Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center.

The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades.1 IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear. Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence). Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation (a probiotic formulation) participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION: At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS: The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

ANTECEDENTES: La reservoritis ocurre en aproximadamente el 50% de los pacientes después de la anastomosis entre la bolsa ileal y el ano (IPAA, por sus siglas en inglés) para la colitis ulcerosa crónica (CU). OBJETIVOS: El objetivo primario fue determinar la eficacia y la seguridad de los tratamientos médicos para la prevención o el tratamiento de la reservoritis aguda o crónica. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, Embase y en CENTRAL, desde su inicio hasta el 25 julio 2018. También se buscó en las listas de referencias, registros de ensayos en curso y actas de congresos. CRITERIOS DE SELECCIÓN: Se consideraron para inclusión los ensayos controlados aleatorios de prevención o tratamiento de la reservoritis aguda o crónica en adultos a los que se les realiza IPAA para la CU. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron la elegibilidad de los estudios, extrajeron los datos y analizaron el riesgo de sesgo. La calidad de la evidencia se evaluó mediante los criterios GRADE. El resultado primario la mejoría clínica o remisión en los pacientes con reservoritis aguda o crónica, o la proporción de pacientes sin episodios de reservoritis después de IPAA. Se incluyeron los eventos adversos como resultado secundario. Se calculó el cociente de riesgos (CR) y el intervalo de confianza (IC) del 95% correspondiente para los resultados dicotómicos. RESULTADOS PRINCIPALES: Se incluyeron 15 estudios (547 participantes). Cuatro estudios evaluaron el tratamiento de la reservoritis aguda. Cinco estudios evaluaron el tratamiento de la reservoritis crónica. Seis estudios evaluaron la prevención de la reservoritis. Tres estudios presentaban bajo de riesgo de sesgo. En tres estudios el riesgo fue alto y en los otros estudios fue poco claro. reservoritis aguda: Todos los pacientes que recibieron ciprofloxacina (7/7) lograron la remisión a las dos semanas en comparación con el 33% (3/9) de los pacientes que recibieron metronidazol (CR 2,68; IC del 95%: 1,13 a 6,35) (evidencia de certeza muy baja). Ninguno de los participantes que recibieron ciprofloxacina (0/7) presentó eventos adversos en comparación con el 33% (3/9) de los participantes que recibieron metronidazol (CR0,18; IC del 95%: 0,01 a 2,98; evidencia de certeza muy baja). Los eventos adversos incluyeron vómitos, disgeusia o neuropatía periférica transitoria. El 40% (6/14) de los participantes que recibieron metronidazol lograron la remisión a las 6 semanas en comparación con el 50% (6/12) de los participantes que recibieron enema de budesonida (CR 0,86; IC del 95%: 0,37 a 1,96; evidencia de certeza muy baja). El 50% (7/14) de los participantes del grupo de metronidazol mejoraron clínicamente a las 6 semanas en comparación con el 58% (7/12) de los participantes que recibieron enema de budesonida (CR 0,86; IC del 95%: 0,42 a 1,74; evidencia de certeza muy baja). El 57% (8/14) de los participantes del grupo de metronidazol presentaron eventos adversos en comparación con el 25% (3/12) de los participantes que recibieron enema de budesonida (CR 2,29; IC del 95%: 0,78 a 6,73; evidencia de certeza muy baja). Los eventos adversos incluyeron anorexia, náuseas, cefalea, astenia, sabor metálico, vómitos, parestesia y depresión. El 25% (2/8) de los participantes que recibieron rifaximina lograron la remisión a las 4semanas en comparación con el 0% (0/10) de los participantes que recibieron placebo (CR 6,11; IC del 95%: 0,33 a 111,71; evidencia de certeza muy baja). El 38% (3/8) de los participantes del grupo de rifaximina mejoraron clínicamente a las 4 semanas en comparación con el 30% (3/10) de los participantes que recibieron placebo (CR 1,25; IC del 95%: 0,34 a 4,60; evidencia de certeza muy baja). El 75% (6/8) de los participantes del grupo de rifaximina presentaron un evento adverso en comparación con el 50% (5/10) de los participantes que recibieron placebo (CR 1,50; IC del 95%: 0,72 a 3,14; evidencia de certeza muy