RESUMEN
BACKGROUND: Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients. METHODS: New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment. RESULTS: Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1-97.8) and 94.5% (95% CI: 90.8-98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction. CONCLUSION: The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.
Asunto(s)
Antituberculosos , Ofloxacino , Tuberculosis Ganglionar , Humanos , Ofloxacino/administración & dosificación , Ofloxacino/efectos adversos , Ofloxacino/uso terapéutico , Adulto , Masculino , Femenino , Tuberculosis Ganglionar/tratamiento farmacológico , Antituberculosos/uso terapéutico , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Resultado del Tratamiento , Persona de Mediana Edad , India , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Rifampin/efectos adversos , Adulto Joven , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Quimioterapia Combinada , Pirazinamida/uso terapéutico , Pirazinamida/administración & dosificación , Pirazinamida/efectos adversos , Etambutol/uso terapéutico , Etambutol/administración & dosificación , Etambutol/efectos adversos , Esquema de Medicación , AdolescenteRESUMEN
OBJECTIVES: Adequate anti-tuberculosis (TB) treatment is an important factor that can affect the patient's outcome. Higher mortality is found in patients who do not receive optimal treatment that includes isoniazid and rifampicin. The objective of this study is to evaluate the association of use of alternative TB treatment regimens (without rifampicin and isoniazid) and mortality among patients requiring intensive care. METHODS: Retrospective cohort study, from January 2010 to December 2018. Patients aged > 18 years with a TB diagnosis, admitted to the ICU of a general, tertiary care, university-affiliated hospital (Hospital de Clínicas de Porto Alegre - HCPA) were included. Data on TB treatment used and outcomes of treatment were collected. RESULTS: 462 patients met the inclusion criteria and were included in the analysis; 284 used the usual treatment regimen (rifampicin, isoniazid, pyrazinamide and ethambutol - all orally), and 178 used alternative treatment regimens (IV levofloxacin plus oral ethambutol plus IM streptomycin or IV amikacin, without rifampicin and isoniazid). The mortality was higher among users of alternative treatment regimens (63.5%) than among usual treatment regimen users (51.4%) (P = 0.011). In a multivariate analysis, age, albumin and death were independently associated with alternative treatment regimens use. CONCLUSIONS: TB programmes in which IV rifampicin is not widely available should consider including it, especially for critically ill TB patients, for whom there may be improved survival.
OBJECTIFS: Un traitement antituberculeux (TB) adéquat est un facteur important pouvant influencer les résultats du patient. Une mortalité plus élevée est observée chez les patients qui ne reçoivent pas un traitement optimal comprenant de l'isoniazide et de la rifampicine. L'objectif de cette étude est d'évaluer l'association entre l'utilisation d'autres schémas thérapeutiques anti-TB (sans rifampicine ni isoniazide) et la mortalité chez les patients nécessitant des soins intensifs. MÉTHODES: Etude de cohorte rétrospective, de janvier 2010 à décembre 2018. Les patients âgés de >18 ans avec un diagnostic de TB, admis à l'unité de soins intensifs d'un hôpital général, avec des soins tertiaires, affilié à l'Université (Hôpital de Clínicas de Porto Alegre-HCPA) ont été inclus. Des données sur le traitement anti-TB utilisé et les résultats du traitement ont été collectés. RÉSULTATS: 462 patients répondaient aux critères d'inclusion et ont été inclus dans l'analyse; 284 ont utilisé le schéma thérapeutique habituel (rifampicine, isoniazide, pyrazinamide et éthambutol - tous par voie orale) et 178 ont utilisé des schémas thérapeutiques alternatifs (lévofloxacine IV plus éthambutol oral plus streptomycine IM ou amikacine IV, sans rifampicine ni isoniazide). La mortalité était plus élevée chez les utilisateurs de schémas thérapeutiques alternatifs (63,5%) que chez les utilisateurs de schémas thérapeutiques habituels (51,4%) (P = 0,011). Dans l'analyse multivariée, l'âge, l'albumine et le décès ont été indépendamment associés à l'utilisation de schémas thérapeutiques alternatifs. CONCLUSIONS: Les programmes de lutte contre la TB dans lesquels la rifampicine IV n'est pas largement disponible devraient envisager de l'inclure, en particulier pour les patients atteints de TB et sévèrement malades, pour lesquels la survie peut être améliorée.
