Microbial composition analysis of Clostridium difficile infections in an ulcerative colitis patient treated with multiple fecal microbiota transplantations

Fecal microbiota transplantation (FMT) is a promising therapy for Clostridium difficile infection (CDI). However, questions remain regarding efficacy and safety in inflammatory bowel disease (IBD) patients, as well as longitudinal stability of donor stool composition. This report describes an IBD patient with two CDIs 18 months apart, each successfully treated with FMT with no IBD flares or complications. Microbiome composition analysis of patient samples during each infection revealed low-diversity microbiota patterns similar to those previously described in non-IBD patients with CDI and active IBD alone. Samples taken after each transplant demonstrated quick remodeling towards the donor's sample composition coinciding with symptom resolution. Of note, samples taken from the same donor 18 months apart reflected marked differences in microbiota abundances, suggesting that the use of single donors in FMT programs offers little benefit in ensuring predictability of donor stool composition over time. This report describes similar microbial composition patterns during CDI in IBD patients to those described previously in non-IBD patients, and supports FMT as safe and effective treatment for recurring CDI in this patient population.     

Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment

Clostridium difficile(C.difficile)is the leading cause of antibiotic associated colitis and nosocomial diarrhea.Patients with inflammatory bowel disease(IBD)are at increased risk of developing C.difficile infection(CDI),have worse outcomes of CDI-including higher rates of colectomy and death,and experience higher rates of recurrence.However,it is still not clear whether C.difficile is a cause of IBD or a consequence of the inflammatory state in the intestinal environment.The burden of CDI has increased dramatically over the past decade,with severe outbreaks described in many countries,which have been attributed to a new and more virulent strain.A parallel rise in the incidence of CDI has been noted in patients with IBD.IBD patients with CDI tend be younger,have less prior antibiotic exposure,and most cases of CDI in these patients represent outpatient acquired infections.The clinical presentation of CDI in these patients can be unique-including diversion colitis,enteritis and pouchitis,and typical findings on colonoscopy are often absent.Due to the high prevalence of CDI in patients hospitalized with an IBD exacerbation,and the prognostic implications of CDI in these patients,it is recommended to test all IBD patients hospitalized with a disease flare for C.difficile.Treatment includes general measures such as supportive care and infection control measures.Antibiotic therapy with either oral metronidazole,vancomycin,or the novel antibiotic-fidaxomicin,should be initiated as soon as possible.Fecal macrobiota transplantation constitutes another optional treatment for severe/recurrent CDI.The aim of this paper is to review recent data on CDI in IBD:role in pathogenesis,diagnostic methods,optional treatments,and outcomes of these patients.     

Recurrent Clostridium difficile infections: The importance of the intestinal microbiota

Clostridium difficile infections (CDI) are a leading cause of antibiotic-associated and nosocomial diarrhea. Despite effective antibiotic treatments, recurrent infections are common. With the recent emergence of hypervirulent isolates of C. difficile, CDI is a growing epidemic with higher rates of recurrence, increasing severity and mortality. Fecal microbiota transplantation (FMT) is an alternative treatment for recurrent CDI. A better understanding of intestinal microbiota and its role in CDI has opened the door to this promising therapeutic approach. FMT is thought to resolve dysbiosis by restoring gut microbiota diversity thereby breaking the cycle of recurrent CDI. Since the first reported use of FMT for recurrent CDI in 1958, systematic reviews of case series and case report have shown its effectiveness with high resolution rates compared to standard antibiotic treatment. This article focuses on current guidelines for CDI treatment, the role of intestinal microbiota in CDI recurrence and current evidence about FMT efficacy, adverse effects and acceptability.     

