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1.
Medicine (Baltimore) ; 99(44): e22258, 2020 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-33126298

RESUMEN

We aimed to investigate the effect of interval between food intake and drug administration at fasting condition on the plasma concentrations of first-line anti- tuberculosis (TB) drugs in Chinese population. Newly diagnosed TB patients administered the anti-TB drugs under fasting conditions orally, and then had prepared breakfast at 30 minutes and 120 min after dosing, respectively. Blood sampling was also performed 120  minutes after dosing for the detection of Cmax purpose. Overall, twenty-five participants were included in our analysis. The Cmaxs of 30  minutes interval and 120  minutes interval were 21.8 ±â€Š2.0 and 19.2 ±â€Š2.0 µg/mL for rifampin, 1.6 ±â€Š0.2 and 2.1 ±â€Š0.2 µg/mL for isoniazid (INH), 1.5 ±â€Š0.1and 1.5 ±â€Š0.2 µg/mL for ethambutol (EMB), and 49.2 ±â€Š3.7 and 41.5 ±â€Š3.9 µg/mL for pyrazinamide, respectively. Statistical analysis revealed that there was no statistical difference between 2 groups. Additionally, 88.0% and 72.0% of the 25 participants at 2-hour interval group had peak concentrations less than the lower limit of the reference range for INH and EMB, respectively. The Cmaxs of INH were 0.9 ±â€Š0.4 µg/ml for rapid acetylator, which was significantly lower than those of intermediate (1.4 ±â€Š1.0 µg/mL), and slow acetylator (2.5 ±â€Š1.0 µg/mL), respectively (P < .01). In conclusion, our data demonstrate that early food intake at 30 minutes after drug administration had no significant influence on the plasma concentrations. In addition, a high proportion of patients receiving first-line anti-TB regimen fail to achieve the expected plasma drug ranges of INH and EMB (P > .05).


Asunto(s)
Antituberculosos/sangre , Ingestión de Alimentos , Ayuno/sangre , Factores de Tiempo , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/tratamiento farmacológico , Administración Oral , Adulto , Antituberculosos/administración & dosificación , China , Esquema de Medicación , Etambutol/administración & dosificación , Etambutol/sangre , Femenino , Humanos , Isoniazida/administración & dosificación , Isoniazida/sangre , Masculino , Pirazinamida/administración & dosificación , Pirazinamida/sangre , Rifampin/administración & dosificación , Rifampin/sangre , Resultado del Tratamiento
2.
Saudi Med J ; 41(7): 753-756, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32601645

RESUMEN

Elizabethkingia meningoseptica (E. meningoseptica ) are Gram-negative bacteria commonly associated with nosocomial infections in neonates. This is a case study of E. meningoseptica, presented as meningitis and sepsis in a term baby. The female infant was born by vaginal delivery at 37 weeks gestational age. The case was peculiar because the baby was neither premature nor immuno-compromised, which are known risk factors for E. meningoseptica infection. The onset began on the second day of the neonate's life. On day 3, peripheral blood culture and cerebrospinal fluid findings isolated a gram-negative bacteria identified as E. meningoseptica. The first-line antibiotics therapy was changed to ciprofloxacin, vancomycin, and rifampicin, based on the laboratory determination of antimicrobial sensitivity. The patient's clinical condition improved, although post hemorrhagic ventricular dilatation was revealed by imaging studies. Clinicians should possess proper awareness of the antibiotic sensitivity of E. meningoseptica, as it is important in preventing high rates of morbidity and mortality.


Asunto(s)
Antibacterianos/administración & dosificación , Ciprofloxacino/administración & dosificación , Infecciones por Flavobacteriaceae , Flavobacteriaceae , Meningitis Bacterianas/tratamiento farmacológico , Meningitis Bacterianas/microbiología , Rifampin/administración & dosificación , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Vancomicina/administración & dosificación , Antibacterianos/farmacología , Ciprofloxacino/farmacología , Farmacorresistencia Bacteriana , Quimioterapia Combinada , Femenino , Flavobacteriaceae/efectos de los fármacos , Flavobacteriaceae/aislamiento & purificación , Humanos , Recién Nacido , Rifampin/farmacología , Arabia Saudita , Resultado del Tratamiento , Vancomicina/farmacología
3.
J Med Vasc ; 45(4): 177-183, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32571557

