Resistencia cruzada entre isoniacida y etionamida y su alta correlación con la mutación C-15T en aislamientos de Mycobacterium tuberculosis de Perú / Cross-resistance between isoniazid and ethionamide and its strong association with mutation C-15T in Mycobacterium tuberculosis isolates from Peru

Resumen Diversos estudios han evidenciado una resistencia cruzada entre isoniacida y etionamida, 2 de los fármacos utilizados en el tratamiento de la tuberculosis multirresistente.El objetivo del presente estudio fue determinar la resistencia cruzada entre ambos fármacos en aislados de Mycobacterium tuberculosis obtenidos en un hospital de Lima (Perú), conalta proporción de pacientes con tuberculosis. Se calculó la frecuencia de mutaciones asociadas con la resistencia a la isoniacida (INH) evaluando el gen katG y la región promotorainhA mediante la prueba molecular Genotype MTBDRplus v2.0. El método gold standard conocido como agar proporciones en placa (APP) permitió la identificación de resistencia a INH yetionamida. De 107 aislamientos resistentes a INH, 54 fueron multirresistentes (identificadosmediante la prueba Genotype MTBDRplus) y 49 (es decir, el 45,8% del total) también fueronresistentes a etionamida por el método APP. En los aislamientos resistentes a INH, se encontraron mutaciones en el gen katG en el 50,5% (54/107); en la región promotora inhA en el23,3% (25/107), y un 14,0% (15/107) presentaron mutaciones en ambos. Un 12,1% (13/107)fueron resistentes a INH por ausencia de banda wild type y banda de mutación. La mutaciónC-15T en la región promotora inhA presentó una fuerte asociación con la resistencia a etionamida y alcanzó el 73,4% (36/49) de los aislamientos resistentes a dicho fármaco. Los resultadosdel presente estudio sugieren que la identificación de mutaciones relacionadas con resistenciaa INH, sobre todo en la región promotora inhA, podría ser de gran utilidad para identificarla resistencia cruzada a etionamida y mejorar el tratamiento de las personas afectadas portuberculosis.© 2019 Asociacion Argentina de Microbiolog´ía. Publicado por Elsevier Espana, S.L.U. Este es unart´ículo Open Access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract Several studies have shown cross-resistance between isoniazid and ethionamide, 2of the drugs used in the treatment of multidrug-resistant tuberculosis. The objective of this study was to determine the cross-resistance between both drugs in Mycobacterium tuberculosis isolates from a hospital with high incidence of tuberculosis in Lima, Peru. The frequency of mutations to isoniazid in the katG gene and the inhA promoter region was identified by the Genotype MTBDRplus v2.0 molecular test. The gold standard Agar Proportion method (APM) allowed todetect resistance to isoniazid and ethionamide. Of 107 isoniazid-resistant isolates (54 multidrug-resistant isolates identified by the Genotype MTBDRplus test, 45.8% (49/107) were also resistant to ethionamide by the APM. Mutations were found in the katG gene in 50.5% (54/107), in the promoter region inhA in 23.3% (25/107) and 14.0% (15/107) that share both mutations in the resistant isolates to INH. The absence of the wild type and mutation bands indicated that 12.1% (13/107) of the isolates were resistant to INH. The mutation C-15T in the inhA promoter region showed a strong association with resistance to ethionamide in 73.4% (36/49) of the isolates analyzed. The results of the present study suggest that the identification of mutations related to resistance to isoniazid, especially in the inhA promoter region, could be very useful to identify cross-resistance to ethionamide and improve the treatment of individuals suffering from this disease.

GenoType MTBDR plus 1.0 ® para la detección de resistencia cruzada entre isoniacida y etionamida en aislamientos de Mycobacterium tuberculosis multirresistentes / GenoType MTBDR plus 1.0 ® for the detection of cross-resistance between isoniazide and ethionamide in isolates of multidrug-resistant Mycobacterium tuberculosis

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 MTBDR plus ® detecta las mutaciones asociadas con la resistencia a isoniacida y podría detectar la resistencia cruzada a la etionamida. Objetivo. Evaluar la prueba GenoType MTBDR plus ® 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 MTBDR plus 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 MTBDR plus ® , el índice kappa fue de 1. Todos los aislamientos resistentes a la isoniacida y la etionamida tenían las mutaciones detectadas con la prueba GenoTypeMTBDR plus ® 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 MTBDR plus ® . Conclusión. La prueba GenoTypeMTBDR plus ® 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.