Fecal microbial transplant for the treatment of pediatric inflammatory bowel disease

The role of fecal microbial transplant(FMT) in the treatment of pediatric gastrointestinal disease has become increasingly popular among pediatric practitioners, patients, and parents. The success of FMT for the treatment of recurrent Clostridium difficile infection(RCDI) has bolstered interest in its potential application to other disease states, such as inflammatory bowel disease(IBD). FMT has particular interest in pediatrics, given the concerns of patients and parents about rates of adverse events with existing therapeutic options, and the greater cumulative medication burden associated with childhoodonset disease. Published literature on the use of FMT in pediatrics is sparse. Only 45 pediatric patients treated for RCDI have been reported, and only 27 pediatric patients with pediatric IBD. The pediatric microbiome may uniquely respond to microbial-based therapies. This review will provide a comprehensive overview of fecal microbial transplant and its potential role in the treatment of pediatric inflammatory bowel disease. We will discuss the microbiome in pediatric inflammatory bowel disease, existing adult and pediatric literature on the use of FMT in IBD treatment, and pediatric FMT trials that are currently recruiting patients. This review will also discuss features of the microbiome that may be associated with host response in fecal transplant, and potential challenges and opportunities for the future of FMT in pediatric IBD treatment.     

Physician attitudes toward the use of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection

BACKGROUND:

Fecal microbiota transplantation (FMT) is a safe and effective, yet infrequently used therapy for recurrent Clostridium difficile infection (CDI).

OBJECTIVE:

To characterize barriers to FMT adoption by surveying physicians about their experiences and attitudes toward the use of FMT.

METHODS:

An electronic survey was distributed to physicians to assess their experience with CDI and attitudes toward FMT.

RESULTS:

A total of 139 surveys were sent and 135 were completed, yielding a response rate of 97%. Twenty-five (20%) physicians had treated a patient with FMT, 10 (8%) offered to treat with FMT, nine (7%) referred a patient to receive FMT, and 83 (65%) had neither offered nor referred a patient for FMT. Physicians who had experience with FMT (performed, offered or referred) were more likely to be male, an infectious diseases specialist, >40 years of age, fellowship trained and practicing in an urban setting. The most common reasons for not offering or referring a patient for FMT were: not having ‘the right clinical situation’ (33%); the belief that patients would find it too unappealing (24%); and institutional or logistical barriers (23%). Only 8% of physicians predicted that the majority of patients would opt for FMT if given the option. Physicians predicted that patients would find all aspects of the FMT process more unappealing than they would as providers.

CONCLUSIONS:

Physicians have limited experience with FMT despite having treated patients with multiple recurrent CDIs. There is a clear discordance between physician beliefs about FMT and patient willingness to accept FMT as a treatment for recurrent CDI.     

Efficacy and safety of,and patient satisfaction with,colonoscopic-administered fecal microbiota transplantation in relapsing and refractory community- and hospital-acquired Clostridium difficile infection

OBJECTIVE:

To report the efficacy and safety of, and patient satisfaction with, colonoscopic fecal microbiota transplantation (FMT) for community- and hospital-acquired Clostridium difficile infection (CDI).

METHODS:

A retrospective medical records review of patients who underwent FMT between July 1, 2012 and August 31, 2013 was conducted. A total of 22 FMTs were performed on 20 patients via colonoscopy. The patients were divided into ‘community-acquired’ and ‘hospital-acquired’ CDI. Telephone surveys were conducted to determine procedure outcome and patient satisfaction. Primary cure rate was defined as resolution of diarrhea without recurrence within three months of FMT, whereas secondary cure rate described patients who experienced resolution of diarrhea and return of normal bowel function after a second course of FMT.

RESULTS:

Nine patients met the criteria for community-acquired CDI whereas 11 were categorized as hospital-acquired CDI. A female predominance in the community-acquired group (88.89% [eight of nine]) was found (P=0.048). The primary cure rate was 100% (nine of nine) and 81.8% (nine of 11 patients) in community- and hospital-acquired CDI groups, respectively (P=0.189). Two patients in the hospital-acquired group had to undergo a repeat FMT for persistent symptomatic infection; the secondary cure rate was 100%. During the six-month follow-up, all patients were extremely satisfied with the procedure and no complications or adverse events were reported.

CONCLUSION:

FMT was a highly successful and very acceptable treatment modality for treating both community- and hospital-acquired CDI.     