Asunto(s)
Antibióticos Antituberculosos/administración & dosificación , Unidades de Cuidados Intensivos , Tuberculosis/tratamiento farmacológico , Tuberculosis/mortalidad , APACHE , Adulto , Amicacina/administración & dosificación , Brasil/epidemiología , Vías de Administración de Medicamentos , Esquema de Medicación , Quimioterapia Combinada/métodos , Etambutol/administración & dosificación , Femenino , Humanos , Isoniazida/administración & dosificación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pirazinamida/administración & dosificación , Estudios Retrospectivos , Rifampin/administración & dosificación , Estreptomicina/administración & dosificaciónRESUMEN
BACKGROUND: The number of patients with nontuberculous mycobacteriosis (NTM) has increased exponentially in recent years. In Japan, approximately 88.8% of patients with NTM suffer from Mycobacterium avium-intracellulare complex (MAC) lung disease. Incidence of MAC lung disease is increasing in particularly among the middle-aged and elderly women owing to a rapid increase in nontuberculous mycobacterial infections. General treatment for MAC lung disease is chemotherapy. The type of chemotherapy recommended by specialists to prevent the development of a drug-resistant strain of the bacteria consists of a combination of clarithromycin (CAM), rifampicin, and ethambutol (EB). CAM monotherapy is contraindicated by specialists owing to its high potential to induce drug-resistant bacterial strains in patients with MAC lung disease. In addition, administering EB at doses not less than 1000 mg d-1 is not recommended to avoid adverse drug reactions. However, it is unclear how much such treatment cases exist in real world clinical settings. This is because no long-term investigation has been carried out. MATERIALS AND METHODS: This study investigated treatment with these drugs from 2005 to 2017, by studying 1135 patients with MAC lung disease based on health insurance claims database. RESULTS: Results showed that approximately 9.2% (101 cases) were prescribed long-term CAM monotherapy for 3 months or longer and approximately 3.6% (18 cases) were prescribed high doses of EB. CONCLUSION: CAM monotherapy over a long period of time is potentially detrimental to some patients. Better awareness of the types of treatments and their potential negative effects will be beneficial to clinical practitioners.
Asunto(s)
Claritromicina/administración & dosificación , Bases de Datos Factuales , Etambutol/administración & dosificación , Revisión de Utilización de Seguros , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antituberculosos/administración & dosificación , Niño , Preescolar , Claritromicina/efectos adversos , Estudios de Cohortes , Bases de Datos Factuales/estadística & datos numéricos , Esquema de Medicación , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/fisiología , Quimioterapia Combinada , Femenino , Humanos , Lactante , Recién Nacido , Revisión de Utilización de Seguros/estadística & datos numéricos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Complejo Mycobacterium avium/efectos de los fármacos , Complejo Mycobacterium avium/fisiología , Infección por Mycobacterium avium-intracellulare/epidemiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Ethambutol hydrochloride (ETB), high dose anti-tubercular drug exhibits poor micromeritics and compressibility. The current study aimed to enhance flow, compressibility and packing characteristics, thereby improving processability of ETB by spherical agglomeration. Quasi emulsion solvent diffusion method was used for agglomeration process in which saturated aqueous ETB solution was prepared and the crystallization was carried out subsequently at different ratios of acetone and ethyl acetate which act as anti-solvent. Further the process was optimised statistically using 32 factorial design keeping 'speed of stirring' and 'ratio acetone and ethyl acetate' as independent variables and particle size as dependent variable. Optimised batch of ethambutol hydrochloride spherical agglomerates (ETB-SA) was characterised for sieve analysis, solid state characteristics and Kawakita analysis. The uniformity of ETB-SA was observed with SEM while XRPD studies revealed reduction in crystallinity for ETB-SA. DSC and FTIR indicated no polymeric or chemical alteration during crystallization process. The flow properties of ETB-SA were found superior and its Kawakita parameters indicated improved packability and flowability compared to ETB. ETB has high solubility in water therefore was no significant difference was observed in in vitro dissolution of ETB and ETB-SA. Thus spherical agglomeration, a revered particle engineering technique, continues to be a salient approach for enhancing processability of high-dose drugs like ETB.
