Efficacy and safety of a four-drug fixed-dose combination regimen versus separate drugs for treatment of pulmonary tuberculosis : a systematic review and meta-analysis

Introduction: tuberculosis, particularly multi-drug-resistant tuberculosis, is a major cause of morbidity and mortality worldwide. To the best of our knowledge, however, no study to date has assessed the combined use of the four available drugs for tuberculosis treatment, which is an issue of great clinical relevance. Objective: to determine whether the four-drug fixed-dose combination is safer or more effective than separate drugs for treatment of pulmonary tuberculosis. Methods: a systematic review of the literature was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: in pooled results from five randomized controlled trials with 3502 patients across Africa, Asia, and Latin America, four-drug fixed-dose combination therapy was no better than separate drugs therapy in terms of culture conversion after 2 and 6 months of treatment. There were no significant differences between the groups in overall incidence of adverse effects. However, the meta-analytic measure (log odds ratio) revealed that separate drugs treatment had a 1.65 [exp (0.5) = 1.65] increased chance of gastrointestinal adverse effects compared to four-drug fixed-dose combination treatment. Conclusions: the reviewed studies showed that four-drug fixed-dose combination therapy provides greater patient comfort by reducing the number of pills and the incidence of gastrointestinal adverse effects, as well as simplifying pharmaceutical management at all levels

Evaluation of resistance to first-line tuberculostatic drugs in isolates of Mycobacterium Tuberculosis complex in Federal District

Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2015.A tuberculose (TB) continua sendo uma das principais causas de morbidade e mortalidade em todo o mundo, necessitando a TB multirresistente de medidas para ser evitada por ser uma ameaça para o mundo. Determinar se a terapia com quatro drogas em dose fixa combinada (4-DFC) é mais eficaz e mais segura que aquela com drogas separadas (DS) para o tratamento de tuberculose pulmonar na literatura e avaliar a resistência aos tuberculostáticos de primeira linha nos isolados do Complexo Mycobacterium tuberculosis no Distrito Federal foram os objetivos deste trabalho. Para analisar o novo tratamento para TB pulmonar foi realizada uma revisão sistemática com meta-análise dos estudos encontrados e para avaliar a resistência aos tuberculostáticos de primeira linha foi realizado um estudo transversal descritivo no LACEN-DF com cepas coletadas no período de 2001 a 2013 que comparou os perfis de sensibilidade antes e após a introdução do novo tratamento para TB. No período de 2011 a 2013 foi comparado um método tradicional de detecção de resistência (SIRE BACTEC MGIT 960®) com um teste molecular (Genotype MTBDRplus®), capaz de detectar as principais mutações nos genes associados à resistência à rifampicina e à isoniazida. As taxas de resistência secundária aos tuberculostáticos de primeira linha no período de 2001 a 2013 foram de 4,8% à isoniazida, 1,3% à rifampicina e 4,7% à estreptomicina. As taxas de MDR-TB, XDR-TB e de outras resistências foram de 7,7%, 0,7% e 0,7%, respectivamente. Comparando o período de 2001-2003 com 2011-2013 pôde-se observar uma tendência de diminuição da multirresistência e uma elevação da monorresistência aos tuberculostáticos de primeira linha nos períodos analisados. A taxa de multirresistência secundária caiu após a introdução do novo tratamento, permitindo ao paciente maior chance de cura com a utilização de medicamentos menos tóxicos e de menor custo para o Estado. A monorresistência à estreptomicina aumentou, indicando uma possível reativação endógena por cepas anteriores à década de 1980. As mutações encontradas no gene rpoB, responsável pela resistência à rifampicina, se localizavam no códon 531, enquanto as associadas à resistência à isoniazida, no códon 315 do gene KatG e no códon 15 do gene inhA. A acurácia do teste GenoType MTBDRplus® no DF para a detecção da resistência à rifampicina e à isoniazida foi confirmada quando comparada ao teste de sensibilidade convencional com menor tempo de resposta na detecção de resistência aos fármacos. Em decorrência dos resultados encontrados neste trabalho o ensaio GenoType MTBDRplus® foi incluído na rotina do LACEN-DF para o diagnóstico precoce da TB e controle de sua multidroga resistência no DF, trazendo assim benefícios substanciais para o diagnóstico rápido da TB e do seu perfil de resistência.Tuberculosis (TB) continues to be a major cause of morbidity and mortality worldwide and the multi-drug resistant TB is a threat to the world and needs measures to be avoided. To evaluate whether the four-drug therapy in fixed dose combination (4-FDC) is more effective and safer than the separate drugs (SD) therapy for the treatment of pulmonary TB in the literature and determine the resistance to first-line antituberculosis drugs in isolates of Mycobacterium tuberculosis in the Federal District were the objectives of this work. A systematic review with meta-analysis of studies found was conducted to analyze the new treatment for pulmonary TB, and to evaluate the resistance to first-line tuberculostatic drugs in isolates of Mycobacterium tuberculosis complex in Federal District of Brazil a crosssection descriptive study was undertaken in LACEN-DF in isolates collected from 2001 to 2013. A comparison of the sensitivity profiles before and after the introduction of the fixeddose combination treatment for tuberculosis. From 2011 to 2013 (sensitivity tests using the SIRE BACTEC MGIT 960® system were compared with a molecular one using Genotype MTBDRplus®, capable to detect the main mutations of genes associated to resistance to rifampicine and to isoniazide. The secondary resistance rates to first-line antituberculosis drugs in the period 2001-2013 were 4.8% to isoniazid, 1.3% to rifampicin and 4.7% to streptomycin. The rates of MDR-TB, XDR-TB and other resistances were 7.7%, 0.7% and 0.7%, respectively. Comparing the period 2001-2003 with 2011-2013, a tendency of decrease in multidrug resistance was observed, with an increase of monoresistance to first-line antituberculosis drugs in the analyzed periods. The rate of secondary multi-resistance has fallen after the introduction of the new treatment, which gives patients higher chance of healing taking less toxic drugs that are cheaper for the government. The mono-resistance to streptomicine increased, indicating a possible endogenous reactivation by isolates before 1980 decade. The mutations found in the rpoB gene, responsible for resistance to rifampicin, were located at codon 531 and those responsible for resistance to isoniazid in the katG gene at codon 315 and in the inhA gene at codon 15. The accuracy of GenoType MTBDRplus® in DF for detecting the resistance to rifampicine and to isoniazide was confirmed when compared with the conventional sensitivity test with less response time for detecting the resistance. According to results found in this work the GenoType MTBDRplus® essays was included in the routine of LACEN-DF for the early diagnose and control of multidrugresistant tuberculosis in Federal District, producing substantial benefits for the fast diagnosis confirmation and its resistance profile

Perfil farmacoterapêutico dos pacientes do ambulatório de pneumologia do Hospital Universitário de Brasília

