Hélio Ribeiro de Siqueira

Antituberculosis drugs: drug interactions, adverse effects, and use in special situations - part 2: second line drugs

Os objetivos principais do tratamento da tuberculose sao curar o paciente e minimizar a possibilidade de transmissao do bacilo para individuos saudaveis. Reacoes adversas ou interacoes das drogas antituberculose entre si e com outros farmacos podem causar modificacao ou descontinuacao da terapeutica. Revisamos sucintamente o novo tratamento farmacologico da tuberculose introduzido pelo Ministerio da Saude do Brasil em 2009 e mostramos os mecanismos gerais de acao, absorcao, metabolizacao e excrecao dos medicamentos utilizados no esquema basico. Descrevemos as reacoes adversas e as interacoes (com medicamentos, alimentos e antiacidos) assim como a abordagem mais adequada para situacoes especiais, como gravidez, amamentacao, insuficiencia hepatica e renal. Tambem descrevemos os mecanismos pelos quais as interacoes das drogas antituberculose do esquema basico podem causar hepatite medicamentosa e as possiveis alternativas nessa situacao.

Resistência aos medicamentos anti-tuberculose de cepas de Mycobacterium tuberculosis isoladas de pacientes atendidos em hospital geral de referência para tratamento de AIDS no Rio de Janeiro

BACKGROUND:Tuberculosis become important challenge to health care settings. Brazil has high prevalence of the disease and Rio de Janeiro has high incidence rates with 30% of cases notified at hospitals. OBJECTIVE: To evaluate prevalence of initial and acquired drug resistance at a general hospital, reference for aids treatment in Rio de Janeiro and to identify associated factors. METHODS: Mycobacterium tuberculosis strains from 165 patients were analyzed, between August 1996 and February 1998. RESULTS: Twenty per cent (33/165) were resistant to at least one drug; 13% (12/165) to isoniazid; 3.64% (6/165) to rifampin and 3.64% (6/165) to both. Among HIV seropositive subjects (52/165); 28.85% (15/52) were resistant to at least one drug. Acquired resistance occurred in 15.79% of 19 patients that mentioned previous antiTB treatment. Association statistically significant was found with non cavitation on X-ray in bivariate analyses (P=0.05). Eighty four patients refereed no previous treatment (NPT). Resistance to 1 or more drugs was found in 28.57% (24/84) of NPT patients. Association statistically significant with initial resistance was found with health care workers (P=0.004), unemployment (P=0.03), and diarrhea (P=0.01) in bivariate analyses. On multivariate analyses, health care workers (P=0.002) remained significantly associated with initial resistance. CONCLUSIONS: High resistance rates was found. It corroborates that hospitals needs attention for TB control especially which concerns to health care works infection.

Multidrug resistant Mycobacterium tuberculosis: a retrospective katG and rpoB mutation profile analysis in isolates from a reference center in Brazil.

Background Multidrug resistance is a critical factor in tuberculosis control. To gain better understanding of multidrug resistant tuberculosis in Brazil, a retrospective study was performed to compare genotypic diversity and drug resistance associated mutations in Mycobacterium tuberculosis isolates from a national reference center. Methods and Findings Ninety-nine multidrug resistant isolates from 12 Brazilian states were studied. Drug-resistance patterns were determined and the rpoB and katG genes were screened for mutations. Genotypic diversity was investigated by IS6110-RFLP and Luminex 47 spoligotyping. Mutations in rpoB and katG were seen in 91% and 93% of the isolates, respectively. Codon 315 katG mutations occurred in 82.8% of the isolates with a predominance of the Ser315Thr substitution. Twenty-five isolates were clustered in 11 groups with identical IS6110-RFLP patterns while 74 showed unique patterns with no association between mutation frequencies or susceptibility profiles. The most prevalent spoligotyping lineages were LAM (47%), T (17%) and Haarlen (12%). The Haarlen lineage showed a higher frequency of codon 516 rpoB mutations while codon 531 mutations prevailed in the other isolates. Conclusions Our data suggest that there were no major multidrug resistant M. tuberculosis strains transmitted among patients referred to the reference center, indicating an independent acquisition of resistance. In addition, drug resistance associated mutation profiles were well established among the main spoligotyping lineages found in these Brazilian multidrug resistant isolates, providing useful data for patient management and treatment.

Isoniazid-resistant Mycobacterium tuberculosis strains arising from mutations in two different regions of the katG gene

OBJECTIVE To analyze and compare the mutations in two different regions of the katG gene, which is responsible for isoniazid (INH) resistance. METHODS We analyzed 97 multidrug-resistant Mycobacterium tuberculosis strains isolated in cultures of sputum samples obtained from the Professor Hélio Fraga Referral Center, in Brasília, Brazil. Another 6 INH-sensitive strains did not present mutations and were included as controls. We used PCR to amplify two regions of the katG gene (GenBank accession no. U06258)-region 1, (from codon 1 to codon 119) and region 2 (from codon 267 to codon 504)-which were then sequenced in order to identify mutations. RESULTS Seven strains were resistant to INH and did not contain mutations in either region. Thirty strains carried mutations in region 1, which was characterized by a high number of deletions, especially at codon 4 (24 strains). Region 2 carried 83 point mutations, especially at codon 315, and there was a serine-to-threonine (AGC-to-ACC) substitution in 73 of those cases. The analysis of region 2 allowed INH resistance to be diagnosed in 81.4% of the strains. Nine strains had mutations exclusively in region 1, which allowed the proportion of INH-resistant strains identified to be increased to 90.6%. CONCLUSIONS The number of mutations at codon 315 was high, which is consistent with cases described in Brazil and in other countries, and the analysis of region 1 resulted in a 9.2% increase in the rate at which mutations were identified.