Asunto(s)
Antituberculosos/administración & dosificación , Química Farmacéutica/métodos , Etambutol/administración & dosificación , Solventes/química , Antituberculosos/química , Cristalización , Emulsiones , Etambutol/química , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Solubilidad , Tecnología Farmacéutica , Difracción de Rayos XRESUMEN
BACKGROUND: Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. OBJECTIVES: To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. METHODS: We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies. RESULTS: We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. CONCLUSIONS: Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.
Asunto(s)
Antituberculosos/administración & dosificación , Antituberculosos/farmacocinética , Coinfección/tratamiento farmacológico , Etambutol/administración & dosificación , Etambutol/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Disponibilidad Biológica , Botswana , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Ethambutol hydrocloride (EMB) is an anti-tuberculosis drug, which is commonly used as a protection agent against of unrecognized resistance to other drugs employed to treat this disease. Since oral form of EMB has some side effects and cellular toxicity, direct administration of EMB into lungs seems to be an attractive and reasonable option in order to overcome these side effects. Our main goal in this study was assessment of pulmonary administration through dry powder inhaler (DPI) using EMB-loaded solid lipid nanoparticles (SLNs). We prepared EMB-loaded SLNs using two techniques (hot homogenization and ultrasonication). DPI formulations were made by spray drying of EMB-loaded SLNs with and without mannitol. For investigation of flowbility of the prepared powders, Carr's index and Hausner ratio, and for in vitro deposition of the powders, Next Generation Impactor (NGI) analysis were used. The encapsulation efficiency and particle size of obtained particles were higher than 98% and sub-100 nm, respectively. Toxicity investigation of EMB-loaded SLNs via MTT assay showed biocompatibility and non-toxicity of the SLNs. Results of flowability and aerodynamic traits assessment of EMB-loaded SLN DPI powder confirmed the suitability of prepared powders. Overall, the attained results showed that EMB-loaded SLN DPI has high potential for direct treatment of tuberculosis.
Asunto(s)
Antituberculosos/administración & dosificación , Antituberculosos/química , Etambutol/administración & dosificación , Etambutol/química , Células A549 , Administración por Inhalación , Antituberculosos/uso terapéutico , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Composición de Medicamentos , Inhaladores de Polvo Seco , Etambutol/uso terapéutico , Humanos , Liposomas , Ensayo de Materiales , Nanopartículas , Tamaño de la Partícula , Tuberculosis/tratamiento farmacológicoAsunto(s)
Antituberculosos/administración & dosificación , Imidazoles/administración & dosificación , Mycobacterium tuberculosis/efectos de los fármacos , Piperidinas/administración & dosificación , Piridinas/administración & dosificación , Tuberculosis Pulmonar/tratamiento farmacológico , Administración Oral , Antituberculosos/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Etambutol/administración & dosificación , Humanos , Imidazoles/efectos adversos , Isoniazida/administración & dosificación , Piperidinas/efectos adversos , Pirazinamida/administración & dosificación , Piridinas/efectos adversos , Rifampin/administración & dosificaciónRESUMEN
Background & objectives: Mycobacterium avium causes atypical infection in both immunocompetent and immunocompromised individuals. Conventional chemotherapy for M. avium infection is not efficient due to lengthy course of treatment and drug-associated toxic side effects. The present study was aimed at reducing dosing frequency of antimicrobial regimen consisting of azithromycin (AZM), rifabutin (RBT) and ethambutol (EMB) by encapsulation of drugs in nanoparticles (NPs) in experimental M. avium infection in mice. Methods: Poly (DL-lactide-co-glycolide) NPs containing anti-M. avium drugs were prepared, characterized and studied for their pharmacokinetics and pharmacodynamics parameters. Drug-loaded NPs were further analyzed for their therapeutic efficacy against experimental M. avium infection in mice. Results: Drug-loaded NPs were of size 227.3±16.4 for RBT, 334.35±11.7 for AZM and 509.85±20.5 for EMB with smooth surface morphology and negative zeta potential. AZM, EMB and RBT from NPs were detectable for 6, 4 and 5 days, respectively, in the mice plasma, whereas free drugs were cleared from mice circulation within 24 h. Chemotherapeutic effects of weekly administered drug-loaded NPs were equivalent to daily administered free drugs. Interpretation & conclusions: Our findings showed that NPs gave sustained release of drugs inside plasma and organs, thus decreasing dosage frequency, and their weekly dosage had therapeutic efficacy equivalent to daily dosage of free drugs.