RESUMEN

OBJECTIVE: To evaluate the short and long-term results of in situ prosthetic graft treatment using rifampicin-soaked silver polyester graft in patients with aortic infection. MATERIAL AND METHOD: All the patients surgically managed in our center for an aortic infection were retrospectively analyzed. The primary endpoint was the intra-hospital mortality, secondary outcomes were limb salvage, persistent or recurrent infection, prosthetic graft patency, and long-term survival. RESULTS: From January 2004 to December 2015, 18 consecutive patients (12 men and 6 women) were operated on for aortic infection. Six mycotic aneurysms and 12 prosthetic infections, including 8 para-entero-prosthetic fistulas, were treated. In 5 cases, surgery was performed in emergency. During the early postoperative period, we performed one major amputation and two aortic infections were persistent. Intra-hospital mortality was 27.7%. The median follow-up among the 13 surviving patients was 26 months. During follow-up, none of the 13 patients presented reinfection or bypass thrombosis. CONCLUSION: This series shows that in situ revascularization with rifampicin-soaked silver polyester graft for aortic infection have results in agreement with the literature in terms of intra-hospital mortality with a low reinfection rate.


Asunto(s)
Aneurisma Infectado/cirugía , Antibacterianos/administración & dosificación , Aneurisma de la Aorta/cirugía , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Poliésteres , Infecciones Relacionadas con Prótesis/cirugía , Rifampin/administración & dosificación , Plata , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aneurisma Infectado/diagnóstico por imagen , Aneurisma Infectado/microbiología , Aneurisma Infectado/mortalidad , Antibacterianos/efectos adversos , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/microbiología , Aneurisma de la Aorta/mortalidad , Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Femenino , Francia , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Poliésteres/efectos adversos , Diseño de Prótesis , Infecciones Relacionadas con Prótesis/diagnóstico por imagen , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/mortalidad , Estudios Retrospectivos , Rifampin/efectos adversos , Factores de Riesgo , Plata/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
5.
PLoS One ; 15(5): e0232482, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32357366

RESUMEN

The study was designed to assess whether plant extracts / phytochemical (D-Pinitol) synergistically combine with antituberculosis drugs and act on Mycobacterium smegmatis (M. smegmatis) as well as assess their mode of action on Mycobacterium tuberculosis (M.tb) Filamenting temperature sensitive mutant Z (FtsZ) protein. Resazurin microtitre plate assay (Checker board) was performed to analyze the activity of plant extracts against M. smegmatis. Synergistic behaviour of plant extracts / D-Pinitol with Isoniazid (INH) and Rifampicin (RIF) were determined by time-kill and checker board assays. Elongation of M. smegmatis cells due to this treatment was determined by light microscopy. The effect of Hexane methanol extract (HXM) plant extracts on cell viability was determined using PI/SYTO9 dual dye reporter Live/Dead assay. Action of HXM plant extracts / D-Pinitol on inhibition of FtsZ protein was done using Guanosine triphosphatase (GTPase) light scattering assay and quantitative Polymerase Chain Reaction (qPCR). The Hexane-methanolic plant extract of Acacia nilotica, Aegle marmelos and Glycyrrhiza glabra showed antimycobacterial activity at 1.56 ± 0.03, 1.32 ± 0.02 and 1.25 ± 0.03 mg/mL respectively and that of INH and RIF were 4.00 ± 0.06 µg/mL and 2.00 ± 0.04 µg/mL respectively. These plant extracts and major phytochemical exudate D-Pinitol was found to act synergistically with antimycobacterial drugs INH and RIF with an FIC index ~ 0.20. Time-Kill kinetics studies indicate that, these plant extracts were bacteriostatic in nature. D-Pinitol in conjunction with INH and RIF exhibited a 2 Log reduction in the growth of viable cells compared to untreated. Attempt to elucidate their mode of action through phenotypic analysis indicated that these plant extracts and D-Pinitol was found to interfere in cell division there by leading to an abnormal elongated cellular morphology. HXM extracts and D-Pinitol synergistically combined with the first line tuberculosis drugs, INH and RIF, to act on M. smegmatis. The increase in the length of M. smegmatis cells on treatment with D-Pinitol and HXM extract of the plants indicated that they hinder the cell division mechanism thereby leading to a filamentous phenotype, and finally leading to cell death. In addition, the integrity of the bacterial cell membrane is also altered causing cell death. Further gene expression analysis showed that these plant extracts and D-Pinitol hampers with function of FtsZ protein which was confirmed through in vitro inhibition of FtsZ-GTPase enzymatic activity.


