Fecal microbiota transplantation (FMT) for Clostridium difficile colitis

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1 Fecal microbiota transplantation (FMT) for Clostridium difficile colitis Patrick Knight 1, John P. Anagnostakos 1, Maggie J. Lin 1, Berhanu Geme 1, Stanislaw P. A. Stawicki 1,2 1 St. Luke s University Health Network, Bethlehem, Pennsylvania, USA 2 OPUS 12 Foundation, Bethlehem, Pennsylvania, USA ABSTRACT Fecal microbiota transplantation (FMT) has emerged as a viable adjunct to traditional therapies used in the treatment of Clostridium difficile colitis. Despite the encouraging early results, wider implementation of FMT continues to be limited by the paucity of high-quality clinical evidence and logistical challenges. The purpose of this evidence table is to present the reader with the most up-to-date information (years ) regarding clinical FMT applications, including novel methods of delivery and outcome-based focus. Cite as: Knight P, Anagnostakos J, Lin MJ, Geme B, Stawicki SPA. Evidence table: Fecal microbiota transplantation (FMT) for Clostridium difficile colitis. OPUS 12 Scientist 2015;9(1):1-8. Correspondence to: Stanislaw P. A. Stawicki, MD, Department of Research & Innovation, St. Luke s University Health Network, Bethlehem, PA USA. stanislaw.stawicki@sluhn.org. Keywords: Evidence table, Fecal microbiota transplantation (FMT), Clostridium difficile infection, Clinical experience. BACKGROUND, DEFINITIONS, AND METRICS [Background] Despite promising early results, fecal microbiota transplantation (FMT) continues to be a controversial treatment for Clostridium difficile infection (CDI) In addition to its role in treatment of recurrent or antibiotic-resistant CDI (RCDI), FMT appears to be emerging as a potential first-line treatment of CDI. 4 [Purpose] The goal of this evidence table is to highlight some of the most important clinical developments in management of CDI using FMT. [Metrics] Clinically-focused reports published between 2010 and 2015 were reviewed by our Editorial Team. Articles deemed to be of highest clinical value were subsequently included herein, focusing on case reports/series, case-control studies, prospective clinical investigations, and novel routes of FMT delivery Although the list of included publications is by no means exhaustive, it provides a solid foundation for further scientific exploration in this important clinical area. ARTICLE SUMMARIES Russell et al. (2010) [1] A case report of a 2-year old child diagnosed with CDI that was refractory to probiotic, antibiotic, and nontraditional (rifamixin, nitazoxanide) therapies. The child was treated with FMT delivered via nasogastric tube. This paper focused on the success of FMT treatment in RCDI. The case involves a 2-year old girl who presented to her primary care physician with diarrhea. CDI was confirmed via cytotoxin assay (EIA test). She was prescribed flagyl 125 mg TID x10 days initially. This treatment was ineffective. The patient was switched to vancomycin 125 mg QID x30 days with a probiotic supplement, but diarrhea recurred with this treatment. Vancomycin and rifaximin was then started, but diarrhea still recurred. Pulsed vancomycin therapy was attempted as well, but likewise failed. A FMT was prepared using the child s father as a donor according to a modified bacteriotherapy protocol after successful donor screening. The transplant was administered via nasogastric tube. Symptoms resolved 36 hours after FMT administration. The patient remained symptom-free up to 6 months after FMT. Clostridium difficile cytotoxin assays were negative at 2 weeks, 3 weeks, and 6-month follow-up. This case study demonstrated the safety and efficacy of using FMT in a pediatric patient who exhausted conventional treatments for CDI. Given the invasiveness of nasogastric insertion and expense of screening, further research needs to be conducted evaluating the safety and efficacy of FMT in the pediatric population before it becomes a first or second line therapy for RCDI in children. Silverman et al. (2010) [2] Prospective study evaluating the use of self-administered fecal transplants in 7 patients with hospital acquired RCDI. This study focused on the efficacy of fecal transplants in preventing recurrences of CDI. This is a prospective study of 7 patients, all of whom had hospital-acquired C. difficile infection. These patients failed treatment with both flagyl 500 mg TID x14 days and oral vancomycin 125 mg PO TID x14 days. Patients had a mean duration of symptoms of 13 months. Four of 7 patients were male and the mean age was 65 years. Stool material for transplantation was collected from family members of the participants with the following exclusion criteria: (a) history of GI illness/pathology; (b) malignancy; (c) antibiotic use or hospitalization during the past 3 months. Study participants were prepared for the transplant with oral S. boulardii therapy 500 mg PO BID and flagyl 500 mg PO TID or vancomycin 125 mg PO QID. This maintenance therapy was given to ensure patients were asymptomatic