d Ethionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in the Mycobacterium tuberculosis population. ETH resistance in M. tuberculosis is phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in the inhA promoter and in the following genes: katG, ethA, ethR, mshA, ndh, and inhA. We sequenced the above genes in 64 M. tuberculosis isolates (n ؍ 57 ETH-resistant MDR-TB isolates; n ؍ 3 ETH-susceptible MDR-TB isolates; and n ؍ 4 fully susceptible isolates). Each isolate was tested for susceptibility to first-and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% in katG, 72% in ethA, 45.6% in mshA, 8.7% in ndh, and 33.3% in inhA or its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations in katG; one had a mutation in ethA, and another, in mshA and inhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations in mshA gene unrelated to the resistance. Mutations not previously reported were found in the ethA, mshA, katG, and ndh genes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in the M. tuberculosis isolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB. E thionamide (ETH), a structural analog of isoniazid (INH), is a second-line drug used in the treatment of multidrug-resistant tuberculosis (MDR-TB) (1). Both ETH and INH are classified as prodrugs that are activated by different mycobacterial enzymes. INH is activated by the katG-encoded catalase-peroxidase, and ETH is activated by the ethA-encoded monooxygenase (2, 3). The activated INH and ETH drugs share the same molecular target, i.e., the NADH-dependent enoyl-acyl carrier protein reductase InhA, which is involved in the long-chain mycolic acid biosynthesis pathway (4). Therefore, the cross-resistance between INH and ETH can be detected in Mycobacterium tuberculosis clinical isolates in the case of mutations affecting the common target, which may occur when patients have previously been treated with INH and not with ETH (5). The frequency of cross-resistance differs between countries: 100% in Korea (6), 95.12% in Argentina (7), 94% in Brazil (8), 62% in France (9), and 13.8% in Thailand (10).Resistance to INH and ETH is mainly due to the chromosomal mutations. The mutation-carrying genes, such as those encoding the enzymes KatG (11,12) and EthA (13,14), are associated with individual resistance to INH and ETH, respectively. Mutations at the inhA promoter region or inhA gene result in the ove...
Contribución de los autores:Johana Rueda: ejecución del proyecto, análisis e interpretación de los datos y redacción del manuscrito Teresa Realpe: análisis e interpretación de los datos Gloria Mejía y Elsa Zapata: aplicación de la metodología Jaime Robledo: diseño y gestión del proyecto Todos los autores participaron en la asesoría, la revisión y la aprobación del artículo. Introducción. Una parte de los aislamientos de Mycobacterium tuberculosis multirresistente también presenta resistencia a la etionamida. Es importante determinar si la resistencia a la isoniacida es independiente o se cruza con la resistencia a la etionamida, ya que si sucede lo segundo habría que reevaluar el tratamiento antituberculoso de segunda línea. La prueba molecular GenoType MTBDRplus ® detecta las mutaciones asociadas con la resistencia a isoniacida y podría detectar la resistencia cruzada a la etionamida. Objetivo. Evaluar la prueba GenoType MTBDRplus ® y comparar su desempeño con el de la secuenciación, en la detección de mutaciones en el gen katG y en el promotor inhA en aislamientos clínicos de M. tuberculosis multirresistente. Materiales y métodos. Se utilizaron el estuche comercial GenoType MTBDRplus 1.0 ® y la secuenciación para evaluar mutaciones en el gen katG y en el promotor inhA en 30 aislamientos de M. tuberculosis multirresistente con resistencia a la etionamida. La cepa de laboratorio H37Rv y tres aislamientos sensibles a los medicamentos de primera línea, sirvieron de control. Resultados. Al comparar los resultados de la secuenciación y de la prueba GenoType MTBDRplus ® , el índice kappa fue de 1. Todos los aislamientos resistentes a la isoniacida y la etionamida tenían las mutaciones detectadas con la prueba GenoTypeMTBDRplus ® en el gen katG, y 40 % de ellos, las detectadas en el promotor inhA. Mediante secuenciación se encontraron, además, mutaciones en katG en posiciones diferentes a las detectadas por la prueba GenoType MTBDRplus ® . GenoType Conclusión. La prueba GenoTypeMTBDRplus® tiene la capacidad de detectar rápidamente la resistencia a isoniacida. Además, los resultados del estudio sugieren que también podría utilizarse como prueba de tamización para detectar la resistencia cruzada a etionamida.Palabras clave: Mycobacterium tuberculosis, tuberculosis resistente a múltiples medicamentos, etionamida, isoniacida, análisis de secuencia, mutación.
