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1.
Internist (Berl) ; 60(11): 1155-1175, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31641790

RESUMO

Tuberculosis is a bacterial infectious disease that is usually transmitted by inhalation of droplets containing the bacteria. The World Health Organization (WHO) estimates that approximately 10 million patients were newly diagnosed with tuberculosis in 2017. Rapid diagnosis relies on a combination of imaging and microbiological, molecular, and, rarely, immunological tests. Genotypic methods enable early diagnosis and allow highly accurate prediction of drug resistance. Phenotypic (culture-based) methods are the diagnostic gold standard. Standard management of patients with pan drug-susceptible pulmonary tuberculosis includes a combination of rifampicin, isoniazid, ethambutol and pyrazinamide for 2 months followed by rifampicin and isoniazid for additional 4 months, which leads to cure rates of >80%. With individualized treatment schemes, similar cure rates can be achieved for patients with multidrug-resistant tuberculosis.


Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Etambutol/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
2.
Medicine (Baltimore) ; 98(41): e17523, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593125

RESUMO

Therapeutic drug monitoring has been employed in anti-tuberculosis (TB) drugs to assess optimal dose for maximum therapeutic effects and minimal toxicity. But the determinants of serum concentration need further evidences.In a retrospective case-control study, clinical and laboratory data were collected from 717 in-patients with TB at Xi'an Chest Hospital, China. Two hours serum concentrations of isoniazid, rifampicin, pyrazinamide as well as ethambutol were obtained and analyzed by liquid chromatography-tandem mass spectrometry.The month 2 culture conversion group had lower concentration of isoniazid, pyrazinamide, and ethambutol than month 1 group. Statistical analysis showed that serum concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol revealed a positive relationship with dose (mg/kg) (P < .001, P < .001, P < .001, and P = .003, respectively). Furthermore, isoniazid concentration was related to smoking (P = .009) and prior TB (P = .011), while rifampicin and pyrazinamide concentrations were correlated to sex (P = .004 and 0.025, respectively). Ethambutol concentration was associated with creatinine clearance (Ccr, P = .002).It is necessary to optimize drug doses using therapeutic drug monitoring while considering the following determinants: weight, smoking status, prior TB, sex, and Ccr. Furthermore, low 2 hours serum concentrations can be associated with longer culture conversion.


Assuntos
Etambutol/sangue , Isoniazida/sangue , Pirazinamida/sangue , Rifampina/sangue , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/sangue , Antituberculosos/metabolismo , Antituberculosos/uso terapêutico , Estudos de Casos e Controles , China/epidemiologia , Cromatografia Líquida/instrumentação , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Etambutol/metabolismo , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/metabolismo , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirazinamida/metabolismo , Pirazinamida/uso terapêutico , Estudos Retrospectivos , Rifampina/metabolismo , Rifampina/uso terapêutico , Fatores Sexuais , Fumar/efeitos adversos , Tuberculose/sangue , Adulto Jovem
3.
BMC Infect Dis ; 19(1): 794, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500572

RESUMO

BACKGROUND: Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy. METHODS: A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy. RESULTS: Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa's high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation. CONCLUSIONS: Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose/tratamento farmacológico , Adulto , Diarilquinolinas/uso terapêutico , Humanos , Cadeias de Markov , Nitroimidazóis/uso terapêutico , Prevalência , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , África do Sul/epidemiologia , Resultado do Tratamento , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
4.
Brasília; CONITEC; set. 2019. tab.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1024747