Fecal microbiota transplantation and emerging applications

Fecal microbiota transplantation (FMT) has been utilized sporadically for over 50 years. In the past few years, Clostridium difficile infection (CDI) epidemics in the USA and Europe have resulted in the increased use of FMT, given its high efficacy in eradicating CDI and associated symptoms. As more patients request treatment and more clinics incorporate FMT into their treatment repertoire, reports of applications outside of CDI are emerging, paving the way for the use of FMT in several idiopathic conditions. Interest in this therapy has largely been driven by new research into the gut microbiota, which is now beginning to be appreciated as a microbial human organ with important roles in immunity and energy metabolism. This new paradigm raises the possibility that many diseases result, at least partially, from microbiota-related dysfunction. This understanding invites the investigation of FMT for several disorders, including IBD, IBS, the metabolic syndrome, neurodevelopmental disorders, autoimmune diseases and allergic diseases, among others. The field of microbiota-related disorders is currently in its infancy; it certainly is an exciting time in the burgeoning science of FMT and we expect to see new and previously unexpected applications in the near future. Well-designed and well-executed randomized trials are now needed to further define these microbiota-related conditions.     

Impact of Clostridium difficile infection on inflammatory bowel disease outcome: A review

Although a considerable number of studies support a substantial increase in incidence, severity, and healthcare costs for Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD), only few evaluate its impact on IBD outcome. Medline and several other electronic databases from January 1993 to October 2013 were searched in order to identify potentially relevant literature. Most of the studies showed that IBD patients with CDI present a greater proportion of worse outcomes than those without CDI. These patients have longer length of hospital stay, higher rates of colectomies, and increased mortality. Patients with ulcerative colitis are more susceptible to CDI and have more severe outcomes than those with Crohn’s disease. However, studies reported variable results in both short- and long-term outcomes. Contrasting results were also found between studies using nationwide data and those reporting from single-center, or between some North-American and European studies. An important limitation of all studies analyzed was their retrospective design. Due to contrasting data often provided by retrospective studies, further prospective multi-center studies are necessary to evaluate CDI impact on IBD outcome. Until then, a rapid diagnosis and adequate therapy of infection are of paramount importance to improve IBD patients’ outcome. The aim of this article is to provide up to date information regarding CDI impact on outcome in IBD patients.     

Novel Indications for Fecal Microbial Transplantation: Update and Review of the Literature

Background and Aims

Fecal microbial transplantation (FMT) is an established successful treatment modality for recurrent Clostridium difficile infection (CDI). The safety profile and potential therapeutic advantages of FMT for diseases associated with dysbiosis and immune dysfunction have led to many publications, mainly case series, and while many studies and reviews have been published on the use of FMT for inflammatory bowel disease (IBD), its potential use for other disease conditions has not been thoroughly reviewed. The aim of this review was to investigate the evidence surrounding the use of FMT in conditions other than IBD and CDI.

Methods

A PubMed search was performed using the terms “Fecal microbiota transplantation” OR “FMT” OR “Bacteriotherapy.”

Results

A total of 26 articles describing the use of FMT in a variety of both intra-and extraintestinal disease conditions including gastrointestinal, hematologic, neurologic, metabolic, infectious, and autoimmune disorders have been included in this review and have demonstrated some positive results. The studies included were case reports, case series, controlled trials, and cohort studies.

Conclusions

The findings of these studies demonstrate that FMT, particularly in conditions associated with gastrointestinal dysbiosis, shows promise to provide another effective tool in the therapeutic armament of the practicing physician. FMT was found to be possibly effective in various diseases, mostly associated with enteric dysbiosis or with immune dysfunction. Randomized clinical studies on large populations should be performed to explore the effectiveness of this therapy, and basic research studies should be designed to gain understanding of the mechanisms through which impact these disorders.

