Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection

Clostridium difficile infection (CDI) is a gastrointestinal disease believed to be causally related to perturbations to the intestinal microbiota. When standard treatment has failed, intestinal microbiota transplantation (IMT) is an alternative therapy for patients with CDI. IMT involves infusing intestinal microorganisms (in a suspension of healthy donor stool) into the intestine of a sick patient to restore the microbiota. However, protocols and reported efficacy for IMT vary. We conducted a systematic literature review of IMT treatment for recurrent CDI and pseudomembranous colitis. In 317 patients treated across 27 case series and reports, IMT was highly effective, showing disease resolution in 92% of cases. Effectiveness varied by route of instillation, relationship to stool donor, volume of IMT given, and treatment before infusion. Death and adverse events were uncommon. These findings can guide physicians interested in implementing the procedure until better designed studies are conducted to confirm best practices.     

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.     

Gastrointestinal dysbiosis and the use of fecal microbial transplantation in Clostridium difficile infection

The impact of antibiotics on the human gut microbiota is a significant concern. Antibiotic-associated diarrhea has been on the rise for the past few decades with the increasing usage of antibiotics. Clostridium difficile infections (CDI) have become one of the most prominent types of infectious diarrheal disease, with dramatically increased incidence in both the hospital and community setting worldwide. Studies show that variability in the innate host response may in part impact upon CDI severity in patients. That being said, CDI is a disease that shows the most prominent links to alterations to the gut microbiota, in both cause and treatment. With recurrence rates still relatively high, it is important to explore alternative therapies to CDI. Fecal microbiota transplantation (FMT) and other types of bacteriotherapy have become exciting avenues of treatment for CDI. Recent clinical trials have generated excitement for the use of FMT as a therapeutic option for CDI; however, the exact components of the human gut microbiota needed for protection against CDI have remained elusive. Additional investigations on the effects of antibiotics on the human gut microbiota and subsequent CDI will help reduce the socioeconomic burden of CDI and potentially lead to new therapeutic modalities.     

Complicated fecal microbiota transplantation in a tetraplegic patient with severe Clostridium difficile infection

A 65-year-old male suffering from acute spinal cord injury leading to incomplete tetraplegia presented with severe recurrent Clostridium difficile(C. difficile) infection subsequent to antibiotic treatment for pneumonia. After a history of ineffective antimicrobial therapies, including metronidazole, vancomycin, fidaxomicin, rifaximin and tigecycline, leading to several relapses, the patient underwent colonoscopic fecal microbiota transplantation from his healthy son. Four days subsequent to the procedure, the patient showed a systemic inflammation response syndrome. Without detecting an infectious cause, the patient received antimicrobial treatment, including tigecycline, metronidazole, vancomycin via polyethylene glycol and an additional enema for a period of seven days, leading to a prompt recovery and no reported C. difficile infection relapse during a 12 wk follow up.     

Clostridium difficile infection: a review of the literature

Clostridium difficile is a Gram-positive, strictly anaerobic, spore-forming bacterium. It is the most common cause of antibiotic-associated diarrhea in hospitals and other healthcare facilities and is of significant concern because of the increasing morbidity and mortality rates as well as increased health care costs. Spectrum of presentation of Clostridium difficile infection ranges from mild, self-limiting diarrhea, to serious diarrhea, pseudomembranous colitis and life-threatening fulminant colitis, which may result in death. Prompt identification of patients with symptomatic Clostridium difficile infection is essential as the majority of patients respond quickly to antimicrobial therapy. Prevention is best accomplished by implementation of infection-control measures and by judicious use of antimicrobial agents.     

Treatment of recurrent Clostridium difficile infection: a systematic review

Background

Clostridium difficile infection (CDI) recurs in nearly one-third of patients who develop an initial infection. Recurrent CDI (RCDI) is associated with considerable morbidity, mortality, and cost. Treatment for RCDI has not been not well examined.

Methods

A systematic review.

