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1.
Clin Infect Dis ; 77(11): 1504-1510, 2023 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-37539715

RESUMEN

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.


Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Microbiota , Adulto , Humanos , Femenino , Anciano , Masculino , Prevalencia , Antibacterianos/uso terapéutico , Infecciones por Clostridium/tratamiento farmacológico , Recurrencia
2.
Emerg Infect Dis ; 29(4): 846-848, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36696625

RESUMEN

We describe a case of mpox characterized by a circularly distributed facial rash but no identified risk factors. Fomite transmission of monkeypox virus from contaminated linen at a massage spa was suspected. Clinicians should consider mpox in patients with consistent clinical syndromes, even in the absence of epidemiologic risk factors.


Asunto(s)
Ropa de Cama y Ropa Blanca , Mpox , Femenino , Humanos , Factores de Riesgo , Massachusetts , Monkeypox virus , Síndrome
3.
N Engl J Med ; 383(19): 1813-1826, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-32445440

RESUMEN

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/uso terapéutico , Administración Intravenosa , Adulto , Anciano , Alanina/administración & dosificación , Alanina/efectos adversos , Alanina/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/terapia , Método Doble Ciego , Oxigenación por Membrana Extracorpórea , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia por Inhalación de Oxígeno , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/terapia , Respiración Artificial , SARS-CoV-2 , Factores de Tiempo , Adulto Joven , Tratamiento Farmacológico de COVID-19
4.
N Engl J Med ; 381(21): 2043-2050, 2019 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-31665575

RESUMEN

Fecal microbiota transplantation (FMT) is an emerging therapy for recurrent or refractory Clostridioides difficile infection and is being actively investigated for other conditions. We describe two patients in whom extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli bacteremia occurred after they had undergone FMT in two independent clinical trials; both cases were linked to the same stool donor by means of genomic sequencing. One of the patients died. Enhanced donor screening to limit the transmission of microorganisms that could lead to adverse infectious events and continued vigilance to define the benefits and risks of FMT across different patient populations are warranted.


Asunto(s)
Bacteriemia/etiología , Disbiosis/terapia , Escherichia coli/aislamiento & purificación , Trasplante de Microbiota Fecal/efectos adversos , Heces/microbiología , Anciano , Bacteriemia/microbiología , Farmacorresistencia Bacteriana , Disbiosis/etiología , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Resultado Fatal , Encefalopatía Hepática/complicaciones , Encefalopatía Hepática/terapia , Humanos , Masculino , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/terapia , beta-Lactamasas/metabolismo
5.
Nature ; 534(7606): 259-62, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27279224

RESUMEN

Human-associated microbial communities have a crucial role in determining our health and well-being, and this has led to the continuing development of microbiome-based therapies such as faecal microbiota transplantation. These microbial communities are very complex, dynamic and highly personalized ecosystems, exhibiting a high degree of inter-individual variability in both species assemblages and abundance profiles. It is not known whether the underlying ecological dynamics of these communities, which can be parameterized by growth rates, and intra- and inter-species interactions in population dynamics models, are largely host-independent (that is, universal) or host-specific. If the inter-individual variability reflects host-specific dynamics due to differences in host lifestyle, physiology or genetics, then generic microbiome manipulations may have unintended consequences, rendering them ineffective or even detrimental. Alternatively, microbial ecosystems of different subjects may exhibit universal dynamics, with the inter-individual variability mainly originating from differences in the sets of colonizing species. Here we develop a new computational method to characterize human microbial dynamics. By applying this method to cross-sectional data from two large-scale metagenomic studies--the Human Microbiome Project and the Student Microbiome Project--we show that gut and mouth microbiomes display pronounced universal dynamics, whereas communities associated with certain skin sites are probably shaped by differences in the host environment. Notably, the universality of gut microbial dynamics is not observed in subjects with recurrent Clostridium difficile infection but is observed in the same set of subjects after faecal microbiota transplantation. These results fundamentally improve our understanding of the processes that shape human microbial ecosystems, and pave the way to designing general microbiome-based therapies.


Asunto(s)
Ecosistema , Microbiota/fisiología , Clostridioides difficile/fisiología , Infecciones por Clostridium/microbiología , Simulación por Computador , Estudios Transversales , Conjuntos de Datos como Asunto , Ambiente , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiología , Voluntarios Sanos , Humanos , Intestinos/microbiología , Metagenómica , Boca/microbiología , Especificidad de Órganos , Piel/microbiología , Especificidad de la Especie
6.
Clin Infect Dis ; 72(12): 2132-2140, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-32255488

RESUMEN

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. METHODS: In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. RESULTS: 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11-2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. CONCLUSIONS: Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. CLINICAL TRIALS REGISTRATION: NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.


Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Microbiota , Anciano , Clostridioides , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/prevención & control , Drogas en Investigación , Femenino , Humanos , Masculino , Recurrencia
7.
PLoS Med ; 17(3): e1003051, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32150549

RESUMEN

BACKGROUND: There is intense interest about whether modulating gut microbiota can impact systemic metabolism. We investigated the safety of weekly oral fecal microbiota transplantation (FMT) capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity. METHODS AND FINDINGS: FMT-TRIM was a 12-week double-blind randomized placebo-controlled pilot trial of oral FMT capsules performed at a single US academic medical center. Between August 2016 and April 2018, we randomized 24 adults with obesity and mild-moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks. The primary outcome, assessed by intention to treat, was change in insulin sensitivity between 0 and 6 weeks as measured by hyperinsulinemic euglycemic clamps. Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure by indirect calorimetry. Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing. Our study population was 71% female, with an average baseline BMI of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively. There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+5% ± 12% in FMT group versus -3% ± 32% in placebo group, mean difference 9%, 95% CI -5% to 28%, p = 0.16). There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI -0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference -0.1 kg, 95% CI -1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95% CI -0.6 to 3.0 kg, p = 0.18), over the 12-week study. We observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study. There were no significant differences in adverse events (AEs) (10 versus 5, p = 0.09), and no serious AEs related to FMT. Limitations of this pilot study are the small sample size, inclusion of participants with relatively mild insulin resistance, and lack of concurrent dietary intervention. CONCLUSIONS: Weekly administration of FMT capsules in adults with obesity results in gut microbiota engraftment in most recipients for at least 12 weeks. Despite engraftment, we did not observe clinically significant metabolic effects during the study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02530385.


Asunto(s)
Metabolismo Energético , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Resistencia a la Insulina , Intestinos/microbiología , Obesidad/terapia , Adulto , Biomarcadores/sangre , Boston , Método Doble Ciego , Trasplante de Microbiota Fecal/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/diagnóstico , Obesidad/metabolismo , Obesidad/microbiología , Proyectos Piloto , Factores de Tiempo , Resultado del Tratamiento
9.
Biol Blood Marrow Transplant ; 25(1): e17-e22, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30408565

RESUMEN

Disruption of the intestinal microbiome early after allogeneic hematopoietic cell transplantation (allo-HCT) has been linked to adverse outcomes in transplant recipients. To date, whether microbiome-directed interventions will be able to impact important clinical endpoints remains unknown. Fecal microbiota transplantation (FMT) is a compelling intervention to restore healthy diversity to the intestinal microenvironment after allo-HCT, but currently has no established role in transplant recipients. In this review, we examine the use of FMT as treatment for Clostridium difficile infection and acute graft-versus-host disease, and also as a restorative intervention early after allo-HCT. Ongoing and planned studies will help determine the ultimate role of FMT in allo-HCT recipients.


Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Aloinjertos , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/terapia , Enfermedad Injerto contra Huésped/microbiología , Enfermedad Injerto contra Huésped/terapia , Humanos
10.
Clin Gastroenterol Hepatol ; 17(4): 791-793, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29859984

RESUMEN

The incidence of recurrent and refractory Clostridium difficile (rCDI) is increasing.1 Cirrhotic patients are at increased risk of CDI as a result of frequent hospitalizations, prophylactic antibiotics, proton pump inhibitor use, and comorbidities.2 In addition, cirrhotic patients with CDI have a higher mortality rate, longer length of stay, and a higher cost compared with noncirrhotic patients.3.


