Citations

Abstract Background We sought to compare the dysplasia detection rate of high-definition white light endoscopy (HDWLE) with that of chromoendoscopy in patients with long-standing inflammatory bowel disease (IBD). Methods This is a retrospective observational cohort of patients with IBD who underwent surveillance colonoscopy between October 1, 2016 and September 30, 2017. We assessed the association between dysplasia detection and multiple variables. Results A total of 808 unique colonoscopies were performed, of which 150 (18.6%) included chromoendoscopy. Primary sclerosing cholangitis was a comorbid diagnosis in 24.5% of patients. The performing endoscopist was an IBD specialist with 37.1% of patients and had >10 years’ experience with 64.9% of patients. Prior dysplasia had been seen in 245 (30.3%) patients: 102 (68.0%) and 143 (22.0%) among patients who had chromoendoscopy and HDWLE, respectively. Dysplasia in polyps was found in 129 procedures (15.1%). Among patients who had chromoendoscopy and HDWLE, polypoid dysplasia was identified in 50 (33.0%) and 79 (12.0%) patients, respectively, P < 0.01. Dysplasia in random biopsies was found in 39 patients (4.8%): 15 (10%) who had chromoendoscopy and 24 (3.6%) who had HDWLE (P < 0.001). On multivariate analysis, patient and disease characteristics significantly associated with an increased odds for polypoid dysplasia included older age at diagnosis (odds ratio [OR] = 1.3 per 10 years; 95% confidence interval [CI], 1.07-1.60), having an IBD physician endoscopist (OR = 1.6; 95% CI, 1.01-2.67), having an endoscopist with less than 10 years’ experience (OR = 1.8; 95% CI (1.16-2.89), and prior random dysplasia (OR = 4.2; 95% CI (1.93-9.17). Concomitant primary sclerosing cholangitis was significantly associated with random dysplasia (OR = 2.3; 95% CI, 1.02-5.07). After multivariate analysis adjusting for these variables, chromoendoscopy was no more likely to identify dysplasia than was HDWLE. Conclusions Chromoendoscopy and HDWLE had a similar diagnostic yield for dysplasia detection in patients with chronic IBD-colitis after adjusting for multiple known risk factors.

Abstract 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.

AbstractBackgroundClostridioides difficile infection (CDI) is associated with poor outcomes in inflammatory bowel disease (IBD) patients. Data are scarce on efficacy of fecal microbiota transplant (FMT) for recurrent CDI in IBD patients.MethodsWe reviewed health records of IBD patients (18 years of age or older) with recurrent CDI who underwent FMT. Outcomes of FMT for CDI were assessed on the basis of symptoms and stool test results.ResultsWe included 145 patients (75 women [51.7%]; median age, 46 years). Median IBD duration was 8 (range, 0–47) years, 36.6% had Crohn disease, 61.4% had ulcerative colitis, and 2.1% had indeterminate colitis. Median number of prior CDI episodes was 3 (range, 3–20), and 61.4% had received vancomycin taper. Diarrhea resolved after FMT in 48 patients (33.1%) without further testing. Ninety-five patients (65.5%) underwent CDI testing owing to post-FMT recurrent diarrhea; 29 (20.0%) had positive results. After FMT, 2 patients received empiric treatment of recurrent CDI without symptom resolution, suggesting IBD was the cause of symptoms. The overall cure rate of CDI after FMT was 80.0%, without CDI recurrence at median follow-up of 9.3 (range, 0.1–51) months. Forty-three patients (29.7%) had planned IBD therapy escalation after CDI resolution; none de-escalated or discontinued IBD therapy. Overall, 7.6% had worsening IBD symptoms after FMT that were treated as new IBD flares. No clinical predictors of FMT failure were identified.ConclusionsFew patients had new IBD flare after FMT. Fecal microbiota transplantation effectively treats recurrent CDI in IBD patients but has no apparent beneficial effect on the IBD course.