RESUMO

CONTEXTO: A TB pode ser causada por qualquer uma das sete espécies que integram o complexo Mycobacterium tuberculosis, a espécie mais importante é a M. tuberculosis, conhecida também como bacilo de Koch. Estima-se que em 2015 cerca de 10,4 milhões de pessoas desenvolveram tuberculose (TB) dos quais 10% correspondem a tuberculose em crianças. TECNOLOGIA: Rifampicina 75 mg + isoniazida 50 mg + pirazinamida 150 mg e Rifampicina 75 mg + isoniazida 50 mg comprimidos dispersíveis. PERGUNTA: O uso do esquema terapêutico dose fixa combinada de rifampicina 75mg + isoniazida 50mg + pirazinamida 150mg seguida de rifampicina 75mg + isoniazida 50mg é eficaz, seguro e custo-efetivo em pacientes com tuberculose menores de 10 anos de idade quando comparado às formulações individualizadas de rifampicina 20 mg/ml (2%), rifampicina + isoniazida 150 mg + 75 mg, Isoniazida 100 mg, Pirazinamida 30 mg/ml (3%) ? EVIDÊNCIAS CIENTÍFICAS: Não foram encontrados estudos em pacientes pediátricos comparando a dose fixa combinada, em sua forma dispersível, com a dose padrão individualizada. Uma revisão sistemática não detectou diferença significativa entre as estratégias farmacológicas em relação à falha de tratamento (RR 1,28, IC95% 0,82 a 2,00), morte (RR 0,96, IC 95% 0,56 a 1,66), eventos adversos (RR 1,45 IC 95% 0,90 a 2,33) e eventos que levassem a descontinuação do tratamento (RR 0,56 IC 95% 0,56 a 1,66). AVALIAÇÃO ECONÔMICA: Assumindo-se que as duas estratégias de tratamento são similares, uma analise de custo-minimização foi realizada. A dose fixa combinada dispersível apresentou um custo de R$ 18,06 reais a menos por tratamento em relação a dose individualizada. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto em cinco anos da substituição do tratamento individualizado pela dose fixa combinada poderá resultar em uma economia de R$ 118.239,62. Cenários alternativos com a variação da taxa de câmbio em 10% podem variar em uma economia de recursos na ordem de R$ 68.420,88 a 166.936,09 em cinco anos. EXPERIÊNCIA INTERNACIONAL: Há um consenso nas diretrizes internacionais sobre o tratamento da tuberculose infantil. Não há recomendações específicas relacionadas à forma farmacêutica dispersível exceto pela OMS que recomenda formulações em dose fixa como parte das estratégias de combate a tuberculose. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As pesquisas apontaram não haver medicamentos em fase de desenvolvimento clínico para o tratamento da tuberculose pediátrica. RECOMENDAÇÃO PRELIMINAR: A CONITEC, em sua 78ª reunião ordinária, realizada no dia 05 de junho de 2019, recomendou a incorporação da dose fixa combinada de Rifampicina 75 mg + isoniazida 50 mg + pirazinamida 150 mg e Rifampicina 75 mg + isoniazida 50 mg comprimidos dispersíveis. Considerou que o medicamento já vem sendo utilizado no tratamento da tuberculose pediátrica com sucesso e a nova forma farmacêutica em dose fixa combinada na forma dispersível, por sua melhor aceitabilidade, permitiria a melhor adesão ao tratamento e consequentemente aumento das taxas de curas da doença na população pediátrica. CONSULTA PUBLICA: Foram recebidas 31 contribuições técnico-científicas e 48 contribuições de experiência ou opinião, a maioria em concordância com as recomendações da Conitec. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 80ª reunião ordinária, no dia 08 de agosto de 2019, deliberaram, por unanimidade, por recomendar a incorporação no SUS da dose fixas pediátricas RHZ (Rifampicina 75 mg + Isoniazida 50 mg + Pirazinamida 150 mg) e RH (Rifampicina 75 mg + Isoniazida 50 mg) comprimidos dispersíveis para tratamento da tuberculose em crianças menores de 10 anos. Foi assinado o Registro de Deliberação nº 463/2019. DECISÃO: Incorporar as doses fixas pediátricas RHZ (rifampicina 75mg + isoniazida 50mg + pirazinamida 150mg) e RH ( rifampicina 75mg + isoniazida 50mg) comprimido dispersíveis para tratamento de turbeculose em crianças menores de 10 anos, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 43, publicada no Diário Oficial da União nº 174, seção 1, página 190, em 09 de setembro de 2019.


Assuntos
Humanos , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Isoniazida/uso terapêutico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
6.
Folia Med (Plovdiv) ; 61(2): 312-316, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301651

RESUMO

BACKGROUND: Sarcoidosis and tuberculosis are chronic diseases that rarely occur concomitantly. We present the case of a 39-year-old woman with microbiological confirmation of pulmonary tuberculosis and concomitant sarcoidosis. Four weeks after corticosteroid therapy for sarcoidosis was introduced we had positive findings of mycobacterium culture from bronchial aspirate. Based on these results, corticosteroid therapy was discontinued and the patient received anti-tuberculosis therapy for six months as required by the national guidelines. During this period, new nodes on face, nose, and ear appeared and the patient was diagnosed with skin sarcoidosis. The patient received colchicine and corticosteroids as per the national guidelines. CONCLUSION: In cases of diagnostic uncertainty between sarcoidosis and tuberculosis we should administer corticosteroid therapy until we have microbiological confirmation of mycobacterium culture.


Assuntos
Sarcoidose Pulmonar/complicações , Tuberculose Pulmonar/complicações , Adulto , Antituberculosos/uso terapêutico , Desprescrições , Etambutol/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Prednisolona/uso terapêutico , Pirazinamida/uso terapêutico , Radiografia Torácica , Rifampina/uso terapêutico , Romênia , Sarcoidose Pulmonar/diagnóstico por imagem , Sarcoidose Pulmonar/tratamento farmacológico , Tomografia Computadorizada por Raios X , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Vitamina B 6/uso terapêutico , Complexo Vitamínico B/uso terapêutico
7.
PLoS One ; 14(2): e0212798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30817803

RESUMO

OBJECTIVES: Automated online software tools that analyse whole genome sequencing (WGS) data without the need for bioinformatics expertise can motivate the implementation of WGS-based molecular drug susceptibility testing (DST) in routine diagnostic settings for tuberculosis (TB). Pyrazinamide (PZA) is a key drug for current and future TB treatment regimens; however, it was reported that predictive power for PZA resistance by the available tools is low. Therefore, this low predictive power may make users hesitant to use the tools. This study aimed to elucidate why and to uncover the real performance of the tools when taking into account their variation calling lists (manual inspection), not just their automated reporting system (default setting) that was evaluated by previous studies. METHODS: WGS data from 191 datasets comprising 108 PZA-resistant and 83 susceptible strains were used to evaluate the potential performance of the available online tools (TB Profiler, TGS-TB, PhyResSE, and CASTB) for predicting phenotypic PZA resistance. RESULTS: When taking into consideration the variation calling lists, 73 variants in total (47 non-synonymous mutations and 26 indels) in pncA were detected by TGS-TB and PhyResSE, covering all mutations for the 108 PZA-resistant strains. The 73 variants were confirmed by Sanger sequencing. TB Profiler also detected all but three complete loss, two large deletion at the 3'-end, and one relatively large insertion of pncA. On the other hand, many of the 73 variants were lacking in the automated reporting systems except by TGS-TB; of these variants, CASTB detected only 20. By applying the 'non-wild type sequence' approach for predicting PZA resistance, accuracy of the results significantly improved compared with that of the automated results obtained by each tool. CONCLUSION: Users can obtain more accurate predictions for PZA resistance than previously reported by manually checking the results and applying the 'non-wild type sequence' approach.


Assuntos
Antituberculosos/farmacologia , Biologia Computacional/métodos , Mycobacterium tuberculosis/genética , Pirazinamida/farmacologia , Amidoidrolases/genética , Antituberculosos/uso terapêutico , Biologia Computacional/instrumentação , DNA Bacteriano/genética , Conjuntos de Dados como Assunto , Farmacorresistência Bacteriana/genética , Genoma Bacteriano/genética , Humanos , Internet , Testes de Sensibilidade Microbiana/métodos , Mutação , Pirazinamida/uso terapêutico , Software , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Sequenciamento Completo do Genoma
8.
BMC Infect Dis ; 19(1): 129, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732572

RESUMO

BACKGROUND: Tuberculosis (TB) is the leading cause of death from an infectious disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a steady rise in the number of patients with multidrug-resistant (MDR)-TB referred for treatment. Pyrazinamide is used in susceptible TB treatment for 6 months when used in combination with rifampin, isoniazid and ethambutol and is an important companion drug in novel MDR-TB trials. This study was undertaken to determine the prevalence of pyrazinamide resistance by either phenotypic or pncA testing among patients admitted to a referral hospital in Tanzania for drug-susceptible and MDR-TB treatment. METHODS: Surveillance sputa were sent among subjects beginning TB therapy at the national MDR-TB referral hospital during a 6 month period in 2013-2014. Mycobacterial cultures of pretreatment sputa were performed at the Kilimanjaro Clinical Research Institute (KCRI) in the BACTEC mycobacterial growth indicator tubes (MGIT) 960 system. Speciation of M. tuberculosis complex was confirmed by MTBc assay. Isolates were sub-cultured on to Lowenstein-Jensen (LJ) slants. Phenotypic resistance to pyrazinamide was performed in the MGIT system while a real-time PCR with High Resolution Melt (HRM) technique was used to determine mutation in the pncA gene from the same pure subculture. Sputa were then collected monthly to determine the time to culture negativity. Final treatment outcome was determined. RESULTS: Ninety-one M. tuberculosis isolates from individual patients were available for analysis of which 30 (32.9%) had MDR-TB, the mean (±SD) age was 33 ± 10 years, and the majority 23 (76.7%) were males. Of the 30 MDR-TB patients, 15(50%) had isolates with pyrazinamide resistance by conventional MGIT testing. This proportion expectedly exceeded the number with pyrazinamide resistance in the 61 patients without MDR-TB, 13 (21.3%) (p = 0.008). Six (20%) of MDR-TB patients had a poor outcome including treatment failure. Among patients with treatment failure, 5 (83%) had pyrazinamide resistance compared to only 10 (41.6%) with treatment success (p = 0.08). Two patients died, and both had isolates with pyrazinamide resistance. No other pretreatment characteristic was associated with treatment outcome. CONCLUSION: Pyrazinamide susceptibility appears to be important in clinical outcomes for MDR-TB patients, and susceptibility testing appears to be a critical adjunct to TB care. The high proportion of PZA resistance in non-MDR TB cases calls for further local investigation.


Assuntos
Antituberculosos/uso terapêutico , Pirazinamida/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose/tratamento farmacológico , Adulto , Amidoidrolases/genética , Amidoidrolases/metabolismo , Antituberculosos/farmacologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/metabolismo , Prevalência , Pirazinamida/farmacologia , Tanzânia/epidemiologia , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto Jovem
9.
Mucosal Immunol ; 12(3): 772-783, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30783183

RESUMO

Current treatments for tuberculosis (TB) are effective in controlling Mycobacterium tuberculosis (Mtb) growth, yet have significant side effects and do not prevent reinfection. Therefore, it is critical to understand why our host defense system is unable to generate permanent immunity to Mtb despite prolonged anti-tuberculosis therapy (ATT). Here, we demonstrate that treatment of mice with the most widely used anti-TB drugs, rifampicin (RIF) or isoniazid (INH) and pyrazinamide (PYZ), significantly altered the composition of the gut microbiota. Unexpectedly, treatment of mice with the pro-Mtb drugs INH and PYZ, but not RIF, prior to Mtb infection resulted in an increased bacterial burden, an effect that was reversible by fecal transplantation from untreated animals. Mechanistically, susceptibility of INH/PYZ-treated mice was associated with impaired metabolism of alveolar macrophages and defective bactericidal activity. Collectively, these data indicate that dysbiosis induced by ATT administered to millions of individuals worldwide may have adverse effects on the anti-Mtb response of alveolar macrophages.


Assuntos
Antibióticos Antituberculose/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/fisiologia , Macrófagos Alveolares/metabolismo , Mycobacterium tuberculosis/fisiologia , Tuberculose Pulmonar/tratamento farmacológico , Animais , Modelos Animais de Doenças , Disbiose/etiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/efeitos dos fármacos , Imunomodulação , Isoniazida/uso terapêutico , Macrófagos Alveolares/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico
10.
Indian J Tuberc ; 66(1): 111-117, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30797266

RESUMO

BACKGROUND/OBJECTIVE: Vitamin D deficiency may contribute to the therapeutic failure of antituberculosis therapy (ATT). The aim of this study is to explore the role of adding cholecalciferol to the standard ATT in improving the therapeutic outcome among the naïve patients with pulmonary tuberculosis (TB). METHODS: A randomized, controlled, clinical study, which included 496 naïve patients with pulmonary TB, was carried out. The patients were randomly allocated to two groups. Group-A included 247 patients who received ATT, while group-B included 249 patients who received ATT with cholecalciferol. RESULTS: The rate of therapeutic failure among the study population was 29.4%; it was significantly lower among patients of group-B compared to those of group-A (22.1% (95% CI 14.7-26.2) vs 38.1% (95% CI 31.5-46.1), p 0.036). In addition, the rate of early therapeutic response was significantly higher among patients of group-B compared to those of group-A (35.3% (95% CI 29.6-42.3) vs 19.4% (95% CI 15.1-24.6), p 0.041). Incidence rate of adverse effects was 19.3%; it was higher (although not statistically significant) among patients of group-A compared to those of group-B (21.9% vs 16.9%). CONCLUSIONS: In conclusion, cholecalciferol-augmented ATT can be more efficacious in treating naïve patients with pulmonary TB compared to the standard ATT. In addition, adding vitamin D3 to ATT provides extra protection against the hepatic and muscular adverse effects of ATT.


Assuntos
Antituberculosos/uso terapêutico , Colecalciferol/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Vitaminas/uso terapêutico , Adulto , Quimioterapia Combinada , Egito , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/uso terapêutico , Masculino , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Falha de Tratamento , Resultado do Tratamento , Adulto Jovem
11.
Indian J Tuberc ; 66(1): 12-19, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30797268

RESUMO

Tuberculosis (TB) being the leading infectious killer in the domain wherein globally, almost 20% of all TB strains are resistant to at least 1 major TB drug and there's a growing incidence of multi-drug resistance tuberculosis (MDR-TB). Looking at the current scenario and challenges the existing strategies fall back in terms of treatment of TB. So, to overcome this new, stronger, improved TB drug pipeline and a new standard for the development of novel anti-TB drugs are required in order to make more drug-resistant and efficient drug which also lower the duration period of the treatment of the TB. This review article aims to highlight the recent developments in the anti-tuberculosis agents, those are currently in the clinical development stage.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Diarilquinolinas/uso terapêutico , Desenvolvimento de Medicamentos , Quimioterapia Combinada , Etambutol/uso terapêutico , Etilenodiaminas/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Macrolídeos/uso terapêutico , Adesão à Medicação , Nitroimidazóis/uso terapêutico , Oxazolidinonas/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico
12.
Indian J Tuberc ; 66(1): 64-69, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30797286

RESUMO

Metformin (MET) is a potential combination drug to elevate anti-TB efficacy. However, the clinical effect, especially smear reversion, during metformin applied with anti-tuberculosis and insulin in patients with type 2 DM newly TB co-infection were remain unknown. An observational clinical study was done in DM newly TB co-infection outpatients at Surabaya Paru Hospital. This study evaluated MET therapy, at least 2 months, accompanying with insulin and anti-TB regimens and compared to comparison group. The smear, microtubule-associated Protein1 Light Chain 3B (MAP1LC3B) level, as the presentation of autophagy, Superoxide Dismutase (SOD) level, Interferon (IFN)-γ and Interleukin (IL)-10 levels were evaluated twice. From 42 participants in this study, 22 participants of observation group that received additional MET therapy, 100% had sputum smear reversion after 2-months intensive phase of anti-TB therapy. Whereas 25% of 20 participants of comparison group did not undergo reversion inserts sputum smear. As conclusion, MET has the potential of being an additive combination therapy to enhance the bactericidal effect of anti-TB on DM-TB coinfection patients. Metformin enhances the effects of anti-TB and insulin therapy in increasing the smear reversion by increasing autophagy.


Assuntos
Antituberculosos/uso terapêutico , Autofagia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico , Tuberculose/tratamento farmacológico , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada , Etambutol/uso terapêutico , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Isoniazida/uso terapêutico , Leucócitos Mononucleares/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Escarro/microbiologia , Superóxido Dismutase/metabolismo , Tuberculose/complicações , Tuberculose/metabolismo
13.
Am J Trop Med Hyg ; 100(2): 392-398, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30594266

RESUMO

Multidrug-resistant tuberculosis (MDR-TB) outcomes are poor partly because of the long treatment duration; the World Health Organization conditionally recommends a shorter course regimen to potentially improve treatment outcomes. Here, we describe the drug susceptibility patterns of a cohort of MDR-TB patients in Haiti and determine the number of likely effective drugs if they were treated with the recommended shorter course regimen. We retrospectively examined drug susceptibility patterns of adults initiating MDR-TB treatment between 2008 and 2015 at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections in Port-au-Prince, Haiti. First- and second-line drug susceptibility testing (DST) was analyzed and used to determine the number of presumed effective drugs. Of the 239 patients analyzed, 226 (95%), 183 (77%), 135 (57%), and 38 (16%) isolates were resistant to high-dose isoniazid, ethambutol, pyrazinamide, and ethionamide, respectively. Eight patients (3%) had resistance to either a fluoroquinolone or a second-line injectable and none had extensively resistant TB. Of the 239 patients, 132 (55%) would have fewer than five likely effective drugs in the intensive phase of the recommended shorter course regimen and 121 (51%) would have two or fewer likely effective drugs in the continuation phase. Because of the high rates of resistance to first-line TB medications, about 50% of MDR-TB patients would be left with only two effective drugs in the continuation phase of the recommended shorter course regimen, raising concerns about the effectiveness of this regimen in Haiti and the importance of using DST to guide treatment.