Asunto(s)
Infecciones por Clostridium/prevención & control , Trasplante de Microbiota Fecal/métodos , Cirrosis Hepática/complicaciones , Prevención Secundaria , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cápsulas/administración & dosificación , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven
11.
J Infect Dis ; 218(suppl_4): S214-S221, 2018 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-28961918

RESUMEN

Background: In South Asia, data on enteric fever are sparse outside of urban areas. We characterized enteric fever diagnosis patterns and the burden of culture-confirmed cases in peri-urban and rural Nepal. Methods: We used national reports to estimate enteric fever diagnosis rates over 20 years (1994-2014) and conducted a prospective study of patients presenting with a >72-hour history of fever to 4 peri-urban and rural healthcare facilities (during August 2013-June 2016). We compared clinical characteristics of patients with culture-confirmed Salmonella Typhi or Paratyphi infection to those of patients without enteric fever. We used generalized additive models with logistic link functions to evaluate associations of age and population density with culture positivity. Results: National rates of enteric fever diagnosis were high, reaching 18.8 cases per 1000 during 2009-2014. We enrolled 4309 participants with acute febrile illness. Among those with a provisional clinical diagnosis, 55% (1334 of 2412) received a diagnosis of enteric fever; however, only 4.1% of these had culture-confirmed typhoidal Salmonella infection. Culture positivity was highest among young adults and was strongly associated with higher population density (P < .001). Conclusions: Enteric fever diagnosis rates were very high throughout Nepal, but in rural settings, few patients had culture-confirmed disease. Expanded surveillance may inform local enteric fever treatment and prevention strategies.


Asunto(s)
Población Rural , Fiebre Tifoidea/epidemiología , Adolescente , Adulto , Niño , Preescolar , Notificación de Enfermedades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nepal/epidemiología , Salmonella typhi , Adulto Joven
13.
N Engl J Med ; 371(7): 668-75, 2014 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-25119613

RESUMEN

A 37-year-old man with ulcerative colitis was admitted to the hospital because of abdominal cramping, diarrhea, hematochezia, fever to a peak temperature of 38.8 °C, and drenching night sweats. Several weeks earlier, he had performed home fecal transplantation.


Asunto(s)
Colitis Ulcerosa/patología , Colon/patología , Infecciones por Citomegalovirus/patología , Adulto , Colitis Ulcerosa/complicaciones , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Diagnóstico Diferencial , Diarrea/etiología , Hemorragia Gastrointestinal/etiología , Humanos , Masculino , Espasmo/etiología
14.
J Infect Dis ; 214(2): 173-81, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-26908752

RESUMEN

BACKGROUND: Patients with recurrent Clostridium difficile infection (CDI) have a ≥60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. METHODS: Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 10(9) spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 10(8) spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. RESULTS: Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. CONCLUSIONS: SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.


Asunto(s)
Terapia Biológica/métodos , Clostridioides difficile/crecimiento & desarrollo , Infecciones por Clostridium/prevención & control , Microbioma Gastrointestinal , Tracto Gastrointestinal/microbiología , Prevención Secundaria/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Biológica/efectos adversos , Diarrea/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
15.
BMC Med ; 14(1): 134, 2016 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-27609178

RESUMEN

BACKGROUND: Fecal microbiota transplantation (FMT) has been shown to be safe and effective in treating refractory or relapsing C. difficile infection (CDI), but its use has been limited by practical barriers. We recently reported a small preliminary feasibility study using orally administered frozen fecal capsules. Following these early results, we now report our clinical experience in a large cohort with structured follow-up. METHODS: We prospectively followed a cohort of patients with recurrent or refractory CDI who were treated with frozen, encapsulated FMT at our institution. The primary endpoint was defined as clinical resolution whilst off antibiotics for CDI at 8 weeks after last capsule ingestion. Safety was defined as any FMT-related adverse event grade 2 or above. RESULTS: Overall, 180 patients aged 7-95 years with a minimal follow-up of 8 weeks were included in the analysis. CDI resolved in 82 % of patients after a single treatment, rising to a 91 % cure rate with two treatments. Three adverse events Grade 2 or above, deemed related or possibly related to FMT, were observed. CONCLUSIONS: We confirm the effectiveness and safety of oral administration of frozen encapsulated fecal material, prepared from unrelated donors, in treating recurrent CDI. Randomized studies and FMT registries are still needed to ascertain long-term safety.


Asunto(s)
Infecciones por Clostridium/terapia , Trasplante de Microbiota Fecal/métodos , Heces/microbiología , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Cápsulas , Niño , Clostridioides difficile , Farmacorresistencia Bacteriana , Estudios de Factibilidad , Femenino , Congelación , Humanos , Masculino , Microbiota , Persona de Mediana Edad , Proyectos Piloto , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
16.
Proc Natl Acad Sci U S A ; 110(17): 7003-8, 2013 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-23569246

RESUMEN

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet-induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.


Asunto(s)
Fosfatasa Alcalina/metabolismo , Fosfatasa Alcalina/farmacología , Síndrome Metabólico/tratamiento farmacológico , Absorción/efectos de los fármacos , Administración Oral , Fosfatasa Alcalina/administración & dosificación , Fosfatasa Alcalina/genética , Animales , Compuestos Azo , Línea Celular , Cartilla de ADN/genética , Lipopolisacáridos , Hígado/metabolismo , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microvellosidades/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Triglicéridos/metabolismo
17.
Clin Infect Dis ; 58(11): 1515-22, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24762631

RESUMEN

BACKGROUND: Recurrent Clostridium difficile infection (CDI) with poor response to standard antimicrobial therapy is a growing medical concern. We aimed to investigate the outcomes of fecal microbiota transplant (FMT) for relapsing CDI using a frozen suspension from unrelated donors, comparing colonoscopic and nasogastric tube (NGT) administration. METHODS: Healthy volunteer donors were screened and a frozen fecal suspension was generated. Patients with relapsing/refractory CDI were randomized to receive an infusion of donor stools by colonoscopy or NGT. The primary endpoint was clinical resolution of diarrhea without relapse after 8 weeks. The secondary endpoint was self-reported health score using standardized questionnaires. RESULTS: A total of 20 patients were enrolled, 10 in each treatment arm. Patients had a median of 4 (range, 2-16) relapses prior to study enrollment, with 5 (range, 3-15) antibiotic treatment failures. Resolution of diarrhea was achieved in 14 patients (70%) after a single FMT (8 of 10 in the colonoscopy group and 6 of 10 in the NGT group). Five patients were retreated, with 4 obtaining cure, resulting in an overall cure rate of 90%. Daily number of bowel movements changed from a median of 7 (interquartile range [IQR], 5-10) the day prior to FMT to 2 (IQR, 1-2) after the infusion. Self-ranked health score improved significantly, from a median of 4 (IQR, 2-6) before transplant to 8 (IQR, 5-9) after transplant. No serious or unexpected adverse events occurred. CONCLUSIONS: In our initial feasibility study, FMT using a frozen inoculum from unrelated donors is effective in treating relapsing CDI. NGT administration appears to be as effective as colonoscopic administration. CLINICAL TRIALS REGISTRATION: NCT01704937.


Asunto(s)
Terapia Biológica/métodos , Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/terapia , Diarrea/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Colonoscopía/métodos , Diarrea/microbiología , Femenino , Humanos , Intubación Gastrointestinal/métodos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Recurrencia , Encuestas y Cuestionarios , Resultado del Tratamiento , Donante no Emparentado , Adulto Joven
18.
Am J Physiol Gastrointest Liver Physiol ; 306(10): G826-38, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24722905

RESUMEN

The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.


Asunto(s)
Fosfatasa Alcalina/fisiología , Intestinos/microbiología , Adenosina Trifosfato/farmacología , Fosfatasa Alcalina/antagonistas & inhibidores , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/farmacología , Ampicilina/farmacología , Animales , Desoxirribonucleótidos/farmacología , Farmacorresistencia Bacteriana , Enterococcus faecalis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Heces/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morganella morganii/efectos de los fármacos , Fenilalanina/farmacología , Inanición/fisiopatología , Estreptomicina/farmacología
19.
Am J Gastroenterol ; 109(7): 1065-71, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24890442

RESUMEN

OBJECTIVES: Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients. METHODS: A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT. RESULTS: Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT. CONCLUSIONS: This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.


Asunto(s)
Clostridioides difficile , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/terapia , Heces/microbiología , Huésped Inmunocomprometido , Microbiota , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Encuestas y Cuestionarios , Resultado del Tratamiento
20.
J Pediatr Gastroenterol Nutr ; 58(5): 588-92, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24792627

RESUMEN

Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or long-term follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician's Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT.


Asunto(s)
Clostridioides difficile , Infecciones por Clostridium/terapia , Heces/microbiología , Enfermedades Inflamatorias del Intestino/complicaciones , Microbiota/fisiología , Trasplante/métodos , Adolescente , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Niño , Preescolar , Infecciones por Clostridium/complicaciones , Colonoscopía , Femenino , Humanos , Lactante , Intubación Gastrointestinal , Masculino , Microbiota/efectos de los fármacos , Recurrencia , Resultado del Tratamiento , Adulto Joven
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