RESUMO
An imbalance in the redox state, increased levels of lipid precursors and overactivation of de novo lipogenesis determine the development of fibrosis during nonalcoholic steatohepatitis (NASH). We evaluated the modulation of NADPH-producing enzymes associated with the antifibrotic, antioxidant and antilipemic effects of nicotinamide (NAM) in a model of NASH induced by excess fructose consumption. Male rats were provided drinking water containing 40% fructose for 16 weeks. During the last 12 weeks of fructose administration, water containing NAM was provided to some of the rats for 5 h/day. The biochemical profiles and the ghrelin, leptin, lipoperoxidation and TNF-α levels in serum and the glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and NADP+-dependent isocitric dehydrogenase (IDP) levels, the reduced/oxidized glutathione (GSH/GSSG) and reduced/oxidized nicotinamide adenine dinucleotide (phosphate) (NAD(P)H/NAD(P)+) ratios, and the levels of various lipogenic and fibrotic markers in the liver were evaluated. The results showed that hepatic fibrosis induced by fructose consumption was associated with weight gain, hunger-satiety system dysregulation, hyperinsulinemia, dyslipidemia, lipoperoxidation and inflammation. Moreover, increased levels of hepatic G6PD and ME activity and expression, the NAD(P)H/NAD(P)+ ratios, and GSSG concentration and increased expression of lipogenic and fibrotic markers were detected, and these alterations were attenuated by NAM administration. Specifically, NAM diminished the activity and expression of G6PD and ME, and this effect was associated with a decrease in the NADPH/NADP+ ratios, increased GSH levels and decreased lipoperoxidation and inflammation, ameliorating fibrosis and NASH development. NAM reduces liver steatosis and fibrosis by regulating redox homeostasis through a G6PD- and ME-dependent mechanism.
Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Niacinamida/farmacologia , Animais , Antioxidantes/metabolismo , Frutose/efeitos adversos , Frutose/metabolismo , Glucose/metabolismo , Glutationa/metabolismo , Homeostase , Metabolismo dos Lipídeos/fisiologia , Lipídeos/biossíntese , Lipogênese/fisiologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Masculino , NAD/metabolismo , NADP/metabolismo , Niacinamida/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) regimens often contain pyrazinamide (PZA) even if susceptibility to the drug has not been confirmed. This gap is due to the limited availability and reliability of PZA susceptibility testing. OBJECTIVES: To estimate the prevalence of PZA resistance using the Wayne assay among TB patients in Lima, Peru, to describe characteristics associated with PZA resistance and to compare the performance of Wayne with that of BACTEC™ MGIT™ 960. METHODS: PZA susceptibility using the Wayne assay was tested in patients diagnosed with culture-positive pulmonary TB from September 2009 to August 2012. Factors associated with PZA resistance were evaluated. We compared the performance of the Wayne assay to that of MGIT 960 in a convenience sample. RESULTS: The prevalence of PZA resistance was 6.6% (95%CI 5.8-7.5) among 3277 patients, and 47.7% (95%CI 42.7-52.6) among a subset of 405 MDR-TB patients. In multivariable analysis, MDR-TB (OR 86.0, 95%CI 54.0-136.9) and Latin American-Mediterranean lineage (OR 3.40, 95%CI 2.33-4.96) were associated with PZA resistance. The Wayne assay was in agreement with MGIT 960 in 83.9% of samples (κ 0.66, 95%CI 0.56-0.76). CONCLUSION: PZA resistance was detected using the Wayne assay in nearly half of MDR-TB patients in Lima. This test can inform the selection and composition of regimens, especially those dependent on additional resistance.
