SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.

BACKGROUND: Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed. RESULTS: Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination. CONCLUSIONS: In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).

The Progression of Microbiome Therapeutics for the Management of Gastrointestinal Diseases and Beyond.

There has been an increased ability to investigate human microbiota through next-generation sequencing and functional assessment. This advancement has rapidly expanded our ability to study and manipulate the gastrointestinal microbiome to mitigate disease. Fecal microbiota transplantation, a therapy that broadly transfers the entire intestinal ecosystem, has been explored as a potential therapeutic in a variety of gastrointestinal, hepatic, and extraintestinal conditions. The field, however, continues to evolve, with a movement toward precision microbiome therapeutics individualizing care for various disorders. This review will describe the use of fecal microbiota transplantation, microbiota restoration, and precision microbiome therapeutics focusing on gastrointestinal and hepatic diseases.

Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

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.

A Clinical Severity Index for Eosinophilic Esophagitis: Development, Consensus, and Future Directions.

BACKGROUND & AIMS: Disease activity and severity of eosinophilic esophagitis (EoE) dictate therapeutic options and management, but the decision-making process for determining severity varies among practitioners. To reduce variability in practice patterns and help clinicians monitor the clinical course of the disease in an office setting, we aimed to create an international consensus severity scoring index for EoE. METHODS: A multidisciplinary international group of adult and pediatric EoE researchers and clinicians, as well as non-EoE allergy immunology and gastroenterology experts, formed 3 teams to review the existing literature on histology, endoscopy, and symptoms of EoE in the context of progression and severity. A steering committee convened a 1-day virtual meeting to reach consensus on each team's opinion on salient features of severity across key clinicopathologic domains and distill features that would allow providers to categorize disease severity. RESULTS: Symptom features and complications and inflammatory and fibrostenotic features on both endoscopic and histologic examination were collated into a simplified scoring system-the Index of Severity for Eosinophilic Esophagitis (I-SEE)-that can be completed at routine clinic visits to assess disease severity using a point scale of 0-6 for mild, 7-14 for moderate, and ≥15 for severe EoE. CONCLUSIONS: A multidisciplinary team of experts iteratively created a clinically usable EoE severity scoring system denominated "I-SEE" to guide practitioners in EoE management by standardizing disease components reflecting disease severity beyond eosinophil counts. I-SEE should be validated and refined using data from future clinical trials and routine clinical practice to increase its utilization and functionality.

Fecal Microbiota, Live-jslm for the Prevention of Recurrent Clostridioides difficile Infection : Subgroup Analysis of PUNCH CD2 and PUNCH CD3.

GOALS: To assess fecal microbiota, live-jslm (REBYOTA, abbreviated as RBL, formerly RBX2660) efficacy and safety in participants grouped by recurrent Clostridioides difficile infection (rCDI) risk factors and treatment-related variables. BACKGROUND: RBL is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration for the prevention of rCDI in adults after antibiotic treatment for rCDI. STUDY: Treatment success rates across subgroups for PUNCH CD3 (NCT03244644) were estimated using a Bayesian hierarchical model, borrowing data from PUNCH CD2 (NCT02299570). Treatment-emergent adverse events were summarized for the double-blind treatment period within 8 weeks. RESULTS: Treatment differences between RBL and placebo at 8 weeks were similar to the total population for most subgroups. Treatment effect sizes were similar between CDI tests, higher for oral vancomycin courses >14 days versus ≤14 days and higher for antibiotic washout periods of 3 days versus ≤2 days. The largest reductions in the rate of rCDI with RBL versus placebo were observed for participants with a 3-day CDI antibiotic washout period and participants with ≥4 previous CDI episodes. Most RBL-treated participants experienced TEAEs that were mild or moderate in severity and related to preexisting conditions. CONCLUSION: This analysis provides further evidence of RBL efficacy and safety across subgroups, including those at high risk for rCDI.

The burden of CDI in the United States: a multifactorial challenge.

Clostridioides difficile infection (CDI) affects approximately 500,000 patients annually in the United States, of these around 30,000 will die. CDI carries significant burdens including clinical, social and economic. While healthcare-associated CDI has declined in recent years, community-associated CDI is on the rise. Many patients are also impacted by recurrent C. difficile infections (rCDI); up to 35% of index CDI will recur and of these up to 60% will further recur with multiple recurrences observed. The range of outcomes adversely affected by rCDI is significant and current standard of care does not alter these recurrence rates due to the damaged gut microbiome and subsequent dysbiosis. The clinical landscape of CDI is changing, we discuss the impact of CDI, rCDI, and the wide range of financial, social, and clinical outcomes by which treatments should be evaluated.