Asunto(s)
Proteínas Bacterianas/genética , Proteínas del Citoesqueleto/genética , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/genética , Plantas Medicinales , Antituberculosos/administración & dosificación , Proteínas Bacterianas/antagonistas & inhibidores , División Celular/efectos de los fármacos , Proteínas del Citoesqueleto/antagonistas & inhibidores , Sinergismo Farmacológico , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Genes Bacterianos/efectos de los fármacos , Humanos , Técnicas In Vitro , Inositol/administración & dosificación , Inositol/análogos & derivados , Isoniazida/administración & dosificación , Pruebas de Sensibilidad Microbiana , Mutación , Mycobacterium smegmatis/citología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Extractos Vegetales/administración & dosificación , Rifampin/administración & dosificación , Temperatura
6.
Am J Med Sci ; 359(6): 372-377, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32317167

RESUMEN

Tuberculosis is a global burden with an unacceptably high mortality rate, especially in low- and middle-income countries. We reported the case of 34-year-old Somali female with no significant risk factors who initially presented with headache and blurred vision. The patient subsequently developed altered mental status and significant vision changes. Initial lumbar puncture showed lymphocytic pleocytosis with negative gram stain, acid-fast bacilli stain, and culture. Initial polymerase chain reaction for tuberculosis was negative. The patient worsened despite receiving broad-spectrum antibiotics. The patient had a prolonged hospital course and eventually required lumbar drain placement for hydrocephalus. Repeated polymerase chain reactions for Mycobacterium tuberculosis from the lumbar drain samples was positive, and the diagnosis of tuberculous meningitis was confirmed. The patient improved after lumbar drain placement and treatment with isoniazid, rifampin, pyrazinamide, ethambutol and steroid tapering. This case illustrated the challenge of diagnosing tuberculous meningitis.


Asunto(s)
Tuberculosis Meníngea/diagnóstico por imagen , Tuberculosis Meníngea/tratamiento farmacológico , Adulto , Antituberculosos/administración & dosificación , Asma/complicaciones , Etambutol/administración & dosificación , Femenino , Cefalea/complicaciones , Hospitalización , Humanos , Hidrocefalia/complicaciones , Hidrocefalia/cirugía , Isoniazida/administración & dosificación , Leucocitosis , Imagen por Resonancia Magnética , Reacción en Cadena de la Polimerasa , Pirazinamida/administración & dosificación , Rifampin/administración & dosificación , Somalia , Punción Espinal , Tuberculosis Meníngea/complicaciones , Estados Unidos , Trastornos de la Visión/complicaciones
7.
Fontilles, Rev. leprol ; 32(4): 263-271, ene.-abr. 2020. tab, graf
Artículo en Español | IBECS | ID: ibc-193432

RESUMEN

OBJETIVO: La profilaxis post-exposición de la lepra con dosis única de rifampicina (SDR-PEP) ha demostrado ser efectiva y aplicable y está recomendada por la OMS desde 2018. Esta caja de herramientas SDR-PEP se desarrolló a través de la experiencia de la profilaxis lepra post-eliminación (LPEP). Se ha diseñado para facilitar y estandarizar la implementación del seguimiento de contactos y la administración SDR-PEP en regiones y países que iniciaron la intervención. RESULTADOS: Se desarrollaron cuatro instrumentos, incorporando la evidencia existente actual para SDR-PEP y los métodos y enseñanzas del proyecto LPEP en ocho países. (1) El conjunto de diapositivas Powerpoint política/apoyo que ayudarán a los programadores sobre la evidencia, practicabilidad y recursos necesarios para SDR-PEP, (2) La colección de diapositivas PowerPoint sobre formación e implementación en el campo para formar al personal implicado en el seguimiento de contactos y PEP con SDR, (3) manual genérico de campo SDR-PEP que puede ser usado para formar un protocolo específico de campo para el seguimiento de contactos y SDR-PEP como referencia para el personal directamente implicado. Finalmente, (4) el manual director SDR-PEP, que resume los distintos componentes de la caja de herramientas y contiene las instrucciones para su uso. CONCLUSIÓN: En respuesta al interés manifestado por varios países de implementar el seguimiento de contactos de lepra con PEP con SDR, con las recomendaciones OMS sobre SDR-PEP, esta caja de herramientas basada en la evidencia concreta pero flexible, ha sido diseñada para servir a los directores de programas nacionales de lepra con un medio práctico para trasladar los planteamientos a la práctica. Está disponible gratuitamente en la página de Infolep y actualizada constantemente: https://www.leprosy-information.org/keytopic/leprosy-post-exposure-prophylaxis-lpep-programme