Assuntos
Antituberculosos/uso terapêutico , Etambutol/uso terapêutico , Etionamida/uso terapêutico , Fluoroquinolonas/uso terapêutico , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Coinfecção , Farmacorresistência Bacteriana Múltipla , Feminino , HIV/crescimento & desenvolvimento , Infecções por HIV/patologia , Infecções por HIV/virologia , Haiti , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Estudos Retrospectivos , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/patologia
14.
Neurol India ; 66(6): 1672-1677, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504561

RESUMO

Background: Stroke is common in tuberculous meningitis (TBM), and aspirin has been shown to reduce mortality. A combination of aspirin and corticosteroid may be more useful in this condition. Aim: To evaluate the effect of aspirin and corticosteroid adjunctive therapy alone or in combination in determining the outcome of TBM. Materials and Methods: One hundred and fifty-three patients with TBM were evaluated from a prospectively maintained registry. The diagnosis of TBM was based on the clinical, magnetic resonance imaging (MRI)/computed tomography (CT), and cerebrospinal fluid criteria. The baseline clinical, laboratory, and radiological findings were noted. All patients received the standard 4-drug antituberculous (rifampicin, isoniazid, pyrazinamide, and ethambutol) treatment. Group I patients received in addition, aspirin, in the dose of 150 mg daily; group II patients received aspirin 150 mg plus prednisolone 40 mg daily; and, group III patients received none of these adjunctive therapies. The outcome at 3 months was defined in terms of death or functional disability. Results: Group I had 44, group II had 50, and group III had 41 patients. The baseline characteristics of all these patients were similar, except in group II, where patients had more severe meningitis and focal deficits compared to the patients in group I and III. At 3 months, 32 (23%) patients died; 8 (18.2%) in group I, 9 (18%) in group II, and 14 (34.1%) in group III. There was insignificant survival benefit in group II (hazard ratio [HR], 1.55; 95% confidence interval (CI), 0.96-26.49; P = 0.07). The three-month functional outcome and side effects were not significantly different in the three groups. Conclusion: Aspirin with corticosteroid adjunctive treatment seems to be beneficial in reducing mortality in TBM.


Assuntos
Corticosteroides/uso terapêutico , Antituberculosos/uso terapêutico , Aspirina/uso terapêutico , Encéfalo/diagnóstico por imagem , Acidente Vascular Cerebral/prevenção & controle , Tuberculose Meníngea/tratamento farmacológico , Adolescente , Adulto , Quimioterapia Combinada , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Tuberculose Meníngea/complicações , Tuberculose Meníngea/diagnóstico por imagem , Adulto Jovem
15.
J Med Case Rep ; 12(1): 371, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30554566

RESUMO

BACKGROUND: Cutaneous tuberculosis represents only 1-2% of extrapulmonary forms of tuberculosis. Scrofuloderma is an endogenous form of cutaneous tuberculosis and can present as isolated or coexist with pulmonary and disseminated forms of tuberculosis. Pathologically confirmed scrofuloderma coexisting with disseminated tuberculosis with a good treatment response is presented and discussed. CASE PRESENTATION: A 12-year-old African Ethiopian girl presented with bilateral neck swelling with purulent discharge and skin ulceration of 3 months' duration. Dry cough, low-grade fever, decreased appetite, drenching night sweats, global throbbing headache, and a significant amount of weight loss were also reported. Biopsy of the skin identified scrofuloderma, and Mycobacterium tuberculosis was also identified by Xpert MTB/RIF assay. Cerebrospinal fluid analysis and brain computed tomographic scans showed tuberculous meningitis and tuberculoma. Antituberculosis therapy with rifampicin, isoniazid, pyrazinamide, and ethambutol; prednisolone; pyridoxine; and wound care were provided. The patient was discharged for outpatient directly observed antituberculosis therapy in a nearby health center after acute complications were treated and once the skin lesion had started to dry or heal. CONCLUSIONS: Cutaneous tuberculosis should be considered in a child presenting with a skin lesion or discharge. Cutaneous tuberculosis cases should be investigated for coexisting pulmonary and extrapulmonary forms of tuberculosis. Histopathologic diagnosis should be considered to rule out other skin pathologies and also to prevent delay in treatment. Better tuberculosis prevention strategies, including vaccination scale-up, are warranted.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Pele/patologia , Tuberculose Cutânea/diagnóstico , Criança , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/uso terapêutico , Pescoço/patologia , Prednisolona/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose Cutânea/tratamento farmacológico
16.
mBio ; 9(6)2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459198