Introduction: A variable proportion of isolates of multidrug-resistant Mycobacterium tuberculosis also presents resistance to ethionamide. It is important to determine whether resistance to isoniazid is independent or crossed with resistance to ethionamide, given that this could lead to the re-evaluation of second-line anti-tuberculosis treatment. The GenoType MTBDR plus ® molecular test is used for the detection of MDR-MTB, as it identifies mutations associated with resistance to isoniazide and could detect cross-resistance with ethionamide. Objective: To evaluate the performance of GenoType MTBDR plus ® in comparison with sequencing in the detection of mutations in gene katG and promotor inhA in clinical isolates of multidrug-resistant M. tuberculosis . Materials and methods: The GenoType MTBDR plus 1.0 ® commercial kit and sequencing were used to evaluate mutations in gene katG and promotor inhA in 30 multidrug-resistant M. tuberculosis isolates that were resistant to ethionamide. The laboratory strain H37Rv and three pan-sensitive isolates acted as controls. Results: The kappa index for the comparison between the results of sequencing and GenoType MTBDR plus ® was 1. All the isolates resistant to isoniazid and ethionamide had the mutations detected by GenoTypeMTBDR plus ® in the katG gene and 40% of them in promotor inhA. Sequencing also revealed katG mutations in positions different to those detected by GenoType MTBDR plus ® . Conclusion: GenoType MTBDR plus ® is able to detect resistance to isoniazid rapidly. Our results suggest that it could also be used to screen for cross-resistance with ethionamide.

Outcomes and Use of Therapeutic Drug Monitoring in Multidrug-Resistant Tuberculosis Patients Treated in Virginia, 2009-2014 / 결핵및호흡기질환

BACKGROUND: Reports of therapeutic drug monitoring (TDM) for second-line medications to treat multidrug-resistant tuberculosis (MDR-TB) remain limited. METHODS: A retrospective cohort from the Virginia state tuberculosis (TB) registry, 2009-2014, was analyzed for TDM usage in MDR-TB. Drug concentrations, measured at time of estimated peak (Cmax), were compared to expected ranges. RESULTS: Of 10 patients with MDR-TB, 8 (80%) had TDM for at least one drug (maximum 6 drugs). Second-line drugs tested were cycloserine in seven patients (mean C2hr, 16.6+/-10.2 microg/mL; 4 [57%] below expected range); moxifloxacin in five (mean C2hr, 3.2+/-1.5 microg/mL; 1 [20%] below); capreomycin in five (mean C2hr, 21.5+/-14.0 microg/mL; 3 [60%] below); para-aminosalicylic acid in five (mean C6hr, 65.0+/-29.1 microg/mL; all within or above); linezolid in three (mean C2hr, 11.4+/-4.1 microg/mL, 1 [33%] below); amikacin in two (mean C2hr, 35.3+/-3.7 microg/mL; 1 [50%] below); ethionamide in one (C2hr, 1.49 microg/mL, within expected). Two patients died: a 38-year-old woman with human immunodeficiency virus/acquired immune deficiency syndrome and TB meningitis without TDM, and a 76-year-old man with fluoroquinolone-resistant (pre-extensively drug-resistant) pulmonary TB and low linezolid and capreomycin concentrations. CONCLUSION: Individual pharmacokinetic variability was common. A more standardized approach to TDM for MDR-TB may limit over-testing and maximize therapeutic gain.