Idiopathic myointimal hyperplasia of the mesenteric veins: A systematic review and individual patient data regression analysis.

BACKGROUND AND AIM: Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is an uncommon cause of colonic ischemia for which surgical treatment is typically curative. We describe clinical, radiologic, and endoscopic findings in IMHMV patients to provide clinicians with a framework for pre-surgical identification of this rare disease. METHODS: We performed a systematic review of seven databases for IMHMV cases and identified additional cases from Yale New Haven Hospital records. To identify features specifically associated with colonic ischemia due to IMHMV, we performed multivariate logistic regression analysis incorporating data from a large cohort of patients with biopsy-proven ischemic colitis. RESULTS: A total of 124 patients with IMHMV were identified (80% male, mean age 53 years, 56% Caucasian). Presenting symptoms were most commonly abdominal pain (86%) and diarrhea (68%). The most affected areas were the sigmoid colon (91%) and rectum (61%). Complications associated with diagnostic delay occurred in 29% of patients. Radiologic vascular abnormalities including non-opacification of the inferior mesenteric vein were observed in 35% of patients. Of the patients, 97% underwent curative surgical resection. Compared with non-IMHMV colonic ischemia, IMHMV was significantly associated with younger age, male sex, absence of rectal bleeding on presentation, rectal involvement, and mucosal ulcerations on endoscopy. CONCLUSION: IMHMV is a rare, underreported cause of colonic ischemia that predominantly involves the rectosigmoid. Our findings suggest younger age, rectal involvement, and absence of rectal bleeding as clinical features to help identify select patients presenting with colonic ischemia as having higher likelihood of IMHMV and therefore consideration of upfront surgical management.

First Clostridioides difficile Recurrence Is Highest Following Concomitant Antimicrobial Administration During and Within 30 Days of Treatment.

BACKGROUND: Clostridioides difficile infection (CDI) is an epidemic with the strongest risk factor being antibiotic usage. Patients who get CDI frequently require concomitant antibiotics for other indications around the time of their infection. AIMS: To assess the recurrence of CDI (rCDI) in patients receiving concomitant antibiotics at the same time or shortly thereafter treatment of CDI. METHODS: We retrospectively reviewed records for patients with their first inpatient CDI episode. Patients were grouped into those who didn't receive concomitant antibiotics (noABx), those receiving antibiotics at the same time as treatment of CDI (ABxDURING), those receiving antibiotics within 30-days of completion of CDI therapy (ABxAFTER) and those who received antibiotics both during and after CDI treatment (ABxDuringAfter). Our primary outcome was recurrence within 14-90 days; other outcomes included ICU stay at the time of diagnosis, 30-day ICU transfer, 30-day colectomy, and readmission. RESULTS: 457 patients had CDI during admission (mean age: 66.4 years, 51.9% female). 64.1% were exposed to concomitant antibiotics. Recurrence rates were 4.3%, 6.1%, 13.8% and 19.1%, for noABx, ABxDURING, ABxAFTER and ABxDuringAfter, respectively. Patients with ABxDuringAfter had the highest rates of rCDI when compared to noABx [OR 5.67, 95% CI (2.18-14.72)]. CONCLUSIONS: There is a high rate of utilization of non-CDI antibiotics during or shortly after completing CDI treatment with high rates of recurrence within 90-days. Concomitant antimicrobials alter the opportunity for the microbiota to re-grow and worsens dysbiosis leading to increases in recurrence. Concomitant antimicrobial stewardship remains important in patients being treated for CDI and shortly after treatment.

A Clinical Severity Index for Eosinophilic Esophagitis: Development, Consensus, and Future Directions.

BACKGROUND & AIMS: Disease activity and severity of eosinophilic esophagitis (EoE) dictate therapeutic options and management, but the decision-making process for determining severity varies among practitioners. To reduce variability in practice patterns and help clinicians monitor the clinical course of the disease in an office setting, we aimed to create an international consensus severity scoring index for EoE. METHODS: A multidisciplinary international group of adult and pediatric EoE researchers and clinicians, as well as non-EoE allergy immunology and gastroenterology experts, formed 3 teams to review the existing literature on histology, endoscopy, and symptoms of EoE in the context of progression and severity. A steering committee convened a 1-day virtual meeting to reach consensus on each team's opinion on salient features of severity across key clinicopathologic domains and distill features that would allow providers to categorize disease severity. RESULTS: Symptom features and complications and inflammatory and fibrostenotic features on both endoscopic and histologic examination were collated into a simplified scoring system-the Index of Severity for Eosinophilic Esophagitis (I-SEE)-that can be completed at routine clinic visits to assess disease severity using a point scale of 0-6 for mild, 7-14 for moderate, and ≥15 for severe EoE. CONCLUSIONS: A multidisciplinary team of experts iteratively created a clinically usable EoE severity scoring system denominated "I-SEE" to guide practitioners in EoE management by standardizing disease components reflecting disease severity beyond eosinophil counts. I-SEE should be validated and refined using data from future clinical trials and routine clinical practice to increase its utilization and functionality.

Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers. METHODS: Patients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes. RESULTS: Of the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%). CONCLUSIONS: This prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT.

Bad blood: ischemic conditions of the large bowel.

PURPOSE OF REVIEW: Colon ischemia is the most common form of intestinal ischemic injury and is seen frequently in an elderly population. This disease is usually self-limited, and many causes have been identified. The recent literature has focused on estimates of prognosis, triaging appropriate level of care, and identification of optimal treatments. In this review, we will address our current understanding of colon ischemia including epidemiology, pathophysiology, segmental distribution, presentation, diagnosis, and management. RECENT FINDINGS: Research has recently been focused on factors associated with poor outcome. The medical comorbidities identified include chronic obstructive pulmonary disease (COPD), hepatic cirrhosis, and chronic aspirin use. Serological markers are noninvasive tools that can triage severity. Recent studies have shown procalcitonin, C-reactive protein, D-dimer, and neutrophil counts can help predict those at greatest risk for poor outcome. The timing of colonoscopy relative to symptomatic onset also can help predict severity. Early colonoscopy allows for quicker identification of ischemic stigmata, reducing the chance of misdiagnosis and potentially unnecessary and harmful treatment. The treatment of colon ischemia has classically been conservative with antimicrobials reserved for those with moderate or severe disease. Recent retrospective analysis calls into question the utility of antibiotics in the treatment of colon ischemia, although the data is not convincing enough to advise against antimicrobial treatment in patients with severe and fulminant disease. SUMMARY: It is an exciting time for research focused on colon ischemia. With an improved knowledge, awareness of associated risk factors and predictors of severity, clinicians now have enhanced clinical tools to diagnose and triage patients earlier in the disease. This should help institute prompt and appropriate therapies ultimately improving outcomes.

Heterogeneity of Randomized Controlled Trials of Fecal Microbiota Transplantation in Recurrent Clostridioides difficile Infection.

INTRODUCTION: Clinical trials have demonstrated the efficacy of FMT for reduction in CDI recurrences (rCDI), but this treatment and its reporting in the literature has significant heterogeneity. Recent publications (e.g., Ramai et al. in Dig Dis Sci 2020. https://doi.org/10.1007/s10620-020-06185-7 ) present the clinical outcomes for different FMT methodologies. However, to understand, compare, and contextualize outcomes, this heterogeneity in methods and reporting must be understood. METHODS: We performed a literature review of randomized controlled trials (RCTs) of FMT for rCDI to evaluate heterogeneity among trials. A methodical search between January 2010 and May 2019 of Medline, Embase, and Cochrane was conducted for studies investigating FMT in adults with rCDI. RCTs were evaluated for a variety of methodological and reporting criteria. RESULTS: Eight RCTs were identified, wherein 14 different FMT preparations were considered (each with distinct protocols for processing, storage, administration, and dosing). Sample sizes were generally small, with only two studies performing FMT in more than 100 patients. Three studies used non-FMT controls (vancomycin), while the remaining compared FMT with differing routes of administration or formulations. Across the identified studies, there was no standardized manner for reporting the timing of the FMT procedure. All studies tracked adverse events; however, follow-up periods were limited. CONCLUSIONS: Considerable variability exists among RCTs, with marked differences in study design, control groups, and outcome assessment. Lack of a standard-of-care control in many trials may impact reproducibility of FMT trial outcomes in patients with rCDI. Widespread use of FMT for rCDI is still investigational; therefore, these foundational studies provide opportunities to optimize future trials.

Review Article: Mesenteric Ischemia.