OBJECTIVE: Leprosy post-exposure prophylaxis with single-dose rifampicin (SDRPEP) has proven effective and feasible, and is recommended by WHO since 2018. This SDR-PEP toolkit was developed through the experience of the leprosy post-exposure prophylaxis (LPEP) programme. It has been designed to facilitate and standardise the implementation of contact tracing and SDR-PEP administration in regions and countries that start the intervention. RESULTS: Four tools were developed, incorporating the current evidence for SDRPEP and the methods and learnings from the LPEP project in eight countries. (1) the SDR-PEP policy/advocacy PowerPoint slide deck which will help to inform policy makers about the evidence, practicalities and resources needed for SDR-PEP, (2) the SDR-PEP field implementation training PowerPoint slide deck to be used to train front line staff to implement contact tracing and PEP with SDR, (3) the SDR-PEP generic field guide which can be used as a basis to create a location specific field protocol for contact tracing and SDR-PEP serving as a reference for frontline field staff. Finally, (4) the SDR-PEP toolkit guide, summarising the different components of the toolkit and providing instructions on its optimal use. CONCLUSION: In response to interest expressed by countries to implement contact tracing and leprosy PEP with SDR in the light of the WHO recommendation of SDRPEP, this evidence-based, concrete yet flexible toolkit has been designed to serve national leprosy programme managers and support them with the practical means to translate policy into practice. The toolkit is freely accessible on the Infolep homepages and updated as required: https://www.leprosy-information.org/keytopic/leprosy-postexposure-prophylaxis-lpep-programme


Asunto(s)
Humanos , Profilaxis Posexposición/métodos , Lepra/prevención & control , Rifampin/administración & dosificación , Leprostáticos/administración & dosificación , Dosis Única
8.
Lancet HIV ; 7(6): e401-e409, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32240629

RESUMEN

BACKGROUND: Short-course preventive therapy with 12 doses of once-weekly rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive. METHODS: DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load (<40 copies per mL) after at least 8 weeks of efavirenz-based or dolutegravir-based regimens were recruited in three consecutive groups, subject to approval by the independent safety monitoring committee. Participants received 50 mg of daily dolutegravir in place of efavirenz for 8 weeks, then began once-weekly rifapentine (900 mg)-isoniazid (900 mg) for 12 weeks. Groups 1A (n=12) and 1B (n=18) had intensive dolutegravir pharmacokinetic sampling at week 8 (before rifapentine-isoniazid), at week 11 (after the third dose of rifapentine)-isoniazid and at week 16 after the eighth dose. Group 2 (n=30) were treated with the same schedule and had sparse dolutegravir pharmacokinetic sampling at weeks 8, 11, and 16. Participants were followed 4 weeks after completion of prophylactic tuberculosis treatment. HIV viral loads were measured at baseline and at weeks 11 and 24. Primary endpoints were adverse events (grade 3 or higher) and dolutegravir population pharmacokinetics, assessed in participants who began rifapentine-isoniazid. This trial was registered at ClinicalTrials.gov, NCT03435146. FINDINGS: Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35-48), CD4 cell count was 683 cells per µL (447-935), and body-mass index was 28·9 kg/m2 (24·0-32·9). Three grade 3 adverse events occurred; two elevated creatinine and one hypertension. Rifapentine-isoniazid increased dolutegravir clearance by 36% (relative standard error 13%) resulting in a 26% decrease in dolutegravir area under the curve. Overall geometric mean ratio of trough concentrations with versus without rifapentine-isoniazid was 0·53 (90% CI 0·49-0·56) though this ratio varied by day after rifapentine-isoniazid dose. All but one trough value was above the 90% maximal inhibitory concentration for dolutegravir and HIV viral loads were less than 40 copies per mL in all patients. INTERPRETATION: Our results suggest 12 doses of once-weekly rifapentine-isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed. FUNDING: UNITAID.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Isoniazida/administración & dosificación , Rifampin/análogos & derivados , Tuberculosis/prevención & control , Adulto , Esquema de Medicación , Femenino , Infecciones por VIH/virología , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Isoniazida/efectos adversos , Masculino , Persona de Mediana Edad , Rifampin/administración & dosificación , Rifampin/efectos adversos , Sudáfrica , Resultado del Tratamiento , Carga Viral
9.
Lancet ; 395(10232): 1259-1267, 2020 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-32171422

RESUMEN

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.


Asunto(s)
Úlcera de Buruli/tratamiento farmacológico , Claritromicina/administración & dosificación , Rifampin/administración & dosificación , Estreptomicina/administración & dosificación , Administración Oral , Adolescente , Adulto , Antibacterianos , Benin , Niño , Claritromicina/efectos adversos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Quimioterapia Combinada , Femenino , Ghana , Humanos , Masculino , Rifampin/efectos adversos , Estreptomicina/efectos adversos , Cicatrización de Heridas/efectos de los fármacos , Adulto Joven
13.
Int J Nanomedicine ; 15: 1073-1094, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32103956

RESUMEN

Purpose: This study demonstrated improved transdermal delivery of rifampicin-loaded cationic nanoemulsion gel to treat systemic and cutaneous tuberculosis using capmul, labrasol, and acconon, which exert anti-Mycobacterium activities. This approach enhanced drug permeation across the skin, increased therapeutic efficacy, and reduced dose-related side effects. Methods: Design Expert® was used to optimize formulations (Smix ratio and capmul as independent factors), which were prepared using a slow spontaneous titration method. The optimized nanoemulsion was incorporated into carbopol gel to allow for topical application and comparative assessments. Nanoemulsions and gels were evaluated for size, size distribution, shape, zeta potential, percent spread, viscosity, in vitro hemolysis, in vitro release, and ex vivo skin permeation and deposition. A mechanistic evaluation was performed using scanning electron microscopy. Furthermore, in vivo pharmacokinetic and irritation studies were performed. Results: The optimized cationic nanoemulsion (OCNE-1) was characterized by small particle size (≤100 nm), had optimal viscosity, percent spread, zeta potential, and percent drug release, and was hemocompatible. The OCNE-1T gel exhibited higher permeation flux (51.32 ± 0.5 µg/cm2 hr), permeation coefficient (2.566 ± 0.08 cm/hr), drug deposition (994.404 µg/cm2), and enhancement ratio (7.16) than those of the OCNE-1 nanoemulsion or drug solution. Scanning electron microscopy was used to characterize the mechanism of enhanced permeation. An In vivo study showed that the Cmax and area under the curve following transdermal application were 4.34- and 4.74-fold higher than those following oral administration. Conclusion: Transdermal delivery of rifampicin could be a promising alternative to conventional approaches to treat systemic and local tuberculosis, and other bacterial infections.


Asunto(s)
Antituberculosos/administración & dosificación , Emulsiones/administración & dosificación , Rifampin/administración & dosificación , Tuberculosis/tratamiento farmacológico , Resinas Acrílicas/química , Administración Cutánea , Animales , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Disponibilidad Biológica , Caprilatos/química , Cationes/química , Emulsiones/farmacología , Excipientes/química , Geles/química , Geles/farmacología , Glicéridos/química , Mycobacterium/efectos de los fármacos , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Tamaño de la Partícula , Ratas Sprague-Dawley , Rifampin/farmacocinética , Rifampin/farmacología , Piel/efectos de los fármacos , Tuberculosis Cutánea/tratamiento farmacológico
14.
Nat Med ; 26(4): 529-534, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32066976

RESUMEN

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure1. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments2. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans3. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study4 using dynamic [11C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [11C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.


Asunto(s)
Antituberculosos/farmacocinética , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Rifampin/farmacocinética , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Adulto , Animales , Antituberculosos/administración & dosificación , Antituberculosos/sangre , Disponibilidad Biológica , Quimioterapia Combinada , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Mycobacterium tuberculosis/fisiología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Conejos , Rifampin/administración & dosificación , Rifampin/sangre , Distribución Tisular , Tuberculosis/metabolismo , Tuberculosis/patología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/metabolismo , Tuberculosis Pulmonar/patología
15.
Clin Pharmacol Ther ; 107(4): 1023-1033, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31956998

RESUMEN

The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2-93.8) to 82.5 hour·mg/L (range 8.7-161.0) in plasma and from 3.5 hour·mg/L (range 1.2-9.6) to 6.0 hour·mg/L (range 0.7-15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.


Asunto(s)
Antituberculosos/administración & dosificación , Antituberculosos/sangre , Tuberculosis Meníngea/sangre , Tuberculosis Meníngea/tratamiento farmacológico , Adulto , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Levofloxacino/administración & dosificación , Levofloxacino/sangre , Masculino , Rifampin/administración & dosificación , Rifampin/sangre , Resultado del Tratamiento , Tuberculosis Meníngea/diagnóstico
16.
Drug Dev Ind Pharm ; 46(2): 309-317, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31944867

RESUMEN

Objective: Develop a child-friendly Fixed Dose Combination (FDC) water-dispersible tablet for Tuberculosis (TB) treatment, with 50, 150, and 75 mg of isoniazid, pyrazinamide and rifampicin respectively. This new formulation must contain the lowest number of excipients accepted for pediatrics and fulfill all the pharmacopeia requirements.Significance: At present, there is no adequate market dosage form available for children. There is, however, one in a prequalification phase by the World Health Organization but its composition contains excipients which may not be suitable for pediatrics. Therefore, this new formulation would cover this therapeutic gap.Methods: A factorial design, based on three quantitative factors (compression force and concentration of AcDiSol® and Explosol®) at three levels each, was performed to elucidate their influence over disintegration time and friability. In addition, the influence of the press speed on disintegration time, friability, tensile strength, fineness of dispersion and content uniformity over the target tablet was tested. A stability test was done following ICH guideline for accelerated conditions.Results: Tablets developed with 9% w/w of Explosol® and a compression force of 16 kN disintegrated in less than 3 min and showed a friability below 1% when 15-mm punches were used. The tableting process could be done up to 25 and 50 cycles/minute ensuring good quality attributes when 15 and 12-mm punches were used, respectively. All APIs remained inside the limit of ± 5% of drug content till 6 months of storage.Conclusion: A high-quality child-friendly FDC water-dispersible tablet was developed improving the treatment of TB in pediatric.


Asunto(s)
Antituberculosos/administración & dosificación , Antituberculosos/química , Isoniazida/química , Pirazinamida/química , Rifampin/química , Comprimidos/química , Tuberculosis/tratamiento farmacológico , Química Farmacéutica/métodos , Niño , Composición de Medicamentos/métodos , Excipientes/química , Dureza/efectos de los fármacos , Humanos , Isoniazida/administración & dosificación , Pediatría/métodos , Pirazinamida/administración & dosificación , Rifampin/administración & dosificación , Solubilidad/efectos de los fármacos , Comprimidos/administración & dosificación , Resistencia a la Tracción
18.
BMC Infect Dis ; 19(1): 1033, 2019 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-31805862

RESUMEN

BACKGROUND: Leprosy is an ancient infectious disease with a global annual incidence that has plateaued above 200,000 new cases since over a decade. New strategies are required to overcome this stalemate. Post-exposure prophylaxis (PEP) with a single dose of Rifampicin (SDR) has conditionally been recommended by the World Health Organization (WHO), based on a randomized-controlled-trial in Bangladesh. More evidence is required. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial will assess effectiveness of different modalities of PEP on the Comoros and Madagascar. METHODS: PEOPLE is a cluster-randomized trial with villages selected on previous leprosy-incidence and randomly allocated to four arms. Four annual door-to-door surveys will be performed in all arms. All consenting permanent residents will be screened for leprosy. Leprosy patients will be treated according to international guidelines and eligible contacts will be provided with SDR-PEP. Arm-1 is the comparator in which no PEP will be provided. In arms 2, 3 and 4, SDR-PEP will be provided at double the regular dose (20 mg/kg) to eligible contacts aged two years and above. In arm 2 all household-members of incident leprosy patients are eligible. In arm 3 not only household-members but also neighbourhood contacts living within 100-m of an incident case are eligible. In arm 4 such neighbourhood contacts are only eligible if they test positive to anti-PGL-I, a serological marker. Incidence rate ratios calculated between the comparator arm 1 and each of the intervention arms will constitute the primary outcome. DISCUSSION: Different trials on PEP have yielded varying results. The pivotal COLEP trial in Bangladesh showed a 57% reduction in incidence over a two-year period post-intervention without any rebound in the following years. A study in a high-incidence setting in Indonesia showed no effect of PEP provided to close contacts but a major effect of PEP provided as a blanket measure to an entire island population. High background incidence could be the reason of the lack of effect of PEP provided to individual contacts. The PEOPLE trial will assess effectiveness of PEP in a high incidence setting and will compare three different approaches, to identify who benefits most from PEP. TRIAL REGISTRATION: Clinicaltrials.Gov. NCT03662022. Initial Protocol Version 1.2, 27-Aug-2018.


Asunto(s)
Leprostáticos/uso terapéutico , Lepra/prevención & control , Profilaxis Posexposición/métodos , Rifampin/uso terapéutico , Preescolar , Comoras/epidemiología , Composición Familiar , Femenino , Humanos , Incidencia , Leprostáticos/administración & dosificación , Lepra/epidemiología , Madagascar/epidemiología , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Rifampin/administración & dosificación
19.
Rev. esp. patol. torac ; 31(4): 262-266, dic. 2019. ilus
Artículo en Español | IBECS | ID: ibc-187187

RESUMEN

La tuberculosis continúa siendo un problema de salud a nivel mundial. Existe una gran variabilidad clínica de esta entidad dependiendo, entre otros factores, del lugar del organismo donde se asiente el bacilo. Existe una entidad específica de tuberculosis, denominada Tuberculosis Endobronquial (EBTB), que se define como una infección tuberculosa del árbol traqeuobronquial con evidencia microbiológica y/o histopatológica. Ésta puede presentarse sola o junto con afectación parenquimatosa. Las manifestaciones clínicas de esta entidad son inespecíficas, lo cual dificulta el diagnóstico. Para este es fundamental la realización de una TC de tórax y una broncoscopia. Ésta última nos permitirá observar las características del árbol traqueobronquial y tomar muestras para poder hacer el diagnóstico de certeza. El tratamiento es similar al de la tuberculosis pulmonar y el objetivo fundamental de este es erradicar el bacilo y prevenir complicaciones, siendo la más frecuente la estenosis bronquial


Tuberculosis continues to be a health problem worldwide. There is a large degree of clinical variability for this disease which depends, among other factors, on the part of the organism where the bacillus settles. There is a specific type of tuberculosis, called endobronchial tuberculosis (EBTB), which is defined as a tuberculous infection of the tracheobronchial tree with microbiological and/or histopathological signs. It can present on its own or alongside parenchymal involvement. The clinical manifestations of this disease are non-specific, which makes diagnosis difficult. That is why performing a chest CT and bronchoscopy is essential. The latter will allow the characteristics of the tracheobronchial tree to be seen and samples to be taken in order to make an accurate diagnosis. Treatment is similar to that of pulmonary tuberculosis and the main objective is to eradicate the bacillus and prevent complications, the most frequent of which is bronchial stenosis


Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Broncoscopía/métodos , Tuberculosis Pulmonar/diagnóstico , Tejido Parenquimatoso/microbiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Hemodiafiltración , Isoniazida/administración & dosificación , Rifampin/administración & dosificación , Pirazinamida/administración & dosificación , Etambutol/administración & dosificación , Bronquios/lesiones , Bronquios/patología
20.
Eklem Hastalik Cerrahisi ; 30(3): 333-7, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31650935

RESUMEN

Brucellosis is a zoonosis seen all over the world and is still endemic in certain parts of the world. Brucellosis is a systemic infection which involves multiple organs and tissues. Although musculoskeletal system involvement is frequent in brucellosis, bursal involvement is seen rarely. In this article, we present a case of subacromial and subdeltoid brucellar bursitis with positive serology and aspiration culture. Patient achieved complete recovery with rifampicin and doxycycline treatment, without any evidence of relapse. A high clinical suspicion is required for the diagnosis of brucellar bursitis.


Asunto(s)
Brucelosis/diagnóstico , Bursitis/diagnóstico , Articulación del Hombro , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Brucelosis/tratamiento farmacológico , Brucelosis/microbiología , Bursitis/tratamiento farmacológico , Bursitis/microbiología , Diagnóstico Diferencial , Doxiciclina/administración & dosificación , Doxiciclina/uso terapéutico , Quimioterapia Combinada , Humanos , Masculino , Rifampin/administración & dosificación , Rifampin/uso terapéutico
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