Sorry there’s been a delay in getting anything new out. I’ve had some exams, a quick trip to Colorado, and am now just finding my feet on my surgery clerkship. I have a bunch of things I intend to write about soon, but this paper popped up the other day and it ties in really nicely to some of the things I’ve already written about. I just had to write about it! I promise that in my upcoming posts I will get away from bowels and microbiota (though these subjects are incredibly important!).
You may remember Clostridium difficile from one of my previous posts on the appendix. C. diff is an anaerobic bacterium that frequently resides in the large intestine. After a course of antibiotics, when other gut-inhabitants have been killed, an overgrowth of C. diff can lead to a very nasty spectrum of symptoms ranging from mild diarrhea to death. Because of the frequent use of antibiotics and because of new hyper-virulent strains of C. diff, infection with this bacterium has reached epidemic levels. Alas, this is one of the most common infections found in hospitals, nursing homes, and other medical facilities.
The incidence of C. diff is on the rise, with both the number of cases and the mortality from infection recently doubling. There are approximately 3 million cases of C. diff infection in the US each year, and it’s estimated that care for these cases is in excess of $3.2 billion. C. diff infection leads to a number of discomforts, including abdominal pain, diarrhea, fatigue, and flu-like symptoms. Alas, treatment can be difficult, and symptoms can persist for months or even years.
As I mentioned in a previous post, the usual treatment for C. diff is further antibiotic treatment. C. diff infection usually occurs after all the normal gut flora has been eliminated and further antibiotics (sometimes given with probiotics to encourage the return of commensal bacteria) are targeted at eliminating C. diff (there’s even a new antibiotic (Dificid) specifically targeted at C. diff). The problem, of course, is that IF these antibiotics are effective, you now have a relatively unpopulated gut that is barren and ready for the taking by whatever stray bacteria have survived the courses of antibiotics or whatever quick growing bacteria happens to make their way to the intestines to claim the empty territory- unfortunately C. diff is frequently the victor in this foot race!
Recurrent rates of C. diff infection range from 15-30%, and once you’ve had one recurrence, you’re more likely to have another: a 40% chance of having a second, and a 65% chance of having a third. Obviously antibiotics are of limited efficacy here, so what is an appropriate course of action?
In my previous post, I discussed a paper that showed that having an appendix (and thus having a safe house for normal commensal bacteria that can repopulate your gut after infection or antibiotic treatment), is protective against a recurrence of C. diff . But what if you don’t have that safe house, or if you get a recurrence despite having an appendix? Again, as mentioned in a previous post, a Fecal Microbiota Transplant (FMT) seems to do the trick.
A paper published at the end of March , combined data from 5 sites and showed that FMT can provide RESOUNDING cure rates in people suffering from recurrent C. diff infections. Here’s a quick review: 77 patients, with average symptom duration of 11 months (range 1-28) underwent FMT at 1 of 5 medical centers in an attempt to cure their chronic infection. On average, these patients had already undergone 5 treatment regimes to try and cure their infection. FMT (most donors were family members, spouses, partners, or friends) was infused by colonoscopy into the terminal ileum, cecum, and (depending on the site) parts of the colon. Resolution of a number of symptoms- abdominal pain, fatigue, and diarrhea, were recorded.
In 70% of patients, pain resolved with FMT, while it improved in an additional 23%. 42% of patients saw a resolution of fatigue, with an additional 51% reporting an improvement. An astounding 82% saw a resolution of diarrhea and 17% saw an improvement within 5 days of FMT. These are patients, remember, that have been suffering from symptoms for an average of 11 months.
Alas, 7 patients (just under 10%) experienced an early recurrence (less than 90 days after FMT), and required a secondary treatment (either antibiotics targeted at C. diff or another FMT), which successfully treated the recurrence. Thus, the “primary cure rate” (resolution of diarrhea within 90 days of FMT) was 91%, and the “secondary cure rate” (resolution of infection after a further course of antibiotics or a second FMT), brought the cure rate to 98%. (It is worth noting that the one not “cured” patient died in hospice and was not re-treated after failure of a primary cure).
Some patients did have late recurrent infections of C. diff. Not surprisingly, these cases all occurred in patients that took a course (or multiple courses) of antibiotics to treat an unrelated infection. Recurrence occurred in 8 of the 30 patients that took a course of antibiotics. Interestingly, recurrence may also be associated with the use of proton-pump inhibitors (perhaps not a surprise, as PPIs inadvertently affect our microbiota )
This paper is excellent evidence to support FMT becoming a first-line therapy for the treatment of C. diff infection (and I will add especially for those that lack an appendix). FMT restores a natural biodiversity to the intestine of someone who has had their own microbiota disturbed by disease and/or antibiotics. For many people (those that experienced a primary cure), the restoration of the biodiversity was enough to overcome C. diff infection. For others, the restored biodiversity gave them the edge to overcome infection with a further targeted antibiotic or a second transplant. Remember- these are patients that had failed MULTIPLE treatments for C. diff and had been experiencing symptoms for an average of 11 months.
While there are definitely risks to FMT (it is important that donors be screened to rule out dangerous transmissible infections such as HIV, hepatitis, and parasitic infections), there are arguably additional benefits. One patient in this study reported a significant decrease in allergic sinusitis and another reported an improvement in arthritis. Both associated the improvement of symptoms with FMT. Indeed, FMT has been reported as a successful treatment for a number of conditions including inflammatory bowel disease (such as ulcerative colitis), irritable bowel disease, idiopathic constipation and insulin resistance .
It is important to recognize that some of the patients in this trial did suffer from subsequent disorders that should be further explored. While the conditions were not apparently associated with FMT, 4 patients that received this therapy later developed conditions including peripheral neuropathy, Sjogren’s disease, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. Further studies need to determine if there is an association between FMT and autoimmune or rheumatologic disorders. If associations are found, I would expect that this would call into question the appropriate selection of donors for individual patients.
It is becoming increasingly obvious that an appropriate and diverse microbiome is important for health. When this microbiome is thrown out of whack, be it by an evolutionary-novel lifestyle, infection, or antibiotic treatment, the restoration of this environment should be the focus of medical treatment. Fecal Microbiota Transplant is a rational and effective method of restoring a healthy and diverse intestinal microbiome.
(It is worth mentioning that 97% of the patients in this study stated that they would undergo another FMT if they experienced a recurrence of C. diff, and 53% would choose FMT as their first treatment option before a trial of antibiotics. Yes, the idea of FMT may seem gross, but it is effective. For those that have suffered for upwards of a year, this treatment truly is a life-changing option.).
1. Im, G.Y., R.J. Modayil, C.T. Lin, S.J. Geier, D.S. Katz, M. Feuerman, and J.H. Grendell, The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol Hepatol, 2011. 9(12): p. 1072-7.
2. Brandt, L.J., O.C. Aroniadis, M. Mellow, A. Kanatzar, C. Kelly, T. Park, N. Stollman, F. Rohlke, and C. Surawicz, Long-Term Follow-Up of Colonoscopic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. Am J Gastroenterol, 2012.
3. Vesper, B.J., A. Jawdi, K.W. Altman, G.K. Haines, 3rd, L. Tao, and J.A. Radosevich, The effect of proton pump inhibitors on the human microbiota. Curr Drug Metab, 2009. 10(1): p. 84-9.