Introduction: Multidrug-resistant tuberculosis treatment is effective in 50% of patients due to several factors including antibiotic susceptibility of the microorganism, adverse treatment reactions, social factors, and associated comorbidities.Objectives: In this study, we describe the demographics, clinical characteristics, and factors associated with treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) patients in Medellín, Colombia.Materials and methods: We conducted a retrospective analysis using data from patients diagnosed with MDR-TB attending Hospital La María in Medellín, Colombia, for treatment between 2010 and 2015. Patients were categorized as having successful (cured) or poor (failure, lost to follow-up, and death) treatment outcomes. Associations between demographic, clinical factors, laboratory results, treatment outcomes, and follow-up information were evaluated by univariate, multivariate, and multiple correspondence analyses.Results: Of the 128 patients with MDR-TB, 77 (60%) had successful outcomes. Of those with poor outcomes, 26 were lost to follow-up, 15 died, and 10 were treatment failures. Irregular treatment, the presence of comorbidities, and positive cultures after more than two months of treatment were associated with poor outcomes compared to successful ones (p<0.05 for all). The multiple correspondence analyses grouped patients who were lost to follow-up, had HIV, and drug addiction, as well as patients with treatment failure, irregular treatment, and chronic obstructive pulmonary disease.Conclusion: The recognition of factors affecting treatment is essential and was associated with treatment outcomes in this series of patients. Early identification of these factors should increase the rates of treatment success and contribute to MDR-TB control.
BackgroundAfter over a decade of use of biological agents (BA), is widely known to be effective in the treatment of Rheumatoid Arthritis (RA). With the increasingly widespread use of these drugs, a thorough knowledge of their long-term behavior is fundamental.ObjectivesTo evaluate survival of BA, as well as causes of discontinuation, in a cohort of elderly patients with RA.MethodsWe conducted a retrospective longitudinal observational study of 13 years follow-up. Subjects: RA patients followed in our out-patient clinic, which started treatment with BA at ages over 65 years old, between January 1st 2000 and November 18th 2013. Primary endpoint: discontinuation of BA (etanercept (ETN), golimumab (GOLI), certolizumab (CTZ), infliximab (IFX) and adalimumab (ADA); other biological: rituximab (RTX), abatacept (Fold), tozilizumab (TZL)) due to: a) adverse event (AE) (moderate: suspension of the drug regardless of the impact; severe: suspension and hospitalization or death); b) inefficacy; c) decision of the patient; d) remission or improvement, e) other. Secondary variables: sociodemographic (age, sex); clinical (duration of illness, type of BA). Analysis: description of sociodemographic and clinical characteristics of patients included and the reasons of discontinuation with frequency distribution, and the mean and standard deviation. The exposure time was defined from the start date of each BA to the date of discontinuation, loss of follow-up or end of the study. Discontinuation rates of BA by survival techniques, expressing the incidence per 100 patients * year with their respective 95% confidence interval (95% CI).Results146 patients with RA were included in the study, which began 286 different courses of treatment with BA, follow-up was 604.5 patients * year. Of these, 78% were women with a mean age at diagnosis of 66.5±7 years and a median time to the start of the first BA of 6±5 years. The most frequently used drug was ADA (27.3%), followed by IFX (22.4%), ETN (21.3%) and RTX (19.2%). 24% of patients continued treatment at the time the end of monitoring. We found 199 discontinuations in 87 patients: 21.7% due to inefficacy, 39% to EA (6% exitus), 2.8% to patient choice and 2.8% to improvement. The median survival of BA was 1.7 years (95% CI 1.2 to 1.9), with an incidence of discontinuation of 33 (95% CI 28.6 to 37.8). The incidence of discontinuation by BA is shown in the table. The discontinuation rate due to AE was 18.4 (95% CI 15.2 to 22.1). The discontinuation rate due to inefficacy was 10.3 (95% CI 8 to 13.5) and to improvement was 1.3 (95% CI 0.66 to 2.64).BAnPatients*yearIncidence95% CIIFX53176.83023–39.2ETN40117.23425–46.5ADA54185.529.122.3–38RTX3691.639.228.3–54.4Other BA1633.447.829.3–78.1ConclusionsAfter 2 years of treatment, half of patients over 65 have discontinuated BA due to different reasons. Discontinuation rate is estimated at 33 per 100 patient * year, the most frequent cause being inefficacy, followed by AE. This study contributes to increasing knowledge of long-term survival of these drugs in...
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