Assuntos
Antituberculosos/administração & dosagem , Pirazinamida/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos de Coortes , Farmacorresistência Bacteriana , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Análise Multivariada , Peru , Prevalência , Estudos Prospectivos , Reprodutibilidade dos Testes , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia , Adulto JovemRESUMO
SETTING: In 2012, Peru's National TB Program (NTP) reported approximately 2400 incident cases of tuberculosis (TB) disease in children aged <15 years. Peru's TB burden is concentrated in the Lima metropolitan area, particularly in poor districts such as El Agustino and La Victoria, where this study was conducted. OBJECTIVE: To identify barriers to the treatment of childhood tuberculous infection and TB disease in Lima from the perspective of front-line providers and patients' families. DESIGN: We conducted 10 semi-structured focus groups with 53 purposefully sampled primary care providers, community health workers, and parents/guardians of pediatric TB patients. We also completed nine in-depth interviews with National TB Program administrators and pulmonologists specializing in TB. Two authors performed inductive thematic analysis and identified emerging themes. RESULTS: Four main treatment barriers emerged from the data: 1) dosing errors, 2) time- and labor-intensive preparation and administration of medications, 3) provider concern that isoniazid preventive therapy (IPT) generates isoniazid resistance, and 4) poor adherence to IPT. CONCLUSION: Our findings highlight the urgent need for child-friendly formulations, provider and parent/guardian education about IPT, and strategies to promote adherence to IPT, including support and supervision by health workers and/or regimens with fewer doses.
Assuntos
Antituberculosos/administração & dosagem , Isoniazida/administração & dosagem , Adesão à Medicação , Tuberculose/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Agentes Comunitários de Saúde , Farmacorresistência Bacteriana , Feminino , Grupos Focais , Humanos , Masculino , Erros de Medicação , Programas Nacionais de Saúde , Pais , Peru , Atenção Primária à SaúdeRESUMO
SETTING: In 2012, Peru's National Tuberculosis Program (NTP) reported that children aged 0-14 years accounted for 7.9% of the country's tuberculosis (TB) incidence. This figure is likely an underestimate due to suboptimal diagnosis of childhood TB. OBJECTIVE: To identify barriers to childhood TB diagnosis in Lima, Peru. DESIGN: Using semi-structured guides, moderators conducted in-depth interviews with four NTP administrators and five pulmonologists specializing in TB and 10 focus groups with 53 primary care providers, community health workers (CHWs), and parents and/or guardians of pediatric TB patients. Two authors independently performed inductive thematic analysis and identified emerging themes. RESULTS: Participants identified five barriers to childhood TB diagnosis: ignorance and stigma among the community, insufficient contact investigation, limited access to diagnostic tests, inadequately trained health center staff, and provider shortages. CONCLUSION: Recent efforts to increase childhood TB detection have centered on the development of new technologies. However, our findings demonstrate that many diagnostic barriers are rooted in socio-economic and health system problems. Potential solutions include implementing multimedia campaigns and community education to reduce ignorance and stigma, prioritizing contact investigation for high-risk households, and training primary care providers and CHWs to recognize and evaluate childhood TB.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Acessibilidade aos Serviços de Saúde , Tuberculose/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Grupos Focais , Pessoal de Saúde/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Entrevistas como Assunto , Masculino , Pais , Peru/epidemiologia , Tuberculose/epidemiologiaRESUMO
SETTING: Observational cohort study in Lima, Peru. OBJECTIVE: To determine the association between exposure to a smoking tuberculosis (TB) case and latent tuberculous infection (LTBI). METHOD: Between September 2009 and August 2012, we identified 2132 patients with drug-susceptible TB and their 2054 child household contacts. Data were collected on active and secondhand smoking status and other risk factors for infection specific to the index case, the household and the exposed contacts. Contacts underwent a tuberculin skin test (TST) to determine their tuberculous infection status at baseline, 6-month and 12-month follow-up. We estimated the association between exposure to a smoking index case and LTBI using a modified Poisson regression model. RESULTS: The 21 children (age â©¿15 years) exposed to smoking index TB patients were more likely to be TST-positive at baseline (RR 2.64, 95%CI 1.78-3.91), by 6 months (RR 1.91, 95%CI 1.40-2.60) and by 12 months (RR 1.48, 95%CI 1.07-2.06), than those who were not exposed. TST positivity among children at these time points did not vary with secondhand smoke exposure. CONCLUSIONS: TB patients who smoke may be more likely to transmit infection to their contacts. Interventions designed to reduce smoking among TB patients may minimise further spread of the disease.
Assuntos
Tuberculose Latente/epidemiologia , Fumar/epidemiologia , Poluição por Fumaça de Tabaco , Tuberculose/transmissão , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Busca de Comunicante , Feminino , Seguimentos , Humanos , Lactente , Tuberculose Latente/diagnóstico , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Distribuição de Poisson , Fatores de Risco , Fatores de Tempo , Teste Tuberculínico , Adulto JovemRESUMO
BACKGROUND: Confirmation of cure for multidrug-resistant tuberculosis (MDR-TB) patients requires laboratory tests for Mycobacterium tuberculosis growth on culture media. Outcome decisions dictate patient management, and inaccuracies place patients at an increased risk of morbidity and mortality, and may contribute to continued transmission of MDR-TB. OBJECTIVE: To examine concordance between programmatic and laboratory-based MDR-TB treatment outcomes. METHODS: The study population included 1658 MDR-TB patients in Peru treated between 1996 and 2002 with both program and laboratory-based outcomes. Laboratory-based outcomes were assigned according to international standards requiring at least five consecutive negative cultures in the last 12 months of treatment to confirm cure. RESULTS: Compared to the global culture-defined standard classification, only 1.1% of treatment successes, but 54.3% of failures, were misclassified programmatically. Overall, 10.4% of patients identified by a clinician as having a successful treatment outcome still had cultures positive for MDR-TB. CONCLUSION: Most patients with successful treatment outcomes by strict culture definitions were also classified by clinicians as having successful outcomes. However, many culture-confirmed failures were missed. In light of delays and incomplete access to culture in MDR-TB programs, efforts should be made to improve the accuracy of programmatically determined treatment outcomes.
Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Peru , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto JovemRESUMO
Chagas disease is still an important health problem in Central and South America. However, the only drugs currently available for specific treatment of this disease may induce toxic side effects in the host. The aim of this work was to determine the activity of N-benzenesulfonylbenzotriazole (BSBZT) against the protozoan parasite Trypanosoma cruzi. The effects of BSBZT and benzotriazole (BZT) were compared to those of benznidazole (BZL) on epimastigote and trypomastigote forms. BSBZT was found to have an in vitro growth inhibitory dose-dependent activity against epimastigotes, with flow cytometry analysis confirming that the treated parasites presented size reduction. BSBZT showed an IC(50) of 21.56 µg/mL (81.07 µM) against epimastigotes at 72 h of incubation, whereas BZT did not affect the growth of this parasite form. Furthermore, the toxic effect of BSBZT, was stronger and appeared earlier (at 24h) in trypomastigotes than in epimastigotes, with the LC(50) of this compound being 28.40 µg/mL (106.79 µM) against trypomastigotes. The concentrations of BSBZT used in this study presented low hemolytic activity and cytotoxicity. Consequently, at concentrations near IC(50) and LC(50) (25µg/mL), BSBZT caused only 2.4% hemolysis and 15% of RAW 264.7 cell cytotoxicity. These results reveal the potential of BSBZT as a prototype in drug design for developing new anti-T. cruzi compounds.
Assuntos
Nitroimidazóis/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença de Chagas/parasitologia , Eritrócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nitroimidazóis/toxicidade , Sulfonamidas/toxicidade , Triazóis/toxicidade , Tripanossomicidas/toxicidade , Trypanosoma cruzi/crescimento & desenvolvimentoRESUMO
BACKGROUND: Multidrug-resistant tuberculosis programs in DOTS-Plus pilot sites in five countries. OBJECTIVES: To calculate sputum conversion time and its relationship to treatment outcome, document the frequency of culture reversions and examine concordance of smear and culture to assess the potential consequences of monitoring by smear microscopy alone. DESIGN: Retrospective cohort analysis of 1926 patients receiving individualized, second-line therapy. RESULTS: Among 1385 sputum culture-positive cases at baseline, 1146 (83%) experienced at least one culture conversion during treatment. Conversion, however, was not sustained in all patients: 201 (15%) experienced initial culture conversion and at least one subsequent culture reversion to positive; 1064 (77%) achieved sustained culture conversion. Median time to culture conversion was 3 months. Among 206 patients whose nal conversion occurred 7-18 months after the initiation of therapy, 71% were cured or had completed treatment. CONCLUSIONS: Prolonged treatment for patients with delayed conversion may be beneficial, as 71% of late converters still achieved cure or completed treatment. This has implications for programs with de ned end points for treatment failure. The interval between rst and nal conversion among patients whose initial con- version is not sustained raises concern with respect to the ongoing debate regarding duration of treatment and the definition of cure.
Assuntos
Antituberculosos/administração & dosagem , Técnicas Bacteriológicas , Terapia Diretamente Observada , Monitoramento de Medicamentos/métodos , Farmacorresistência Bacteriana Múltipla , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Esquema de Medicação , Estônia , Feminino , Humanos , Letônia , Masculino , Testes de Sensibilidade Microbiana , Microscopia , Mycobacterium tuberculosis/isolamento & purificação , Peru , Filipinas , Projetos Piloto , Estudos Retrospectivos , Federação Russa , Escarro/microbiologia , Fatores de Tempo , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
BACKGROUND: There is no gold standard on how national tuberculosis programs should design retreatment regimens. Often drug susceptibility testing (DST) is not available for all patients, and representative DST patterns in patient populations are used to guide therapy. OBJECTIVES: To examine DST patterns in different patient populations based on previous treatment and to estimate the number of effective anti-tuberculosis agents in several retreatment regimens. METHODS: We reviewed DST results from patients treated with individualized regimens in Peru between January 1998 and July 2004. We stratified patients into four groups based on previous treatment exposure from Group 1 who had failed only one regimen to Group 4 who had failed three regimens. We compared resistance frequencies across the four groups. In Groups 1 and 3, the number of likely effective agents under six possible retreatment regimen scenarios was estimated. RESULTS: Resistance to second-line drugs was significantly higher in groups with more previous courses of treatment. A few retreatment regimens could be identified that would allow at least 80% of patients to receive at least four likely effective drugs. CONCLUSION: Because it is associated with resistance frequencies, previous treatment exposure can serve to guide the design of non-individualized MDR-TB regimens.
Assuntos
Antituberculosos/uso terapêutico , Projetos de Pesquisa/normas , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Feminino , Humanos , Incidência , Masculino , Peru/epidemiologia , Retratamento/métodos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Pulmonar/epidemiologiaRESUMO
SETTING: Public ambulatory centers in northern Lima, Peru. OBJECTIVE: To compare two retreatment strategies in Category I failures. DESIGN: Retrospective cohort study of Category I failures enrolled between February 1997 and October 2001. Strategy A was a nationwide approach, applying a Category II regimen; if that regimen failed, a standardized regimen including second-line drugs was used. Strategy B was a pilot protocol designed to diagnose and treat multidrug-resistant tuberculosis (MDR-TB); this strategy included drug susceptibility testing (DST) and eliminated the Category II regimen. RESULTS: Of 125 patients that Category I failed to cure, 73 entered Strategy A and 52 entered Strategy B. Almost 90% of those with DST results had MDR-TB. Strategy B was three times more likely than Strategy A to cure patients (79% vs. 38%, RR = 2.9, 95% CI 1.7-5.1) and five times more likely to cure patients than the Category II regimen alone (79% vs. 15%, RR 5.2, 95% CI 3.0-9.2). Strategy B also significantly reduced delays to MDR-TB diagnosis and to the initiation of MDR-TB therapy. CONCLUSIONS: Under program conditions, a retreatment strategy based on DST and eliminating the Category II regimen can improve clinical outcomes among Category I treatment failures found to have active, infectious MDR-TB.
Assuntos
Tuberculose/tratamento farmacológico , Adolescente , Adulto , Idoso , Antituberculosos/administração & dosagem , Criança , Esquema de Medicação , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Falha de Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
SETTING: Lima, Peru. OBJECTIVE: To describe drug resistance profiles of TB isolates from patients at risk for multidrug-resistant tuberculosis (MDR-TB), and to consider the implications of these findings for treatment. DESIGN: Descriptive study of drug susceptibility testing (DST) results for TB isolates from 1680 patients referred for suspicion of MDR-TB between 1996 and 2001. RESULTS: Of 1680 isolates tested, 1144 (68%) were resistant to at least one anti-tuberculosis drug and 926 (55%) were MDR-TB strains. Of 926 MDR isolates, 50 (5%) were resistant to INH and RMP alone, while 367 (40%) were resistant to at least five first-line drugs. We identified 146 unique drug resistance profiles, the most common of which accounted for 11% of drug-resistant isolates. The annual prevalence of isolates with resistance to at least five first-line drugs rose significantly during the study period, from 29% to 37% (P = 0.00086). CONCLUSIONS: This is a group of patients with TB disease among whom the prevalence of a broad spectrum of often highly drug-resistant strains appears to be increasing over time. A single standardized retreatment regimen may be inadequate to cure most patients. Capacity for drug sensitivity testing is essential for development of multiple standardized retreatment or individualized treatment regimens and epidemiological surveillance for planning.