baja). Los eventos adversos incluyeron diarrea, flatulencias, náuseas, proctalgia, vómitos, sed, cándida, infección de las vías respiratorias superiores, aumento de las enzimas hepáticas y cefalea en racimos. El 10% (1/10) de los participantes del grupo de Lactobacillus GGmejoraron clínicamente a las 12 semanas en comparación con el 0% (0/10) de los participantes que recibieron placebo (CR 3,00; IC del 95%: 0,14 a 65,90; evidencia de certeza muy baja). Reservoritis crónica: El 85% (34/40) de los pacientes que recibieron la formulación De Simone mantuvieron la remisión de nueve a 12 meses en comparación con el 3% (1/36) de los participantes que recibieron placebo (CR 20,24; IC del 95%: 4,28 a 95,81; dos estudios; evidencia de certeza baja). El 2% (1/40) de los participantes que recibieron la fórmula De Simone presentaron un evento adverso, en comparación con el 0% (0/36) de los participantes que recibieron placebo (CR 2,43; IC del 95%: 0,11 a 55,89; evidencia de certeza baja). Los efectos secundarios incluyeron cólicos abdominales, vómitos y diarrea. Cuarenta y tres por ciento (3/6) de los pacientes en el grupo de adalimumab lograron una mejoría clínica a las 4 semanas en comparación con un 43 (3/7) de los pacientes del grupo de placebo (CR 1,17, IC del 95%: 0,36 a 3,76; evidencia de certeza baja). El 60% (6/10) de los participantes del grupo de glutamina mantuvieron la remisión a las 3 semanas en comparación con el 33% (3/9) de los participantes que recibieron placebo (CR 1,80; IC del 95%: 0,63 a 5,16; evidencia de certeza muy baja). El 45% (9/20) de los participantes del grupo de enema de espuma de carbómero de bismuto mejoraron clínicamente a las 3 semanas en comparación con el 45% (9/20) de los participantes que recibieron placebo (CR 1,00; IC del 95%: 0,50 a 1,98; evidencia de certeza muy baja). El 25% (5/20) de los participantes del grupo de aceite de cannabis presentaron un evento adverso en comparación con el 35% (7/20) de los participantes que recibieron placebo (CR 0,71; IC del 95%: 0,27 a 1,88; evidencia de certeza muy baja). Los eventos adversos incluyeron diarrea, síntomas de empeoramiento, cólicos, sinusitis y dolor abdominal. Prevención: A los 12 meses, el 90% (18/20) de los pacientes que recibieron la formulación De Simone no presentaron episodios de reservoritis aguda en comparación con el 60% (12/20) de los pacientes que recibieron placebo (CR 1,50: IC del 95%: 1,02 a 2,21; evidencia de certeza baja). Otro estudio halló que el 100% (16/16) de los participantes que recibieron la fórmula De Simone no presentaron episodios de reservoritis aguda a los 12 meses en comparación con el 92% (11/12) de los pacientes del grupo control sin tratamiento (CR 1,10: IC del 95%: 0,89 a 1,36; evidencia de certeza muy baja). El 86% (6/7) de los participantes del grupo de Bifidobacterium longum no presentaron episodios de reservoritis aguda a los 6 meses en comparación con el 60% (3/5) de los participantes que recibieron placebo (CR 1,43; IC del 95%: 0,66 a 3,11; evidencia de certeza muy baja). El 11% (1/9) de los participantes del grupo de Clostridium butyricum MIYAIRI no presentaron episodios de reservoritis aguda a los 24 meses en comparación con el 50% (4/8) de los participantes que recibieron placebo (CR 0,22; IC del 95%: 0,03 a 1,60; evidencia de certeza muy baja). El 46% (43/94) de los participantes del grupo de alopurinol no presentaron episodios de reservoritis a los 24 meses en comparación con el 43% (39/90) de los participantes que recibieron placebo (CR1,06; IC del 95%: 0,76 a 1,46; evidencia de certeza baja). El 81% (21/26) de los participantes del grupo de tinidazol no presentaron episodios de reservoritis a los 12 meses en comparación con el 58% (7/12) de los participantes que recibieron placebo (CR 1,38; IC del 95%: 0,83 a 2,31; evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: No se conocen los efectos de los antibióticos, probióticos y otras intervenciones para el tratamiento y la prevención de la reservoritis. Se necesitan estudios bien diseñados con poder estadístico suficiente para determinar la forma óptima de tratamiento y prevención de la reservoritis.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear.Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence).Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION: At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS: The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis.

