Fecal Transplantation for C difficile: An Evolving "Art"
A Need for New Treatments for Clostridium difficile Colitis
Hello. I am Dr. David Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. I wanted to chat with you briefly about 2 articles that just came out, one in Alimentary Pharmacology and Therapeutics[1] and the other in The American Journal of Gastroenterology,[2] about fecal transplantation and its role in the treatment of Clostridium difficile colitis. Who would have thought that we would be doing this as gastroenterologists, much less as endoscopists? The data are emerging and we need to be pragmatic and say, "This is something that is very real, very effective, and simple to do." Let me review the data.
First, what is the rationale that we need treatment beyond our current treatments? I don't know what you see in your practice, but I see that relapsing C difficile is an increasing problem. It is a problem that results in hospitalization and one that has very limited access to therapy beyond a tapering course of vancomycin or the use of rifaximin. These drugs, particularly vancomycin, can breed resistant organisms. We see vancomycin-resistant Enterococcus emerging as a common pathogen in the hospital, and we are really strapped as to what we can do for these patients. After the first episode of C difficile colitis, the relapse rate is more than 15%; after a second episode, 40%; and after a third episode, in excess of 65%. So, you can see the spiraling course, and I certainly have seen patients who have gone to surgery for fulminant C difficile colitis that is refractory to current therapies. We have an imminent need for better therapies.
An (Unusual) Idea Is Born
The idea of fecal transplantation dates back to a veterinary school of thought in the 17th century, when they were doing what was called "transfaunation." They were transplanting bacteria into the colon of animals to attempt to reset the biologic composition to bacteria that may be commensal.
The idea of fecal transplantation in humans was initially considered in the late 1950s, and it was delivered primarily by fecal enemas. Subsequently, it was delivered orally through an orogastric tube or through endoscopy. The practice didn't gain much traction because, obviously, it doesn't have much aesthetic appeal. Fecal transplantation started to gain traction with case reports, and the most recent data are becoming more striking that the procedure has very strong efficacy.
Why do we need new treatments? The epidemiology of C difficile has been explosive. The incidence of C difficile infection has more than doubled over the past decade. The consequent mortality has increased from 1.3% to 2.4% -- all unadjusted, all-cause mortality, but nonetheless associated with this diagnosis. The estimates for hospitalization cost last year were estimated at $3.2 billion. We are certainly seeing this in our practices.
What can we do with these patients? A tapering course of vancomycin is a course of action. I have occasionally used rifaximin. The idea of reintroducing other bacterial flora that may reset the bacterial resistance of the normal colonic flora makes intrinsic sense.
Emerging Data: Effectiveness of Fecal Transplant
The data reported in The American Journal of Gastroenterology by Brandt and colleagues[1] were from a composite follow-up of a staged evaluation by the American Gastroenterological Association (AGA) fecal microbiota transplant group. This was published last year in Clinical Gastroenterology and Hepatology.[3] If you are going to provide this treatment, this is a key resource. That group decided that data were emerging to show that fecal microbiota transplant should be considered as a treatment option for selected candidates. If a patient had 3 episodes of C difficile relapse, that would be one indication for fecal microbiota transplant. Two severe episodes that result in hospitalization or organ compromise is another indication. Disease that is refractory to vancomycin after a week of therapy is another indication, as is fulminant disease unresponsive to conventional therapy after 48 hours. Each of these categories plays a role. The type of patient that I see is the relapsing, hospitalized patient. In the multiple-relapse patient who requires repeated does of vancomycin, vancomycin-resistant organisms can be a problem down the road.
Everything You Need to Know (But Are Afraid to Ask)
How is it done? First you have to find a donor. Brandt and colleagues reported that 75% of donors are first-degree relatives or spouses, and the donor is screened as vigorously as you would screen a blood donor. The questionnaire for blood donors is routinely used, and this is available in the article in Clinical Gastroenterology and Hepatology.[3] Serologic screening for transmissible diseases (hepatitis, HIV, etc) is the same as for blood donors. It is important to do stool studies to make sure that the donor is not infected with C difficile and that they don't have other enteric pathogens to transmit.
The stool then is procured from the donor and delivered within 6-24 hours. I give the donor a purgative before they deliver the stool. The stool should be gently refrigerated, not frozen or kept in the heat. The stool should be delivered as fresh as possible. I have the donor deliver it the morning of the procedure. The stool is then put into a blender. I tell my patients that this is a "BYOB" (bring your own blender) situation because we are not in the business of cleaning the blenders used for this procedure. The blender is used to homogenize the stool with nonbacteriostatic saline. Make sure that you use a preservative-free nonbacteriostatic saline. The fecal matter and saline are blended, under a hood if possible. Fecal matter is a level 2 biologic agent, so anyone in the room should wear masks, gloves, goggles, and protective clothing. The stool is homogenized and strained through a gauze pad. The target is an effluent volume of 250-700 cc. By straining it, you allow the stool to be delivered through the biopsy channel of the colonoscope without occluding the colonoscope. You don't want to have much particulate matter. Brandt used the term "malted milk" to describe the consistency; however, this may take your appetite away the next time you go for a milkshake at the local sundae place. The blended stool can be delivered fairly easily with a 50-60 cc syringe down the biopsy channel.
Fecal microbiota transplant is delivered during a colonoscopy. Before the procedure, we ensure a vigorous purge of the patient. The recommendation from the consensus group is to vigorously purge the bowel, to make sure that the bowel is biologically clean of normal flora as much as possible. I use a very aggressive prep for these patients, and sometimes I use an additional dose of the prep solution to make sure that the patient is clear.
The delivery is targeted towards the terminal ileum and the right colon. Brandt and colleagues initially delivered transplants to the right colon and terminal ileum only, and then to the left colon. Eventually, they switched and used the right colon and terminal ileum, and I think that makes sense. There are no prospective, randomized trials for this, but the emphasis should certainly be on delivering a high volume in the right colon and terminal ileum. Whether to use antimotility agents after this procedure remains to be seen. This is optional; the AGA microbiota consensus was to use antimotility agents with discretion. It makes sense to delay bowel transit, because you put a significant volume into these patients. Patients should be instructed about positioning (eg, lying on their right or left side) and when they can return to normal activity. I tell my patients to lie with their right side down, take a double dose of loperamide, and retain the fecal transplant as long as they can.
Impressive Cure Rates
The data to date from the consensus recommendation suggest that fecal microbiota transplant is beneficial.[1] Brandt and colleagues found a 91% primary cure rate and a 98% secondary cure rate (a second course of therapy or antibiotics).The patients who recurred did so on antibiotics. In 72% of these patients, however, antibiotics did not result in recurrence, so the transplant was fairly resistant to a challenge of antibiotics. These patients responded very nicely to a subsequent course of vancomycin. The meta-analysis from Guo and colleagues[2] also suggests that fecal transplant is very effective. The duration of protection is at least 17 months (the mean duration of the follow-up in the study).
Putting this into perspective, it makes sense to consider this for your practice. It is ridiculous for us to continue to treat these patients with significant amounts of antibiotics that breed resistance. Fidaxomicin is available, but I have seen relapses so far in 2 patients who took fidaxomicin. These patients are candidates for fecal transplantation.
A word of caution from Brandt and colleagues is that 2 of their patients had improvement in preexisting diseases, including rheumatoid arthritis and sinusitis. Four patients had subsequent complaints of development of rheumatoid arthritis, idiopathic thrombocytopenic purpura, or neuropathy. Whether these effects are related to fecal transplant remains to be seen. We need prospective, randomized controlled trials, but at the present time, fecal transplant is a viable option for your practice. This is not rocket science. Don't put this off and say, "I need to wait; I need to repeat antibiotics in these patients; they could have life-threatening complications." Think about it. It's easy to do. I can't even screw it up, having done this now myself. The development of the blenderized stool is not the greatest moment in life. I don't clean the blender afterwards. I give it back to the patient to keep or throw away. I will leave this to your discretion.
Although not yet the standard of care, fecal transplant should be an option for your patients. Look at these references, in particular the article in Clinical Gastroenterology and Hepatology. If you choose to do this, you will find this to be a practical resource.
References
- Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 Mar 27. doi: 10.1038/ajg.2012.60. [Epub ahead of print]
- Guo B, Harstall C, Louie T, Veldhuyzen van Zanten S, Dieleman LA. Systematic review: faecal transplantation for the treatment of Clostridium difficile-associated disease. Aliment Pharmacol Ther. 2012;35:865-875. Abstract
- Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-1049. Abstract
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