In vitro antimicrobial efficacy of a fixed-dose combination of RHZE against M. tuberculosis

ABSTRACT The use of drugs in fixed-dose combination (FDC) is now recommended by the World Health Organization (WHO) due to the emergence of multidrug-resistant strains of Mycobacterium tuberculosis. FDC uses different drugs against tuberculosis (TB) in a single tablet for phase-intensive therapeutic intervention. This therapy aims to optimize treatment, to prevent inappropriate use of drugs, and to prevent the emergence of new resistant strains. This study aims to evaluate the susceptibility of clinical isolates of M. tuberculosis against rifampicin, isoniazid, ethambutol, and pyrazinamide. The antimicrobials were tested separately and in associations according to FDC. This was used for broth microdilution method, which was compared to the proportions method previously considered as the gold standard. In antimicrobials testing alone, several strains were resistant to one, two, or three drugs. However, when applied to association of drugs in FDC, there was no antimicrobial resistance. The results strengthen the FDC's concept, which aims to unite the four anti-TB drugs to combat bacterial resistance.

Evaluation of crystal violet decolorization assay for minimal inhibitory concentration detection of primary antituberculosis drugs against Mycobacterium tuberculosis isolates

In this study we evaluated the crystal violet decolorization assay (CVDA) for detection of minimum inhibitory concentration (MIC) of antituberculosis drugs. 53 isolates were tested in this study and 13 of them were multidrug resistant (MDR) isolates. The antibiotics concentrations were 2-0.06 mg/L for isoniazid (INH) and rifampicin (RIF) and were 16-0.25 mg/L for streptomycin (STM) and ethambutol (EMB). Crystal violet (CV-25 mg/L) was added into the microwells on the seventh day of incubation and incubation was continued until decolorization. Decolorization of CV was the predictor of bacterial growth. Overall agreements for four drugs were detected as 98.1%, and the average time was detected as 9.5 ± 0.89 day after inoculation. One isolate for INH and two isolates for STM were determined resistant in the reference method, but susceptible by the CVDA. One isolate was susceptible to EMB by the reference method, but resistant by the CVDA. All results were concordant for RIF. This study shows that CVDA is a rapid, reliable and suitable for determination of MIC values of Mycobacterium tuberculosis. And it can be used easily especially in countries with limited-sources.

Rifapentine for latent tuberculosis infection treatment in the general population and human immunodeficiency virus-positive patients: summary of evidence

AbstractLatent tuberculosis infection (LTBI) and human immunodeficiency virus (HIV)-coinfection are challenges in the control of tuberculosis transmission. We aimed to assess and summarize evidence available in the literature regarding the treatment of LTBI in both the general and HIV-positive population, in order to support decision making by the Brazilian Tuberculosis Control Program for LTBI chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, Embase, LILACS, SciELO, Trip database, National Guideline Clearinghouse, and the Brazilian Theses Repository to identify systematic reviews, randomized clinical trials, clinical guidelines, evidence-based synopses, reports of health technology assessment agencies, and theses that investigated rifapentine and isoniazid combination compared to isoniazid monotherapy. We assessed the quality of evidence from randomized clinical trials using the Jadad Scale and recommendations from other evidence sources using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The available evidence suggests that there are no differences between rifapentine + isoniazid short-course treatment and the standard 6-month isoniazid therapy in reducing active tuberculosis incidence or death. Adherence was better with directly observed rifapentine therapy compared to self-administered isoniazid. The quality of evidence obtained was moderate, and on the basis of this evidence, rifapentine is recommended by one guideline. Available evidence assessment considering the perspective of higher adherence rates, lower costs, and local peculiarity context might support rifapentine use for LTBI in the general or HIV-positive populations. Since novel trials are ongoing, further studies should include patients on antiretroviral therapy.

Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life.