Abstract Background and Aims We aimed to evaluate the relationship of serum adalimumab trough levels (ATL) with disease activity of inflammatory bowel disease (IBD) patients in a large, well-characterized referral center-based cohort. Methods We compared serum ATL between those with clinical, biochemical, or endoscopic/radiologic disease activity and those without. Results A total of 236 patients with IBD were included. Higher cutoff levels were associated with endoscopic and/or radiologic responses (cutoff value: 5.3 mcg/mL, P = 0.003) compared with improvement in C-reactive protein (cutoff value: 4.3 mcg/mL, P = 0.031). Conclusions Higher cutoff ATL was associated with endoscopic and/or radiologic response.

Abstract Background: Patients with hematological malignancies are at an increased risk for developing both primary and recurrent Clostridium difficile Infection (RCDI) along with complications such as toxic mega colon and treatment failure likely due to underlying immunosuppression and frequent use of broad spectrum antibiotics that lead to altered gut microbiome. Fecal Microbiota Transplantation (FMT) is an effective treatment for RCDI (Brandt et. al; 2012). However, experience in patients with hematologic malignancies is sparse and most clinical trials exclude these patients due to potential complications. We report the largest case series to date from a single institution evaluating the safety and efficacy of FMT for RCDI in patients with hematologic malignancies. Methods: After IRB approval, a database of 452 RCDI patients treated with FMT between August 2012 and June 2016 was reviewed to identify those with an underlying hematologic malignancy. Data regarding demographics, hematologic disease, C. difficile history, treatments, and outcomes were retrospectively abstracted from the electronic medical record. Results: Sixteen patients (median age 74 years; male 50%) with known hematologic malignancies underwent FMT during the study period. The underlying diagnoses are outlined in Table 1. Five patients had received hematopoietic cell transplantation (3 allogeneic and 2 autologous) prior to FMT. Patients had a median of 4.5 (range 2-9) CDI episodes before FMT, and 4 of them had severe/severe-complicated CDI at some stage. Prior treatments included a median of 3 (range 1-5) standard vancomycin/metronidazole courses, median of 2 (range 0-4) vancomycin taper courses, fidaxomicin in 3 patients, and chronic vancomycin suppression in one patient. Diarrheal symptoms were in remission in all but 3 patients in the week before FMT. FMT was performed via colonoscopy in all patients. At the time of FMT, hematologic malignancies were in complete remission in 9 patients, stable on active treatment in 4, stable off treatment in 2, and relapsed awaiting treatment in 1 patient. Median time from last anti-neoplastic treatment (n = 14) and from last neutropenia (n = 8) to FMT were 10 (range 0-301) and 9.5 (0-68) months, respectively. One patient with hairy cell leukemia was still neutropenic and on prophylactic oral trimethoprim/sulfamethoxazole at the time of FMT. Five patients were on active immunosuppressive medications, including prednisone (n = 2), methotrexate (n = 2), sirolimus (n =1), and cyclosporine (n =1) for related comorbidities at the time of FMT (Table 2). At last follow up (median 12, range 0-32 months), 6 patients had active/relapsed hematological disease, 6 had received additional antineoplastic treatments, and 7 had received additional antibiotics. RCDI developed in two (12%) patients at 8 and 22 months post FMT secondary to exposure to broad spectrum antimicrobials. These patients were successfully treated with a second FMT and with metronidazole, respectively. Severe adverse events included death in one patient that occurred 3 days post FMT due to unexpected cardiac arrest and was deemed unrelated to the procedure. Another patient developed community-acquired pneumonia 15 days post FMT and was treated successfully with oral azithromycin. Minor adverse events within the first two weeks post FMT were noted in 6 (38%) patients (self-limited diarrhea in 3, fecal urgency in 2, abdominal cramps in 2, and constipation in one patient) (Table 3). Only one patient had persistent diarrhea shortly after FMT, with the cause attributed to underlying Crohn's disease. No complications related to the colonoscopy procedure were noted. Conclusion: FMT appears to be a safe and effective therapeutic option for RCDI in patients with hematological malignancies. Considering very few adverse events and particularly no infectious complications in our series, we conclude that immunosuppression should not preclude the use of FMT for treatment of RCDI in this high risk population. These results need prospective validation. Disclosures No relevant conflicts of interest to declare.

Abstract Background CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance. Methods SERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks. Results SER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3). Conclusion In this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. Disclosures All authors: No reported disclosures.