RESUMO

Recent reports indicate that the sputum of 80% or more of treatment-naive subjects with tuberculosis recruited in England or South Africa contained more viable Mycobacterium tuberculosis cells detected by limiting dilution (LD) in liquid culture than detected as CFU. Efforts to generate such differentially detectable (DD) M. tuberculosis populations in vitro have been difficult to reproduce, and the LD assay is prone to artifact. Here, we applied a stringent version of the LD assay to sputum from 33 treatment-naive, HIV-negative Haitian subjects with drug-sensitive tuberculosis (TB) and to a second sputum sample after two weeks of standard treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) for 13 of these subjects. Twenty-one percent had statistically defined levels of DD M. tuberculosis in their pretreatment sputum at an average proportional excess over CFU of 3-fold. Sixty-nine percent of those who received HRZE had statistically defined levels of DD M. tuberculosis in their sputum, and of these, the mean proportionate excess over CFU was 7.9-fold. Thus, DD M. tuberculosis is detectable in pretreatment sputum from a significant proportion of subjects in the Western Hemisphere, and certain drugs or drug regimens, while reducing CFU, may at the same time increase the proportional representation of DD M. tuberculosis among the surviving bacilli. Monitoring DD M. tuberculosis may improve our ability to predict the efficacy of efforts to shorten treatment.IMPORTANCE Measurement of the reduction in CFU in sputum of patients with TB up to 2 weeks after the initiation of treatment is the gateway test for a new TB treatment. Reports have suggested that CFU assays fail to detect the majority of viable M. tuberculosis cells in sputum samples from the majority of patients when the number of M. tuberculosis is estimated by limiting dilution (LD). In an effort to avoid potential methodologic confounders, we applied a modified version of the LD assay in a study of a geographically distinct population. We confirmed that differentially detectable (DD) M. tuberculosis is often found before treatment, albeit at lower proportionate levels than in earlier reports. Strikingly, the prevalence and proportionate representation of DD M. tuberculosis increased during standard treatment. Sublethal exposure to certain antibiotics may help generate DD M. tuberculosis cells or enrich their representation among the surviving bacteria, and this may contribute to the need for prolonged treatment with those agents in order to achieve durable cures.


Assuntos
Antituberculosos/uso terapêutico , Técnicas Microbiológicas , Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Adulto , Contagem de Colônia Microbiana , Quimioterapia Combinada , Feminino , Haiti , Humanos , Isoniazida/uso terapêutico , Masculino , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pirazinamida/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto Jovem
17.
BMJ Case Rep ; 20182018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279249

RESUMO

The use of biologic drugs has expanded since its introduction in the late 1990s. With growing medical use and newer biologic drugs in development, opportunistic infections like Mycobacterium tuberculosis remain important adverse effects. It carries major public health concerns, yet evidence-based clinical guidelines for more routine interval screening in patients taking immunosuppressants and exposed to tuberculosis (TB) are lacking. We illustrate a case of an elderly Indian-born man living in the USA with psoriatic arthritis who was on adalimumab for 10 years. He presented with disseminated TB and herpes simplex virus type 1 (HSV-1) pharyngitis, a year after an innocuous trip to India. Our case draws attention to the adverse effects of biologic drugs and highlights the importance of regular rescreening for a high-risk population. As the use of biologic treatment increases, physicians must be vigilant in more frequent screening, monitoring and identifying related opportunistic infections, notably M. tuberculosis infections.


Assuntos
Adalimumab/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Herpes Simples/diagnóstico , Faringite/diagnóstico , Tuberculose Miliar/diagnóstico , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Antirreumáticos/uso terapêutico , Antituberculosos/uso terapêutico , Artrite Reumatoide/complicações , Países em Desenvolvimento , Diagnóstico Diferencial , Herpes Simples/complicações , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1 , Humanos , Índia , Isoniazida/uso terapêutico , Levofloxacino/uso terapêutico , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Masculino , Infecções Oportunistas/complicações , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Faringite/complicações , Faringite/tratamento farmacológico , Pirazinamida/uso terapêutico , Tomografia Computadorizada por Raios X , Doença Relacionada a Viagens , Teste Tuberculínico , Tuberculose Miliar/complicações , Tuberculose Miliar/tratamento farmacológico , Vitamina B 6/uso terapêutico
18.
Artigo em Inglês | MEDLINE | ID: mdl-30126955

RESUMO

Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration (C max) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed. Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in the C max of pyrazinamide and isoniazid (but not rifampin) with DM or increasing HbA1c values. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations (adjusted geometric mean ratio = 0.74, P = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, P = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, P < 0.001), and the pyrazinamide C max (aHR = 0.99, P = 0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampin concentrations were associated with a faster time to culture conversion in patients with DM only. A pyrazinamide C max above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, P = 0.04). DM and higher HbA1c values increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampin.