leading up to the procedure. Antibiotics were discontinued 48 hours before the procedure, but S. boulardii was continued during transplant and for 60 days post-procedure. Follow-up was scheduled for 2 weeks post procedure. A mix of 50mL stool and 200mL normal saline was self-administered via low volume enema. None of the patients that participated in this study had recurrences of CDI within the time of follow up after the procedure. One patient developed irritable bowel symptoms after the procedure, but stool was negative for C. difficile toxin. Two patients developed urinary tract infections (UTI) after FMT and were treated with antibiotics but did not experience CDI relapse. This was a nonrandomized prospective cohort study consisting of a small number of patients. It provided support for the efficacy of low volume FMT enemas, similar to high volume enemas, in the ability to recolonize the remainder of the colon with normal flora. Furthermore, this FMT protocol seems to be practical, simple and well tolerated. However, a large study is necessary to determine efficacy. Though S. boulardii was given in these highly refractory patients, it has not been shown previously to be efficacious in treating CDI. Consequently, its role in the overall effectiveness of the above-described FMT regimen remains unclear. Copyright OPUS 12 Foundation, Inc. 1

2 Yoon & Brandt (2010) [3] A case series involving 12 patients with either recurrent or RCDI. The report investigates the efficacy of fecal transplants administered via colonoscopy. A retrospective study of 12 patients with RCDI confirmed by positive cytotoxin assays. A total of 9 men and 3 women were studied. The mean age of the study group was 66 years. Nine of 12 patients had diverticulosis. Mean duration of illness before FMT attempt was approximately 350 days. Treatment using FMT with donated stool were administered during colonoscopy. All 12 patients (100%) experienced complete clinical response, supporting the clinical safety and efficacy of colonoscopyadministered FMT. Brandt et al. (2011) [4] An editorial highlighting FMT as a proposed first-line therapy for severe C. difficile infection The authors provide a brief overview of the literature describing the magnitude of the C. difficile problem in the modern healthcare environment. It is pointed out that disease recurrence occurs in 20% to 60% of patients, often within 2-4 weeks following completion of vancomycin (traditional) therapy. The authors report that patients with CDI exhibit deficiencies of Bacteroides and Firmicutes on fecal flora studies. This phenomenon is most likely attributable to previous antibiotic use. The authors build a case for the use of FMT as first-line therapy for severe CDI. This represents a departure from traditional approaches advocating for FMT use in the setting of recurrent CDI. The authors argue that antibiotic therapy fails to correct the underlying floral deficiencies within the gastrointestinal tract. Even vancomycin, traditionally used as treatment for severe CDI, should be considered a broad-spectrum antibiotic targeting both aerobic and anaerobic Gram-positive bacteria. This editorial advocates for FMT as a practical approach to eradicating CDI and correcting microbiotic deficiencies. Given the relative ease of endoscopic delivery, the authors propose using FMT as 1 st line therapy before attempting more traditional antibiotic treatment(s). Kelly et al. (2012) [5] A case series describing the efficacy of FMT in treating patients with RCDI. A protocol for FMT is also proposed. A retrospective series of 26 patients with a minimum of 3 episodes of RCDI treated with FMT. Patients had previously been treated with the following: Metronidazole (26), Saccharomyces boulardii (26), Vancomycin (26), Rifaximin (19), Lactobacillus spp (4), and IVIG (2). At the time of study entry, patients were taking either vancomycin or metronidazole and ceased treatment hours prior to FMT. They received polyethylene glycol the night before treatment. Twenty-four of the 26 patients exhibited clinical resolution of diarrhea. One patient had another bout of diarrhea 2 months post-fmt. She was given a 1-week course of vancomycin and recovered. Another patient restarted vancomycin after having diarrhea. This same patient exhibited a relapse of her RCDI 11 months after FMT following a course of cephalexin. This study demonstrated 92% efficacy of FMT in 26 patients with CDI in preventing CDI relapse or recurrent diarrhea. FMT was performed using stool samples originating from family members. Stool was screened for infectious entities, and donors could not take antibiotics within a 3-month period preceding the FMT. A stool and water solution was infused into the colon via colonoscopy, starting at the cecum. The patients were instructed not to have a bowel movement(s) within minutes of the FMT. Follow-up with these patients did not include standardized stool testing for Clostridium difficile toxin. Neemann et al. (2012) [6] A case report on the utilization of FMT for CDI in a patient with a history