Asunto(s)
Antibióticos Antituberculosos/administración & dosificación , Azitromicina/administración & dosificación , Etambutol/administración & dosificación , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Nanocápsulas , Rifabutina/administración & dosificación , Animales , China , Quimioterapia Combinada , Ratones , Mycobacterium avium , Complejo Mycobacterium aviumRESUMEN
More-permissive preclinical models may be useful in evaluating antituberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing, and drug exposures, athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, isoniazid, pyrazinamide, and ethambutol, followed by 4 months of rifampin/isoniazid, either daily or twice weekly with one of two isoniazid doses. Test groups received the same intensive regimen followed by once-weekly rifapentine or isoniazid/rifapentine with rifapentine doses of 10, 15, or 20 mg/kg of body weight plus one of two isoniazid doses. All combination regimens rendered BALB/c mouse cultures negative but selected mutants resistant to isoniazid (8.5%, 12/140) or rifampin (3.5%, 5/140) in nude mice (P < 0.001). Intermittently dosed intensive-phase therapy selected isoniazid and rifampin resistance in 10% (8/80, P < 0.001) and 20% (16/80, P = 0.009) of nude mice, respectively, compared to 0% treated with a daily regimen. Once-weekly rifapentine-containing continuation-phase regimens selected rifampin-resistant mutants at a rate of 18.0% (18/100, P = 0.035 compared to rifampin/isoniazid regimens). Higher isoniazid doses in the intermittent-treatment control regimen and higher rifapentine doses in once-weekly regimens were associated with less selection of isoniazid resistance. Acquired resistance, including rifamycin monoresistance, was more likely to occur in nude mice despite administration of combination therapy. These results recapitulate clinical outcomes and indicate that nude mice may be useful for evaluating the ability of novel regimens to prevent the selection of resistance.
Asunto(s)
Antituberculosos/administración & dosificación , Farmacorresistencia Bacteriana/efectos de los fármacos , Rifamicinas/administración & dosificación , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunología , Animales , Antituberculosos/farmacología , Recuento de Colonia Microbiana , Esquema de Medicación , Farmacorresistencia Bacteriana/genética , Quimioterapia Combinada , Etambutol/administración & dosificación , Femenino , Isoniazida/administración & dosificación , Pulmón/efectos de los fármacos , Pulmón/microbiología , Ratones Endogámicos BALB C , Ratones Desnudos , Pruebas de Sensibilidad Microbiana , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Rifampin/administración & dosificación , Rifampin/análogos & derivados , Rifamicinas/farmacología , Tuberculosis/mortalidadRESUMEN
Hyperuricemia can lead to direct kidney damage. Taurine participates in several renal physiological processes and has been shown as a renoprotective agent. It has been reported that taurine could reduce uric acid levels in diabetic rats, but to date there was no research on the effects of taurine on hyperuricemic rats with kidney injury. In present study, hyperuricemic rat models were induced by intragastric administration of adenine and ethambutol hydrochloride for 10 days, and taurine (1% or 2%) were added in the drinking water 7 days in advance for consecutively 17 days. The results showed that taurine alleviated renal morphological and pathological changes as well as kidney dysfunction in hyperuricemic rats. Taurine could efficiently decrease the elevated xanthine oxidase activities in hyperuricemic rats, indicating its effect on the regulation of uric acid formation. The reabsorption and secretion of uric acid are dependent on a number of urate transporters. Expressions of three urate transporters were significantly down-regulated in hyperuricemic rats, while taurine prevented the decrease of mRNA and protein expression levels of these urate transporters. The results indicate that taurine might play a role in the regulation of renal uric acid excretion. Therefore, taurine could be a promising agent for the treatment of hyperuricemia.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Taurina/farmacología , Ácido Úrico/metabolismo , Lesión Renal Aguda/sangre , Lesión Renal Aguda/orina , Adenina/administración & dosificación , Administración Oral , Animales , Etambutol/administración & dosificación , Hiperuricemia/sangre , Hiperuricemia/orina , Masculino , Ratas , Ratas Wistar , Taurina/administración & dosificación , Ácido Úrico/sangre , Ácido Úrico/orinaRESUMEN