Assuntos
Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Diabetes Mellitus/fisiopatologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/fisiopatologia , Adulto , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Isoniazida/farmacocinética , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirazinamida/farmacocinética , Pirazinamida/uso terapêutico , Rifampina/farmacocinética , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Pulmonar/metabolismo , Adulto Jovem
19.
J Exp Med ; 215(8): 1975-1986, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30018074

RESUMO

In the 1970s, inclusion of pyrazinamide (PZA) in the drug regimen of tuberculosis (TB) patients for the first 2 mo achieved a drastic reduction of therapy duration. Until now, however, the mechanisms underlying PZA's unique contribution to efficacy have remained controversial, and animal efficacy data vary across species. To understand how PZA kills bacterial populations present in critical lung lesion compartments, we first characterized a rabbit model of active TB, showing striking similarities in lesion types and fates to nonhuman primate models deemed the most appropriate surrogates of human TB. We next employed this model with lesion-centric molecular and bacteriology readouts to demonstrate that PZA exhibits potent activity against Mycobacterium tuberculosis residing in difficult-to-sterilize necrotic lesions. Our data also indicate that PZA is slow acting, suggesting that PZA administration beyond the first 2 mo may accelerate the cure. In conclusion, we provide a pharmacodynamic explanation for PZA's treatment-shortening effect and deliver new tools to dissect the contribution of immune response versus drug at the lesion level.


Assuntos
Antituberculosos/uso terapêutico , Pirazinamida/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Animais , Antituberculosos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Viabilidade Microbiana/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Necrose , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Pirazinamida/farmacologia , Coelhos , Tuberculose/microbiologia , Tuberculose/patologia
20.
Tuberculosis (Edinb) ; 111: 109-113, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30029894

RESUMO

Outbreak of drug resistant tuberculosis in the Western province, Papua New Guinea is a concern to Queensland, Australia due to migration. We performed pncA mutation analysis and genotyping of multi-drug/pyrazinamide (MDR/PZA) resistant isolates from 18 Queensland (Qld) migrants and 81 Papua New Guinea (PNG) residents, to compare with phenotypic evidence of PZA resistance and to evaluate the genotypes obtained from the two countries. Seven different mutations were seen from Qld isolates of which 2 have not been described previously. A cluster of mutations were found between amino acids L35 and S65. Amongst the PNG isolates, 10 mutations were identified, of which 6 were unique and have not been described previously. Majority of the mutations formed 2 clusters, between amino acids Q10 to A20 and W68 to W119. Mutations identified at nucleotide (nt) position 202 and 307 were found to be the most common types, occurring in 25% and 51% of the PNG isolates respectively. The majority of the mutations were seen in MDR/PZA resistant isolates. These mutations could be utilized for direct screening of PZA resistance from PNG patient samples. Genotypic analysis of the isolates showed strong clustering amongst the PNG isolates as opposed to Qld isolates. A diversity of mutations and genotypes were seen amongst the Qld migrant isolates. Majority of PNG isolates had one genotype with two distinct pncA mutation patterns (T202C and T307G) which highlight on-going transmission. pncA mutation analysis provided a satisfactory alternative to PZA culture DST with high positive predictive value and an improved result turnaround time.


Assuntos
Amidoidrolases/genética , Antituberculosos/uso terapêutico , DNA Bacteriano/genética , Farmacorresistência Bacteriana Múltipla/genética , Emigração e Imigração , Mutação , Mycobacterium tuberculosis/genética , Pirazinamida/uso terapêutico , Migrantes , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Grupo com Ancestrais do Continente Africano/genética , Análise Mutacional de DNA , Genótipo , Humanos , Epidemiologia Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Grupo com Ancestrais Oceânicos/genética , Papua Nova Guiné/etnologia , Fenótipo , Queensland/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/etnologia , Tuberculose Resistente a Múltiplos Medicamentos/transmissão
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