BACKGROUND: Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridium difficile infection (CDI) in observational studies (>90%), but cure rates in clinical trials are lower. We performed a systematic review and meta-analysis to assess the efficacy of FMT for recurrent CDI in open-label studies and clinical trials . METHODS: A systematic search from January 1978 to March 2017 was performed to include clinical trials of FMT for CDI. We analyzed CDI resolution by calculating weighted pooled rates (WPRs). RESULTS: Thirteen trials were included, comprising 610 patients with CDI treated with single FMT. Overall, 439 patients had clinical cure (WPR, 76.1%; 95% confidence interval (CI), 66.4%-85.7%). There was significant heterogeneity among studies (I2 = 91.35%). Cure rates were lower in randomized trials (139/216 patients; WPR, 67.7%; 95% CI, 54.2%-81.3%) than in open-label studies (300/394 patients; WPR, 82.7%; 71.1%-94.3%) (P < .001). Subgroup analysis by FMT delivery modality showed lower cure rates with enema than colonoscopy (WPR, 66.3% vs 87.4%; P < .001) but no difference between colonoscopy and oral delivery (WPR, 87.4% vs 81.4%; P = .17). Lower rates were seen for studies including both recurrent and refractory CDI than for those including only recurrent CDI (WPR, 63.9% vs 79%; P < .001). CONCLUSIONS: FMT was associated with lower cure rates in randomized trials than in open-label and in observational studies. Colonoscopy and oral route are more effective than enema for stool delivery. The efficacy also seems to be higher for recurrent than for refractory CDI.

A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection.

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.

Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: Results of the PUNCH CD Study.