OBJECTIVES: To investigate the performance of the two backbone drugs in the standard combination therapy regimen in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) infection. METHODS: Six HFS were inoculated with human-derived monocytes infected with MAC, and treated with 15 mg/kg of ethambutol and 500 mg of azithromycin daily for 28 days to recapitulate the concentration-time profiles seen in the lungs of humans treated with these drugs and doses. The concentration-time profiles achieved were validated by sampling the central compartment at seven timepoints over 24 h. The total MAC burden, as well as the subpopulation resistant to 3 × MIC of each drug, was identified based on sampling the peripheral compartment of each system on days 0, 3, 7, 14, 21 and 28 of therapy. The experiment was performed twice. RESULTS: In non-treated control HFS, MAC grew from 5.0 to 8.53 log10 cfu/mL in 28 days. The dual therapy killed a maximum of 1.52â±â0.43 log10 cfu/mL during the first 7 days, after which it failed. By day 28 there was no difference in MAC burden between the combination-therapy-treated and non-treated systems. Failure arose in parallel with the emergence of acquired ethambutol resistance. By day 28, 100% of the bacterial population was ethambutol resistant in the combination-therapy-treated HFS replicates. CONCLUSIONS: The backbone combination of macrolide and ethambutol has poor MAC kill rates and is ineffective. Microbial kill is rapidly abrogated by acquired drug resistance. This backbone should be replaced.
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Antibacterianos/uso terapéutico , Antituberculosos/uso terapéutico , Azitromicina/uso terapéutico , Etambutol/uso terapéutico , Complejo Mycobacterium avium/efectos de los fármacos , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antituberculosos/administración & dosificación , Azitromicina/administración & dosificación , Farmacorresistencia Bacteriana Múltiple , Etambutol/administración & dosificación , Humanos , Modelos Biológicos , Células THP-1RESUMEN
OBJECTIVES: To develop a thioridazine/moxifloxacin-based combination regimen for treatment of pulmonary infection due to Mycobacterium avium-intracellulare complex (MAC) that kills bacteria faster than the standard treatment regimen. METHODS: Monocytes were infected with MAC and inoculated into the hollow-fibre system model for pulmonary MAC disease (HFS-MAC). We co-administered ethambutol plus azithromycin daily for 28 days, to achieve the same human concentration-time profiles that result from standard doses, in three HFS-MAC systems. Two experimental regimens consisted of thioridazine at an exposure associated with optimal kill, given intermittently on days 0, 3, 7 and 10. Regimen A consisted of thioridazine in combination with standard dose azithromycin for the entire study duration. Regimen B was thioridazine plus moxifloxacin at concentration-time profiles achieved by the standard daily dose administered for 14 days, followed by daily azithromycin. Each HFS-MAC was sampled for bacterial burden every 7 days. RESULTS: The bacteria in the non-treated HFS-MAC grew at a rate of 0.11â±â0.01 log10 cfu/mL/day. The azithromycin/ethambutol regimen decreased bacterial burden by 1.21â±â0.74 log10 cfu/mL below baseline during the first 7 days, after which it failed. Regimen A killed 3.28â±â0.32 log10 cfu/mL below baseline up to day 14, after which regrowth occurred once thioridazine treatment stopped. Regimen B killed bacteria to below the limits of detection in 7 days (≥5.0 log10 cfu/mL kill), with rebound in the azithromycin continuation phase. CONCLUSIONS: The thioridazine/moxifloxacin regimen demonstrated that rapid microbial kill could be achieved within 7 days. This is a proof of principle that short-course chemotherapy for pulmonary MAC is possible.