Tratamiento directamente observado de la tuberculosis en un hospital de la Ciudad de Buenos Aires / Directly observed treatment for tuberculosis in a Buenos Aires City hospital

Se describe la experiencia en la aplicación del tratamiento directamente observado de tuberculosis (TDO) en el período 1/1/1979-31/12/2009 y la comparación de los resultados obtenidos en el periodo 1979-1999 versus los de 2000- 2009. En un hospital de la Ciudad de Buenos Aires, 582 pacientes HIV negativos recibieron inicialmente rifampicina, isoniazida, pirazinamida y etambutol o estreptomicina. En la segunda fase 424 de estos pacientes tratados entre 01/01/1979 y 31/12/1999 (G1), recibieron esquemas bisemanales con rifampicina/isoniazida o isoniazida/estreptomicina y otros 158 pacientes, tratados entre 01/01/2000 y 31/12/2009 (G2) recibieron un esquema bisemanal o trisemanal con rifampicina/isoniazida. Se siguieron las recomendaciones de los programas de control de la Nación y la Ciudad. Los pacientes bajo TDO tuvieron tasas de tratamiento completo más elevadas (82.8% versus 48.7%), (p < 0.0001) con respecto a otros 483, que siguieron tratamiento autoadministrado (AUTO); la edad promedio fue de 36.3 ± 15.3 años, 63.1% eran varones y 69.4% tenían nacionalidad argentina. Presentaron tratamiento previo el 8.9%, comorbilidades el 6.1% y el 70.6% de las formas pulmonares fueron confirmadas bacteriológicamente. El 9.5% presentó efectos adversos a drogas y el sexo masculino presentó mayor frecuencia de abandonos (p = 0.004). Con respecto al G1, en el G2 hubo menor proporción de pacientes argentinos (48.7% vs. 77.1%), (p ≤ 0.0001), mayor frecuencia de comorbilidades (10.7% vs. 4.4%), (p = 0.005), de formas clínicas pulmonares con confirmación bacteriológica (95% vs. 87%), (p = 0.02) y de efectos adversos a drogas (17% vs. 6.6%), (p ≤ 0.0001). Hallamos tasas de cumplimiento total elevadas en TDO (82.8%), similares a las otras publicaciones.

The outcomes of directly observed therapy of tuberculosis (DOT) between 1/1/1979 and 12/31/2009 were analyzed. Results obtained in the 1979-1999 period were compared with those achieved in the 2000-2009 period. In a Buenos Aires City hospital, 582 HIV negative TB patients received rifampin, isoniazid, pyrazinamide and ethambutol or streptomycin in the initial stage, followed by a second stage where patients were included in two groups: G1 composed by 424 patients (period 1/1/1979-12/31/1999) who received either rifampin and isoniazid or rifampin and streptomicin twice a week, and G2, with 158 patients (period 1/1/2000-12/31/2009) who received either rifampin and isoniazid twice or three times a week. National and Buenos Aires City TB Control Programs recommendations were followed. Patients who underwent DOT had higher completeness rates than those included in self-administered therapy (82.8% vs. 48.7%), (p <0.0001). Mean age: 36.3±15.3 years, males: 63.1% and 69.4% were Argentine citizens. A 8.9% had been previously treated, 6.1% had co-morbidities. A 70.6% of pulmonary cases was bacteriologically confirmed, 82.8% of them completed the treatment, while 11.5% defaulted. Adverse effects to antituberculosis drugs were observed in 9.5% of cases; male patients showed higher rates of non adherence. G2 had a lower proportion of native people (48.7% vs. 77.1%), (p ≤ 0.0001), higher frequency of co-morbidities (10.7% vs. 4.4%), (p = 0.005), of bacteriologically confirmed pulmonary cases (95% vs. 87%), (p = 0.02) and more adverse effects than G1 (17% vs. 6.6%), (p ≤ 0.0001). In coincidence with other experiences, this work shows high treatment success rates in patients treated under DOT strategy.

Clinical response of newly diagnosed HIV seropositive & seronegative pulmonary tuberculosis patients with the RNTCP Short Course regimen in Pune, India.

Background & objectives In the Revised National Tuberculosis Control Programme (RNTCP) in India prior to 2005, TB patients were offered standard DOTS regimens without knowledge of HIV status. Consequently such patients did not receive anti-retroviral therapy (ART) and the influence of concomitant HIV infection on the outcome of anti-tuberculosis treatment remained undetermined. This study was conducted to determine the results of treatment of HIV seropositive pulmonary tuberculosis patients with the RNTCP (DOTS) regimens under the programme in comparison with HIV negative patients prior to the availability of free ART in India. Methods Between September 2000 and July 2006, 283 newly diagnosed pulmonary TB patients were enrolled in the study at the TB Outpatient Department at the Talera Hospital in the Pimpri Chinchwad Municipal Corporation area at Pune (Maharashtra): they included 121 HIV seropositive and 162 HIV seronegative patients. They were treated for tuberculosis as per the RNTCP in India. This study was predominantly conducted in the period before the free ART become available in Pune. Results At the end of 6 months of anti-TB treatment, 62 per cent of the HIV seropositive and 92 per cent of the HIV negative smear negative patients completed treatment and were asymptomatic; among smear positive patients, 70 per cent of the HIV-seropositive and 81 per cent of HIV seronegative pulmonary TB patients were cured. Considering the results in the smear positive and smear negative cases together, treatment success rates were substantially lower in HIV positive patients than in HIV negative patients, (66% vs 85%). Further, 29 per cent of HIV seropositive and 1 per cent of the HIV seronegative patients expired during treatment. During the entire period of 30 months, including 6 months of treatment and 24 months of follow up, 61 (51%) of 121 HIV positive patients died; correspondingly there were 6 (4%) deaths among HIV negative patients. Interpretation & conclusions The HIV seropositive TB patients responded poorly to the RNTCP regimens as evidenced by lower success rates with chemotherapy and high mortality rates during treatment and follow up. There is a need to streamline the identification and management of HIV associated TB patients in the programme with provision of ART to achieve high cure rates for TB, reducing mortality rates and ensuring a better quality of life.

Variantes genéticas da N-acetiltransferase 2, CYP2E1 e glutationa S-transferase: relação com a segurança terapêutica em pacientes com tuberculose / Genetic variants of N-acetyltransferase 2, CYP2E1 and glutathione S-transferase: relation with therapeutic safety in patients with tuberculosis

Polimorfismos nos genes da n-acetiltransferase 2 (NAT2), CYP2E1 e glutationa S-transferase (GST) têm sido associados a diferenças na resposta ao tratamento da tuberculose. O papel de variantes dos genes NAT2, CYP2E1 e GSTM1/GSTT1, no perfil de segurança do tratamento da tuberculose, foi avaliado em 99 pacientes com tuberculose, sem co-infecção por HIV ou vírus da hepatite, tratados por 6 meses. Amostras de sangue foram colhidas antes e durante o tratamento para avaliação de marcadores de lesão hepatocelular (ASL T e AST), colestase (ALP, GGT e bilirrubinas) e função renal (creatinina). O DNA genômico foi extraído de sangue colhido em EDTA pelo método precipitação salina. Os polimorfismos NAT2 foram analisados por PCR-RFLP e seqüenciamento de DNA. Os polimorfismos da região promotora do CYP2E1 foram detectados por PCR-RFLP e para a análise dos genótipos nulos de (GSTM1*0) foi utilizada a PCR multiplex. Durante o tratamento, 59,6% dos pacientes apresentaram reações adversas aos medicamentos (RAM) e alterações nos marcadores de lesão hepatocelular e colestase, com aumento de 1 a 4 vezes o limite superior de referência. Foi observada forte relação entre RAM e alterações nos marcadores séricos (p< 0,05) e também com o uso de medicação concomitante (p< 0,001)...

Tuberculose: como eu trato / Tuberculosis: how I deal

Historicamente, o Brasil teve papel pioneiro na organização das ações de controle da tuberculose. Desde os primeiros anos do século XX, por meio de estratégias diagnósticas e terapêuticas padronizadas simples e efetivas, baseadas na patobiologia da doença e nas características do agente etiológico, o Programa de Controle da Tuberculose vem contribuindo para o controle da doença e para a organização do sistema público de saúde. A padronização terapêutica em todo o território nacional, associada à garantia de fornecimento gratuito dos medicamentos a todos os doentes identificados, são instrumentos fundamentais para a redução do impacto da tuberculose na população. Os esquemas medicamentosos padronizados para cada situação, previamente testados e validados, possibilitam a cura da maior parte dos doentes. Atualmente, os maiores obstáculos ao controle desejado da doença incluem a infecção pelo HIV e o desenvolvimento de bacilos resistentes aos principais agentes quimioterápicos.

Historically, Brazil has had a major role in the organization of tuberculosis control activities. Since the beginning of the XX Century, using simple and effective standardized diagnostic and therapeutic strategies, based on an understanding of the pathophysiology of the disease and on the characteristics of the etiologic agent, the Tuberculosis Control Program has contributed to the control of the disease and to the organization of the public health system. Nationwide standardization of the treatment, along with the quarantee of free medicines to all patients, are fundamental tools for reducing the impact of the disease. A structured approach to care lead to the cure of the majority of the patients. At present, the major obstacles to the desired level of tuberculosis control include HIV infection and the development of Mycobacterium tuberculosis strains resistant to the most important anti tubercular drugs.

Isoniazid induced gynaecomastia: a case report.

Gynaecomastia due to anti-tubercular chemotherapy is a rare side effect. Isoniazid causing breast tissue enlargement has been very rarely reported. We report a 60-year old, male patient of Pulmonary Tuberculosis who was started on antituberculous treatment (ATT) with rifampicin (R), isoniazid (H), ethambutol (E) and pyrazinamide (Z) together for initial two months and R, H & E thereon. After five months of initiation of treatment, while receiving RHE, he developed painful bilateral gynaecomastia. Isoniazid was stopped and patient was continued on R & E till completion of the treatment up to nine months. After stopping isoniazid, his breast swelling subsided to some extent and became non-tender. Follow up, at six months, after stopping the course of treatment, patient was asymptomatic except for slight bilateral non-tender breast enlargement.

High frequency of resistance to the drugs isoniazid and rifampicin among tuberculosis cases in the city of Cabo de Santo Agostinho, an urban area in Northeastern Brazil

The objective of the present study was to investigate the frequency and risk factors for developing multidrug-resistant tuberculosis in Cabo de Santo Agostinho, PE. This was a prospective study conducted from 2000 to 2003, in which suspected cases were investigated using bacilloscopy and culturing. Out of 232 confirmed cases of tuberculosis, culturing and antibiotic susceptibility tests were performed on 174. Thirty-five of the 174 cultures showed resistance to all drugs. The frequencies of primary and acquired resistance to any drug were 14 percent and 50 percent respectively, while the frequencies of primary and acquired multidrug resistance were 8.3 percent and 40 percent. Previous tuberculosis treatment and abandonment of treatment were risk factors for drug resistance. The high levels of primary and acquired resistance to the combination of isoniazid and rifampicin contributed towards the difficulties in controlling tuberculosis transmission in the city.

O objetivo do presente estudo foi investigar a freqüência e fatores de risco para o desenvolvimento de tuberculose multidroga resistente, na Cidade do Cabo de Santo Agostinho, PE. Este é um estudo prospectivo realizado entre 2000-2003 onde casos suspeitos foram investigados por baciloscopia e cultura. De 232 casos de tuberculose confirmados, 174 tiveram cultura e antibiograma realizados. Trinta e cinco das 174 culturas mostraram resistência a qualquer uma das drogas. A freqüência de resistência primária e adquirida a qualquer droga foi 14 por cento e 50 por cento respectivamente enquanto a freqüência primária e adquirida para multidroga resistência foi 8,3 por cento e 40 por cento. Tratamento prévio para tuberculose ou abandono de tratamento consistiu em fatores de risco para resistência a drogas. Os altos níveis de resistência primária e adquirida a combinação isoniazida e rifampicina contribuem para as dificuldades no controle da transmissão da tuberculose no Cabo.

Isolated tubercular liver abscess in children treated with percutaneous isoniazid infusion.

Isolated Tubercular liver abscess is mainly reported in adult patients. We report two cases of isolated tubercular liver abscess in paediatric patients. Diagnosis was made by clinical and ultrasound guided aspiration of pus showing acid fast bacilli in one case. In second case, biopsy of the abscess wall was confirmatory. In both cases percutaneous drainage of pus and transcatheter infusion of Isoniazid was given. After two weeks of infusion no acid fast bacilli was detected and cavity size decreased. Direct infusion of anti-tubercular drugs is more efficient than systemic therapy alone. This is first of its kind in treating isolated tubercular abscess in paediatric patients. So, percutaneous infusion of anti-tubercular agents can be considered in the treatment of tubercular liver abscess.

Evaluation of a non-rifampicin continuation phase (6HE) following thrice-weekly intensive phase for the treatment of new sputum positive pulmonary tuberculosis.

SETTING: Tuberculosis Research Centre, Chennai and Madurai, South India. OBJECTIVE: To assess response to treatment, relapse and emergence of MDR TB in newly diagnosed patients with sputum-positive tuberculosis using an intermittent intensive phase followed by a non-rifampicin continuation phase. DESIGN: Patients were treated in a controlled clinical trial with 2HRZE3/6HE with thrice-weekly direct dosing in the intensive phase and once-weekly with six doses self-administered in the continuation phase. Clinical and bacteriologic evaluation was done every month for 24 months. RESULTS: The overall outcome was good, with 92% favourable response (cure) and 4.8% relapse in 450 patients including 103 who did not receive extension of intensive phase for positive smear, 38 with initial H-resistant cultures, 4 with MDR TB and 15 who received less than 75% of chemotherapy. In 392 patients with drug-susceptible cultures, 96%were cured and only 4% relapsed. There was no emergence of MDR TB among failures and relapses; toxicity was low. CONCLUSION: Newly-diagnosed Category I patients can be effectively treated with this regimen without emergence of MDR TB. It has immense potential in programmes where directly observed therapy cannot be ensured throughout, and when rifampicin is contraindicated in HIV-TB patients who require concomitant therapy with anti-retroviral

Adherencia a quimioprofilaxis de niños chilenos expuestos a tuberculosis del adulto / Chemoprofilaxis compliance in chilean children exposed to tuberculosis

The protection of exposed children (EC) is one of the cornerstones of tuberculosis (TB) control. There are limited information about chemoprophylaxis (CP) compliance in Chile and worldwide. We evaluate this situation in South Eastern Metropolitan Health Service located in a poor district, providing free care for more than 400,000 children. We enroll in this study all kids under five years old, living in close contact with TB all forms patients. The children were referred between 2003 and 2005 to the Pediatric Pneumology Unit. Our TB contacts management protocol considers four visits: The first one for CXR, sputum smear (BAAR) and tuberculin (PPD 2 UT). The 2nd on is for diagnosis. The 3rd one 3 month follow up to check compliance and repeat PPD if previously negative; and 6 mo CXR for discharge. We indicate QP with isoniacide (HIN) 5 mg/k/day for 6 mo to all exposed (CXR and BAAR negative independently of PPD). We stop QP on visit 3 if index case became BAAR (-) and if PPD is (-) twice. We follow with QP to all PPD (+) children till 6 mo. Primary Care Centers had the responsibility to administer HIN weekly to parents. Compliance was evaluated verifying attendance to follow up in the Pediatric Unit. TB index case patients were 123, they had 318 exposed children, were excluded 21: moved houses 6; developed HIN allergy 2; non pulmonary TB contacts PPD (-) 11; secondary cases 2 (in DOT). At the second visit (diagnosis), 27 children quit (8 percent). 270 left for analysis. At the third visit, 160 turned up (59 percent) and 136 turned up for the 6 mo checkup (50 percent). It is possible some degree of inaccuracy in the information provided by parents about drugs administration but is clear that in our environment, compliance is deficient and increase with length of chemoprophylaxis.

Se desconoce el grado de cumplimiento de la quimioprofilaxis (QP) en Chile y las publicaciones disponibles en el mundo son escasas. Las tasas de tuberculosis (TBC) del país al año 2002 habían bajado a 20 por 100.000 y continúan bajando. Se está enfatizando ahora la protección de los expuestos, lo que se hace mediante administración de isoniacida (HIN). El manejo de contactos infantiles en nuestro hospital consiste en seguimiento de todos los expuestos a TBC bacilífera por 6 meses mediante 4 visitas. 1ª ingreso para PPD 2 UT, radiografía de tórax (RXT) y Koch en caso de expectoración. 2a visita 72 h diagnóstico, 3ª visita al tercer mes para control y eventualmente repetir PPD y 4ª visita al 6º mes para dar alta con RXT. Evaluamos el grado de cumplimiento de QP verificando la asistencia a controles de los niños contactos de enfermos TBC referidos desde 2003 a 2005 a la Unidad de Neumología Pediátrica. Se indicó QP según tuberculina: si PPD > 10 mm HIN 6 meses. Si PPD < 10 mm recibían HIN hasta repetir PPD en control de 3 meses. Si este resultaba positivo se continuaba con HIN hasta el sexto mes. Sin PPD (falla ocasional) HIN 6 meses. El HIN era entregado semanalmente desde los centros de atención primaria a los padres o personas a cargo de los niños. Los casos índices estudiados fueron 123, contactos infantiles menores de 15 años 318. Fueron excluidos 21: 6 traslados, 2 alergias HIN, 11 contactos de TBC extra pulmonar con PPD negativo (no se les indica control), 2 casos secundarios (en tratamiento directamente observado). Faltaron al 2º control (de diagnóstico) 27 (8 por ciento), quedando para análisis posterior 270 niños. Asistieron al 3º control habiendo cumplido 3 meses de QP 160 niños (59 por ciento) y al 6º mes 136 (50 por ciento). Cuando el PPD era positivo el cumplimiento fue mejor (75 por ciento y 69 por ciento respectivamente). Se concluye que en nuestro sector el cumplimiento de asistencia a controles es deficiente a los 3 meses y...

Alginate nanoparticles as antituberculosis drug carriers: formulation development, pharmacokinetics and therapeutic potential.

BACKGROUND: Reduction in the dosing frequency of antituberculosis drugs (ATDs) by applying drug delivery technology has the potential to improve the patient compliance in tuberculosis (TB). Alginate (a natural polymer) based nanoparticulate delivery system was developed for frontline ATDs (rifampicin, isoniazid, pyrazinamide and ethambutol). METHODS: Alginate nanoparticles were prepared by the controlled cation induced gelification method and administered orally to mice. The drug levels were analysed by high performance liquid chromatography (HPLC) in plasma/tissues. The therapeutic efficacy was evaluated in M. tuberculosis H37Rv infected mice. RESULTS: High drug encapsulation efficiency was achieved in alginate nanoparticles, ranging from 70%-90%. A single oral dose resulted in therapeutic drug concentrations in the plasma for 7-11 days and in the organs (lungs, liver and spleen) for 15 days. In comparison to free drugs (which were cleared from plasma/organs within 12-24 h), there was a significant enhancement in the relative bioavailability of encapsulated drugs. In TB-infected mice three oral doses of the formulation spaced 15 days apart resulted in complete bacterial clearance from the organs, compared to 45 conventional doses of orally administered free drugs. CONCLUSIONS: Alginate nanoparticles appear to have the potential for intermittent therapy of TB.

Comparative molecular study of Mycobacterium tuberculosis strains, in times of antimicrobial drug resistance / Estudio molecular comparativo de cepas de Mycobacterium tuberculosis, en tiempos de resistencia antimicrobiana a los fármacos

Strains of Mycobacterium tuberculosis were compared using two DNA fingerprinting techniques: Restriction Fragment Length Polymorphism (RFLP) and Double-Repetitive-Element-PCR (DRE-PCR). Two of these strains: IH1 (susceptible to isoniazid) and IH2 (resistant to isoniazid) were recovered from cases of pulmonary tuberculosis which occurred in two brothers who lived together. The first one was recognized on July 1999, and the second was diagnosed one year later. IH1 and IH2 showed the same pattern of bands with both molecular tests. These results suggest that single drug chemoprophylaxis may occasionally select resistant strains for that drug, which can eventually cause disease and be recognized through these tests. Strains IH3, IH4 and IH5 were obtained from sputum samples of 3 different patients, and intra-laboratory cross-contamination was suspected when it was realized that the 3 positive materials had been consecutively processed the same day by the same worker in the same biological safety cabinet. Again, the 3 strains revealed identical band patterns with RFLP and DRE-PCR, confirming the posed suspicion. The results with DRE-PCR were obtained after only 8 hours of work, without the need for subcultures. This procedure allows quick correction of treatment conducts, avoiding unnecessary exposure of people and bacteria to antimicrobial drugs.

Se compararon cepas de Mycobacterium tuberculosis utilizando 2 procedimientos de ADN fingerprinting: polimorfismo de los fragmentos de restricción (RFLP) y Double-Repetitive-Element-PCR (DRE-PCR). Dos de las cepas: IH1 (susceptible a isoniazida) e IH2 (resistente a isoniazida) se recuperaron a partir de casos de tuberculosis pulmonar que ocurrieron en dos hermanos convivientes. La primera fue aislada en julio de 1999 y la segunda un año después. IH1 e IH2 mostraron el mismo patrón de bandas por ambos procedimientos. Estos resultados sugieren que la quimioprofilaxis con una sola droga puede ocasionalmente seleccionar mutantes resistentes, las cuales pueden causar enfermedad y ser reconocidas por estos procedimientos. Las cepas IH3, IH4 e IH5 fueron aisladas de 3 pacientes diferentes, y examinadas por probable contaminación cruzada dentro del laboratorio ya que fueron procesadas el mismo día, por el mismo operador y en la misma cabina de seguridad biológica. Nuevamente, las 3 cepas revelaron el mismo patrón de bandas por RFLP y por DRE-PCR, confirmando la sospecha. Los resultados de la DRE-PCR se obtuvieron luego de 8 horas de trabajo, sin necesidad de subcultivos. Esta técnica permitiría la rápida correción de pautas de tratamiento, evitando la exposición innecesaria de personas y bacterias a drogas antimicrobianas.

Adverse drug reactions observed during DOTS.

A total of 8.37% of the 1195 patients treated at NDTB Centre with DOTS under RNTCP between January 2002 to June 2003 presented with adverse drug reactions. Patients showing any sort of adverse reactions were studied in detail by personal interviews and a semi-structured questionnaire. The profile of patients presenting with adverse reactions showed that majority of the patients (53%) had gastrointestinal reactions, the commonest presenting complaint being nausea and vomiting. General aches and pains were complained by about 35% and giddiness was the presenting complaint in 27% irrespective of the use of streptomycin, although giddiness was observed more often in Category II patients (59%). Skin rash and itching was complained by about 17% of patients and 11% complained of arthralgia, while only 1% had hepatotoxicity during treatment. Majority of the adverse reactions (67%) were observed within the first four weeks of treatment and only 0.25% of patients treated with DOTS had interruption of treatment for short periods.

Quimioprofilaxia na prevenção da tuberculose / Chemoprophylaxis in the prevention of tberculosis

A quimioprofilaxia da tuberculose constitui-se numa medida terapêutica para a prevenção da infecção pelo Mycobacterium tuberculosis ou para evitar o desenvolvimento da doença nos indivíduos infectados. Geralmente baseia-se na administração de isoniazida. Entretanto, o uso de rifampicina e pirazinamida vem sendo recentemente introduzido. Este trabalho tem como objetivo revisar os resultados dos principais estudos que avaliaram as indicações da quimioprofilaxia com isoniazida e sua associação com outras drogas, sua efetividade na prevenção da tuberculose considerando os diversos grupos de risco, e as alternativas do uso de outros esquemas. Procedeu-se à revisão sistemática da literatura, com ênfase em ensaios clínicos e meta-análises. Foram consultados também os documentos oficiais. Foram selecionados aqueles estudos que envolveram ensaios clínicos ramdomizados com uso de isoniazida, rifampicina ou pirazinamida em pacientes HIV positivos ou negativos. Concluiu-se que a isoniazida continua sendo efetiva na prevenção da tuberculose na população de indivíduos HIV negativos e de HIV positivos. A dose padrão de 5 a 15 mg/kg/dia tem mostrado proteção similar para períodos de tratamento de seis e doze meses. O risco de desenvolver hepatite foi menor que 1 por cento, sendo recomendada sua utilização com acompanhamento nos indivíduos com idade superior a 35 anos e usuários de álcool. Os estudos com esquemas de tratamento utilizando outros medicamentos não foram conclusivos, sendo necessária a realização de novos estudos para avaliação da efetividade desses esquemas em populações de alto risco de desenvolver tuberculose.