Assuntos
Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Farmacorresistência Bacteriana , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Peru/epidemiologia , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
In many developing countries and outside hospital settings, the characteristics of endemic Mycobacterium tuberculosis strains resistant to multiple drugs remain unknown. In a community-based referral and therapy program in northern Lima, Peru, beginning in 1996, patients found to be failures on standard regimens were referred for drug-susceptibility testing of their isolates, and those found to be infected with M. tuberculosis isolates resistant to at least rifampin were treated with individualized regimens based on their infecting strains. Isolates from 42 of these patients were subjected to DNA sequencing of the rpoB gene region responsible for rifampin resistance. We determined the frequency of types of mutations in the rpoB gene among these Peruvian isolates.
Assuntos
Antibióticos Antituberculose/farmacologia , RNA Polimerases Dirigidas por DNA/genética , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Resistência Microbiana a Medicamentos/genética , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Peru/epidemiologia , Análise de Sequência de DNA , Tuberculose Pulmonar/microbiologiaRESUMO
SETTING: National mycobacteriology reference laboratory in Peru conducting routine testing of susceptibility to isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin, in Mycobacterium tuberculosis isolates from previously treated patients. OBJECTIVE: To determine the percentage of isolates resistant to each of five anti-tuberculosis agents and to ascertain in these data the presence of trends of clinical relevance. DESIGN: Retrospective study of a national registry of M. tuberculosis isolates from patients referred for drug susceptibility testing between 1994 and 2001. RESULTS: Among 14,736 isolates tested, 10,837 (73.5%, 95%CI 72.8-74.3) demonstrated anti-tuberculosis resistance, and 8455 (57.4%, 95%CI 56.6-58.2) demonstrated resistance to at least both isoniazid and rifampin, by convention defined as multidrug-resistant tuberculosis (MDR-TB). A significant increasing trend could be discerned for resistance to each of the drugs tested and in isolates classified as MDR-TB (P < 0.001 for trend). Additional clinically relevant trends were found in polyresistance and multidrug resistance percentages. CONCLUSIONS: Data from a national reference laboratory can be used to inform the design of retreatment regimens.
Assuntos
Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Sistema de Registros , Tuberculose/tratamento farmacológico , Etambutol/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Peru , Pirazinamida/uso terapêutico , Estudos Retrospectivos , Rifampina/uso terapêutico , Estreptomicina/uso terapêutico , Resultado do TratamentoRESUMO
SETTING: Ambulatory, public tuberculosis treatment facilities, central Lima, Peru. OBJECTIVE: To identify risk factors for failure on directly observed Category I therapy. DESIGN: Case-control study. All failures of Category I (2HREZ/4H2R2) therapy in 2000 (2.9% of smear-positive TB patients) were included as cases; two controls per case were matched on health center and approximate time of treatment initiation. RESULTS: The study included 38 cases and 76 controls, all new smear-positive, pulmonary TB patients treated with Category I therapy in central Lima in 2000. Neither treatment irregularity nor incidence of adverse events predicted failure in the study group. Mean baseline body mass index was lower in cases than in controls (P = 0.06). Cases gained less weight during therapy (P = 0.01). Smear positivity at 2 months of therapy was strongly associated with failure (OR 11.7; 95%CI 2.4-57.5). No controls had positive smears at or after 3 months of therapy (OR [corrected] 144.9; 95%CI 8.4-2500). Nearly 75% of cases with isolates tested for susceptibility to first-line drugs had multidrug-resistant TB (MDR-TB). CONCLUSION: A large proportion of failures on Category I therapy can be identified early. As three-quarters of patients with susceptibility results have MDR-TB, early referral for culture and drug susceptibility testing is critical for prompt initiation of appropriate therapy and improved outcomes.
Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Países em Desenvolvimento , Terapia Diretamente Observada , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Incidência , Masculino , Cooperação do Paciente , Peru/epidemiologia , Probabilidade , Medição de Risco , Escarro/microbiologia , Estatísticas não Paramétricas , Falha de Tratamento , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologiaRESUMO
Oxidative stress induced by ciprofloxacin and pyoverdin, a leukotoxic pigment, was studied by comparing their effect in bacteria and leukocytes. Chemiluminescence (CL) assays with lucigenin or luminol were adapted to measure the stimuli of superoxide anion (O2 -) and other reactive species of oxygen (ROS) in bacteria. Ciprofloxacin principally induced the production of O2 - in the three species studied: Staphylococcus aureus, Enterococcus faecalis and Escherichia coli. Lucigenin CL assay showed high oxidative stress in S. aureus due to its low superoxide dismutase (SOD) activity, whereas E. coli exhibited important SOD activity, responsible for little production of O2 - in absence or presence of ciprofloxacin. Reduction of nitroblue of tetrazolium (NBT) was applied. This assay indicated that there was higher oxidative stress in S. aureus and E. faecalis than in E. coli. The comparison of oxidative stress generated in bacteria and leukocytes was used to check the selective toxicity of ciprofloxacin in comparison with pyoverdin. Ciprofloxacin did not generate significant stimuli of O2 - in neutrophils, while pyoverdin duplicated the production of O2 -. CL and NBT were useful to study the leukotoxicity of ciprofloxacin. Oxidative stress caused by the antibiotic and the leukotoxic pigment was similar in bacteria.
Assuntos
Antibacterianos/toxicidade , Ciprofloxacina/toxicidade , Oligopeptídeos , Estresse Oxidativo , Pigmentos Biológicos/toxicidade , Animais , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Enterococcus faecalis/metabolismo , Escherichia coli/metabolismo , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Espécies Reativas de Oxigênio/análise , Staphylococcus aureus/metabolismoRESUMO
SETTING: Two regions of metropolitan Lima, Peru. OBJECTIVE: To determine the outcomes of two contact investigation strategies used in therapy enrollment cohorts of patients with multidrug-resistant tuberculosis (MDR-TB). DESIGN: From 28 August 1996 to 31 December 1999, 91 index patients received individualized MDR-TB therapy (Group A), and from 1 October 1997 to 31 December 1999, another 101 index patients received a standardized MDR-TB regimen (Group B). We conducted a retrospective chart review and home visits to identify secondary cases among close contacts of both of these groups. Group A secondary cases with MDR-TB received therapy based on the drug susceptibility profile of their infecting strain, while Group B secondary cases received standard short-course therapy. RESULTS: Among 945 close contacts, 72 secondary TB cases (8%) were found. Of 42 who had drug-susceptibility testing, 35 (84%) were MDR-TB, but only seven (17%) had the same drug susceptibility profile as the index case. Cure exceeded 80% in Group A secondary cases, while only half of Group B secondary cases were cured (RR 1.6, 95%CI 1.1-2.2). CONCLUSION: Contact investigation protocols coupled with enrollment in MDR-TB therapy are a useful means of detecting and promptly treating persons with infectious MDR-TB. In settings with endemic MDR strains of Mycobacterium tuberculosis, effective therapy of contacts of MDR-TB patients requires knowledge of drug susceptibility for each contact with active disease.
Assuntos
Busca de Comunicante , Avaliação de Processos e Resultados em Cuidados de Saúde , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/prevenção & controle , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Peru , Estudos Retrospectivos , Fatores de Tempo , Tuberculose Resistente a Múltiplos Medicamentos/transmissãoRESUMO
Staphylococcus aureus with multiple sensitivity to ciprofloxacin, was investigated to detect alterations in the production of superoxide anion (O(2)(-)), other reactive oxidant species (ROS), and superoxide dismutase (SOD), and to relate them with ciprofloxacin accumulation and sensitivity. Oxidative stress was studied by means of Nitroblue Tetrazolium reaction (NBT) and chemiluminescence (CL); lucigenin was employed to detect O(2)(-), and luminol was used to measure other ROS. Sensitive strains exhibited higher intracellular O(2)(-) increase than resistant ones when incubated with ciprofloxacin. SOD was determined in normal conditions and induction was investigated in the presence of ciprofloxacin. These assays demonstrated that resistant and sensitive strains exported a great amount of SOD and that the induction of SOD intracellular was insufficient to counteract the augment of O(2)(-) in the cytoplasm of sensitive strains. Accumulation of ciprofloxacin, researched by spectrofluorometry, showed high levels of antibiotic in sensitive strains which increased the O(2)(-) causing more oxidative stress than in resistant S. aureus.