BACKGROUND: Managing recurrent Clostridium difficile infection (CDI) presents a significant challenge for clinicians and patients. Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent CDI, yet availability of a standardized, safe, and effective product has been lacking. Our aim in this study was to assess the safety and effectiveness of RBX2660 (microbiota suspension), a commercially prepared FMT drug manufactured using standardized processes and available in a ready-to-use format. METHODS: Patients with at least 2 recurrent CDI episodes or at least 2 severe episodes resulting in hospitalization were enrolled in a prospective, multicenter open-label study of RBX2660 administered via enema. Intensive surveillance for adverse events (AEs) was conducted daily for 7 days following treatment and then at 30 days, 60 days, 3 months, and 6 months. The primary objective was product-related AEs. A secondary objective was CDI-associated diarrhea resolution at 8 weeks. RESULTS: Of the 40 patients enrolled at 11 centers in the United States between 15 August 2013 and 16 December 2013, 34 received at least 1 dose of RBX2660 and 31 completed 6-month follow-up. Overall efficacy was 87.1% (16 with 1 dose and 11 with 2 doses). Of 188 reported AEs, diarrhea, flatulence, abdominal pain/cramping, and constipation were most common. The frequency and severity of AEs decreased over time. Twenty serious AEs were reported in 7 patients; none were related to RBX2660 or its administration. CONCLUSIONS: Among patients with recurrent or severe CDI, administration of RBX2660 via enema appears to be safe and effective. CLINICAL TRIALS REGISTRATION: NCT01925417.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis. OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies (including antibiotics, probiotics, and other agents) for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, EMBASE and the Cochrane Library from inception to October 2014. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for ulcerative colitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was the proportion of patients with clinical improvement or remission of pouchitis in patients with acute or chronic pouchitis, or the proportion of patients with no episodes of pouchitis after IPAA. The proportion of patients who developed at least one adverse event was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Thirteen studies (517 participants) were included in the review. Four studies assessed treatment of acute pouchitis. One study (16 participants) compared ciprofloxacin and metronidazole; another (26 participants) compared metronidazole to budesonide enemas; another (18 participants) compared rifaximin to placebo; and the fourth study (20 participants) compared Lactobacillus GG to placebo. Four studies assessed treatment of chronic pouchitis. One study (19 participants) compared glutamine to butyrate suppositories; another (40 participants) compared bismuth enemas to placebo; and two studies (76 participants) compared VSL#3 to placebo. Five studies assessed prevention of pouchitis. One study (40 participants) compared VSL#3 to placebo; another (28 participants) compared VLS#3 to no treatment; one study (184 participants) compared allopurinol to placebo; another (12 participants) compared the probiotic Bifidobacterium longum to placebo; and one study (38 participants) compared tinidazole to placebo. Three studies were judged to be of high quality. Two studies were judged to be low quality and the quality of the other studies was unclear. Treatment of acute pouchitis: The results of one small study (16 participants) suggest that ciprofloxacin may be more effective than metronidazole for the treatment of acute pouchitis. One hundred per cent (7/7) of ciprofloxacin patients achieved remission at two weeks compared to 33% (3/9) of metronidazole patients. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (no blinding) and very sparse data (10 events). There was no difference in the proportion of patients who had at least one adverse event (RR 0.18, 95% CI 0.01 to 2.98). Adverse events included vomiting, dysgeusia or transient peripheral neuropathy. There were no differences between metronidazole and budesonide enemas in terms of clinical remission, clinical improvement or adverse events. Adverse events included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. There were no differences between rifaximin and placebo in terms of clinical remission, clinical improvement, or adverse events. Adverse events included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. There was no difference in clinical improvement between Lactobacillus GG and placebo. The results of these studies are uncertain due to very low quality evidence. Treatment of chronic pouchitis: A pooled analysis of two studies (76 participants) suggests that VSL#3 may be more effective than placebo for maintenance of remission. Eighty-five per cent (34/40) of VLS#3 patients maintained remission at 9 to 12 months compared to 3% (1/36) of placebo patients (RR 20.24, 95% CI 4.28 to 95.81). A GRADE analysis indicated that the quality of evidence supporting this outcome was low due to very sparse data (35 events). Adverse events included abdominal cramps, vomiting and diarrhea. There was no difference in effectiveness between glutamine and butyrate suppositories for maintenance of remission. There was no difference in clinical improvement or adverse event rates between bismuth carbomer foam enemas and placebo. Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. The results of these studies are uncertain due to very low quality evidence. Prevention of pouchitis: The results of one small study (40 participants) suggest that VSL#3 may be more effective than placebo for prevention of pouchitis. Ninety per cent (18/20) of VSL#3 patients had no episodes of acute pouchitis during the 12 month study compared to 60% (12/20) of placebo patients (RR 1.50, 95% CI 1.02 to 2.21). A GRADE analysis indicated that the quality of evidence supporting this outcome was low due to very sparse data (30 events). Another small study (28 participants) found that VLS#3 was not more effective than no treatment for prevention of pouchitis. Bifidobacterium longum, allopurinol and tinidazole were not more effective than placebo for prevention of pouchitis. The results of these studies are uncertain due to very low quality evidence. AUTHORS' CONCLUSIONS: For acute pouchitis, very low quality evidence suggests that ciprofloxacin may be more effective than metronidazole. For chronic pouchitis, low quality evidence suggests that VSL#3 may be more effective than placebo for maintenance of remission. For the prevention of pouchitis, low quality evidence suggests that VSL#3 may be more effective than placebo. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis may occur following ileal pouch-anal anastomosis for chronic ulcerative colitis in approximately 30% of patients. OBJECTIVES: The primary objective was to determine the efficacy of medical therapies for pouchitis (including antibiotic, probiotic, and other agents) as substantiated by data from randomized controlled trials (RCTs). SEARCH STRATEGY: A search for RCTs from 1966 to October 2009 was performed using the MEDLINE, Cochrane Library, EMBASE, Web of Science, and Scopus databases. SELECTION CRITERIA: Randomized controlled treatment or prevention trials of adult patients who underwent ileal pouch-anal anastomosis for ulcerative colitis who subsequently developed pouchitis or were at risk for pouchitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Extracted data were converted to 2X2 tables and then synthesized in to a summary statistic using the Peto odds ratio (OR) and [95% confidence intervals], or weighted mean difference (WMD), using RevMan-5 for Mac OS 10.6. MAIN RESULTS: Eleven RCTs fulfilled the inclusion criteria and were included in the review. The efficacy of 10 different pharmacologic agents was assessed. For the treatment of acute pouchitis (4 RCTS, 5 agents), ciprofloxacin was more effective at inducing remission than metronidazole. Neither rifaximin nor lactobacillus GG were more effective than placebo, while budesonide enemas and metronidazole were similarly effective, for inducing remission of acute pouchitis. For the treatment and maintenance of remission of chronic pouchitis (4 RCTs, 4 agents), glutamine suppositories were not more effective than butyrate suppositories, and bismuth carbomer foam enemas were not more effective than placebo, while VSL#3 was more effective than placebo in maintaining remission of chronic pouchitis in patients with chronic pouchitis who achieved remission with antibiotics. For the prevention of pouchitis (3 RCTs, 2 agents), in one study VSL#3 was more effective than placebo while in another study VSL#3 was not more effective than no treatment. Allopurinol was not more effective than placebo, while inulin was more effective than placebo but the results were not clinically significant. AUTHORS' CONCLUSIONS: For acute pouchitis, ciprofloxacin was more effective than metronidazole, while budesonide enemas and metronidazole were similarly effective. For chronic pouchitis, VSL#3 was more effective than placebo. For the prevention of pouchitis, VSL#3 was more effective than placebo. Larger RCTs are needed to determine the optimal agent(s) for the treatment and prevention of pouchitis.