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Antibacterianos/farmacología , Antipsicóticos/farmacología , Fluoroquinolonas/farmacología , Complejo Mycobacterium avium/efectos de los fármacos , Tioridazina/farmacología , Antibacterianos/administración & dosificación , Antipsicóticos/administración & dosificación , Azitromicina/administración & dosificación , Azitromicina/farmacología , Quimioterapia Combinada , Etambutol/administración & dosificación , Etambutol/farmacología , Fluoroquinolonas/administración & dosificación , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Biológicos , Monocitos/microbiología , Moxifloxacino , Complejo Mycobacterium avium/crecimiento & desarrollo , Células THP-1 , Tioridazina/administración & dosificaciónRESUMEN
This study explores the antitubercular activity of α-viniferin, a bioactive phytochemical compound obtained from Carex humilis. α-Viniferin was active against both drug-susceptible and -resistant strains of Mycobacterium tuberculosis at MIC50s of 4.6 µM in culture broth medium and MIC50s of 2.3-4.6 µM inside macrophages and pneumocytes. In combination with streptomycin and ethambutol, α-viniferin exhibited an additive effect and partial synergy, respectively, against M. tuberculosis H37Rv. α-Viniferin also did not show cytotoxicity in any of the cell lines tested up to a concentration of 147 µM, which gives this compound a selectivity index of >32. Moreover, α-viniferin was active against 3 Staphylococcus species, including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE).
Asunto(s)
Antituberculosos/farmacología , Benzofuranos/farmacología , Carex (Planta)/química , Mycobacterium tuberculosis/efectos de los fármacos , Células A549 , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Animales , Antibacterianos/administración & dosificación , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antituberculosos/administración & dosificación , Antituberculosos/aislamiento & purificación , Benzofuranos/administración & dosificación , Benzofuranos/aislamiento & purificación , Farmacorresistencia Bacteriana , Sinergismo Farmacológico , Etambutol/administración & dosificación , Etambutol/farmacología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Raíces de Plantas , Células RAW 264.7 , Estreptomicina/administración & dosificación , Estreptomicina/farmacologíaRESUMEN
There are no data in the literature regarding the safety of re-treatment with ethambutol for recurrent mycobacterial infection after prior ethambutol-induced optic neuropathy. We describe a patient who developed optic neuropathy attributed to ethambutol, recovered fully after drug withdrawal, and tolerated a 14-month long re-treatment 10 years later without developing recurrent optic neuropathy.
Asunto(s)
Etambutol/efectos adversos , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Enfermedades del Nervio Óptico/inducido químicamente , Células Ganglionares de la Retina/patología , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Relación Dosis-Respuesta a Droga , Etambutol/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Complejo Mycobacterium avium/aislamiento & purificación , Infección por Mycobacterium avium-intracellulare/microbiología , Enfermedades del Nervio Óptico/diagnóstico , RetratamientoRESUMEN
Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients' noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century old standard chemotherapy have been made based on a nanoformulation strategy to improve pharmacokinetic efficacy. In this study, we have designed a new nanodelivery formulation, using graphene oxide as the nanocarrier, loaded with the anti-TB antibiotic, ethambutol. The designed formulation was characterized using a number of molecular analytical techniques. It was found that sustained release of the drug resulted in better bioavailability. In addition, the designed formulation demonstrated high biocompatibility with mouse fibroblast cells. The anti-TB activity of the nanodelivery formulation was determined using whole-cell resazurin microtiter plate assay, modified-spot culture growth inhibition assay, and biofilm inhibition assay. The nanodelivery formulation showed good anti-mycobacterial activity. The anti-mycobacterial activity of Ethambutol was unaffected by the drug loading and release process. The results of this study demonstrated the potential of this new nanodelivery formulation strategy to be considered for modifying existing chemotherapy to yield more efficacious antibiotic treatment against TB.
