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Fecal microbiota transplantation (FMT) is recommended for the prevention of recurrent Clostridioides difficile infection (CDI).1Kelly C.R. et al.Am J Gastroenterol. 2021; 116: 1124-1147Crossref PubMed Scopus (202) Google Scholar Randomized trials have reported promising efficacy and safety among patients treated with FMT following standard of care (SOC) CDI antibiotics compared with SOC CDI antibiotics alone. However, these trials are small, with methodological limitations.2Moayyedi P. et al.Med J Aust. 2017; 207: 166-172Crossref PubMed Scopus (102) Google Scholar Potential adverse events, especially in immunocompromised patients, highlight the importance of ensuring continued data collection on clinical outcomes.3DeFilipp Z. et al.N Engl J Med. 2019; 381: 2043-2050Crossref PubMed Scopus (693) Google Scholar FMT is operationally challenging, and physicians report high costs and logistical concerns around screening donors and processing stool. Stool banks aim to overcome these barriers by centralizing screening and processing. Using patient-level outcomes data, we undertook a prospective, real-world observational cohort study to evaluate the effectiveness and safety profile of FMT for CDI provided by a stool bank. The intervention consisted of FMT material from a stool bank (OpenBiome, Cambridge, MA). Donors providing material for FMT were evaluated for eligibility through an on-site clinical assessment, blood, and stool testing, as described previously.4Kassam Z. et al.N Engl J Med. 2019; 381: 2070-2072Crossref PubMed Scopus (89) Google Scholar Stool was prepared from each donor sample (unpooled) into a 250-mL (25 g of stool) preparation for lower gastrointestinal delivery (colonoscopy, sigmoidoscopy, or enema), a 30-mL (12.5 g) preparation for upper gastrointestinal delivery (upper endoscopy or nasoenteric delivery), or frozen oral capsules (22.5 g per 30-capsule dose).5Smith M.B. et al.Gastroenterology. 2015; 148 (:S-211)Google Scholar Material was distributed via ultra-cold chain logistics to health care facilities, where treatments were thawed and administered to patients with physician-diagnosed CDI not responsive to standard therapy. Investigational FMT treatments were provided under US Food and Drug Administration enforcement discretion policy for investigational new drug requirements, enabling physicians to provide FMT with informed consent to CDI patients without requiring an investigational new drug application to the US Food and Drug Administration.6US Food and Drug Administration. Published July 2013. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiotaGoogle Scholar All physicians administering FMT for CDI not responsive to standard therapy were required to report deidentified outcomes through a standardized report form as part of a safety and quality assurance program. The study was approved by the New England Institutional Review Board. The primary outcome of physician-reported clinical cure was defined as no recurrence of CDI at an SOC follow-up 8 weeks post-FMT per clinical guidelines.7Debast S.B. et al.Clin Microbiol Infect. 2014; 20: 1-26Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar Other data included donor identification number, hospital, CDI classification (recurrent, severe, and refractory), and delivery modality (upper or lower gastrointestinal tract or capsule). All complete and consecutively collected forms were included in the final analysis. Safety data were reported by the treating clinician through mandatory serious adverse event (SAE) reporting using standard US Food and Drug Administration definitions. In addition to the treating physician’s assessment, each SAE underwent a clinical evaluation and was assessed independently by 2 nontreating clinicians for relatedness (definitely, probably, possibly, unlikely, or not related). Statistical analysis was conducted in R (Vienna, Austria).8R Core Team R Foundation for Statistical Computing, 2013Google Scholar Proportions and percentages were used to describe categorical data. Proportions and percentages were used to summarize safety event terms. From January 16, 2014 and November 14, 2018, patient-level outcomes from recipients of FMT was consecutively collected from 681 health care facilities across 50 US states and 7 countries. The cohort consisted of complete, consecutively collected patient reports (n = 5344). The clinical cure rate from physician-reported outcomes across all delivery modalities and CDI types was 78% (4195 of 5344; 95% CI, 77%–80%). The subtype with the highest cure rate was recurrent CDI subtype (81%; 95% CI, 80%–83%). Lower delivery was reported as the most effective delivery route, with a reported cure rate of 81% (95% CI, 80%–82%) (Table 1).Table 1Multivariate Logistic Regression Assessing Associations of Reported Cure Rate With Clostridioides Difficile Infection Subtype and Delivery ModalityVariableReported cure rate% (95% CI)nOdds ratio of reported cure rate (95% CI)P value (Wald test)Overall78 (77–80)5344——CDI subtypeaCDI subtype definitions: Recurrent81 (80–83)29131 (reference)— Refractory78 (75–81)8890.82 (0.68–0.99).04 Severe71 (69–74)12390.58 (0.49–0.67)<.01Delivery modality Lower81 (80–82)40571 (reference)— Upper70 (67–73)8990.57 (0.48–0.68)<.01 Capsule71 (65–77)2160.59 (0.43–0.81)<.01Recurrent: Recurrence of CDI symptoms for 48 hours or longer within 8 weeks after the completion of at least 10 days of CDI treatment.Refractory: Persistent or worsening of diarrhea characteristic of CDI and 1 of the following:•Ongoing abdominal pain, fever (temperature ≥38.0°C)•Peripheral white blood cell (WBC) counts ≥15,000 cells/mm3 despite treatment with oral vancomycin at a dosage of 500 mg 4 times daily for at least 5 daysSevere: Either severe CDI or severe-complicated CDI defined as;•Severe CDI: Hypoalbuminemia (albumin < 3 g/dL), and WBC count ≥15,000 cells/mm3 or abdominal tenderness•Severe-complicated CDI: Any of the following attributable to CDI:oAdmission to ICU for CDIoHypotension with or without required use of vasopressorsoSerum lactate levels >2.2 mmol/LoEnd organ failure (eg, mechanical ventilation or renal failure)oMental status changesoWBC 35,000 cells/mm3 or < 2000 cells/mm3oFever 38.5°CoIleus or significant abdominal distentiona CDI subtype definitions: Open table in a new tab Recurrent: Recurrence of CDI symptoms for 48 hours or longer within 8 weeks after the completion of at least 10 days of CDI treatment. Refractory: Persistent or worsening of diarrhea characteristic of CDI and 1 of the following:•Ongoing abdominal pain, fever (temperature ≥38.0°C)•Peripheral white blood cell (WBC) counts ≥15,000 cells/mm3 despite treatment with oral vancomycin at a dosage of 500 mg 4 times daily for at least 5 days Severe: Either severe CDI or severe-complicated CDI defined as;•Severe CDI: Hypoalbuminemia (albumin < 3 g/dL), and WBC count ≥15,000 cells/mm3 or abdominal tenderness•Severe-complicated CDI: Any of the following attributable to CDI:oAdmission to ICU for CDIoHypotension with or without required use of vasopressorsoSerum lactate levels >2.2 mmol/LoEnd organ failure (eg, mechanical ventilation or renal failure)oMental status changesoWBC 35,000 cells/mm3 or < 2000 cells/mm3oFever 38.5°CoIleus or significant abdominal distention Overall, the safety profile was favorable among a patient population that is medically complex with poor clinical outcomes. Among the cohort, 194 patients (3.6%) were reported to have experienced 1 or more SAEs. SAEs were more common among patients with severe or severe-complicated CDI (n = 94 [48.5%]). Among the SAEs, 6 reported events (0.1%) were possibly related to FMT—all among patients who were severely immunocompromised. This included 2 patients with fever as well as 1 with abdominal pain in a breast cancer patient with severe-complicated CDI. In addition, there were 2 patients with systemic inflammatory response syndrome—1 post-cardiac transplantation and 1 post-renal transplantation. There was 1 reported case of an inflammatory bowel disease (IBD) flare in a patient with a background of uncontrolled ulcerative colitis on biologics and immunomodulators. No reported SAEs were determined to be definitely related to FMT. Importantly, there were no reported cases of sepsis or infectious disease transmission related to FMT, including multi-drug–resistant organism-related infections. To our knowledge, this is the largest FMT cohort reported and suggests that in a real-world cohort, FMT from a stool bank may be a safe and effective treatment for CDI not responsive to SOC. Lower delivery FMT for recurrent CDI was associated with the highest clinical cure rates consistent with randomized controlled trials.9Quraishi M.N. et al.Aliment Pharmacol Ther. 2017; 46: 479-493Crossref PubMed Scopus (430) Google Scholar Our study has several limitations. First, without a control group, causal inference about treatment effects cannot be made reliably. Second, despite a recommended 8-week time point, there may be variation in the timing of physician-reported outcomes. Third, misdiagnosis of CDI could lead to misclassification bias. Fourth, open-label and real-world data tend to increase the effect of an intervention and large, placebo-controlled trials are required to assess the true effect size. In addition, reporting bias and underreporting of SAEs are possible. Our findings suggest a favorable short-term safety profile. Importantly, there were no reported cases of multi-drug–resistant organism infections after FMT screened for such organisms in the study follow-up period. We observed 2 cases of systemic inflammatory response syndrome and 2 cases of fever possibly related to FMT—all were reported in severely immunocompromised patients. This patient population requires further study and careful selection for FMT. Patients with IBD and concomitant CDI have very poor clinical outcomes and limited therapeutic options. We observed 1 case of IBD worsening in this study, possibly related to FMT. However, findings to date in observational studies and controlled clinical trials of FMT for IBD and IBD in CDI populations have not observed worsening of IBD after FMT.10Allegretti J.R. et al.Gastroenterology. 2020; 159: 1982-1984Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Notably, there are limited long-term safety data; however, efforts are underway to evaluate long-term outcomes (ClinicalTrials.gov, Number: NCT03325855). Overall, our findings suggest that FMT may be a safe and effective treatment for CDI not responsive to standard therapy.