By Ellen Jo Baron, Ph.D., D(ABMM), Professor Emerita, Stanford University School of Medicine, Director of Medical Affairs, Cepheid, Sunnyvale, CA, Associate Editor of Infectious Disease Alert.
Dr. Baron is a stockholder for Cepheid, and Immunogenetics, is Director of Medical Affairs for Cepheid, and is on the Scientific Advisory Board for OpGen, Immunogenetics, and NanoMR. She is co-founder of the Diagnostic Microbiology development Program (www.dmdp.org), a non-profit organization that does laboratory capacity building in the developing world.
Source: van Nood, E., et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407-15.
The distress felt by patients with recurring bouts of Clostridium difficile diarrhea is so acute that they welcome the opportunity to accept another’s feces to bring them back to baseline. There have been more than 30 publications on the topic since it was first introduced in 19581, most of them in the last 10 years. The recent resurgence of severe C. difficile infection (CDI), precipitated in part by the rapid expansion of the highly virulent NAP1/027/BI strain2, has left physicians grasping for effective therapies. Metronidazole, vancomycin, and the newest FDA-cleared option, fidaxomycin, all work, but a significant subset of patients fail to achieve a sustainable cure.3 These are the candidates for the fecal transplant.
The form of this unique therapeutic approach ranges from pooled donor feces (residents and fellows?) to individual donor feces, usually from a family member, reluctantly screened for viruses and other pathogens by the local microbiology diagnostic laboratory with no standard protocol for guidance. There are hints that the FDA may assume regulatory responsibility for this therapeutic, moving it from “food” to “drug” status. In the current situation of multiple disparate donors for feces for transplantation, regulation could prove very difficult. When the majority of patients received their donations via enema, it would have been more difficult to classify the material as food, but nowadays most infusions are via the nasogastric route, which patients seem to tolerate better.4
Excitement has been generated anew by the recently published research of van Nood, E., et al. This Dutch group studied three series of patients randomized to receive vancomycin (500 mg orally, 4x/day for 14 days), vancomycin (same dose) followed by bowel lavage, or the same dosage of vancomycin for 4 days followed by bowel lavage and fecal transplant via a nasoduodenal infusion. All patients were followed for relapse over 10 weeks. The study was stopped after the results of the first 41 patients were assessed. One single donor fecal infusion cured 13 of 16 patients, and a second fecal transplant from a different donor cured 2 of the remaining 3 patients (94%). The 12 vancomycin-only patients had a 31% cure rate and the 13 patients in the vancomycin plus bowel lavage arm had a 23% cure rate. Adverse events were similar for each group.
One aspect of these studies, increasingly utilized by the most progressive groups, is analysis of the diversity and composition of the bacterial content of the patients’ feces before and after treatments, using highly complex molecular methods. In this case, the authors used a human intestinal tract chip-based microarray method to assess the fecal microbiota. Previous studies have shown that patients with CDI display a much reduced diversity of fecal organisms, related primarily to a reduction in the Bacteroidetes group of anaerobes.5 Not surprisingly, patients’ feces after therapy appeared more diverse, reverting toward normal.
Another group is working with a synthetic form of feces comprised of the major microbiota grown independently in the laboratory. Known by the more aesthetically acceptable name, Microbial Ecosystems Therapeutics (MET), the synthetic fecal product may have a better chance of long-term success if the FDA truly does decide to regulate this practice. This Canadian group isolated 62 species from normal stool from one healthy donor and checked the isolates for antibiotic resistance. They ultimately chose 33 susceptible strains for their synthetic fecal mixture, most of them with beautiful and unfamiliar names ranging from Dorea longicatena to Roseburia faecalis.6 (Unfamiliar, that is at least to me, proving that past expertise in anaerobic bacteria does not last very long in this age of molecular microbial characterization.) Two initial patients were treated with the mixture and results mirrored those of normal feces based on extensive deep sequencing and sophisticated statistical tools.7 They call the process “rePOOPulating the gut.”
The Fecal Microbiota Transplantation (FMT) Working Group reported their findings in 2011.8 They coined the term fecal microbiota transplant (FMT) for their definition of the therapeutic agent, which they suggested was less repugnant than “feces.” The extensive publication defines the range of pathogens to search for in the donors and the donors’ feces, including various parasites, viruses, stool pathogens (especially C. difficile itself), and other diseases (syphilis, HIV, and hepatitis, for example); and goes into detail on the various administration methods. The FMT Working Group paper can serve as a source for clinical laboratories being asked to prepare donor feces for transfer in the absence of any other standardized protocol. The same group, working in northern Minnesota, summarized results from 74 patients treated over the last 9 years. Initial therapy resulted in resolution of diarrhea for 79% of patients and 9 of the 16 relapsed patients were cured with a course of vancomycin.9 Once you have a mixture tested, preferably one from a mix of non-related donors, it is possible to freeze it for future patients. Hamilton and colleagues presented such an approach, testing it on 43 patients, some of whom had inflammatory bowel disease and not CDI.10 The IBD patients also seemed to respond favorably to the “poopsickle” approach. In short, the time for coprophagy in the human species seems to have arrived.11
References
- Eiseman, B., et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958; 44:854-9.1.
- O’Connor, J. R., et al. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology. 2009;136:1913-24.
- Louie, T. J., et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31.
- Postigo, R., et al. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis. Infection 2012;40:643-8.
- Chang, J. Y.,et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008;197:435-8.
- Petrof E.O., et al Stool substitute transplant therapy for the eradication of Clostridium difficile infection: “rePOOPulating” the gut. Microbiome 2013;1:3 doi:10.1186/2049-2618-1-3
- Petrof, E. O., et al. Microbial ecosystems therapeutics: A new paradigm in medicine? Benef Microbes 2012;4:53-65.
- Bakken, J. S., et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;1044-9.
- Rubin, T. A., et al. Fecal microbiome transplantation for recurrent Clostridium difficile infection: Report on a case series. Anaerobe 2012;19:22-6.
- Hamilton, M. J.,et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:761-7.
- Allen-Vercoe, E., et al. A Canadian Working Group report on fecal microbial therapy: microbial ecosystems therapeutics. Can J Gastroenterol 2012;26:457-62.
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