Multiple Fecal Microbiota Transplantation Research Articles

Efficacy and safety of fecal microbiota transplant for recurrent Clostridium difficile infection in inflammatory bowel disease: a systematic review and meta-analysis.

the objective of this systematic review and meta-analysis was to evaluate the outcomes of fecal microbiota transplantation (FMT) therapy for recurrent Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) patients. electronic databases were searched for studies reporting on the efficacy and/or safety of FMT therapy for recurrent CDI in IBD. The meta-prop command of the meta package in R was used to assess efficacy and safety. Subgroup analyses were performed to explore heterogeneity regarding all outcomes. eleven trials were included in the study. A pooled analysis showed that the initial cure rate of recurrent CDI among IBD patients was 80 % (95 % CI, 0.76, 0.84), and the overall cure rate after two or more FMT procedures was 90 % (95 % CI, 0.84, 0.94). The recurrence rate post-FMT therapy was 25 % (95 % CI: 0.20, 0.32). Sub-analyses suggested that the initial cure rate of CDI in ulcerative colitis (UC) patients was higher than in Crohn's disease (CD) patients (85 % vs. 79 %), with no statistically significant differences (p > 0.05). No serious adverse events were noted in any of the patients post-FMT. FMT is an effective and safe treatment for recurrent CDI in patients with IBD. FMT should be considered early in cases of recurrent or refractory CDI. Multiple FMT procedures can improve the cure rate of CDI.

Establishment and resilience of transplanted gut microbiota in aged mice

SummaryThe maintenance of healthy and resilient gut microbiota is critical for the life quality and healthspan of the elderly. Fecal microbiota transplantation (FMT) has been increasingly used to restore healthy gut microbiota. We systemically studied the establishment and resilience of transplanted microbiota after autologous versus heterologous FMT in aged recipients. Gut microbiota of aged mice (20 months old) failed to restore their original diversity and composition over 8 weeks via spontaneous recovery after antibiotics treatment; in contrast, FMT using either autologous or heterologous (2 months old from a different vendor) donors facilitated the recovery successfully, established donor-like microbiota states, and affected host gene expression profile. Furthermore, the transplanted microbiota established by heterologous FMT is not resilient during chemical-induced colonic inflammation, in contrast to that of autologous FMT. Our findings highlighted the need to monitor the long-term stability of transplanted gut microbiota and to perform multiple FMT when necessary.

Outcomes of Fecal Microbiota Transplantation for C. difficile Infection in Inflammatory Bowel Disease : A Systematic Review and Meta-analysis.

Fecal microbiota transplantation (FMT) is a safe and effective therapy for recurrent Clostridioides difficile infection (CDI). Data on FMT for CDI in patients with underlying inflammatory bowel disease (IBD) are emerging but conflicting. We performed a systematic review and meta-analysis to describe the efficacy and safety of FMT for CDI in IBD and its impact on IBD outcomes. A systematic search of multiple databases including Embase, Scopus, and Web of Science was performed. Our primary analysis focused on pooled rate of CDI resolution after single and multiple FMTs in IBD patients. Additional analyses included rates of IBD-associated outcomes (flare, surgery, symptom improvement) after FMT. The random-effects model was used to calculate pooled rates. Among 457 adult patients, 363 had CDI resolution after first FMT with a pooled cure rate of 78% [95% confidence interval (CI): 73%-83%; I2 =39%]. Overall pooled rate cure rate with single and multiple FMTs was 88% (95% CI: 81%-94%; I2 =73%). The pooled rate of an IBD flare after FMT was 26.8% (95% CI: 22.5%-31.6%; I2 =9%) and of colectomy was 7.3% (95% CI: 4.7%-10.5%; I2 =56%). Among 141 pediatric patients, 106 had CDI resolution after first FMT with pooled cure rate of 78% (95% CI: 58%-93%; I2 =59%). Overall pooled cure rate with single and multiple FMTs was 77% (95% CI: 50%-96%; I2 =63%). The pooled rate of an IBD flare after FMT was 10.8% (95% CI: 5.7%-18.5% I2 =43%), and of colectomy was 10.3% (95% CI: 2.1%-30.2% I2 =23%). FMT appears to be a highly effective therapy for preventing recurrent CDI in patients with IBD. Patients who fail a single FMT may benefit from multiple FMTs.

Efficacy and Safety of Fecal Microbiota Transplantation and Prospect of Microbe-based Therapies for Inflammatory Bowel Disease

The use of 5-ASA, immunomodulators, biologics, and small molecule drugs are the main treatment for inflammatory bowel disease (IBD), however, fecal microbiota transplantation (FMT) is also drawing attention as a treatment to improve intestinal dysbiosis by transplantaing normal human stool into patients with IBD. FMT demonstrates relatively good effects in inducing clinical remission in IBD, but unlike Clostridium difficile infection, multiple FMT can enhance the clinical effect. There are no reports of the long-term effectiveness and safety of FMT conducted in IBD yet, therefore, well-designed, prospective studies will be needed. Gut microbiota can affect inflammatory response, intestinal barrier function, and host metabolism, so microbe-based therapies are likely to be a new treatment option for IBD. The deeper the understanding of microbe products or effectors, the more likely it is to provide personalized therapy in IBD.

Fecal microbiota transplantation therapy in Crohn's disease: Systematic review.

The gastrointestinal microbiota is the key antigenic drive in the inflammatory bowel diseases. Randomized controlled trials (RCTs) in ulcerative colitis have established fecal microbiota transplantation (FMT) as an effective therapy. We have conducted a systematic review to evaluate the efficacy of FMT in Crohn's disease. A systematic literature search was performed through to August 2020 (MEDLINE; Embase). Studies were included if they reported FMT administration in patients with Crohn's disease, and reported on clinical outcomes. Fifteen studies published between 2014 and 2020, comprising 13 cohort studies and two RCTs, were included in the analysis. The majority of trials evaluated FMT for induction of remission, with follow-up duration varying from 4 to 52weeks. One RCT in 21 patients, of single-dose FMT versus placebo, following steroid-induced remission, showed a higher rate of steroid-free clinical remission in the FMT group compared to the control group: 87.5% vs 44.4% at week 10 (P=0.23). Another RCT, two-dose FMT in 31 patients, showed an overall clinical remission rate of 36% at week 8, however, with no difference in clinical or endoscopic endpoints between FMT administered by gastroscopy and colonoscopy. Considering all studies, the clinical response rates in early follow up were higher following multiple FMT than with single FMT. FMT dose did not appear to influence clinical outcomes, nor did whether FMT was fresh or frozen. FMT delivered via upper gastrointestinal route demonstrated higher early efficacy rates of 75 to 100% compared with lower delivery route rates of 30% to 58%, but on follow up beyond 8weeks, this difference was not maintained. Whether pre-FMT antibiotic administration was beneficial was not able to be determined due to the limited number of patients receiving antibiotics and varying antibiotic regimens. No serious adverse events were reported. Preliminary studies suggest that FMT may be an effective therapy in Crohn's disease. However large controlled trials are needed. No serious safety concerns have been identified.

Establishment and Resilience of Transplanted Gut Microbiota in Aged Mice

The maintenance of healthy and resilient gut microbiota is critical for the life quality and healthspan of the elderly. Many gastrointestinal diseases which are more prevalent in the aged population are believed to be associated with gut microbiota disruption and dysbiosis. Fecal microbiota transplantation (FMT), a procedure in which fecal material is transferred from a donor to a recipient, has been increasingly used as a treatment to restore healthy gut microbiota. However, little is known about the establishment and long-term stability of transplanted microbiota or their resilience to further disruption, especially in aged hosts. In the present investigation, we aimed to study the establishment and resilience of transplanted microbiota after autologous versus heterologous FMT in aged recipients. We demonstrated that gut microbiota of aged mice (20 months old) treated with a broad-spectrum antibiotic cocktail failed to restore its original diversity and composition over 8 weeks via spontaneous recovery; in contrast, FMT using either autologous or heterologous (2 months old from a different vendor) donors facilitated the recovery of gut microbiota diversity. Both autologous and heterologous FMT successfully established donor-like microbiota states and affects the gene expression profile of the aged host for as long as 8 weeks. Furthermore, we evaluated the resilience of transplanted microbiota during further colon environment changes. The transplanted microbiota established by heterologous FMT is not resilient during chemical-induced colonic inflammation, in contrast to that of autologous FMT. Our findings systematically examined the effects of FMT on the gut homeostasis of aged hosts, highlighted the need to monitor the long-term stability of transplanted gut microbiota and to perform multiple FMT when necessary.

