c diff and fecal transplant, a systematic review

There was a systematic review of fecal microbiota transplantation (FMT) for Clostridium difficile infections in the Annals of Internal Medicine recently (see cdiff fecal tx review annals 2015 in dropbox, or DOI: 10.1093/cid/ciu135). Despite the reasonably large number of articles written on this treatment, typically for very difficult recurrent or refractory cases, there have only been 2 small RCTs, and only 1 which compared fecal transplant with medication. There were also 28 case series reported (several of the studies have been blogged in the past: see http://gmodestmedblogs.blogspot.com/search?q=c+difficile for some prior studies and comments on FMT for C diff, and http://gmodestmedblogs.blogspot.com/search?q=microbiome  for some articles on the microbiome). the findings of the systematic review:

--C diff infections (CDI) are common and have a high rate of recurrence (up to 30% after an initial infection, and increasing thereafter). data on the utility of FMT:

--FMT for recurrent CDI

    --in one RCT with 43 patients (mean age 70, 58% men in the Netherlands) randomized to FMT via nasoduodenal tube found 81% achieved resolution of symptoms within 3 months, as compared with 31% on vancomycin and 23% on vancomycin-plus-bowel lavage (unexpectedly low response rates for vanco, not sure why). FMT was done after 4 days of vancomycin. Of note, this study lacked blinding.

    --the other RCT compared nasogastric vs colonoscopic administration of FMT in only 20 patients, with 70% symptom resolution and no difference by method of administration.    --of the 480 patients in 21 case-series, 85% had resolution of symptoms without recurrence. The initial C diff episode was 3-27 months prior to FMT, and patients were commony given antimicrobioals before the FMT

--FMT for refractory CDI

    --7 studies. none compared FMT with standard therapies. Resolution of symptoms ranged from 0% to 100%, with overall resolution rate of 55%

--FMT for initial CDI

    --7 cases only. not very useful....

--Harms of FMT: mild adverse events were reported: diarrhea, cramping, belching, nausea, abdominal pain, bloating, transient fever, dizziness. There were some procedure-related harms (eg, microperforation with colonoscopy). Serious infections were rare, often likely unrelated to the FMT, and this was true for a study of 80 immunocompromised patients.

--patient acceptance of FMT: it was somewhat difficult in some studies to recruit patients after a first recurrence, perhaps related to patient reluctance. However, in one study where previous patients were contacted >3 months after FMT, 97% said they would be willing to take it again in the future.

so, a few comments:

--the concept of FMT is inherently appealing to me, with healthy reconstruction of the colonic microbiome instead of using antibiotics (and using metronidazole may well result in other organisms becoming resistant to that, such as H pylori; using vancomycin could potentially exacerbate the already-emerging vancomycin-resistant enterococci). The data on probiotics also suggest efficacy, though probiotics introduce far less microbial diversity than a healthy colonic microbiome does.

--it is pretty striking that given the frequency of recurrent or resistant C diff infections that  there have not been larger RCTs, leaving several questions hanging, eg:

    --what is the best source of fecal microbiota?

    --are there going to be problems with instilling a potentially pathogenic bacterium from one person to another (the data so far suggest FMT is quite safe even in immunocompromised individuals, which is heartening. but not all FMT harvested will be the same.) for example, older studies have found asymptomatic C diff (ie carriers) in adults and even in infants. should "normal" stools be tested for C diiff? other potential pathogens?

    --how many times and at what frequency should FMT be administered (the studies vary dramatically on this)

    --should we consider FMT for first infections, given lack of adverse effects and essentially no data?

    --is home-administered FMT enema (done in some studies) as good as colonoscopic? (the enema would certainly be cheaper and less hazardous)

    --is it necessary to use antibiotics prior to FMT? if so, what agent and for how long?

--despite the lack of strong evidence supporting FMT, the American College of Gastroenterology in 2013 gave a conditional recommendation (based on moderate-quality evidence) that FMT should be considered if there is a third recurrence after pulsed vancomycin regimen. The 2014 European Society of Clinical Microbiology and infectious Diseases guideline stated that FMT "is strongly recommended (A-1)" after a second recurrence of C diff infection.

--and, the data suggesting that nasogastric instillation of FMT is as good as colonoscopic raises the possibility of pill forms (which hopefully would be coated and flavored). there was in fact a small study of 20 patients showing efficacy by taking oral capsules, which included frozen stool specimens which were harvested up to 4 months previously (seems better than having to harvest fresh stool and use it right away): see http://gmodestmedblogs.blogspot.com/2014/11/more-tolerable-fecal-transplant-for.html ). I guess this might put a positive spin on the frequently used epithet about eating excrement....

--by the way, although the FDA does require an investigational new drug application for human studies on FMT, they do allow FMT for clinical use in treating CDI.