Ilan Youngster1, George H Russell2, Christina Pindar3, Tomer Ziv-Baran4, Jenny Sauk5, Elizabeth L Hohmann6. 1. Division of Infectious Diseases, Massachusetts General Hospital, Boston2Harvard Medical School, Boston, Massachusetts3Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts. 2. Harvard Medical School, Boston, Massachusetts4Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts. 3. Division of Infectious Diseases, Massachusetts General Hospital, Boston. 4. Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 5. Harvard Medical School, Boston, Massachusetts6Division of Gastroenterology, Massachusetts General Hospital, Boston. 6. Division of Infectious Diseases, Massachusetts General Hospital, Boston2Harvard Medical School, Boston, Massachusetts.
Abstract
IMPORTANCE: Fecal microbiota transplantation (FMT) has been shown to be effective in treating relapsing or refractory Clostridium difficile infection, but practical barriers and safety concerns have prevented its widespread use. OBJECTIVE: To evaluate the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from prescreened unrelated donors to patients with recurrent C. difficile infection. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-group, preliminary feasibility study conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. Twenty patients (median age, 64.5 years; range, 11-89 years) with at least 3 episodes of mild to moderate C. difficile infection and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe C. difficile infection requiring hospitalization were enrolled. INTERVENTIONS: Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80°C (-112°F). Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months. MAIN OUTCOMES AND MEASURES: The primary end points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements. RESULTS: No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%-85%) after a single capsule-based FMT. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%-98%) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR], 3-6) the day prior to administration to 2 (IQR, 1-3) at day 3 (P = .001) and 1 (IQR, 1-2) at 8 weeks (P < .001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR, 5-7) for overall health and 4.5 (IQR, 3-7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR, 7-9) after FMT administration for both overall and gastrointestinal health (P = .001). Patients needing a second treatment to obtain resolution of diarrhea had lower pretreatment health scores (median, 6.5 [IQR, 5-7.3] vs 5 [IQR, 2.8-5]; P = .02). CONCLUSIONS AND RELEVANCE: This preliminary study among patients with relapsing C. difficile infection provides data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. Larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01914731.
IMPORTANCE: Fecal microbiota transplantation (FMT) has been shown to be effective in treating relapsing or refractory Clostridium difficileinfection, but practical barriers and safety concerns have prevented its widespread use. OBJECTIVE: To evaluate the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from prescreened unrelated donors to patients with recurrent C. difficileinfection. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-group, preliminary feasibility study conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. Twenty patients (median age, 64.5 years; range, 11-89 years) with at least 3 episodes of mild to moderate C. difficileinfection and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe C. difficileinfection requiring hospitalization were enrolled. INTERVENTIONS: Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80°C (-112°F). Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months. MAIN OUTCOMES AND MEASURES: The primary end points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements. RESULTS: No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%-85%) after a single capsule-based FMT. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%-98%) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR], 3-6) the day prior to administration to 2 (IQR, 1-3) at day 3 (P = .001) and 1 (IQR, 1-2) at 8 weeks (P < .001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR, 5-7) for overall health and 4.5 (IQR, 3-7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR, 7-9) after FMT administration for both overall and gastrointestinal health (P = .001). Patients needing a second treatment to obtain resolution of diarrhea had lower pretreatment health scores (median, 6.5 [IQR, 5-7.3] vs 5 [IQR, 2.8-5]; P = .02). CONCLUSIONS AND RELEVANCE: This preliminary study among patients with relapsing C. difficileinfection provides data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. Larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01914731.
Authors: A Lo Vecchio; L Lancella; C Tagliabue; C De Giacomo; S Garazzino; M Mainetti; L Cursi; E Borali; M V De Vita; E Boccuzzi; L Castellazzi; S Esposito; A Guarino Journal: Eur J Clin Microbiol Infect Dis Date: 2016-09-30 Impact factor: 3.267