Tandem fecal microbiota transplantation cycles in an allogeneic hematopoietic stem cell transplant recipient targeting carbapenem-resistant Enterobacteriaceae colonization: a case report and literature review

BackgroundDue to limited antibiotic options, carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with high non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Also, intestinal CRE colonization is a risk factor for subsequent CRE infection. Several clinical studies have reported successful fecal microbiota transplantation (FMT) for the gut decontamination of a variety of multidrug-resistant bacteria (MDRB), even in immunosuppressed patients. Similarly, other studies have also indicated that multiple FMTs may increase or lead to successful therapeutic outcomes.Case presentationWe report CRE colonization in an allo-HSCT patient with recurrent CRE infections, and its successful eradication using tandem FMT cycles at 488 days after allo-HSCT. We also performed a comprehensive microbiota analysis. No acute or delayed adverse events (AEs) were observed. The patient remained clinically stable with CRE-negative stool culture at 26-month follow-up. Our analyses also showed some gut microbiota reconstruction. We also reviewed the current literature on decolonization strategies for CRE.ConclusionsCRE colonization led to a high no-relapse mortality after allo-HSCT; however, well-established decolonization strategies are currently lacking. The successful decolonization of this patient suggests that multiple FMT cycles may be potential options for CRE decolonization.

Cost‐effectiveness analysis of sequential fecal microbiota transplantation for fulminant Clostridioides difficile infection

Fulminant Clostridioides difficile infections (FCDI) account for 8% of cases and substantial healthcare burden. Fecal microbiota transplantation is recommended for recurrent CDI, but emerging data support use for FCDI. We aimed to assess the cost-effectiveness of a sequential fecal microbiota transplantation (sFMT) protocol for FCDI compared with current standard therapy. A Markov model simulated patients with FCDI in a 1-year time horizon. The treatment algorithm for up to three sFMTs, clinical probabilities, and direct costs were used from published sources. Outcomes were quality-adjusted life years (QALYs) and costs. The healthcare sector perspective was used with a willingness-to-pay threshold of $100000 per QALY. Sequential fecal microbiota transplantation (FMT) for FCDI was associated with lower overall cost ($28309 vs $33980) and higher QALY (0.765 vs 0.686) compared with standard therapy. sFMT is cost-effective in 100% of iterations. sFMT remained cost-effective at cure rates>44.8% for the first FMT and at stool preparation cost<$6944 per instillation. We find a wide range of efficacies for the first versus second FMT at which sFMT is still preferred. Value of information analysis estimates the expected value of perfect information to be low at $1.89 per person, quantified with net monetary benefit. An sFMT strategy strongly dominates standard therapy, with lower cost and higher QALY. Sensitivity analysis demonstrates benefit even if FMT cure rates are lower than expected and when multiple FMTs are required. FMT material in 2020 was priced at $1695 per treatment but remains cost-effective at a much higher cost.

Long-term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection

Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridioides difficile infection (CDI), with emerging data on intermediate and long-term safety. A prospective survey-based study was conducted (September 2012-June 2018) in patients undergoing FMT for recurrent CDI. Data on demographics and comorbidities were abstracted from medical records. Patients were contacted at 1 week, 1 month, 6 months, 1 year (short-term), and ≥2 years post-FMT (long-term). Symptoms and new medical diagnoses were recorded at each time point. Data were weighted to account for survey nonresponse bias. Multivariate logistic regression models for adverse events were built using age (per 10-year increment), sex, time of survey, and comorbidities. P < .05 was considered statistically significant. Overall, 609 patients underwent FMT; median age was 56 years (range, 18-94), 64.8% were women, 22.8% had inflammatory bowel disease (IBD). At short-term follow-up (n= 609), >60% of patients had diarrhea and 19%-33% had constipation. At 1 year, 9.5% reported additional CDI episodes. On multivariable analysis, patients with IBD, dialysis-dependent kidney disease, and multiple FMTs had higher risk of diarrhea; risk of constipation was higher in women and lower in IBD (all P < .05). For long-term follow-up (n= 447), median time of follow-up was 3.7 years (range, 2.0-6.8). Overall, 73 new diagnoses were reported: 13% gastrointestinal, 10% weight gain, 11.8% new infections (all deemed unrelated to FMT). Median time to infections was 29 months (range, 0-73) post-FMT. FMT appears safe with low risk of transmission of infections. Several new diagnoses were reported, which should be explored in future studies.

Recurrence of moderate to severe ulcerative colitis after fecal microbiota transplantation treatment and the efficacy of re-FMT: a case series

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), the pathogenesis of which is complicated, and it is difficult to treat. In recent years, the emerging fecal microbiota transplantation (FMT) has shown good effects in UC treatment and is therefore accepted by increasing numbers of patients. Our hospital has carried out FMT since 2017, and has achieved good results in UC treatment. We have found in our clinical work that the efficacy of re-FMT after recurrence decreased. This is difference from reported literatures. In order to attract clinical attention, here we selected typical cases for analysis.MethodsAmong all UC patients who received FMT in our hospital, 12 patients with moderate to severe UC were selected. They all received multiple FMT and were followed up for 52 weeks. Besides, none of them had other underlying diseases. Colonoscopy images of patients were presentated, SCCAI and UCDAI were used assess the effect of FMT.ResultsOn the whole, FMT has a significant effect on moderate to severe UC. Of the 12 patients, 11 (91.7%) achieved a clinical response, 9 (75.0%) achieved clinical remission, and only one patient did not respond to FMT treatment. However, 6 patients relapsed within 52 weeks after remission, with a recurrence rate of 54.5%. Four of the six relapsed patients received FMT again, but the efficacy of FMT after relapse was significantly lower than that of the initial FMT. Fortunately, compared to before the initial FMT treatment, the severity of the disease after relapse was significantly reduced.ConclusionFMT has a good effect on the relief of moderate to severe UC. However, the effect of FMT treatment after relapse is reduced. For patients who relapse after remission, the efficacy of FMT reapplication requires more experiments to verify.

Fecal Microbiota Transplant in Two Ulcerative Colitis Pediatric Cases: Gut Microbiota and Clinical Course Correlations.

Fecal microbiota transplantation (FMT) is a promising strategy in the management of inflammatory bowel disease (IBD). The clinical effects of this practice are still largely unknown and unpredictable. In this study, two children affected by mild and moderate ulcerative colitis (UC), were pre- and post-FMT monitored for clinical conditions and gut bacterial ecology. Microbiota profiling relied on receipts’ time-point profiles, donors and control cohorts’ baseline descriptions. After FMT, the improvement of clinical conditions was recorded for both patients. After 12 months, the mild UC patient was in clinical remission, while the moderate UC patient, after 12 weeks, had a clinical worsening. Ecological analyses highlighted an increase in microbiota richness and phylogenetic distance after FMT. This increase was mainly due to Collinsella aerofaciens and Eubacterium biforme, inherited by respective donors. Moreover, a decrease of Proteus and Blautia producta, and the increment of Parabacteroides, Mogibacteriaceae, Bacteroides eggerthi, Bacteroides plebeius, Ruminococcus bromii, and B Bacteroides ovatus were associated with remission of the patient’s condition. FMT results in a long-term response in mild UC, while in the moderate form there is probably need for multiple FMT administrations. FMT leads to a decrease in potential pathogens and an increase in microorganisms correlated to remission status.

Risk Factors that Predict the Failure of Multiple Fecal Microbiota Transplantations for Clostridioides difficile Infection.

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection (CDI); however, a small percentage of patients fail to achieve cure even after two FMTs. This high-risk cohort remains poorly understood. We performed a multicenter, multinational retrospective review of patients that underwent at least one FMT for a CDI indication at four academic FMT referrals. Patients' data including CDI, FMT, and FMT variables were assessed. The primary outcome was FMT failure after a second FMT defined as persistent diarrhea and positive laboratory test for C. difficile (PCR or toxin) despite a second FMT within 8weeks of the first FMT. A multivariable logistic regression model was performed to determine predictors of second FMT failure. A total of 540 patients received at least one FMT during the study period, of which 432 patients had success following the first FMT, 108 had documented failure (25%). Among those who failed the first FMT, 63 patients received a second FMT, of which 36 achieved cure, and 24 had documented failure after the second FMT. Patients that failed the first FMT but did not receive a second FMT and those lost to follow-up were excluded leaving 492 patients included in the analysis. The second FMT failure rate was 4.8% (24/492). Risk factors for second FMT failure identified by multivariable logistic regression included: inpatient status (OR 7.01, 95% CI: 2.37-20.78), the presence of pseudomembranes (OR 3.53, 95% CI: 1.1-11.33), and immunocompromised state (OR 3.56, 95% CI: 1.45-8.72) at the time of first FMT. This study identifies clinically relevant risk factors predictive of failing a second FMT. Clinicians can use these variables to help identify high-risk patients and provide a better-informed consent regarding the possibility of needing multiple FMTs.

A265 SERIAL FECAL MICROBIOTA TRANSPLANT PLUS FIDAXOMICIN IN THE TREATMENT OF SEVERE OR FULMINANT CLOSTRIDIOIDES DIFFICILE INFECTION

Abstract Background Severe and fulminant Clostridioides Difficile infection(CDI) is associated with increased mortality and morbidity. Current guidelines recommend high dose vancomycin with metronidazole for treatment. Surgery is a high risk for patients failing medical therapy partly due to multiple comorbidities. Emerging evidence suggests efficacy of sequential fecal microbiota transplantation(FMT) by colonoscopy combined with vancomycin in patients failing maximal medical therapy. Fidaxomicin is non-inferior to vancomycin in treating CDI; however, it has not been studied in severe/fulminant cases. It is not known if FMT by enema combined with fidaxomicin is efficacious and safe in this patient population. Aims This single center, prospective, open-label pilot study aimed to determine the efficacy and safety of combined sequential FMT by enema plus fidaxomicin in severe or fulminant CDI not responding to maximal medical therapy. Primary outcome was resolution of diarrhea 2 weeks following final FMT. Secondary outcomes were resolution of diarrhea 8 weeks following final FMT, safety of proposed treatment protocol and colectomy rate. Methods Consecutive patients with severe or fulminant CDI, who fulfilled study inclusion criteria were recruited. Sequential cycles of FMT, administered by enema daily over three days(720cc followed by 360cc and 180cc), plus fidaxomicin 200mg PO BID were given. Clinical symptoms and inflammatory markers were monitored during the study and subsequent cycles of FMT were administered when clinical or biochemical improvement plateaued. A final FMT was administered with CDI resolution. Results A total of three patients were enrolled between Jan 22 to Aug 8, 2019, shown in Table 1. One patient had fulminant CDI due to shock, and the others had severe CDI. All had severe pseudomembranous colitis seen on endoscopy at enrollment. Two of three patients reached both primary and secondary outcomes with 2 FMT cycles. The only patient who did not reach the primary was successfully managed with long term vancomycin suppression. This patient had failed multiple FMTs prior to enrollment. There were no adverse events noted and no colectomy was required during this study. Conclusions This pilot study is the first to demonstrate efficacy and safety of combined sequential FMT by enema and fidaxomicin in treating severe or fulminant CDI patients. An adequately powered study is required to validate these findings. Funding Agencies CIHRAlberta Health Services, University of Alberta Hospital Foundation

1581 Sequential Fecal Microbiota Transplantation for Severe Acute Refractory Clostridium difficile Colitis: A Life-Saving Treatment Approach

INTRODUCTION: Fecal microbiota transplantation (FMT) is now a commonly used mode of treatment for recurrent Clostridium difficile infection (rCDI) refractory to antibiotics. We report a unique case where two sessions of sequential FMT were used to treat acute rCDI refractory to antibiotics with endoscopically documented marked improvement in disease process. CASE DESCRIPTION/METHODS: A 69 year-old female presented with 4 days of fever, large volume non-bloody diarrhea and poor appetite. She denied abdominal pain, nausea or vomiting. She reported two months before this admission, she was treated for hospital-acquired CDI, but could not recall what she was treated with. Physical examination revealed a non-tender abdomen without guarding or rigidity. Laboratory tests revealed hemoglobin 11.3 g/dL and white blood cell (WBC) count 18,700/mcL. Stool testing was positive for C. difficile toxin assay. Computed tomography of the abdomen showed diffuse pancolitis, compatible with CDI, no evidence of bowel perforation or obstruction. Despite treatment with oral vancomycin (500 mg every 6 hours), intravenous metronidazole and probiotics for 5 days, her leukocytosis increased to 32,000/mcL, hemoglobin dropped to 6 g/dL and her symptoms persisted. The decision was made to try FMT and antibiotics were stopped for 48 hours as per FMT protocol. Colonoscopy showed severe pancolitis (Figure 1) and pseudomembranes consistent with severe C. difficile colitis with distal ascending colonic mucosa concerning for ischemia. 250 mL of donor stool was delivered at the proximal transverse colon. After the first FMT, mild improvement was noted in her symptoms and leukocytosis but she persisted to have severe diarrhea. A second FMT was performed 4 days later. Repeat colonoscopy (Figure 2) showed marked improvement in the appearance of pancolonic erythema, inflammation and pseudomembranes compared to prior. 250 mL of donor stool was infused through the colonoscope into the cecum. The following day after the second FMT, the patient began having formed stool and improved leukocytosis. She was discharged from the hospital 3 days after the second FMT with normal stool consistency and normal WBC count. DISCUSSION: There have been no clear data regarding directing severe rCDI treatment with regards to the length of time in between FMTs. Clinicians should be aware that patients may need multiple FMTs to treat rCDI. A shorter duration in between FMTs may rapidly improve severe rCDI, reduce the duration of hospitalization, and improve outcomes.

500. Efficacy of 30-Day Fidaxomicin for Treatment of Acute Clostridium difficile Infection With History of Multiple Recurrences

BackgroundMultiple recurrent Clostridium difficile (mrCDI) infections pose major challenges to patients and to the healthcare system. mrCDI is associated with multiple, prolonged hospitalizations and significantly higher costs. It can also lead to chronic, severe diarrhea, colectomy, or death. Fecal microbiota transplantation (FMT) is an effective treatment, but its long-term safety remains unknown, and approximately 10% of patients do not respond to multiple FMTs. A 30-day course of fidaxomicin was evaluated for treatment of acute episode of CDI superimposed on mrCDI, including those who did not respond to multiple FMTs. Fidaxomicin was chosen because it disrupts the fecal microbiome less than vancomycin.MethodsTwenty-nine adult patients with at least two episodes of recurrent CDI were initiated on fidaxomicin 200 mg when they experienced new episode of CDI (symptoms plus positive for CD toxin gene by polymerase chain reaction). These patients continued with fidaxomicin 200 mg twice daily for 10 days, and 200 mg once daily for 20 additional days in an open-label clinical trial. The primary endpoints were a clinical response at the completion of 30-day course of fidaxomicin and a sustained clinical response at week 8 from the last dose of fidaxomicin. Patient health-related quality of life was evaluated throughout the treatment using the RAND-36 Item Health Survey (copyright© the RAND Corporation).ResultsTwenty-four of the 29 patients (83%) experienced clinical resolution of CDI-related symptoms at the completion of 30-day fidaxomicin treatment. Twenty-two of the 29 patients had a sustained clinical response with the overall cure rate of 76% (22/29). Eleven of the 29 patients had multiple FMTs and were enrolled into this study as they failed FMTs. Eight of the 11 patients (73%) of these patients had a sustained clinical response. Statistically significant improvements (P < 0.05) in multiple domains of quality of life according to the RAND-36 Item Health Survey were also observed.ConclusionAn extended regimen of fidaxomicin is an effective treatment for adults with multiple rCDI and in restoring quality of life, including those who failed FMTs.Disclosures C. Lee, Rebiotix: Board Member and Grant Investigator, Consulting fee and Research grant. Merck: Research Contractor, Research grant. Pfizer: Grant Investigator, Research grant. Seres: Grant Investigator, Grant recipient. P. Kim, Rebiotix: Board Member, Consulting fee.

Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Immunocompromised Patients: A Systematic Review and Meta-Analysis

Introduction: Fecal microbiota transplantation (FMT) is a safe and effective therapy for recurrent Clostridium difficile infection (CDI). Although immunocompromised patients are at high risk of CDI, the use of FMT may be limited owing to safety concerns. Since most FMT clinical trials exclude these patients, data on efficacy and safety of FMT in these patients are limited. We report results from a systematicreview and meta-analysis to evaluate the efficacy and safety of FMT in immunocompromised patients. Methods: A systematic search of MEDLINE, Embase and Web of Science was performed up to April 2018, followed by manual search of identified studies. We included case series, case-control or cohort studies, and clinical trials of FMT for CDI in immunocompromised patients with prevention of recurrent CDI as the primary outcome. Our primary analysis focused on calculating weighted pooled cure rate after one or more FMT. Results: A total of 18 studies were included. Among these, 566 immunocompromised patients underwent FMT for recurrent CDI. The various reason for immunosuppression included inflammatory bowel diseases, solid organ transplant (SOT), cancer, human immunodeficiency virus infection, graft versus host disease and hematopoietic stem cell transplants. Of the 566 patients, 430 had clinical cure of CDI with a pooled resolution rate after one FMT of 77.4% (95% CI, 71.6%-83.2%, I2= 57%).The pooled resolution rate increased to 91.5% (95% CI, 87.6%-95.4%, I2=21%) with multiple FMTs. No serious adverse events attributed to FMT were reported in any of the studies. On separating the 9 studies with immunosuppressed IBD patients, resolution after 1 FMT was reported in 328/412 patients, the pooled resolution rate 80.7% (95% CI, 76.6%-84.8%). In three studies with 103 SOT patients, FMT cured 58, with pooled cure rate of 50.2% (95% CI, 29.7%-70.6%). Conclusion: FMT appears to be safe and effective therapy for preventing recurrent CDI in immunocompromised patients. However, efficacy is lower in these patients compared to reported rates in immunocompetent patients. Efficacy improves with multiple FMTs. Although data were not available, repeat non-CDI antibiotic exposure in this population could potentially explain these findings. Studies are needed to explore best treatment practices in these patients including predictors of failed FMT which may identify patients who would benefit from early pre-emptive repeat FMT to prevent recurrent CDI

Is a Single Fecal Microbiota Transplant a Promising Treatment for Recurrent Clostridium difficile Infection?

Clostridium difficile infection, a common hospital-associated infection, is a gastrointestinal illness that becomes recurrent in about 25% of infected patients. Fecal microbiota transplantation (FMT) is increasingly supported by clinical trials as an effective treatment for recurrent Clostridium difficile infection, but a number of questions remain about how it can be optimally performed. In this Perspective, we discuss controversies in FMT methodologies and reporting within randomized controlled trials, all of which may influence clinical outcomes in treated patients. Finally, we focus on the question of whether single vs multiple FMTs are necessary to achieve favorable outcomes for the treatment of recurrent Clostridium difficile infection, postulating on why there may be an association between number of FMTs and clinical effectiveness.

Multiple Fecal Microbiota Transplantations for Clostridium difficile Infections in Inflammatory Bowel Disease Patients

Introduction: Patients with inflammatory bowel disease (IBD), Crohn's and ulcerative colitis (UC), are at increased risk for Clostridium Difficile infection (CDI). Fecal microbiota transplantation (FMT) has been established as a safe and effective intervention for recurrent CDI with cure rates of greater than 90%. However, recent studies have demonstrated that FMT has less efficacy in patients with underlying IBD and variably impacts overall IBD activity. Here, we examine the characteristics and outcomes of IBD patients who have received multiple FMTs for recurrent or refractory CDI. Methods: This is a retrospective study following patients with established IBD diagnoses who underwent at least one FMT between 2014 and 2016 for recurrent or refractory CDI at one national high-volume academic center. Qualitative analysis was performed on the 12 patients who received multiple FMTs, focusing on patient characteristics and changes in clinical IBD severity of these patients for up to one year post-FMT. Results: 12 patients (50% female) with an average age of 38.5 years were included in the analysis. This study included 8 UC patients with a baseline Mayo score of 2 (62.5% with mild clinical severity) and 4 Crohn's patients with a baseline SES score of 10.5 (75% with moderate clinical severity). 42% of patients had a history of hospitalization for CDI and 67% of patients were on biologics at the time of their first FMT. On average, patients received 2.58 FMTs with 7 months between their first and second FMT. 25% of the first FMTs occurred in the inpatient setting. CDI recurred after the second FMT in 50% of patients. Overall, IBD clinical severity improved after multiple FMTs for 36% of patients, remained unchanged for 36% and worsened for 27%. One patient received a subtotal colectomy after the second FMT. Changes in clinical severity corresponded with de-escalation of medications in 10% of patients, no change in 60% of patients, and escalation of medications in 30% of patients. Conclusion: The majority of IBD patients who received multiple FMTs in our study had mild-moderate clinical severity and were on biologics at the time of their first FMT. The average time between the first and second FMT was 7 month. 50% CDI recurrence after the second FMT with variable changes in IBD severity after multiple FMTs. This suggests late CDI recurrences may be more common in IBD patients and that CDI may drive IBD activity disproportionately in different patients.Figure: Characteristics of IBD patients with multiple FMTs.Figure: Change in IBD clinical severity for patients who received multiple FMTs.

Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Introduction: Fecal microbiota transplantation (FMT) is a safe and effective therapy for recurrent Clostridium difficile infection (CDI) and is being studied as a treatment for inflammatory bowel disease (IBD). CDI is associated with poor outcomes in patients with IBD including increased risk of surgery and mortality. Data on FMT for CDI in patients with underlying IBD are limited. We performed a systematic review and meta-analysis to describe the efficacy and safety of FMT for CDI in IBD patients and its impact on IBD outcomes. Methods: A systematic search of MEDLINE, Embase and Web of Science was performed up to March 2017, followed by manual search of identified studies. We included case series, case-control or cohort studies, and clinical trials of FMT for CDI in IBD patients with clinical resolution of CDI as the primary outcome. Our primary analysis focused on calculating the pooled cure rate after one or more FMT. Additional analyses included IBD outcomes (flare and surgery) after FMT and improvement in IBD symptoms. Results: A total of 12 studies were included: 9 studies with 307 patients reported resolution rates for CDI after 1 FMT and 3 studies with 41 patients reported rates for >1 FMT. The overall pooled resolution rate for CDI in IBD patients was 89% (95% CI, 84.8%-93.3%) with no significant heterogeneity (I2=41%). The pooled resolution rate after one FMT was 84.6% (95% CI, 77.9%-91.3%; I2= 67%) and pooled resolution rate after >1 FMT was (87.6%; 95% CI, 77.1%-94%; I2=0%). Ten studies reported IBD outcomes after FMT; the pooled rate of IBD worsening and IBD therapy escalation after FMT was 16.6% (95 % CI, 8.3%-24.9%) and the pooled rate of surgery for IBD was 3.3% (95% CI, 1.4%-5.2%). Three studies reported a pooled rate of 37.4% (95% CI, 4.3%-70.4%) for improvement of IBD symptoms after FMT. No serious adverse events attributed to FMT were reported. Conclusion: FMT appears to be a highly effective therapy for CDI in patients with IBD; with single or multiple FMTs. Although safe, some patients experienced worsening of IBD after FMT, with very few patients requiring surgery for underlying IBD. In addition, in some patients, IBD symptoms appear to improve after FMT.

The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema

Clostridium difficile infection (CDI) is one of the most frequent causes of healthcare-associated infections, and its rates are also increasing in the community. The management of CDI has become a major challenge, given growing rates of recurrences and failures with standard antibiotic therapy. Mounting evidence suggests that fecal microbiota transplantation (FMT) may be effective; however, as there is a paucity of data with regard to repeat FMT for primary non-response to this treatment, this study examined the outcome of multiple FMTs for recurrent CDI. Case records were reviewed for 94 patients who underwent FMT via retention enema for recurrent or refractory CDI during the period 2008-2012. Demographic information, treatment data, and clinical resolution rates were examined for single FMT and cumulative resolution was assessed for multiple FMTs in the context of ongoing symptoms. The cumulative clinical resolution following four or more FMTs was 86%. When antibiotic therapy was used between FMTs, the clinical resolution rate increased to 92%. There were no reported adverse events and no patients who were cured with FMT had further episodes of CDI at 6-24 months follow-up. Multiple FMTs administered through enemas is an effective, safe, and simple therapy for the management of recurrent or refractory CDI.