In 2011, Ms. Kaitlin Hunter had been in a severe car accident, in which she suffered a fractured lower spine, lacerated liver and colon, and broke all her toes. After being discharged, she suffered from abdominal pain leading to her rehospitalization where she was diagnosed with Clostridium difficile infection (CDI). This bacterium can cause watery diarrhea up to 15 times a day, as well as other unpleasant symptoms. The Centers for Disease Control and Prevention estimates that, annually within the U.S., approximately 14,000 individuals die due to CDI. Furthermore, within the past couple of decades; CDI has reached epidemic proportions with a recurrence rate between 30-65%, along with associated frequent treatment failures of multiple courses of antibiotics. Her story was very similar to this trend as she received nine regimens of antibiotics, but there appears to be hope with regard to a very intriguing approach to CDI treatment known as fecal microbiota transplant (FMT).
Dr. Lawrence Brandt is a pioneer with regard to FMT for the treatment of CDI. He performed his first transplant in 1999, but points out that this procedure had been around long before that, indicating that the first transplant occurred in 1958 in humans and had been performed in animals for more than a century. He feels that FMT is gaining popularity because antibiotics disturb intestinal microflora, and when altered, dysbiosis (i.e. when natural flora of the gut are thrown out of balance) results and the organisms in the intestinal tract can no longer prevent CDI. In general, FMT is performed through a colonoscopy; thus, the risks of transplantation are fairly equivalent. Furthermore, Dr. Brandt states, “By reintroducing a healthy diversity of bacteria, fecal transplantation can re-establish colonization resistance to prevent CDI from gaining a foothold and becoming a dominant organism in the environment of the gut.”
Now that the biologic mechanism has been briefly explained, what about the empirical evidence? Currently, there are no controlled trials supporting FMT; however, there are over 27 published case series, one multi-center follow-up study and one single site follow-up study. Not surprisingly, the multi-center study was led by Dr. Brandt.
All participants for this study had recurrent CDI and were treated with FMT. Participants completed questionnaires through postal mail or telephone and were asked about primary cure and secondary cure rates (actually proportions, not rates). Primary cure rates were based on resolution of symptoms within 90 days following FMT and secondary cure rates were based on resolution of symptoms after one additional regimen of antibiotics with or without repeat FMT. The results displayed that the primary and secondary cure rates were 91% (70/77) and 98% (76/77), respectively. There doesn’t appear to be significantly associated adverse events to this procedure; however, 4 of the 77 study patients developed immune diseases consisting of: idiopathic thrombocytopenic purpura, peripheral neuropathy, rheumatoid arthritis (RA) or Sjögren syndrome. Nevertheless, skepticism remains based on the procedure being attributable to the development of these factors, as all subjects in the study were already in poor health status.
The single site follow-up study also analyzed patients with recurrent CDI (N = 26) and found that FMT was 92% effective at preventing further symptoms or CDI recurrence.
In closing, Dr. Brandt is trying to secure approval (and funding of course) of a controlled study involving the treatment of CDI by FMT. This would be paramount in order to prove its effectiveness, as well as potentially gain FDA approval. Dr. Brandt also hypothesizes that it is likely that only a few organisms and their metabolic products found in stools may be necessary to treat CDI and in the future, rather than performing FMT, if these factors can be isolated, patients may simply be exposed to just those. Lastly, to end on a positive note, as the title of the original article suggests, after a long battle with CDI, Ms. Hunter was cured with this increasingly popular, yet still esoteric procedure.
References
Brandt LJ. Gastroenterol Hepatol (N Y). Fecal Transplantation for the Treatment of Clostridium difficile Infection. 2012 March; 8(3): 191–194.
Brandt LJ, Aroniadis, OC, Mellow M, Kanatzar A, Kelly C, Park T, et al. Am J Gastroenterol. 2012 Jul;107(7):1079-87. doi: 10.1038/ajg.2012.60.