Abstract Background Fecal microbiota transplantation (FMT) cures ~90% of patients with recurrent Clostridioides difficile infection (rCDI). Ongoing or repeated exposure to risk factors, especially antibiotics (a modifiable risk factor but often necessary), may lead to future CDI. However, it is not known if FMT provides durable protection against future CDI despite subsequent antibiotic exposure. We studied the long-term durability of FMT against antibiotic exposure post-FMT. Methods A retrospective cohort study of patients undergoing FMT via colonoscopy for rCDI from Sep 2012 - Jun 2018 was performed. Patients were followed up for 1 year after FMT; data regarding future CDI episodes (watery diarrhea with positive stool test after interim symptom resolution), healthcare exposure, systemic non-CDI antibiotics and acid blocker therapy were collected. Primary outcome was ‘durability’ of response to FMT (defined as no CDI within 1 year post-FMT). Descriptive statistics, Chi square test, Wilcoxon test and multivariate logistic regression were used as appropriate. Results The study included 460 patients; median age 57 years (range 18–94 years), 65.2% (300) female. Overall 31.6% (144) received antibiotics; median number of courses of antibiotics, 2 (range 1–7). Of those who received antibiotics, the incidence of future CDI was 24.3% (n = 34), compared with 9% (n = 28) of those who did not receive antibiotics (P < .001). Median time to first CDI episode post-FMT was 103 (range 5–338) days. Incremental antibiotic courses did not lead to increased risk of future CDI (comparing 1, 2 or ≥3 courses, p = .68). In patients with antibiotic exposure, age and risk factors were similar in patients with and without future CDI (Table 1). Amongst those without antibiotic exposure, inflammatory bowel disease (IBD) predicted future CDI (p = .02). After controlling for risk factors and comorbidities, antibiotic use (p = .004) and IBD (p = .02) independently increased risk of future CDI. Conclusion The majority of patients with rCDI have a durable response to FMT despite ongoing risk factors. These data suggest that three-fourth of patients who receive antibiotics after FMT do not develop future CDI. IBD and antibiotic exposure independently increase the risk of future CDI. Disclosures All authors: No reported disclosures.

INTRODUCTION: Currently, surgery is the primary treatment option for refractory, severe-complicated Clostridioides difficile infection (CDI) in the inpatient setting. There are limited series reporting the efficacy of Fecal Microbiota Transplantation (FMT) to treat such cases as an alternative to surgery or in patients who are not surgical candidates. We aimed to assess the response rate and prognosis of these patients after inpatient FMT. METHODS: We conducted a retrospective chart review of patients with CDI (watery diarrhea with positive stool assay) admitted in the ICU, and who received FMT from January 2013 to July 2016. Potential cases were identified by diagnosis codes and eligibility was confirmed through manual chart review. Severe-complicated CDI was defined as CDI with any of the following: ICU admission, hypotension, shock, sepsis, megacolon, colectomy or death due to CDI. CDI was termed refractory in the absence of clinical response to antibiotics after 5 days. Recurrence was defined as typical CDI symptoms and positive stool assay within 56 days of treatment with interim symptom resolution. The primary outcome was resolution of CDI (clinical cure with no recurrence). Secondary outcomes included risk of recurrent CDI and mortality. Microsoft Excel was used for descriptive statistical analysis. RESULTS: Of 273 patients screened, 6 cases met inclusion criteria. Five patients received FMT via colonoscopy, one via retention enema. The mean age at time of FMT was 72 (range, 54-88) years, 4 (66%) patients were female. All had severe-complicated CDI, 3 had concomitant diverticulosis and none had inflammatory bowel disease (IBD). The median follow-up after FMT was 8.5 (range, 1-18) months. Three patients received non-CDI antibiotics within 6 months post-FMT, 3 received acid suppression therapy (Table 1). FMT was performed after a median of 3 (range, 1-5) episodes of CDI with a median of 4.5 previous courses of antibiotics (range 2-6 courses) (Table 1). Four of the six patients (66%) had resolution of CDI, 2 patients had recurrence. One patient died due to sepsis secondary to CDI; 3 died due to unrelated causes. CONCLUSION: In this small retrospective study, inpatient FMT was effective for treating refractory severe-complicated CDI. There was one CDI-related mortality by the end of follow up. FMT may be an alternative therapy in patients with severe-complicated CDI.