of allogeneic stem cell transplantation for acute lymphoid leukemia (ALL) undergoing radiation and chemotherapy for relapse. A 21-year-old female with ALL status post allogeneic stem cell transplantation, liposomal vincristine and radiation therapy for relapse presented with abdominal pain, fever and diarrhea. She was treated empirically for neutropenic fever (ANC of 400 cells/mm 3 ) with intravenous cefepime 2g TID, acyclovir and fluconazole prophylaxis. Six days post-presentation, worsening abdominal distension prompted a CT scan that showed pancolitis without pneumatosis, pneumoperitoneum, or megacolon. Tests for C. difficile toxins A/B as well as glutamate dehydrogenase antigen were positive. Metronidazole 500 mg TID was initiated intravenously. After 2 days of monotherapy, oral vancomycin 250 mg QID was added. Over 2 weeks, her neutropenia improved but she developed diarrhea and transfusion-requiring hematochezia. Treatment was changed to fidaxomicin with vancomycin enemas. She then developed peritonitis and was switched to IV tigecycline, PO rifaximin and vancomycin enemas. She was finally given PO immunoglobulin for 2 days after 14 days of failed treatment. She underwent a total of 19 days of CDI treatment without improvement. Two days post-fmt, the patient s diarrhea and hematochezia resolved. She was discharged home 4 days post-fmt. Tests for C. difficile toxins A and B were negative 3 and 11 days post-fmt. She did not manifest any symptoms of CDI during the 2-month follow-up period. This was the first case describing successful use of FMT in RCDI in a cancer patient. The authors also suggest that FMT can delay or prevent the need for bowel resection in RCDI. FMT was used as a last resort to avoid an operative intervention. Antibiotics were stopped and FMT was performed via nasojejunal tube instillation using pre-tested stool sample donated by her husband. Copyright OPUS 12 Foundation, Inc. 2

3 Trubiano et al. (2012) [7] A case report documenting the use of FMT in an ICU patient suffering from CDI. A 75-year-old female patient with multiple comorbidities including ischemic heart disease, obstructive sleep apnea, type II diabetes mellitus had a recent admission for lactic acidosis associated with metformin therapy. She subsequently developed a urinary tract infection and was treated with cephalexin. The patient was readmitted 15 days later due to CDI with diarrhea, given a 14 day course of PO metronidazole 400 mg TID, and sent home. She presented 19 days later with recurrent diarrhea and tested positive for a clinically aggressive strain of C. difficile with positive cultures. She began therapy with PO vancomycin 125mg QID. She developed septic shock complicated by hospital-acquired pneumonia and acute renal failure, requiring high acuity ICU therapy. The patient s WBC count and lactate were normal 10 days post-fmt. Feces were negative for C. difficile toxin and culture at 1, 7, 14, 20, and 30 days post-fmt. The patient eventually died more than 30 days after FMT due to respiratory failure, ventilator-associated pneumonia, and continued renal failure. Abdominal CT scan done prior to death did not reveal any evidence of colitis. This case was the first report to describe a successful clinical response following endoscopically administered FMT in a poor surgical candidate with RCDI in an intensive care setting. She continued to have a high volume of stool output and was started on a regimen of nasogastric vancomycin 126mg QID, IV metronidazole 500 mg TID, and retention enema vancomycin 250mg QID. She experienced no improvement over the next 12 days and required vasopressor support. FMT was considered because she was deemed a poor surgical candidate for colectomy. Her husband provided a stool sample, which was negative for infectious entities. FMT was administered via endoscopy into the patient s jejunum. The patient s clinical/resuscitation endpoints improved, and noradrenaline requirements and stool output decreased. Kleger et al. (2013) [8] A case report of a 73-year old woman with intractable CDI treated with combined colonoscopic FMT and Saccharmoyces cerevisiae. 73-year old female with extensive medical comorbidities including atrial fibrillation, type II diabetes mellitus, and 3- vessel coronary artery disease presented with abdominal pain and diarrhea for 10 days. She was diagnosed with C. difficile pan-colitis through cytotoxin assays and ultrasound of the colon. The patient was initially treated with 400 mg flagyl TID. Patient worsened on this treatment and was switched to 250 mg vancomycin QID. Symptoms did not improve. 