Assuntos
Ciprofloxacina/farmacologia , Estresse Oxidativo/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/genética , Staphylococcus aureus/fisiologiaAssuntos
Terapia Antirretroviral de Alta Atividade , Serviços de Saúde Comunitária/organização & administração , Países em Desenvolvimento , Infecções por HIV/tratamento farmacológico , Recursos em Saúde , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/economia , Controle de Doenças Transmissíveis/organização & administração , Análise Custo-Benefício , Feminino , Haiti , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Pobreza , População Rural , Tuberculose/prevenção & controleRESUMO
SETTING: A community-based treatment program for multidrug-resistant tuberculosis (MDR-TB) in an urban shantytown of Lima, Peru. OBJECTIVES: To ascertain the occurrence of serious adverse effects associated with therapy for MDR-TB in northern Lima, Peru, where therapy was individualized according to drug-susceptibility testing of patients' infecting strains and delivered through a community-based program. DESIGN: A retrospective record review of 60 patients who had received individualized therapy for MDR-TB between September 1996 and October 1998. RESULTS: Although adverse effects were common, they occurred less frequently than previously reported in the literature and were rarely life-threatening. Effects occurring most frequently in this population included: mild gastritis (100%), dermatological effects (43.3%), peripheral neuropathy (16.7%), depression (18.3%), and anxiety (11.7%). These effects never resulted in the discontinuation of anti-tuberculosis therapy, and only occasionally resulted in the suspension of an agent (11.7%). CONCLUSION: In young patients with little comorbid disease, multidrug, long-course regimens rarely caused life-threatening adverse effects. Common side effects may be managed successfully on an out-patient basis through a community-based treatment program in conjunction with MDR-TB experts, even in resource-poor settings. The very low rate of default in this cohort offers hope that strategies to manage the adverse effects may reduce the incidence of abandonment of therapy and increase rates of cure.
Assuntos
Antituberculosos/efeitos adversos , Terapia Diretamente Observada , Tuberculose Resistente a Múltiplos Medicamentos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peru , Estudos RetrospectivosRESUMO
SETTING: Public ambulatory care centers in three districts of northern metropolitan Lima, Peru. OBJECTIVE: To document drug resistance patterns of isolates of Mycobacterium tuberculosis from patients identified as treatment failures under a model tuberculosis (TB) control program based on directly observed, short-course chemotherapy (DOT-SCC). DESIGN: Case series. RESULTS: In a referred, consecutive sample of 173 patients identified as treatment failures on DOT-SCC, 160 (92.5%) had culture-positive TB. Of those 160, 150 (93.8%) had active, pulmonary multidrug-resistant TB (MDR-TB, resistance to at least isoniazid [INH] and rifampicin [RIF]). Sixty of the 150 (40.0%) had isolates resistant to at least INH, RIF, ethambutol (EMB) and pyrazinamide (PZA), the initial first-line empiric treatment regimen used locally. Forty-four (29.3%) had isolates resistant to at least INH, RIF, EMB, PZA and streptomycin (SM), the first retreatment regimen. This series of patients had isolates resistant to a mean of 4.5 of the ten drugs tested. The local profile of multidrug resistance is very different from that obtained from national data from Peru. CONCLUSION: In this setting, treatment failure on DOT-SCC is strongly predictive of active MDR-TB. Because of existing local drug resistance patterns in northern Lima, 89.3% of MDR-TB patients identified as treatment failures will receive ineffective therapy with two or fewer secondary TB drugs if they are given the five-drug empiric retreatment regimen endorsed by the World Health Organization. Further short-course chemotherapy for these patients would only serve to amplify ominous existing drug resistance patterns.