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2010.As doenças respiratórias, entre elas a asma, representam um grave problema de saúde pública em todo o mundo, atingindo todas as faixas etárias e segmentos sociais. A asma é uma doença inflamatória crônica, caracterizada por hiper-responsividade das vias aéreas inferiores e por limitação variável ao fluxo aéreo, reversível espontaneamente ou com tratamento, manifestando-se clinicamente por episódios recorrentes de sibilância, dispneia, aperto no peito e tosse, particularmente à noite e pela manhã ao despertar. Sua fisiopatologia é multifatorial, influenciada por características genéticas, ocupacionais, ambientais e sócio-econômicas. Frequentemente provoca impacto sobre a qualidade de vida e sobre a demanda no Sistema de Saúde. O objetivo deste estudo foi avaliar o perfil farmacoterapêutico de pacientes asmáticos do ambulatório de pneumologia do Hospital Universitário de Brasília (HUB). Foi realizado um estudo transversal com 138 pacientes com atendimento farmacêutico antes e após as consultas médicas. Destes, 88 receberam o diagnóstico de asma. A prevalência de tratamentos que seguiam as IV Diretrizes Brasileiras para o Manejo da Asma era 1,98 (IC 95%: 1,04 a 3,81) vezes maior entre os pacientes do HUB do que entre os provenientes de outros serviços. Os resultados mostraram uma população em sua maioria do gênero feminino, com baixa escolaridade, apresentando em média 2,2 (± 1,06) enfermidades, sendo as mais frequentes hipertensão arterial, diabetes, DPOC, doenças reumatológicas e obesidade. Os pacientes utilizavam em média 4,3 medicamentos. O fator desencadeante estatisticamente significante das crises asmáticas foi de ordem ocupacional, seguido pelos fatores genéticos (marginalmente significantes). Entre os pacientes, 26,5% eram aderentes à farmacoterapia geral, 31,2% utilizavam algum medicamento por automedicação e 66% recorriam à rede privada para acesso aos medicamentos. Com base nos dados obtidos conclui-se que a população em estudo apresentou baixa escolaridade, pouco conhecimento sobre sua doença e seu tratamento, polimedicação, erros de medicação, problemas de acesso aos medicamentos e falta de adesão aos tratamentos. Esses problemas sugerem a necessidade de melhoria da qualidade da assistência aos pacientes portadores de doenças crônicas como a asma. Uma das estratégias propostas seria o atendimento multidisciplinar com inserção de farmacêuticos para atuar na promoção do uso racional de medicamentos. _______________________________________________________________________________ ABSTRACTRespiratory diseases, including asthma, represent a serious public health problem worldwide, affecting all age and social groups. Asthma is a chronic inflammatory disease characterized by hyper-responsiveness of the lower airways and by variable limitation of airflow, reversible spontaneously or with treatment, clinically expressed by recurrent episodes of wheezing, dyspnea, chest tightening and cough, particularly at night and in the morning on awakening. Its pathophysiology is multifactorial, influenced by genetic, occupational and environmental characteristics and socioeconomic status. It frequently provokes impact on the quality of life and on the demand on the Health System. The objective of this study was to evaluate the pharmacotherapeutic profile of asthma patients in the pulmonology clinic of University Hospital of Brasilia (HUB). In a cross-section study with 138 patients they received pharmaceutical orientation before and after the medical appointment. From those, 88 received the diagnosis of asthma. The prevalence of treatments that followed the IV Brazilian Guideline for the Management of Asthma was 1.98 times (IC 95%: 1.0366 to 3.8123) greater among patients from the HUB than among those from other health services. The results show a population composed mostly of women, with low education bracket, presenting on average 2.2 (± 1.06) diseases - the most frequent were arterial hypertension, diabetes, chronic obstructive pulmonary disease (COPD), rheumatoid diseases and obesity. The patients used on average 4.3 medicines. Statistically significant trigger factor of the asthma attacks was occupational exposures followed by genetic factors (marginally significant). Adherence to the pharmacotherapy was 26.5% and self-medication rate reached 31.2%. Sixty-six percent of interviewed patients had access to medicines on private service of health. In conclusion considering the data obtained that population presented low education level, low knowledge of their disease and its treatment, polymedication, medication errors, problems to obtein the medicines and lack of aherence to treatment. Such problems suggest the need to improve the quality of assistance to patients with chronic diseases such as asthma. One of the proposed strategies would be the multidisciplinary care with insertion of pharmacists to act in the promotion of rational use of medicines

Insertion sequences disrupting mgrB in carbapenem-resistant Klebsiella pneumoniae strains in Brazil

Objectives: This study aimed to characterise insertional mutations disturbing themgrB gene in carbapenem-resistant Klebsiella pneumoniae (CRKp). Methods: A total of 118 clinical CRKp isolates were surveyed for polymyxin resistance and insertion sequence (IS) elements disruptingmgrB. Results: Of the 118 isolates, 78 (66.1%) displayed polymyxin resistance, of which 54% (42/78) hadmgrB::IS inserts. Sequencing analyses showed 13 insertion sites in mgrB. mgrB::ISSen4(IS3) was observed for the first time in CRKp. Conclusions: Ten different IS elements disruptedmgrB, with a predominance (76%) of IS5 sequences