500 mg nitazoxanide QD was attempted. After 16 days, symptoms resolved. The patient was evaluated at 14 days, 4 weeks, 3 months, and 6 months post-fmt. She remained symptom-free and had negative cytotoxin assays at follow-up. She developed herpes zoster of the thigh at 2 months post-transplant, but this was likely an incidental finding. This study demonstrated a severe case of RCDI in an elderly woman with multiple comorbidities effectively treated with FMT and adjuvant S. cerevisiae therapy. The patient returned 3 weeks later with diarrhea. Cytotoxin assay for C. difficile toxins A/B were positive. She was given nitazoxanide without clinical improvement. Rifaximin 400mg for 14 days was added with clinical improvement. Three days after completing rifaximin, she had recurrent abdominal pain and diarrhea. FMT was administered at this time. The patient was given 50 mg tigecycline BID for 10 days before administering FMT. FMT was administered via colonoscopy after a 2-day waiting period. Adjuvant Saccharmoyces cerevisiae was also given. Rubin et al. (2013) [9] Retrospective case series investigating the efficacy of FMT in treating RCDI. A retrospective case series of 74 patients with at least 2 incidents of RCDI who underwent 75 combined attempts at FMT. Donors included individuals living with each patient following stool screening for potential transmittable infections. 59 of the 75 (79%) FMT attempts produced clinical recovery. Only 2 patients out of 59 tested positive for C. difficile toxin and were thus assumed to be asymptomatic carriers. Two patients did not submit a post-fmt stool sample for testing. Each patient was treated with PO vancomycin 125 mg QID for a minimum of three days ending 24 hours prior to FMT to minimize diarrhea and overall C. difficile burden. The patients then received 2 doses of a PPI prior to the FMT. A mixture of 25 ml of stool and saline was instilled into the patients stomach using a nasogastric tube (64), PEG tube (4), or endoscope (7). Each patient was followed for a minimum of 60 days after FMT with stool testing for C. difficile toxin. Of the 16 patients that did not respond to the initial treatment with FMT, 9 clinically recovered following treatment with vancomycin. These findings suggest a 79% primary cure rate and a 91% secondary cure rate. This study suggests that FMT can be used to treat RCDI and may have greater efficacy when supplemented with vancomycin. Copyright OPUS 12 Foundation, Inc. 3

4 Smith (2013) [10] A case report on the use of FMT in a patient with newly diagnosed Crohn s disease with concurrent CDI. A 35-year-old female patient presented with frequent watery diarrhea and hematochezia. Her complaints began 3 days into a course of clarithromycin and amoxicillin given after a dilatation and curettage procedure. She was started on metronidazole, but only took it for 2 days and presented again with worsening symptoms. She was started on mesalazine due to concerns that she had inflammatory bowel disease. A colonoscopy revealed evidence of active Crohn s disease. She was given PO prednisolone while remaining on mesalazine. However, she was admitted 5 days later for severe dehydration and fever. Testing for C. difficile toxins A and B was positive. She was given PO vancomycin 125 mg QID and metronidazole 500 mg TID. She improved and was sent home after 2 days on the same antibiotic regimen. She was re-admitted 5 days later after her condition deteriorated. Radiographic imaging revealed toxic megacolon. The patient did not improve immediately following FMT. She was given dexamethasone 8 mg tapered to 4 mg QID for worsening symptoms. Over the next week, her diarrhea completely resolved. However, 6 days post-fmt, her diarrhea recurred. FMT was performed again on 2 occasions via enema, which provided mild relief of her symptoms. One week later, FMT was performed via nasogastric tube inserted into the descending duodenum. She had complete resolution of her symptoms and was discharged home three days following the final FMT treatment. This case describes eventual resolution of RCDI after multiple FMTs in a patient with Crohn s disease. FMT and sub-total colectomy were offered but the patient opted for FMT. Her husband donated a stool sample after stool testing for infectious disease entities was performed. This sample was administered through colonoscopy. van Nood et al. [11] An open-label, randomized, controlled trial including three treatment regimens to compare FMT with standard vancomycin regimens, with and without bowel lavage. This was an open-label, randomized, controlled trial including three treatment regimens: (a) an initial vancomycin regimen (500 mg orally QID for 4 days), followed by bowel lavage and infusion of a solution of donor feces through a nasoduodenal tube; (b) a standard vancomycin regimen (500 mg orally QID for 14 days); or (c) a standard vancomycin regimen with bowel lavage. The clinical goal was resolution of CDI-associated diarrhea without relapse after 10 weeks. Patients included had a relapse of CDI, defined as diarrhea and positive stool test for C. difficile toxin, after at least one course of adequate antibiotic treatment. Donors stool was screened for possible infectious entities. Feces were diluted with 500ml of saline to create an infusion solution. The trial was stopped prematurely since most patients relapsed in the control groups. A total of 81% patients in the infusion group had resolution of CDI-associated diarrhea after the first infusion. Resolution of CDI in