Results

Sixty-four articles were identified evaluating eight different treatment approaches: metronidazole, vancomycin, fidaxomicin, nitazoxanide, rifampin, immunoglobulins, probiotics, and fecal bacteriotherapy. The meta-analysis found vancomycin to have a similar efficacy to metronidazole, although studies used varying doses and durations of therapy. Fidaxomicin was slightly more efficacious than vancomycin, though the number of studies was small. Good evidence for probiotics was limited. Fecal bacteriotherapy was found to be highly efficacious in a single randomized trial.

Conclusion

Metronidazole and vancomycin have good evidence for use in RCDI but heterogeneity in treatment duration and dose precludes robust conclusions. Fidaxomicin may have a role in treatment, but evidence is limited to subgroup analyses. Fecal bacteriotherapy was the most efficacious. Saccharomyces boulardii may have a role as adjunctive treatment.     

Fecal microbiota transplantation for management of Clostridium difficile infection

The widespread use of antibiotics has led Clostridium difficile infection (CDI) to become a common problem with pronounced medical and economic effects. The recurrence of CDI after treatment with standard antibiotics is becoming more common with the emergence of more resistant strains of C. difficile. As CDI is an antibiotic-associated disease, further treatment with antibiotic is best avoided. As the gut flora is severely disturbed in CDI, approaches that restore the gut microbiota may become good alternative modes of CDI therapies. Fecal microbiota transplantation (FMT) is the procedure of transplantation of fecal bacteria from a healthy donor individual into a patient for restoration of the normal colonic flora. Thus, FMT helps in the eradication of C. difficile and resolution of clinical symptoms such as diarrhea, cramping, and urgency. Though this approach to treatment is not new, presently, it has become an alternative and promising way of combating infections. The procedure is not in regular use because of the time required to identify a suitable donor, the risk of introducing opportunistic pathogens, and a general patient aversion to the transplant. However, FMT is gaining popularity because of its success rate as a panacea for recurrent attacks of CDI and is being increasingly used in clinical practice. This review describes the rationale, the indications, the results, the techniques, the potential donors, the benefits as well as the complications of fecal microbiota instillation to CDI patients in order to restore the normal gut flora.     

Relapse versus reinfection: surveillance of Clostridium difficile infection

Molecular typing was used to examine surveillance definitions for recurrent Clostridium difficile-associated diarrhea. Among 102 patients, 85 had a second episode within 8 weeks, 88% of which were relapses. Of 49 second episodes occurring after > 8 weeks, 65% were relapses. Categorization of a recurrent episode occurring after >8 weeks as a new infection may misrepresent the majority of episodes for surveillance.     

Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review

Abstract

Objective. Clostridium difficle-associated infection (CDI) is usually treated with antibiotics; nevertheless, the infection has a high relapse rate. Case series and case reports using fecal microbiota transplant (FMT) for CDI show promising results. However, there are no large studies to provide evidence for the efficacy of this therapy. The aim of this pooled patient data meta-analysis was to determine the efficacy of FMT in CDI. Methods. We performed a literature search for FMT for CDI or pseudomembranous colitis. Individual patient data were obtained from each study. The primary endpoint was to assess the rate of diarrhea resolution. Secondary endpoints were to identify variables associated with treatment failure and side effects of therapy. Results. A total of 289 patients from 25 published articles who received FMT for CDI were included in the pooled data analysis. FMT had an overall success rate of 91.2%. On univariate analysis, shorter duration of symptoms before FMT (< 60 days) and gastroduodenal route of fecal instillation were associated with treatment failure. On multivariate regression analysis, shorter duration of symptoms (< 60 days) before the FMT (OR= 11.08; p = 0.0009) was associated with treatment failure. Reported adverse events following FMT were irritable bowel syndrome (n = 1), symptoms of mild enteritis (n = 3), and suspected peritonitis following the procedure (n = 1). Conclusion. FMT is a safe and effective treatment option for CDI. Shorter duration of symptoms (< 60 days) before administering FMT is associated with treatment failure.     

Relapse versus reinfection: recurrent Clostridium difficile infection following treatment with fidaxomicin or vancomycin

Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (± 2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0-14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15-31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (± 6.4) days for relapses and 14.7 (± 6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates.