Transplantation of Fecal Microbiota for C. Difficile
Abstract and Introduction
Objectives: While fecal microbiota transplantation (FMT) is historically known to be an effective means to treat recurrent Clostridium difficile infection (CDI) refractory to standard antibiotic therapies, the procedure is rarely performed. At least some of the reasons for limited availability are those of practicality, including aesthetic concerns and costs of donor screening. The objective of this study was to overcome these barriers in our clinical FMT program.
Methods: We report clinical experience with 43 consecutive patients who were treated with FMT for recurrent CDI since inception of this program at the University of Minnesota. During this time, we simplified donor identification and screening by moving from patient-identified individual donors to standard volunteer donors. Material preparation shifted from the endoscopy suite to a standardized process in the laboratory, and ultimately to banking frozen processed fecal material that is ready to use when needed.
Results: Standardization of material preparation significantly simplified the practical aspects of FMT without loss of apparent efficacy in clearing recurrent CDI. Approximately 30% of the patients had underlying inflammatory bowel disease, and FMT was equally effective in this group.
Conclusions: Several key steps in the standardization of donor material preparation significantly simplified the clinical practice of FMT for recurrent CDI in patients failing antibiotic therapy.
In 1978, Clostridium difficile was first recognized as a major cause of diarrhea and pseudomembranous colitis associated with the use of antimicrobial agents. Since this time, infection by C. difficile has been steadily growing in incidence, morbidity, and mortality across North America and Europe. Analysis of the US National Hospital Discharge Survey statistics between 1996 and 2003 revealed a doubling in the prevalence of diagnosis of C. difficile infection (CDI), to 0.61/1,000, among inpatients. A 2008 survey of 12.5% of all US acute care facilities indicated a CDI prevalence rate of 13.1/1,000, which is at least an order of magnitude higher than that found previously. While older patients have disproportionately greater rates of CDI than younger individuals, no age group is spared, and the incidence of CDI-related hospitalizations has been rising even in the pediatric population. The increase in incidence has been further compounded by an elevated frequency of severe disease, as evidenced by rising CDI-associated morbidity and case fatality. This is, in part, related to the emergence of more virulent C. difficile strains, such as PCR ribotype 027/North American Pulsed Field type 1 (NAP1), which is characterized by a greater potential for toxin production and antibiotic resistance than other clinically relevant rains.
Recurrent CDI is one of the most difficult and increasingly common challenges associated with CDI. An initial incidence of CDI is followed by a relapse within 30 days in about 20–30% of cases, and the risk of recurrence doubles after two or more occurrences. Older age, intercurrent antibiotic use for non-C. difficile indications, renal insufficiency, immune deficiency, and antacid medications are some of the known risk factors for recurrence. The presence of just three clinical criteria: age >65 years, severe disease, and continued use of antibiotics after treating the initial CDI episode, are predictive of an almost 90% relapse rate. CDI also commonly complicates management of inflammatory bowel disease (IBD), which has recently been recognized as an additional independent risk factor for CDI infection. CDI in patients with underlying IBD is associated with increased severity of colitis and higher rates of recurrence and colectomy.
It is now recognized that the presence of normal, healthy, intestinal microbiota offers protection against CDI. Conversely, severe disruption of normal intestinal microbiota by repeated cycles of antibiotics, including metronidazole and vancomycin that are used to treat CDI, is likely one of the major reason for its recurrence. Chang et al. used 16S rDNA sequencing to analyze the fecal microbiota of seven patients with initial and recurrent CDI. They reported that bacterial species diversity was reduced in all patients compared with normal control subjects. The greatest reduction in species diversity, however, was found in the three patients with recurrent CDI and disruption of their gut microbiota was evident at the phylum level with marked reduction in Bacteriodetes, normally one of the two dominant phyla in the colon. Instead, the gut microbiota in these patients were dominated by members of the Proteobacteria and Verrucomicrobia phyla, which normally are only minor constituents of the colon microbiota.
The general aim of antibiotic treatment of recurrent CDI is to preserve the residual colon microbiota and optimize their restoration. Various antibiotic regimens, including long tapered or pulsed dosing with vancomycin and rifaximin "chaser" protocols have been used to achieve this objective with partial success. Recently, a new macrocyclic antibiotic fidaxomicin, which is narrow in spectrum and spares Bacteroides species, was shown to reduce the initial relapse rate of CDI by 50% compared with vancomycin treatment. However, treatment with fidaxomicin did not alter the recurrence rate of CDI caused by the more virulent PCR 027/NAP1 strain. Therefore, despite these advances, it seems likely that the challenges in the treatment of recurrent CDI will remain for the foreseeable future.
Fecal microbiota transplantation (FMT), also commonly known as "fecal bacteriotherapy," represents the one therapeutic protocol that allows the fastest reconstitution of a normal composition of colon microbial communities. In a recent case report, we showed that FMT resulted in prompt and sustained engraftment of donor fecal bacteria in a patient with recurrent CDI. The patient did not have a clinical response to vancomycin and achieved only partial control of her symptoms with nitazoxanide. In contrast, FMT, administered by infusion during a colonoscopy, resulted in completely normalized bowel functioning within 2 days of treatment.
For many decades, FMT has been offered by select centers across the world, typically as an option of last resort for patients with recurrent CDI. The mostly commonly earliest cited report for FMT was by Eiseman et al. who in 1958 described the use of fecal enemas for patients who likely had severe or fulminant forms of pseudomembranous colitis. Since this time, well over 200 cases have been reported as individual case reports, or small case series, with an ~90% cumulative success rate in clearing recurrent CDI, without any noted adverse events. The history and general methodology used for FMT have been described in several recent reviews. However, despite the long and successful track record, as well as great clinical need, the availability of the procedure for many patients remains very limited.
The lack of wider practice of FMT is due to multiple non-trivial practical barriers and not due to lack of efficacy. These include lack of reimbursement for donor screening, difficulty in material preparation and administration, as well as aesthetic concerns about doing the procedure in endoscopy or medical office. Moreover, the pharmaceutical industry has shown little interest in technological development of FMT-based therapeutics, in large part due to the wide availability of donor material and its complex composition. Instead, development has been driven mostly by individual clinicians faced with desperate need in their patients.
In 2009, we established the FMT program at the University of Minnesota, and the program has evolved since to overcome or minimize some of the associated challenges. This evolution has resulted in movement from the use of patient-identified individual donors to rigorously screened "universal" volunteer donors, and from the use of fresh donor fecal materials that was crudely prepared in the endoscopy suite to a more standardized laboratory protocol done using frozen fecal extracts. The results of this one center's experience are presented here.