed what was previously known about TB. Our study attempts to determine the prevalence of resistance to TB drugs among a local TB/HIV population. Methods: A retrospective study was conducted, which consisted of a review of the clinical records of new and relapsing cases of TB/HIV coinfected patients, with drug susceptibility tests, who attended an advanced medical care centre in Cali, Colombia, between 2007 and 2010. Results: Just over half (52%) of the patients were native from Cali, and 8% were from Buenaventura. An extra-pulmonary presentation of TB was seen in 80% of the subjects. Almost half (48%) were HIV positive before the diagnosis of tuberculosis was made, 40% of whom were on HAART treatment. Of the total cases, 16% were relapses, including one case of multi-drug resistant (MDR)-TB. Among the new cases, 14% were resistant to isoniazid only, making a total of 28% being resistant to this. Conclusions: There was a higher than expected prevalence of resistance in TB/HIV patients. There is an urgent need to improve the team work between public health organizations and private medical institutions, and this cooperation hould be of great priority, as it is a means to control and promote early diagnosis with drug-susceptibility tests.

Prevalence of XDR TB cases - A retrospective study from a tertiary care TB Hospital.

Background: The emergence of XDR –TB strains is a major roadblock in the successful implementation of TB control programmes. This further leads to high morbidity and mortality, especially in immuno-compromised patients. Identification and observation of resistance patterns of XDR-TB strains may help clinicians manage MDR-TB cases, the treatment line of which is expensive, time-taking and involves intake of toxic drugs with many side-effects. Our study is aimed to find out the prevalence of XDR-TB among the MDR-TB strains isolated in a tertiary care hospital. Material & Methods: The study population consisted of 223 patients of tuberculosis who were culture positive and Mycobacterium tuberculosis was resistant to Rifampicin and Isoniazid during January 2007 to December 2009. Each patient had submitted two sputum samples i.e. spot and morning. The identified Mycobacterium tuberculosis complex was subjected to drug sensitivity testing by first and second line drugs by proportion and absolute concentration methods as per standard procedure . Results : The results showed that 20.17% strains (45/223) were XDR-TB strains. Most of these strains showed resistance to four drug combination viz. KM, ETH, OFX & PAS (5.82%), KM & OFX (3.13%), OFX, KM and ETH (1.79%), 1.34% strains showed resistance to all the drugs i.e. pan resistance and other combinations in the remaining strains. Nearly 80% of the XDR-TB strains showed resistance to three or more drugs combination pattern. Conclusion: The multidrug resistant TB cases need urgent and timely sensitivity report for second line ATT drugs to help clinicians start proper drug combinations to treat MDR-TB patients.

Phenotypic and genotypic variant of MDR-Mycobacterium tuberculosis multiple isolates in the same tuberculosis episode, Rio de Janeiro, Brazil

Assuming that the IS6110-restriction fragment length polymorphism (RFLP) changes at a constant rate of 3.2 years, this methodology was applied to demonstrate, for the first time, variant patterns of Mycobacterium tuberculosis (MTB) in multiple isolates obtained at short time intervals from sputum and blood of an HIV+ patient with multiple admissions to the Emergency Room and to the multidrug-resistant tuberculosis (MDR-TB) Reference Center of a secondary-care hospital in Rio de Janeiro, Brazil. In sputum, the IS6110-RFLP appeared in isolates with two variant patterns with 10 and 13 IS6110 copies. However, blood presented only the pattern corresponding to 10 copies, suggesting compartmentalization. With regard to the exact match of 10 of 13 bands, this may be a subpopulation with the same clonal origin and this may be related to the IS6110 transposition. A susceptibility test demonstrated an MDR profile (INH R, RIF R, SM R, and EMB R), with the sputum isolate also exhibiting EMB S (R = resistant; S = sensitive). A gene mutation confirmed resistance only to streptomycin. There was agreement between the results of the phenotypic test and the clinical response to MDR-TB treatment, suggesting serious implications with regard to treatment administration based exclusively on molecular methods, and calling attention to the fact that more effective control strategies against the emergence of MDR strains must be implemented by the TB control program to prevent transmission of MDR-MTB strains at health facilities in areas highly endemic for TB.