Small-bowel imaging in Crohn's disease: a prospective, blinded, 4-way comparison trial.

BACKGROUND: With the introduction of new techniques to image the small bowel, there remains uncertainty about their role for diagnosing Crohn's disease. OBJECTIVE: To assess the sensitivity and specificity of capsule endoscopy (CE), CT enterography (CTE), ileocolonoscopy, and small-bowel follow-through (SBFT) in the diagnosis of small bowel Crohn's disease. METHODS: Prospective, blinded trial. SETTING: Inflammatory bowel disease clinic at an academic medical center. PATIENTS: Known or suspected Crohn's disease. Exclusion criteria included known abdominal abscess and non-steroidal anti-inflammatory drug (NSAID) use. Partial small-bowel obstruction (PSBO) at CTE excluded patients from subsequent CE. INTERVENTIONS: Patients underwent all 4 tests over a 4-day period. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, and accuracy of each test to detect active small-bowel Crohn's disease. The criterion standard was a consensus diagnosis based upon clinical presentation and all 4 studies. RESULTS: Forty-one CTE examinations were performed. Seven patients (17%) had an asymptomatic PSBO. Forty patients underwent colonoscopy, 38 had SBFT studies, and 28 had CE examinations. Small-bowel Crohn's disease was active in 51%, absent in 42%, inactive in 5%, and suspicious in 2% of patients. The sensitivity of CE for detecting active small-bowel Crohn's disease was 83%, not significantly higher than CTE (83%), ileocolonoscopy (74%), or SBFT (65%). However, the specificity of CE (53%) was significantly lower than the other tests (P < .05). One patient developed a transient PSBO due to CE, but no patients had retained capsules. LIMITATION: Use of a consensus clinical diagnosis as the criterion standard-but this is how Crohn's disease is diagnosed in practice. CONCLUSIONS: The sensitivity of CE for active small-bowel Crohn's disease was not significantly different from CTE, ileocolonoscopy, or SBFT. However, lower specificity and the need for preceding small-bowel radiography (due to the high frequency of asymptomatic PSBO) may limit the utility of CE as a first-line test for Crohn's disease.