Optimization of the conventional minimum inhibitory concentration method for drug susceptibility testing of ethionamide

Evaluation of newer methods and optimization of existing methods for the susceptibility testing of second-line drugs, especially ethionamide, are essential when treatment of multidrug-resistant tuberculosis [MDR-TB] is warranted. The ideal method must clearly demarcate sensitive from resistant strains. Hence, optimization of the conventional minimum inhibitory concentration [MIC] method was attempted using diluted inoculum. The optimized MIC method was evaluated using 206 Mycobacterium tuberculosis strains isolated from new and previously treated tuberculosis patients and were compared with the conventional MIC method and proportion sensitivity [PST] method. The sensitivity and specificity of the optimized MIC method in comparison with the PST method was 74% and 90%. Assessment of the optimized MIC method with the conventional MIC method gave a sensitivity of and specificity of 73% and 98%. Overall agreement between the 2 methods was found to be >/= 80%. Endowed with the ability to identify the resistant strains precisely, the optimized MIC method can be used for screening resistance to ethionamide

Consistency of standard laboratory strain Mycobacterium tuberculosis H37Rv with ethionamide susceptibility testing.

Drug susceptibility pattern of standard Mycobacterium tuberculosis strain H37Rv showed discrepancy in minimum inhibitory concentration method for ethionamide and consistent results were obtained for the other second line drugs namely, kanamycin and ofloxacin. It is, therefore, necessary to revisit the susceptibility testing method for ethionamide for effective clinical management of patients with drug resistant tuberculosis.

Desfechos do retratamento de pacientes com tuberculose com o uso do esquema 3 em Porto Alegre, Brasil / Retreatment of tuberculosis patients in the city of Porto Alegre, Brazil: outcomes

OBJETIVO: Descrever os desfechos do retratamento de pacientes com tuberculose com o uso do esquema 3 (estreptomicina, etambutol, etionamida e pirazinamida por 3 meses + etambutol e etionamida por 9 meses) devido à falência do tratamento com o esquema básico (rifampicina, isoniazida e pirazinamida por 2 meses + rifampicina e isoniazida por 4 meses). MÉTODOS: Estudo descritivo de coorte histórica, não controlada, com adultos que foram tratados com o esquema 3. Foram avaliados os desfechos desse tratamento, as reações adversas aos fármacos, as recidivas e os fatores associados. RESULTADOS: Foram incluídos no estudo 229 pacientes. A taxa de cura geral foi de 62 por cento. Entre os pacientes que usaram a medicação regularmente e aqueles que a usaram irregularmente, a taxa de cura foi de 88 por cento e 31 por cento, respectivamente. Observaram-se reações adversas em 95 pacientes (41,5 por cento), principalmente digestivas. Ocorreram 17 recidivas (12,0 por cento) nos cinco anos de seguimento. CONCLUSIONS: Os desfechos com o uso do esquema 3, em geral, não foram satisfatórios, pois esse esquema foi aplicado em uma população selecionada com alto risco de não adesão ao tratamento e apresenta altas taxas de reações adversas, especialmente as de tipo digestivo, possivelmente causadas pela etionamida. No entanto, para aqueles que conseguiram tomar a medicação regularmente, a taxa de cura foi satisfatória. A taxa de recidiva foi superior àquela preconizada por consensos internacionais, possivelmente devido ao tempo de tratamento curto (apenas 12 meses). Acreditamos que o esquema 3 estendido para 18 meses poderia ser uma alternativa para pacientes com comprovada adesão ao tratamento.

OBJECTIVE: To describe the outcomes of retreatment in tuberculosis patients receiving the regimen known, in Brazil, as regimen 3 (streptomycin, ethambutol, ethionamide, and pyrazinamide for 3 months + ethambutol and ethionamide for 9 months) after treatment failure with the basic regimen (rifampin, isoniazid, and pyrazinamide for 2 months + rifampin and isoniazid for 4 months). METHODS: A descriptive, uncontrolled, historical cohort study involving adult tuberculosis patients treated with regimen 3. We evaluated adverse drug effects, recurrence, treatment outcomes, and associated factors. RESULTS: The study included 229 patients. The overall cure rate was 62 percent. For the patients who used the medications regularly and those who did not, the cure rate was 88 percent and 31 percent, respectively. Adverse events occurred in 95 patients (41.5 percent), and most of those events were related to the gastrointestinal tract. In the five-year follow-up period, relapse occurred in 17 cases (12.0 percent). CONCLUSIONS: Overall, the outcomes of treatment with regimen 3 were unsatisfactory, in part because this regimen was administered to a selected population of patients at high risk for noncompliance with treatment, as well as because it presents high rates of adverse effects, especially those related to the gastrointestinal tract, which might be caused by ethionamide. However, for those who took the medications regularly, the cure rate was satisfactory. The recurrence rate was higher than that recommended in international consensus guidelines, which might be attributable to the short (12-month) treatment period. We believe that regimen 3, extended to 18 months, represents an option for patients with proven treatment compliance.

Ethionamide-Induced Hypothyroidism in Children

Ethionamide is a second-line anti-tuberculosis drug used in the management of drug-resistant tuberculosis. Hypothyroidism is reported to be a rare adverse effect. A retrospective descriptive study was done of all children started on treatment for multidrug-resistant tuberculosis from 2006-2009; who received ethionamide as part of their drug regimen. Information collected included age; weight; human immunodeficiency virus (HIV) status; ethionamide dose and thyroid function tests. Seven of 13 (54) children developed hypothyroidism and received thyroxine for the duration of ethionamide treatment. Thyroid function returned to normal within two months of completion of tuberculosis treatment in six of the seven children (one lost to follow-up). Ethionamide-induced hypothyroidism is more common in this small number of patients than previously reported. The results warrant further studies to confirm these findings and elucidate possible reasons

Ethionamide-Induced Hypothyroidism in Children

Ethionamide is a second-line anti-tuberculosis drug used in the management of drug-resistant tuberculosis. Hypothyroidism is reported to be a rare adverse effect. A retrospective descriptive study was done of all children started on treatment for multidrug-resistant tuberculosis from 2006-2009; who received ethionamide as part of their drug regimen. Information collected included age; weight; human immunodeficiency virus (HIV) status; ethionamide dose and thyroid function tests. Seven of 13 (54) children developed hypothyroidism and received thyroxine for the duration of ethionamide treatment. Thyroid function returned to normal within two months of completion of tuberculosis treatment in six of the seven children (one lost to follow-up). Ethionamide-induced hypothyroidism is more common in this small number of patients than previously reported. The results warrant further studies to confirm these findings and elucidate possible reasons

In Vitro efficacy of ethionamide and clarithromycin in mycobacterium tuberculosis isolates

To determine the sensitivity of clinical isolates of Mycobacterium tuberculosis isolates against ethionamide, and clarithromycin. Cross-sectional study. Department of Microbiology, Armed Forces Institute of Pathology [AFIP] Rawalpindi from June 2003 to June 2004. All routine clinical samples received for acid fast bacilli [AFB] culture and yielding positive growth on Lowenstien Jensen medium and Bactec 460 were included in the study. The isolates were from sputum [n=70], bronchioalveolar lavage [n=10], fine needle aspiration [n=6], lymph nodes [n=7], pleural fluid [n=4], endometrium [n=3]. After the identification of M. tuberculosis [MTB] sensitivity was performed against first-line antituberculosis drugs. Then susceptibility of M. tuberculosis isolates against ethionamide and clarithromycin was performed on LJ medium. Mycobacterium H37Rv was used as control strain. Results were interpreted using resistance ratio method. Out of 100 M. tuberculosis isolates, sensitivity to ethionamide was 93% and 9% to clarithromycin. Clarithromycin when used alone is ineffective as antituberculosis drug but its efficacy in combination needs to be tested. However ethionamide may be used as an alternative antituberculosis drug

Susceptibility tests to second line drugs and re-treatment of tuberculosis: revisiting early experiences / Las pruebas de sensibilidad a drogas de segunda línea y el re-tratamiento de la tuberculosis: visión retrospectiva de tres estudios

The value of susceptibility tests in guiding antituberculous therapy with second-line drugs remains controversial. We reanalyzed three reports regarding the relationship between in vitro susceptibility of Mycobacterium tuberculosis and the clinical outcome of in-patients treated with these drugs at the Muñiz Hospital, Buenos Aires, during the sixties. These patients had been irregularly treated with a standard regimen consisting of isoniazid, streptomycin and PAS; they developed resistance to at least the first two drugs and persisted culture-positive. Susceptibility testing to ethionamide, cycloserine and kanamycin were performed by the proportion method on Löwenstein Jensen medium. Some level of resistance was detected among isolates from patients not previously treated with these drugs, that could be due to cross resistance with previously administered first line structural analogs. However, the studies evidenced significant association between resistance to ethionamide and cycloserine and prior treatment with these drugs. Increased resistance to all three drugs was detected within the first three months of treatment. In vitro resistance to ethionamide emerged earlier and was the most frequent followed by resistance to cycloserine and kanamycin. The low frequency of resistance to kanamycin could be related to the low dosage of this drug used at that time. Simultaneous resistance to the three agents, but not to two or one drug, appeared to be a marker of treatment failure. An apparent reversion of drug resistance was observed in near 6% of patients, for whom susceptibility tests were repeated on subsequent isolates, indicating this percentage of inconsistency in reproducibility of test results.

La correlación entre resultados de pruebas de sensibilidad a drogas antituberculosas de segunda línea y evolución de los pacientes en tratamiento, aún es discutida. Se reanalizan aquí tres estudios realizados en la década del 60, sobre la relación entre resultados de pruebas de sensibilidad y tratamiento con estas drogas, en pacientes crónicos, internados en el hospital Muñiz, Buenos Aires, que habían sido tratados con el entonces régimen estándar, integrado por isoniacida, estreptomicina y PAS; se habían hecho resistentes al menos a dos de estas drogas y continuaban con cultivo positivo. La prueba de sensibilidad a etionamida, cicloserina y kanamicina se efectuó por el método de las proporciones en medio Löwenstein Jensen. Entre 4 y 13% de los pacientes previamente no tratados con estas drogas presentó cierto nivel de resistencia, fenómeno atribuido a la administración previa de drogas de primera línea con moléculas análogas. Se halló asociación significativa entre resistencia a etionamida y cicloserina, y tratamiento previo con estas drogas. La resistencia a las tres drogas fue detectada en los primeros tres meses de tratamiento, siendo la resistencia a etionamida la más frecuente, y la primera en emerger, seguida por cicloserina y kanamicina, cuya baja frecuencia en alcanzar resistencia estaría relacionada con las bajas dosis administradas. La resistencia simultánea a las tres drogas, pero no a una o dos, resultó marcadora de fracaso terapéutico. Se observó en cerca del 6% de los pacientes aparente reversión de la resistencia, en pruebas hechas en aislamientos sucesivos, interpretada como falla en la reproducibilidad de resultados.

Efficacy and safety of kanamycin, ethionamide, PAS and cycloserine in multidrug-resistant pulmonary tuberculosis patients.

BACKGROUND: We carried out this study to determine the efficacy and safety of a regimen containing kanamycin, ethionamide, isoniazid, para-aminosalicylic acid (PAS) and cycloserine in the treatment of multidrug-resistant tuberculosis (MDR-TB). METHODS: A prospective, uncontrolled study of 39 pulmonary tuberculosis patients, who had received adequate first-line antituberculosis treatment including supervised category II retreatment regimen, and were still sputum smear positive for acid-fast bacilli (AFB) in whom sputum culture revealed isolates of M. tuberculosis resistant to rifampicin and isoniazid with and without resistance to other antituberculosis drugs. They received kanamycin (initial 4-6 months), ethionamide, isoniazid, PAS and cycloserine for a minimum period of two years. RESULTS: Out of 39 patients, 29 (74.3%) achieved sputum conversion within six months and remained so at the end of two years. Two (5.1%) patients died, six (20.6%) patients were lost to follow up, and two (5.1%) patients remained sputum smear-positive for AFB through out the period of study. Twenty-nine patients, declared cured, were followed for an average period of 16 months (3-48 months), during which two (6.9%) patients relapsed, four (13.8%) patients were lost to follow-up and remaining 23 remained sputum smear-negative. Eight (21.1%) patients developed major side effects which required stoppage/change of drugs. CONCLUSION: In MDR-TB patients, regimen consisting of ethionamide, isoniazid, PAS and cycloserine and kanamycin appears to be effective and safe.

To study the outcome of patients with Multi-Drug Resistant Tuberculosis and see the effectiveness of second line drugs available in Pakistan in the management of MDR TB

MDR TB is a difficult problem to treat specially in countries like Pakistan, where facilities to treat the patients in hospital for the whole course of treatment are limited and also all the effective second line drugs are not available. This study was aimed to see the effectiveness of second line drugs that are available in Pakistan in terms of sputum conversion and cure rate and to see the resistance pattern of MDR TB. This study was carried out from 1st March 1995 to 31st Dec 2001 in a Chest Clinic in Peshawar. All patients having active Pulmonary Tuberculosis with history of irregular treatment in past were included in the study irrespective of age and sex. Their sputum samples were sent for AFB culture and sensitivity and they were started on second line anti tuberculosis drugs. The pattern of drug resistance was noted from results of culture and sensitivity results, when available. The progress of the patient was monitored by clinical assessment, sputum examination and Chest Radiographs on subsequent follow up visits monthly for first three months and then at 2-3 months intervals until completion of treatment. 70 patients, [40 males and 30 females] were included in the study. 05 patients excluded after their sputum C/S showed that they were not having MDR TB. 38% patients had bacilli resistant to all 06 first line drugs, 20% resistant to 05% drugs, 25% resistant to 04 drugs, 12% resistant to 3% drugs and only 05% were only resistant to 02 drugs i-e Rifampicin and INH. Regimen used was Kanamycin 15 mg/kg, Ofloxacin 400-800 mg/day, PAS 150 mg/kg, Ethionamide 15 mg/kg and Thiacetazone and INH 2.5 and 5 mg / kg respectively. The regimen was modified after C/S report with addition of first line drugs to which the bacilli were sensitive. At the end of 02 months the conversion the conversion rate was 79%. Treatment Outcome: 55% patients were cured, 21% lost, 10% had treatment failure and 2% reported dead. Half of the patients cured have been attending for optional follow up for the period ranging from 1 to 6 years and only two patients have relapsed so for. The second line drugs that are available in Pakistan are effective both in terms of sputum conversion and achieving cure. Large number of patients lost signifies the fact that these patients need to be hospitalized and treated under direct supervision for the whole period of treatment as recommended

An Analysis of Antituberculosis Drug Susceptibility Test Results in Kyung Hee Medical Center During Recent Four years / 대한임상미생물학회지

BACKGROUND: Tuberculosis is still one of the most seriously threatening infections in Korea, because of multidrug resistant tuberculosis. Results of antituberculosis drug susceptibility test can provide clinicians very important informations for selection of proper regimens for treatment. METHODS: In this study the results of antituberculosis drug susceptibility test of 298 cases at Kyunghee Medical Center from 2000 to 2003 were retrospectively analysed to evaluate the trend of antituberculosis drug susceptibility. The procedure of drug susceptibility test was based on the absolute concentration method using Lowenstein-Jensen solid media. RESULTS: The resistance rate of Mycobacterium tuberculosis to one or more drugs was increased from 29.3% in 2000 to 48.2% in 2003, and the rates of multiple resistance to two or more drugs increased from 13.3% in 2000 to 20.5% in 2003. The increase in resistance rate to individual drug during study period were 20.0% to 24.1% in isoniazid, 9.3% to 19.3% in rifampicin, 5.3% to 15.7% in ethambutol, 4.0% to 10.8% in para-aminosalicylic acid, 2.7% to 6.0% in kanamycin, 1.3% to 7.2% in ethionamide, 1.3% to 6.0% in capreomycin, 1.3% to 7.2% in prothionamide, 0.0% to 12.1% in ofloxacin, 6.7%to 3.6% in streptomycin, 6.7% to 7.2% in cycloserine, 10.7% to 8.4% in pyrazinamide, respectively. CONCLUSIONS: The resistance rate of M. tuberculosis has been increased with years and multidrug resistant M. tuberculosis was commonly encountered in the specimens from the patients visited Kyunghee Medical center.

Identificaçäo e teste de susceptibilidade a drogas de cepas de Mycobacterium tuberculosis isoladas de pacientes provenientes de Hospital Público de Referência, Goiânia/GO / Identification and drug susceptibility test of Mycobacterium tuberculosis strains isolated from patients at the Public Reference Hospital, Goiânia, Goiás

Com o intuito de identificar e verificar a sensibilidade de cepas de Mycobacterium tuberculosis isoladas de 206 amostras clínicas obtidas de formas pulmonares e extrapulmonares, provenientes de 144 pacientes externos e internos do Hospital de Doenças Tropicais do Estado de Goiás, foi realizado baciloscopia pela técnica de coloraçäo de Ziehl-Neelsen e a cultura em Lowenstein-Jensen e sistema bifásico. A identificaçäo foi realizada através de provas de crescimento na presença de inibidores, produçäo de pigmentos, tempo de crescimento e provas bioquímicas, conjuntamente com a determinaçäo da susceptibilidade às drogas antimicobacterianas. Foram isoladas micobactérias em 13 (6,3 porcento) amostras, sendo 12 (92,3 porcento) identificadas como M. tuberculosis e uma (7,7 porcento) do complexo M. avium (MAC). Das amostras isoladas, 12 apresentaram sensibilidade a isoniazida, etambutol, rifampicina, estreptomicina, pirazinamida, etionamida e somente uma amostra, apresentou resistência à isoniazida, rifampicina, pirazinamida e etionamida

Molecular diagnosis of drug-resistant tuberculosis

The worldwide emergence and spread of multidrug- resistant [MDR] strains of Mycobacterium tuberculosis has adverse effects on tuberculosis [TB] control programs. The goal of this paper is to describe the advances made in the understanding of the molecular basis of M. tuberculosis resistance to first-line anti-TB drugs, and to discuss the potential of molecular methods in early diagnosis of drug-resistant TB. Molecular methods such as DNA sequencing, polymerase chain reaction, DNA hybridization and restriction fragment length polymorphism have been used to identify/detect mutations in gene-encoding proteins or rRNA which are targets for the first-line anti-TB drugs. High level resistance to rifampin [RIF], isoniazid [INH], pyrazinamide [PZA], ethambutol [EMB], and streptomycin [STR] is caused by mutations in rpoB, katG, pncA, embB and rpsL/rrs genes, respectively. The most common mutations conferring high level resistance to RIF, INH, EMB and STR have been identified in rpoB, katG, embB and rpsLgenes, respectively. Molecular methods to detect the most frequent mutations in the gene encoding functions that are targets for first-line anti-TB drugs have provided encouraging results for early diagnosis of MDR-TB

Possibilidades secundárias no tratamento da hanseníase / Secondary possibilities in leprosy's therapy

O autor faz uma revisäo da terapêutica em hanseníase, enfatizando as medicaçöes secundárias, as de apoio ao tratamento e as pouco documentadas. Conclui sugerindo esquemas terapêuticos alternativos, ainda näo experimentados na prática.

Treatment of short course chemotherapy [SHRZE] failure cases with kanamycin, ethionamide and cycloserine

To determine the effectiveness of reserve regimen 93Kon, Eth and Cyc+9Eth and Cyc] with regard to bacteriological conversion, relapse and side-effects. Design: Prospective study of 32 CHRZE treatment failure cases of pulmonary tuberculosis. Setting: Private ward, Institute of Chest Diseases, Kotri. Subjects: Thirty two cases of pulmonary tuberculosis, average age 33 years [ +/- SD 9.2] on retreatment regimen [SHRZE] for an average duration of 7.03 [ +/- SD 4.08] months who remained positive for AFB in their sputa on direct microscopy and culture. Among 26 patients who completed the initial phase, 20 [76.9%] showed sputum conversion on smear microscopy and culture at three months. the mean duration of sputum conversion was 44.9 [SD +/- 24.1] days. Following completion of chemotherapy in 23 patients, 18 [78.2%] remained smear and culture negative at the end of one year. The treatment failure rate during the initial protocol was 22% and relapse rate after one year of post-chemotherapy follow-up was 5.5%. Besides four serious toxicities, all the adverse effects were manageable. The default rate also remained high [22%] because of high cost. Conclusions: For patients with multidrug resistance, the reserve regimen is an effective alternative therapy with manageable side-effects