     

The risk of inflammatory bowel disease flares after fecal microbiota transplantation: Systematic review and meta-analysis

Several studies have suggested worsening in inflammatory bowel disease (IBD) activity following fecal microbiota transplantation (FMT). We aimed to assess the risk of worsening in IBD activity following FMT. An electronic search was conducted using MEDLINE (1946-June 2016), EMBASE (1954-June 2016) and Cochrane Central Register of Controlled Trials (2016). Studies in which FMT was provided to IBD patients for IBD management or (Clostridium difficile infection) CDI treatment were included. The primary outcome was the rate of worsening in IBD activity. Results: Twenty-nine studies with 514 FMT-treated IBD patients were included. Range of follow up was 4 weeks to 3 y. The pooled rate of IBD worsening was 14.9% (95% CI 10–21%). Heterogeneity was detected: I2 D 52.1%, Cochran Q test D 58.1, p D 0.01. A priori subgroup analyses were performed. Although not significant, the pooled rate of worsening in IBD activity following FMT for CDI (22.7% (95% CI: 13–36%)) was higher compared with FMT for IBD (11.1% (95% CI 7–17%)). Rates of worsening in IBD after lower GI FMT delivery revealed a higher rate of worsening in IBD activity (16.5% (95% CI: 11–24%)) compared with upper GI delivery (5.6% (95% CI: 2–16%)). Rates of worsening in high quality studies and randomized controls trials (RCTS) suggested a marginal risk of worsening in IBD activity (4.6%, (95% CI: 1.8–11%). Rates of IBD worsening are overall marginal across high quality RCTS. It is unknown if the FMT itself led to the worsening of IBD in this small fraction or if this represents alternative etiologies.     

Fecal Microbiota Transplantation in Inflammatory Bowel Disease: Beyond the Excitement

The purpose of this article is to perform a systematic review of the literature on the use of fecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD).There is an increasing interest of both physicians and patients in assessing the possible role of the FMT in the treatment of IBD.Electronic and manual bibliographic searches were performed to identify original reports in which subjects with IBD were treated with FMT. Because of the scarcity of studies with adequate sample size, case series and case reports were also considered. A critical appraisal of the clinical research evidence on the effectiveness, safety, and other parameters related to FMT was made. Data extraction was independently performed by 2 reviewers.We found a total of 31 publications on the use of FMT in IBD. The majority were case reports or case series, whereas 8 publications reported data from open-label trials including a very less number of patients. A total of 133 patients with IBD were managed with FMT. Of these, 57 subjects (43%) had a Clostridium difficile infection. A resolution or reduction of symptoms was reported in 80 of 113 (71%) patients with evaluable IBD. Moreover, FMT does not seem to provide the same safety profile showed for non-IBD individuals with C difficile infection.The available evidence is limited and weak. FMT has the potential to be somehow of help in managing patients with IBD, but considerable further efforts are necessary to make this procedure a valid option for these subjects.     

粪菌移植的研究进展

难辨梭状芽孢杆菌感染(CDI)是临床上常见的问题,其发病率、复发率和严重程度逐年升高。CDI治疗手段有限,特别是针对复发性CDI的抗菌药物治疗面临诸多棘手的问题。粪菌移植(FMT)近来重新引起关注,对治疗复发性CDI显示出很好的疗效;此外,FMT在炎症性肠病(IBD)的治疗方面也应用较多。但现阶段FMT的临床应用和普及仍存在诸多问题。     

Helicobacter pylori infection and inflammatory bowel disease: Is there a link?

Helicobacter pylori(H.pylori)infection is one of the most widely spread infectious diseases in humans.It can cause chronic gastritis,peptic ulcer disease and gastric malignancies and has been associated with extra-gastric disorders.H.pylori elicit a chronic systemic inflammatory response which,under certain conditions,may trigger autoimmune reactions and may be implicated in the pathogenesis of autoimmune diseases.Although the pathogenesis of inflammatory bowel disease(IBD)is unknown,it is thought to result from complex interactions between environmental factors and microbiota in the gut of individuals who are genetically susceptible.Several bacterial and viral agents have been implicated in the aetiology of IBD.In theory,H.pylori infection could be involved in the pathogenesis of IBD by inducing alterations in gastric and/or intestinal permeability or by causing immunological derangements resulting in absorption of antigenic material and autoimmunity via various immunological pathways.Similar mechanisms may also be responsible for the co-existence of IBD with other autoimmune diseases and/or extra-intestinal manifestations.However,the epidemiological data fail to support this association.Infact,various studies indicate that the prevalence of H.pylori infection is low in patients with IBD,suggesting a protective role for this infection in the development of IBD.In this report,we aim to shed light on proposed mechanisms and confounding factors underlying the potential link between H.pylori infection and IBD.     

Management of inflammatory bowel disease with Clostridium difficile infection

AIM To address the management of Clostridium difficile(C. difficile) infection(CDI) in the setting of suspected inflammatory bowel disease(IBD)-flare.METHODS A systematic search of the Ovid MEDLINE and EMBASE databases by independent reviewers identified 70 articles including a total of 932141 IBD patients or IBDrelated hospitalizations. RESULTS In those with IBD,CDI is associated with increased morbidity,including subsequent escalation in IBD medical therapy,urgent colectomy and increased hospitalization,as well as excess mortality. Vancomycincontaining regimens are effective first-line therapies for CDI in IBD inpatients. No prospective data exists with regards to the safety or efficacy of initiating or maintaining corticosteroid,immunomodulator,or biologic therapy to treat IBD in the setting of CDI. Corticosteroid use is a risk factor for the development of CDI,while immunomodulators and biologics are not. CONCLUSION Strong recommendations regarding when to initiate IBD specific therapy in those with CDI are precluded by a lack of evidence. However,based on expert opinion and observational data,initiation or resumption of immunosuppressive therapy after 48-72 h of targeted antibiotic treatment for CDI may be considered.     

Therapies to modulate gut microbiota:Past,present and future

The human gut microbiota comprises of a complex and diverse array of microorganisms,and over the years the interaction between human diseases and the gut microbiota has become a subject of growing interest.Disturbed microbial milieu in the gastrointestinal tract is central to the pathogenesis of several diseases including antibiotic-associated diarrhea and Clostridioides difficile infection(CDI).Manipulation of this microbial milieu to restore balance by microbial replacement therapies has proven to be a safe and effective treatment for recurrent CDI.There is considerable heterogeneity in various aspects of stool processing and administration for fecal microbiota transplantation(FMT)across different centers globally,and standardized microbioal replacement therapies offer an attractive alternative.The adverse effects associated with FMT are usually mild.However,there is paucity of data on long term safety of FMT and there is a need for further studies in this regard.With our increasing understanding of the host-microbiome interaction,there is immense potential for microbial replacement therapies to emerge as a treatment option for several diseases.The role of microbioal replacement therapies in diseases other than CDI is being extensively studied in ongoing clinical trials and it may be a potential treatment option for inflammatory bowel disease,irritable bowel syndrome,obesity,multidrug resistant infections,and neuropsychiatric illnesses.Fecal microbiota transplantation for non-CDI disease states should currently be limited only to research settings.     

<Emphasis Type="Italic">Clostridium difficile</Emphasis> Infection in Patients with Inflammatory Bowel Disease

Clostridium difficile infection (CDI) is now the leading cause of nosocomial infection. There has been an upsurge of CDI in patients with inflammatory bowel disease (IBD). IBD patients with CDI have increased morbidity and mortality. The establishment, proliferation, and recurrence of CDI in IBD patients form a complex interplay of microbial, environmental, and host-susceptibility factors. Different risk factors have been found predisposing IBD patients to CDI. Vancomycin performs better than metronidazole in treating IBD patients with CDI. Fecal microbiota transplantation continues to be a very effective therapy. New therapeutic modalities such as vaccinations and bile salts are currently being investigated.     

Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis

Background

Fecal microbiota transplantation (FMT) has been demonstrated to be highly effective for the treatment of recurrent Clostridium difficile infection (CDI). However, the best route of administration has not been established. We present a pooled analysis of the reported cases of CDI treated with FMT via colonoscopy or nasogastric tube (NGT) to evaluate treatment efficacy.

Methods

PubMed was searched for English-written articles published up to December 2011. Studies that reported cases of FMT for recurrent CDI using either colonoscopy or NGT-guided fecal infusion were reviewed.

Results

A total of 182 patients from 12 published studies were identified; 148 patients received FMT via colonoscopy (colonoscopy group) and 34 patients received FMT via NGT (NGT group). The median age in the colonoscopy group as compared with the NGT group was 72 and 82?years, respectively. There were differences regarding pre-FMT treatment for CDI; 134 patients (90.5?%, 134/148) received lavage with/without antibiotic in the colonoscopy group and 34 patients (100.0?%, 34/34) received antibiotic without lavage in the NGT group, P?<?0.001. A higher stool volume was used for FMT in the colonoscopy group (121 patients, 81.8?%, used 100?C400?ml) than in the NGT group (33 patients, 97.0?%, used?<100?ml), P?<?0.001. The treatment efficacy did not differ significantly; 93.2?% (138/148) success for the colonoscopy group as compared to 85.3?% success (29/34) for the NGT group, P?=?0.162. Recurrence of CDI after FMT was also similar in both the colonoscopy group (8/148 5.4?%) versus the NGT group (2/34, 5.9?%), P?=?1.000.

Conclusions

Despite procedural differences, FMT via colonoscopy or NGT appears to be highly effective and safe for the management of recurrent CDI.     

The Impact of Clostridum Difficile on Surgical Rate Among Ulcerative Colitis Patients: A Systemic Review and Meta-analysis

There is growing recognition of the impact of Clostridum difficile infection (CDI) on patients with inflammatory bowel disease. Clostridium difficile infection causes greater morbidity and mortality. This study aimed to evaluate the impact of C. difficile on surgical risk among ulcerative colitis (UC) patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, ACP Journal Club, DARE, CMR, and HTA. Studies were included if fulfilled the following criteria: (1) Cohort or case–control studies, which involved a comparison group that lacked CDI, (2) Patients were given a primary diagnosis of UC, (3) Comorbidity of CDI was evaluated by enzyme immunoassay of stool for C. difficile toxin A and B or C. difficile stool culture, (4) Studies evaluated surgical rate, and (5) Studies reported an estimate of odds ratio, accompanied by a corresponding measure of uncertainty. Five studies with 2380 patients fulfilled the inclusion criteria. Overall, meta-analysis showed that UC with CDI patients had a significant higher surgical rate than patients with UC alone. (OR=1.76, 95% CI=1.36–2.28). C. difficile infection increased the surgical rate in UC patients. However, results should be interpreted with caution, given the limitations of this stud.     

Maintaining standard volumes,efficacy and safety,of fecal microbiota transplantation for C. difficile infection during the COVID-19 pandemic: A prospective cohort study

BackgroundFecal microbiota transplantation (FMT) can be a life-saving treatment against recurrent Clostridioides difficile infection (CDI). It is therefore necessary to maintain this procedure available for these patients during the COVID-19 pandemic while keeping high efficacy and safety standards.AimsTo report outcomes of a FMT service that has adapted its operational workflow during COVID-19 pandemic to continue offering FMT to patients with CDI.MethodsAll patients with CDI referred to our center for FMT during pandemic were prospectively included. Each step of the FMT working protocol was adapted with specific security measures to prevent the transmission of SARS-CoV-2.ResultsOf 26 patients evaluated for FMT, 21 were treated for recurrent or refractory CDI. Eighteen patients completed the 8-week follow-up, and no one recurred after FMT. Follow-up is ongoing in 3 patients, although in all of them diarrhea disappeared after the first procedure. No serious adverse events were reported. Two patients had also COVID-19-related pneumonia, and were cured both from CDI and COVID-19.ConclusionThis is the first report to show that it is possible to maintain standard volumes, efficacy and safety of FMT for recurrent CDI during the COVID-19 pandemic, by adopting specific changes in the operational workflow.