PURPOSE OF REVIEW: Mesenteric ischemia (MI), both acute (AMI) and chronic (CMI), is a challenging diagnosis to make, and early diagnosis and treatment are vital to improve outcomes. This manuscript summarizes the most up to date information on diagnosis and treatment of these disorders. RECENT FINDINGS: There have been several significant advancements in the computed tomography (CT) diagnostic imaging as well as medical and endovascular management of AMI and CMI. In appropriate populations, endovascular interventions appear superior to open surgical management with lower mortality, morbidity, and cost of care. Efficient clinical identification and targeted testing are essential to diagnose AMI and CMI. Aggressive resuscitation and early endovascular (or in select cases, surgical) intervention improve outcomes in those with AMI. In those with CMI, considering this on the differential diagnosis and imaging appropriately can identify those that might benefit from intervention and halt progression to acute episodes.

Chronic Rifaximin Use in Cirrhotic Patients Is Associated with Decreased Rate of C. difficile Infection.

BACKGROUND AND AIM: Rifaximin is an antimicrobial which is used for prophylaxis of hepatic encephalopathy in patients with cirrhosis and has known anti-Clostridioides difficile activity. The aim of this study is to assess whether the rate of C. difficile infection (CDI) is decreased in patients with cirrhosis on chronic rifaximin compared with those who are not. METHODS: We retrospectively identified consecutive patients admitted to Montefiore Medical Center from 2010 to 2014 with cirrhosis and diarrhea who were tested for CDI. Demographics, comorbidities, medication exposure, baseline laboratory data, and outcomes were recorded. Patients with cirrhosis and diarrhea on chronic rifaximin were compared with those not on rifaximin. The chronic rifaximin group was then isolated, and those with and without CDI were compared. RESULTS: Of 701 patients with cirrhosis and diarrhea, 149 were on chronic rifaximin and 552 were not. 12.8% of patients on chronic rifaximin had CDI compared with 29.7% of those not on rifaximin (P < 0.001). Patients on rifaximin had higher MELD (19.7 vs. 15.5, P < 0.001), 30-day mortality (26.2% vs. 16.1%, P < 0.01), and ICU requirement compared with those not on rifaximin. CONCLUSION: Patients with cirrhosis who are on chronic rifaximin have decreased rates of CDI compared with those not on this therapy. Despite its risk for promoting resistance, chronic rifaximin use may have a beneficial effect in preventing CDI in patients with cirrhosis.

Features and Outcomes of Patients With Ischemia Isolated to the Right Side of the Colon When Accompanied or Followed by Acute Mesenteric Ischemia.

BACKGROUND & AIMS: Patients with ischemia isolated to the right side of the colon (IRCI) frequently have poor outcomes. IRCI and acute mesenteric ischemia (AMI) are caused by reductions in blood supply from the superior mesenteric artery and its branches. We investigated a group of patients with IRCI associated with AMI that developed initially or shortly thereafter, and compared outcomes of patients with IRCI and AMI vs those with only IRCI. METHODS: We performed a retrospective study of data collected from 313 consecutive patients with colonic ischemia who were hospitalized at Montefiore Medical Center in New York from 1998 through 2009. Based on colonoscopy, biopsy analyses, and surgery reports, we identified patients with IRCI with concurrent or proximately developing AMI (IRCI+AMI) and those with only IRCI. Demographics, evaluation, disease distribution, and outcome data were compared between groups. RESULTS: Of 313 patients with colonic ischemia, 20.8% had IRCI; of these, 84.6% had only IRCI and 15.4% had IRCI+AMI. Chronic obstructive pulmonary disease was found more frequently in patients with IRCI+AMI (40.0%) than in patients with IRCI alone (12.7%; P < .05). At the time of IRCI diagnosis, mean levels of blood urea nitrogen were significantly higher in patients with IRCI+AMI than with IRCI alone (37.9 ± 14.4 mEq/L vs 26.4 ± 18.8 mEq/L; P < .05), as were mean white blood cell counts (20.3 ± 12.1 vs 12.7 ± 6.8 × 10(3)/µL; P < .01). A higher proportion of patients with IRCI+AMI underwent surgery than patients with only IRCI (100.0% vs 43.1%; P = .001), and 30-day mortality was higher among patients with IRCI+AMI (70.0% vs 14.5% for patients with only IRCI; P < .001). CONCLUSIONS: Based on an analysis of 313 patients with colonic ischemia, patients with IRCI+AMI have even more severe disease than those with IRCI alone. Chronic obstructive pulmonary disease was observed more frequently in patients with IRCI+AMI. Patients with IRCI+AMI had increased levels of blood urea nitrogen and/or white blood cell counts. Patients with IRCI should undergo vascular imaging analyses immediately to detect AMI; patients without AMI should be monitored closely for its subsequent development.