the vancomycin-alone group was 31% and 23% in the vancomycin with bowel lavage group (P<0.01 for both comparisons with infusion group). Adverse events included diarrhea, belching, cramping, and constipation. Analysis of diversity of fecal microbiota after FMT revealed an increase in Bacteroidetes species and Clostridium clusters IV and XIVa and a decrease in Proteobacteria species. This study suggests that FMT has significantly greater efficacy in treating RCDI than vancomycin. A total of 43 patients were randomly assigned to the three treatment groups. Duke & Fardy [12] A case report of a patient with recurrent CDI treated with FMT at home. A 66-year-old female patient presented to her primary care physician with 10 days of diarrhea. CDI was confirmed with a positive Clostridium toxin test. A course of flagyl for 10 days along with supplemental probiotics was initiated. Despite this regimen, her diarrhea recurred 3 days later. She was then treated with vancomycin and then fidaxomicin 200 mg BID for 10 days with the same result. The patient then proposed using FMT at home to her primary care physician. Vancomycin was discontinued two days before FMT. Donor stool was mixed with saline and given via enema. The patient was placed supine for 5 hours to prevent evacuation of the instilled contents. This was repeated 3 days later due to relapse of diarrhea, and a third time 2 weeks following the second treatment. Following the third attempt at FMT, the patient experienced complete resolution of her symptoms and gained 15 pounds over the next two months. This case was successful in demonstrating the possibility of performing multiple FMTs for the treatment of RCDI in the convenience of one s home. Copyright OPUS 12 Foundation, Inc. 4

5 Friedman-Moraco et al. [13] A report describing 2 patients who experienced RCDI following organ transplantation procedures (one patient following lung transplant and the other following renal transplant). Both cases were treated with FMT. Case 1: A 73-year-old female with history of renal transplant on tacrolimus, azathioprine and prednisone presented with frequent UTIs, treated with multiple antibiotic courses. She developed CDI and was treated initially with 125 mg oral vancomycin QID. She continued to have recurrences and was also treated with vancomycin and vancomycin/rifamixin dual therapy. Case 1: The patient remained symptom-free at 1-year follow up. In addition, fewer antibiotic-resistant organisms were found in her urine after FMT. This case suggests that FMT is safe for immunosuppressed patients with CDI. The observation of decreased drug resistance of the patient s UTIs is promising, but more research is needed before any conclusions can be drawn from this isolated, anecdotal report. At 19 months post-transplant, she developed recurrent CDI in the setting of Pseudomonas UTI. She subsequently underwent a FMT donation from her daughter, administered via nasojejunal tube. After the initial FMT, she experienced clinical improvement. However, she was readmitted 2 weeks later with altered mental status and was found to have secondary recurrent CDI. She was treated with 4 days of vancomycin and received another FMT via colonoscopy. Case 2: The patient remained symptom-free after the second FMT. Unfortunately, she died secondary to complications from bronchiolitis obliterans. The long-term efficacy of FMT in this patient was difficult to assess given her abrupt death from bronchiolitis. Case 2: A 65-year-old female status post bilateral lung transplants, on tacrolimus, mycophenolic acid and prednisone. She developed her first CDI at 27 months post-transplant. She was initially treated with flagyl for 14 days with improvement, but CDI recurred 2 weeks later. She developed 3 more episodes of CDI, all treated with vancomycin. After initial FMT discussion, she declined and selected a vancomycin taper. Shortly after, she was hospitalized with bronchitis and developed another episode of CDI. She became dehydrated, lost 26 kg, and was subsequently treated with outpatient FMT administered via colonoscopy. Three weeks after FMT, diarrhea recurred, and she underwent another FMT administered through naso-jejunal tube. Kim et al. [14] A case report of CDI secondary to antibiotics used to treat pneumonia in the inpatient setting that was treated with FMT. An 83-year-old male was treated for pneumonia with respiratory failure as an inpatient. He received the following antibiotics over his hospital course: clarithromycin, ceftriaxone, tazobactam, levofloxacin, meropenem and teicoplanin. The patient developed diarrhea 13 days into his hospitalization. CDI was confirmed with a positive assay for C. difficile toxins A and B. He was receiving meropenem and teicoplanin for his pneumonia at this time. PO flagyl 500mg TID was added to the patient s antibiotic regimen. After 10 days of flagyl, the patient s symptoms worsened. Flagyl was then replaced with PO vancomycin 125 mg QID. The patient developed hematochezia 7 days later. FMT was pursued and delivered via endoscopy to the descending part of his duodenum. The donor stool was from a relative, previously screened for infectious diseases. The patient showed improvement within 24 hours and completely recovered 5 days post-fmt. The patient was treated again for pneumonia 90 days after FMT, but did not experience recurrent CDI. This case described successful use of FMT in the setting of RCDI in a patient exposed to multiple antibiotics during his pneumonia treatment. Lee et al. [15] A retrospective study including 94 patients with RCDI assessing clinical resolution of symptoms in primary non-response patients following multiple FMTs, with and without intermittent antibiotic administration. The authors sought to better define the use of repeated FMT treatments in the management of CDI. This retrospective study evaluated patients who developed CDI between 2008 and Infection was confirmed with either PCR or cytotoxin assays. Inclusion criteria included the following: (a) history of refractory infections, defined as persistent diarrhea after 5 days of PO vancomycin therapy at a minimum dose of 125 mg QID; or (b) a history of recurrent CDI, defined as recurrent diarrhea after 2 days without symptoms. Mean patient age was 71 years in this study. Fifty-three of 94 subjects were female. The majority of patients were hospitalized at the time of treatment. 79.3% of patients were treated with flagyl prior to FMT, 75% were treated with vancomycin, 15.2% with vancomycin taper, 17.4% received both vancomycin and flagyl, with a small fraction treated with probiotic monotherapy. Of 94 patients, 47.9% were cured after only 1 FMT administration. Cumulative clinical response rate was 86.2% when four or more FMTs were administered. 9 patients received vancomycin between 2 FMTs, increasing cumulative cure rate to 91.5%. A total of 8 patients did not respond to FMT therapy. Six of these patients died after FMT. These deaths were attributed to significant comorbid illnesses, and were not thought to be associated with the use of FMT. There were no adverse events or recurrences during 6 to 24 months of follow-up. This study suggests that multiple FMTs administered via enema are safe and effective for treatment of RCDI. Criteria for clinical resolution of CDI included no recurrence of diarrhea for 6 months. FMT was administered via enema. Copyright OPUS 12 Foundation, Inc. 5

6 Patel et al. [16] A case report describing a patient with a history of proctocolectomy for ulcerative colitis with subsequent pouch construction, treated with FMT for recurrent Clostridium difficile pouchitis. A 34-year-old male with recurrent pouch CDI, treated with various antibiotics in the past and currently managed with PO rifaximin. Current symptoms include watery diarrhea. Testing for C. difficile toxin B was positive. PO vancomycin 125 mg QID was added to his current regimen. He initially improved following 10 days of therapy, but deteriorated with active CDI. He was given another 3 weeks of the same therapy with symptomatic resolution and negative testing for CDI. He had recurrent CDI 19 days later. Therapy with PO fidaxomicin 200 mg BID and rifaximin was given with recurrence after 1 week. At this time, fidaxomicin was replaced with the previous vancomycin regimen. FMT was pursued after pouchoscopy revealed ulcerations within the pouch body. A stool sample was provided by a relative who was pre-screened for infectious entities. A stool and water solution was administered via pouchoscopy. Two days post-fmt, the patient s symptoms worsened. Followup pouchoscopy 7 days post-fmt revealed visible worsening of the previous findings. At that time, PO rifaximin and PO vancomycin were restarted. After 2 days on this treatment, the patient tested negative for CDI. His symptoms resolved after 2 additional days on antibiotic therapy. Therapy with vancomycin was continued but symptoms returned after 4 weeks. CDI testing remained negative. He was switched to PO amoxicillin/clavulanic acid 500/125 mg BID and his symptoms resolved. Pouchoscopy 3 and 11 months post-fmt revealed normal findings. The authors describe a presumably successful case of combined FMT and antibiotic treatment for RCDI pouchitis. Pathak et al. [17] A retrospective case series examining the efficacy of FMT for RCDI. This was a retrospective case series including 12 patients treated with FMT for RCDI over a 3-year period in a community hospital. All patients included had RCDI. Patients had previously been on vancomycin, fidaxomicin, and/or flagyl. Three patients received all 3 antibiotics. Severe CDI cases received FMT as first-line therapy. Antibiotics were discontinued 1 day before FMT. Stool was donated by a relative, if possible, or healthy volunteers. Donors were all pre-screened for infectious risk factors and antibiotic use within 3 months of donation. The stool sample was mixed with regular water and administered through colonoscopy using a modified ERCP catheter. Approximately 500 ml was infused into the cecum followed by 50 ml every 10 cm while withdrawing the colonoscope. The patients also took diphenoxylate/atropine to help prevent defecation. One FMT was performed with a nasoduodenal tube. Eleven of the 12 patients exhibited symptomatic recovery within two days of the FMT. The patient who failed to improve received a FMT from her husband who had been in close proximity and was not pre-screened. He may have been a C. difficile carrier. The patient responded to a second FMT from a healthy volunteer. Primary and secondary response rates were 91.66% and 100%, respectively. There were no complications with FMT and symptoms resolved within 48 hours. Patients also received probiotics before FMT treatment, which were discontinued for 1 week after FMT, and were maintained on probiotics for 2 months after FMT. This was unlikely to have a significant impact on the results as improvement in symptoms only occurred after FMT. This case series demonstrates effective RCDI treatment with FMT in a community hospital setting. Russell et al. [18] Retrospective case series describing single-infusion FMT in pediatric patients with CDI with and without inflammatory bowel disease (IBD). A retrospective case series including ten children who received single-infusion fecal microbiome transplant (FMT) between 2009 and Three of 10 patients had active IBD. All patients had at least 3 recurrences of diarrhea with evidence of CDI on lab testing and clinical resolution with conventional treatment. Nine of the 10 (90%) children had a good clinical response after a single-infusion FMT. Two of 3 of the IBD patients had resolution of symptoms with no affect on their IBD activity based on Physician s Global Assessment. Patients were followed from 1 month to 4 years with no concerning adverse events. Healthy, related pre-screened donor stool was used for FMT. All antibiotics were discontinued at 36 to 48 hours prior to FMT. Thirty to 40 grams of stool was mixed with 250ml of saline and filtered. The solution was delivered via nasogastric tube or into the cecum via colonoscope. IBD disease activity was measured by Physician s Global Assessment. This case series demonstrates effective RCDI treatment using FMT in pediatric patients, along with some success in those with IBD without influencing IBD activity. Schunemann et al. [19] A case report on using FMT to treat CDI in a patient with AIDS and other AIDS-related infectious conditions. A 54-year-old male with AIDS presented with global dehydration, resulting in acute kidney failure and metabolic acidosis. He had a history of CDI and was diagnosed again with C. difficile colitis via colonoscopy and tested positive for C. difficile toxins A/B. He also had esophagitis from human herpes simplex (HSV) and cytomegalovirus (CMV) confirmed on biopsy, Candida albicans bacteremia, and spontaneous bacterial peritonitis with ascites culture positive for Candida glabrata, Pseudomonas aeruginosa and vancomycin-resistant Enterococcus (VRE). The patient s initial CD4+ cell count was 54/uL with an HIV viral load of 2,480 copies/ml. The patient was treated with metronidazole, vancomycin, fidaxomicin, ciprofloxacin, meropenem, tigecyline, caspofungin and acyclovir while continuing antiretroviral therapy. He had pneumonia and recovered, but then developed VRE sepsis one week later. Although he was treated for VRE sepsis and maximum CDI therapy for severe CDI, he still developed toxic megacolon. Two courses of FMT were attempted with the mother s stool being used following screening for infectious diseases. The first FMT was done using an intestinal tube, and was followed 10 days later by FMT via colonoscope. The patient s Clostridium difficile infection exhibited total resolution within the first week following FMT. His CD4+ cell count rose to 306/uL by discharge and his viral load became undetectable. He was able to leave the hospital after recovering from a venous catheter infection. This case demonstrates successful treatment using FMT in a severely immunocompromised patient with severe CDI that progressed to toxic megacolon. Copyright OPUS 12 Foundation, Inc. 6

7 Hirsch et al. (2015) [20] FMT has been shown to be highly effective for treating RCDI but is limited by discomfort and inefficiency. This study investigates an alternative method of FMT using orally administered capsules. The goal of this study is to find a convenient strategy to administer FMT that is widely applicable and less invasive. Inclusion criteria included subjects 18 years or older with two or more episodes of RCDI appropriately treated with standard CDI therapy. Donors were three healthy unrelated volunteers who were appropriately screened for infectious entities. Fecal samples were collected and screened for potential pathogens. The bacteria were prepared in sterile conditions to create multi-layered oral capsules. Orally administered capsules were well tolerated. Thirteen individuals responded after the first course and four patients were cured after a second course. Two patients failed therapy. The cumulative clinical cure rate was 89% with 68% cure from a single FMT. This study demonstrates efficacy in treating RCDI with a safe, effective, well-tolerated oral capsule version of FMT that has major implications for the future of FMT administration. Antibiotic treatment was discontinued the day prior to FMT. Thirteen women and six men with RCDI were given FMT with orally administered capsules. Patients ingested 6-22 capsules, sat upright and were not allowed to eat for 1 hour. A successful FMT dose was approximately 2.3g. Candidates were followed via phone interview within 2 days of administration, within 3 weeks and after 90 days. The primary endpoint was resolution of diarrhea without relapse after 90 days. Jang et al. (2015) [21] A case report on the use of FMT in a patient with RCDI and vancomycinresistant enterococci (VRE) colonization. A 33-year- old male patient presented with fever and diarrhea for 7 days. He received ampicillin/sulbactam, ceftriaxone, flagyl and meropenem for pneumonia 3 weeks prior to his presentation. He was diagnosed with CDI on sigmoidoscopy revealing yellow vegetations with mucosal edema, had positive C. difficile culture and C.difficile toxins A and B. His stool culture also grew VRE. The patient received PO vancomycin 125 mg QID, vancomycin 500mg in 100 ml of saline via enema QID and IV metronidazole 500 mg TID. Vancomycin enemas were used due to ileus. Following 8 days of no improvement, FMT was performed. A stool sample donated by his brother was infused through a rectal syringe. Another attempt at FMT was performed after three days via a nasoduodenal tube. Although VRE cultures remained positive throughout the remainder of the follow-up period, the patient s symptoms abated 5 days post-fmt. One week after his symptoms subsided, a sigmoidoscopy revealed resolution of mucosal pseudomembranes. Tests for C. difficile toxin were also negative. The patient remained asymptomatic for the remainder of the 3-month follow-up period. This case reveals successful treatment of RCDI with FMT in the setting of concurrent VRE infection. Tae-Geun et al. (2015) [22] A case report of a patient with toxic megacolon secondary to RCDI treated with FMT. A 76-year-old male patient with multiple comorbidities was transferred from an outside hospital following an unsuccessful 10-day course of IV flagyl 500 mg TID and PO vancomycin 125 mg QID. Surgical treatment was discussed but the patient was a very poor surgical candidate. Therefore, FMT was attempted three times using donated stool from a healthy unrelated individual who was appropriately pre-screened. The initial FMT was unsuccessful due to the patient s inability to retain the FMT. Even so, one day after FMT his abdominal distention improved and the frequency of diarrhea decreased from 10 to 5 times per day. His blood pressure also improved and he was weaned off pressors. The second FMT was also somewhat unsuccessful due to the lack of bowel prep, limiting access to the cecum. However, the patient s ileus resolved 5 days later and a third FMT was attempted via EGD. Five days following the last attempt, the patient s symptoms resolved. This case reveals some limitations of administering FMT but ultimately demonstrates success in treating severe RCDI. Wang et al. (2015) [23] A case report on using FMT to treat a 13-month-old infant with C. difficile pseudomembranous enteritis. A 13-month-old male presented with diarrhea over a 2-month period, previously treated with multiple antibiotics: amoxicillin, flagyl, imipenem, ceftazidime and vancomycin. He also suffered from edema secondary to hypoalbuminemia, which remitted following supplementation of albumin and electrolytes as well as administration of IVIG. Laboratory tests for C. difficile toxin A and B were serially negative, but the patient continued to have diarrhea. He received 2 courses of metronidazole for 10 days as well as vancomycin for a 14-day period. Finally, a FMT was infused using a nasojejunal tube with a stool sample donated by his mother. The patient had total clinical resolution within 5 days after receiving the FMT. He remained symptom free for 4 months post-fmt. Though testing for C. difficile toxin was negative, this was likely a result of chronic antibiotic therapy prior to testing. Though it is difficult to measure whether the infant s condition resolved due to antibiotics, FMT, or a combination of the two, his clinical symptoms of diarrhea responded after FMT. This case describes one of the few pediatric pseudomembranous enteritis cases successfully treated with FMT. Table legend: CDI = Clostridium difficile infection; EIA = enzyme immunoassay; FMT = fecal microbiota transplant; NG = nasogastric; NJ = nasojejunal; PPI = proton pump inhibitor; PEG = percutaneous endoscopic gastrostomy; IVIG = intravenous immunoglobulin; EGD= Esophagogastroduodenoscopy; RCDI= recurrent Clostridium difficile infection; ALL = acute lymphoblastic leukemia; ANC = absolute neutrophil count; ICU = intensive care unit; UTI = urinary tract infection; AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus Copyright OPUS 12 Foundation, Inc. 7

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