Asunto(s)
Antituberculosos/administración & dosificación , Portadores de Fármacos/química , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Etambutol/administración & dosificación , Grafito/química , Nanopartículas/química , Óxidos/química , Animales , Biopelículas/efectos de los fármacos , Liberación de Fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium/efectos de los fármacos , Mycobacterium/crecimiento & desarrollo , Nanopartículas/ultraestructura , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Difracción de Rayos XRESUMEN
Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials.
Asunto(s)
Antituberculosos/farmacocinética , Hígado/efectos de los fármacos , Modelos Estadísticos , Rifampin/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Antituberculosos/administración & dosificación , Antituberculosos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Biotransformación , Peso Corporal , Ensayos Clínicos como Asunto , Estudios de Cohortes , Coinfección , Simulación por Computador , Etambutol/administración & dosificación , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Semivida , Humanos , Isoniazida/administración & dosificación , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Rifampin/administración & dosificación , Rifampin/sangre , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/microbiologíaRESUMEN
Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).
Asunto(s)
Antituberculosos/farmacocinética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Rifabutina/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Antituberculosos/administración & dosificación , Antituberculosos/sangre , Área Bajo la Curva , Recuento de Linfocito CD4 , Coinfección , Etambutol/administración & dosificación , Femenino , Expresión Génica , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Isoniazida/administración & dosificación , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Método de Montecarlo , Transportadores de Anión Orgánico/metabolismo , Pirazinamida/administración & dosificación , Rifabutina/administración & dosificación , Rifabutina/sangre , Rifampin/administración & dosificación , Factores Sexuales , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patologíaRESUMEN
Ethambutol is a common medicine used for the treatment of tuberculosis, which can have serious side effects, such as retinal and liver dysfunction. Although ethambutol has been reported to impair autophagic flux in rat retinal cells, the precise molecular mechanism remains unclear. Using various mammalian cell lines, we showed that ethambutol accumulated in autophagosomes and vacuolated lysosomes, with marked Zn(2+) accumulation. The enlarged lysosomes were neutralized and were infiltrated with Zn(2+) accumulations in the lysosomes, with simultaneous loss of acidification. These results suggest that EB neutralizes lysosomes leading to insufficient autophagy, implying that some of the adverse effects associated with EB in various organs may be of this mechanism.
Asunto(s)
Antituberculosos/administración & dosificación , Etambutol/administración & dosificación , Lisosomas/fisiología , Fagosomas/fisiología , Zinc/farmacocinética , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Lisosomas/efectos de los fármacos , Lisosomas/ultraestructura , Tasa de Depuración Metabólica/efectos de los fármacos , Fagosomas/efectos de los fármacos , Fagosomas/ultraestructura , RatasRESUMEN
A series of 2(5H)-furanone-based compounds were synthesized from commercially available mucohalic acids. From the first-generation compounds, three showed inhibitory activity (10 µg/mL) of at least 35% against Mycobacterium smegmatis mc(2) 155 growth (Bioscreen C system). In screening the active first-generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC99 ) of 8.07 µg/mL (15.8 µM) using BACTEC 460 system. No cross-resistance was observed with some current first-line anti-TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram-positive and Gram-negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time-kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Hamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti-TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 µg/mL (5.6 µM) and 3.07 µg/mL (5.6 µM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC50 = 38.24 µg/mL to IC50 = 45.58 µg/mL when compared to the most active first-generation compound (IC50 = 1.82 µg/mL). The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti-TB drug candidates. © 2016 IUBMB Life, 68(8):612-620, 2016.