Centers for Disease Control and Prevention. Healthcare-associated Infections (HAIs): Clostridium difficile Infection. 6, Mar. 2012. Accessed on September 27, 2012. Available at http://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html
Hudson, W. “Little-known fecal transplant cures woman's bacterial infection.” cnn.com. CNN, 26, Sept. 2012. Accessed on September 26, 2012. Available at: http://www.cnn.com/2012/ 09/ 26/health/fecal-transplant/index.html?hpt=hp_c2.
Kelly CR, de Leon L and Jasutkar N. Fecal Microbiota Transplantation for Relapsing
Clostridium difficile Infection in 26 Patients: Methodology and Results. J Clin Gastroenterol. 2012 Feb;46(2):145-9.
Mayo Clinic. C. difficile. 3, Nov. 2010. Accessed on September 26, 2012. Available at: http://www.mayoclinic.com/health/c-difficile/DS00736.
WebMD. Digestive Disorders Health Center: C. diff. N.d. Accessed on September 26, 2012. Available at: http://www.webmd.com/digestive-disorders/clostridium-difficile-colitis.
Pictures:
http://www.usatoday.com/news/health/2010-03-20-c-diff-bacteria_N.htm
http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and reports/?pageaction=displayproduct&productid=891
http://www.sodahead.com/living/have-you-hear-of-the-cdiff-bactera-it-has-killed-30000-americans/question-3109465/?link=ibaf&q=&imgurl=http://my.telegraph.co.uk/wpcontent/blogs.dir/1/user/paultoner/20071012020742.jpg
I had seen the story on CNN's website earlier in the week and what really shocked me was how many people die every year from CDI. 14,000 is a lot for a bacteria few have heard of.
ReplyDeleteThis is really cool! It must be an interesting idea to sell to the patients. Though I'm sure once people reach a certain level of discomfort/misery they are open to any option. Are you aware of infectious agents that have been transferred through a fecal transplant or what is done to prevent this? Also, does the route of delivery (enema, colonscope, or nasogastric tubing) impact effectiveness or risk of transferring infectious agents?
ReplyDeleteEmily,
ReplyDeleteI agree! I also think it would be an easier sell after several rounds of antibiotics. Transfer of infectious agents is reduced by several donor exclusion criteria:
"In selecting a donor for fecal transplantation, clinicians need to ensure that the stool does not contain any infectious agents that could be transmitted to the patient. Thus, potential donors are excluded if they have known HIV infection, hepatitis B virus infection, or hepatitis C virus infection, or known exposure to these viruses within the previous year. For the same reason, the donation criteria exclude people who participate in high-risk sexual behaviors or use illicit drugs, anyone who has had a tattoo or body piercing within the previous 6 months or has recently been incarcerated, and individuals who have traveled to areas of the world where endemic diarrhea is prevalent.
In terms of gastroenterologic criteria, clinicians should exclude potential donors who have inflammatory bowel disease, irritable bowel syndrome, chronic constipation or chronic diarrhea, or a history of gastrointestinal malignancy or known gastrointestinal polyposis. Also, to address factors that affect the composition of the intestinal microbiota, potential donors are excluded if they have received antibiotics in the preceding 3 months or are currently receiving major immunosup-pressive medications or systemic antineoplastic agents. Finally, criteria also exclude individuals with metabolic syndrome, systemic autoimmunity, atopic diseases, or chronic pain syndrome."
To provide a little evidence for the safety of the procedure, Dr. Brandt has performed several FMTs in immunodeficient patients without problems. Lastly, I don't know the stratified data with regard to route of delivery. However, the usual method is colonoscopy.
This article kept reminding me about the outbreak of E. coli in cattle and that it is related to them not eating what they are meant to eat. Although there is no conclusive evidence to support that claim it just made me think about how you state "within the past couple of decades; CDI has reached epidemic proportions with a recurrence rate between 30-65%" Obviously over the last couple decades the way our food is processed has changed as well. It would be interesting to look at a long-term study that compared "natural or organic" diet versus "processed" diets and see if that does play a role in CDI.
ReplyDeleteTo say what we eat has no effect on the flora of our gut seems foolish to me. So I wonder if Dr. Brandt will be including this in his research.