The challenge of managing extensively drug-resistant tuberculosis at a referral hospital in the state of São Paulo, Brazil: a report of three cases.

ABSTRACT Here, we report the cases of three patients diagnosed with extensively drug-resistant tuberculosis and admitted to a referral hospital in the state of São Paulo, Brazil, showing the clinical and radiological evolution, as well as laboratory test results, over a one-year period. Treatment was based on the World Health Organization guidelines, with the inclusion of a new proposal for the use of a combination of antituberculosis drugs (imipenem and linezolid). In the cases studied, we show the challenge of creating an acceptable, effective treatment regimen including drugs that are more toxic, are more expensive, and are administered for longer periods. We also show that treatment costs are significantly higher for such patients, which could have an impact on health care systems, even after hospital discharge. We highlight the fact that in extreme cases, such as those reported here, hospitalization at a referral center seems to be the most effective strategy for providing appropriate treatment and increasing the chance of cure. In conclusion, health professionals and governments must make every effort to prevent cases of multidrug-resistant and extensively drug-resistant tuberculosis.

Clinical evolution of a group of patients with multidrug-resistant TB treated at a referral center in the city of Rio de Janeiro, Brazil.

OBJECTIVE To analyze the clinical characteristics and evolution of a group of patients with positive sputum cultures for multidrug-resistant (MDR) Mycobacterium tuberculosis and treated at a referral center in the city of Rio de Janeiro, Brazil. METHODS Based on the positive results in sputum cultures for MDR M. tuberculosis, 50 patients were selected, and their clinical data were obtained from the Brazilian Ministry of Health MDR-TB Database. The frequencies of noncompliance, relapses, failures and previous treatments for TB up to diagnosis of MDR-TB were compiled. The radiological patterns were classified as unilateral or bilateral, and with or without cavitation. Two years after the end of the standard treatment for MDR-TB, the outcome (cure, failure, noncompliance or death) for each patient was evaluated and reassessed every two years. The post-treatment follow-up period was eight years. RESULTS The mean number of previous treatments was 2.3 +/- 0.9. The mean interval between the initial diagnosis and the development of MDR-TB was 2.0 +/- 1.7 years. Two years after the initial treatment for MDR-TB, 2 patients had abandoned treatment, 8 had died, 18 had been cured, and 22 had presented treatment failure. The bivariate analysis showed that bilateral pulmonary involvement and cavitary pattern markedly reduced the chances for cure, with a relative risk of 1-0.6 (40%) and 1-0.7 (30%), respectively. At the end of the follow-up period, 2 patients had abandoned treatment, 9 had presented treatment failure, 17 had been cured, and 22 had died. CONCLUSIONS Bilateral pulmonary involvement and cavity pattern greatly reduced the chances for cure of the patients with MDR-TB. Most patients who presented treatment failure died within the 8-year follow-up period.

Perspectives of Patients, Doctors and Medical Students at a Public University Hospital in Rio de Janeiro Regarding Tuberculosis and Therapeutic Adherence.

Introduction The World Health Organization (WHO) identifies 8.7 million new cases of tuberculosis (TB) annually around the world. The unfavorable outcomes of TB treatment prevent the achievement of the WHO’s cure target. Goal To evaluate existing intersections in the conceptions relative to the knowledge of TB, the experience of the illness and the treatment. Methods Doctors, medical students and patients were selected from a public university in Rio de Janeiro, Brazil, from 2011 to 2013. The data were obtained by semi-structured individual and focus group interviews, participant observation and a field journal. The inclusion of patients was interrupted due to saturation, and the inclusion of doctors and medical students stopped due to exhaustion. The theoretical background included symbolic Interactionism, and the analysis used rounded Theory. The analysis prioritized the actions/interactions axis. Results Twenty-three patients with pulmonary TB, seven doctors and 15 medical students were included. In the interviews, themes such as stigma, self-segregation, and difficulties in assistance emerged, in addition to defense mechanisms such as denial, rationalization, isolation and other mental mechanisms, including guilt, accountability and concealment of the disease. Aspects related to the assistance strategy, the social support network, bonding with the healthcare staff and the doctor-patient relationship were highlighted as adherence enablers. Doctors and students recommended an expansion of the theoretical and practical instruction on TB during medical students’ education. The existence of health programs and policies was mentioned as a potential enabler of adherence. Conclusion The main concepts identified were the stigma, self-segregation, guilt, responsibility, concealment and emotional repercussions. In relation to the facilitation of therapeutic adherence, the concepts identified were the bonds with healthcare staff, the doctor-patient relationship, assistance and educational health strategies.