Asunto(s)
Antituberculosos/administración & dosificación , Furanos/administración & dosificación , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Células CHO/efectos de los fármacos , Células CHO/microbiología , Cricetulus , Sinergismo Farmacológico , Etambutol/administración & dosificación , Furanos/síntesis química , Furanos/química , Humanos , Isoniazida/administración & dosificación , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/patogenicidad , Rifampin/administración & dosificación , Tuberculosis/microbiologíaRESUMEN
BACKGROUND: Tuberculosis (TB) of the gastrointestinal tract and any other organ within the abdominal cavity is abdominal TB, and most guidelines recommend the same six-month regimen used for pulmonary TB for people with this diagnosis. However, some physicians are concerned whether a six-month treatment regimen is long enough to prevent relapse of the disease, particularly in people with gastrointestinal TB, which may sometimes cause antituberculous drugs to be poorly absorbed. On the other hand, longer regimens are associated with poor adherence, which could increase relapse, contribute to drug resistance developing, and increase costs to patients and health providers. OBJECTIVES: To compare six-month versus longer drug regimens to treat people that have abdominal TB. SEARCH METHODS: We searched the following electronic databases up to 2 September 2016: the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase (accessed via OvidSP), LILACS, INDMED, and the South Asian Database of Controlled Clinical Trials. We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing trials. We also checked article reference lists. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared six-month regimens versus longer regimens that consisted of isoniazid, rifampicin, pyrazinamide, and ethambutol to treat adults and children that had abdominal TB. The primary outcomes were relapse, with a minimum of six-month follow-up after completion of antituberculous treatment (ATT), and clinical cure at the end of ATT. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and assessed the risk of bias in the included trials. For analysis of dichotomous outcomes, we used risk ratios (RR) with 95% confidence intervals (CIs). Where appropriate, we pooled data from the included trials in meta-analyses. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs, with 328 participants, that compared six-month regimens with nine-month regimens to treat adults with intestinal and peritoneal TB. All trials were conducted in Asia, and excluded people with HIV, those with co-morbidities and those who had received ATT in the previous five years. Antituberculous regimens were based on isoniazid, rifampicin, pyrazinamide, and ethambutol, and these drugs were administered daily or thrice weekly under a directly observed therapy programme. The median duration of follow-up after completion of treatment was between 12 and 39 months.Relapse was uncommon, with two cases among 140 participants treated for six months, and no events among 129 participants treated for nine months. The small number of participants means we do not know whether or not there is a difference in risk of relapse between the two regimens (very low quality evidence). At the end of therapy, there was probably no difference in the proportion of participants that achieved clinical cure between six-month and nine-month regimens (RR 1.02, 95% CI 0.97 to 1.08; 294 participants, 3 trials, moderate quality evidence). For death, there were 2/150 (1.3%) in the six-month group and 4/144 (2.8%) in the nine-month group. All deaths occurred in the first four months of treatment, so was not linked to the duration of treatment in the included trials. Similarly, the number of participants that defaulted from treatment was small in both groups, and there may be no difference between them (RR 0.50, 95% CI 0.10 to 2.59; 294 participants, 3 trials, low quality evidence). Only one trial reported on adherence to treatment, with only one participant allocated to the nine-month regimen presenting poor adherence to treatment. We do not know whether six-month regimens are associated with fewer people experiencing adverse events that lead to treatment interruption (RR 0.53, 95% CI 0.18 to 1.55; 318 participants, 3 trials, very low quality evidence). AUTHORS' CONCLUSIONS: We found no evidence to suggest that six-month treatment regimens are inadequate for treating people that have intestinal and peritoneal TB, but numbers are small. We did not find any incremental benefits of nine-month regimens regarding relapse at the end of follow-up, or clinical cure at the end of therapy, but our confidence in the relapse estimate is very low because of size of the trials. Further research is required to make confident conclusions regarding the safety of six-month treatment for people with abdominal TB. Larger studies that include HIV-positive people, with long follow-up for detecting relapse with reliability, would help improve our knowledge around this therapeutic question.