refractory cdiff and frozen fecal transplant

JAMA just had an article comparing frozen  vs fresh fecal microbiota transplantation (FMT) for patients with recurrent C difficile infections (see cdiff fecal tx frozen jama2015 in dropbox, or JAMA. 2016;315(2):142).  

background:

--in 2011 there were 500K C diff infections in the US and 29,000 deaths

--over the past 10-15 years, there have emerged hypervirulent strains of c diff which are less responsive to therapy (eg, see clin infect dis 2008; 47: 1162, which assessed some of the epidemiology of an increasingly prevalent hypervirulent c diff "ribotype 078", which infected younger people, was more frequently community-associated, had worse diarrhea and attributable mortality)

--c diff is increasingly less responsive to therapy, and with more recurrences (about 25%)

-->60% of patients experience a further episode after a first recurrence, though 10-50% of recurrent infections are actually re-infections.

details:

--219 patients with recurrent or refractory c diff infections were randomized to frozen vs fresh FMT 

    --mean age 73 with 25% <65 yo, 67% women, 48% inpatients, 45% with moderate and 17% severe c diff infections, 58% with abdominal pain, 32% fever, 50% community-associated

    --93% had recurrent and 7% refractory infections, 90% with <2 recurrences, 90 days lapsed from first diagnosis of c diff to FMT. 

    --42% had strain 027, 33% treated with combo of metronidazole and vancomycin prior to FMT, and 93% had at least 1 vancomycin taper regimen prior to FMT

--all patients received their suppressive antibiotics for the most recent episode of c diff; these were discontinued 24-48 hours prior to FMT

--on day 1, patients received 50ml of frozen or fresh FMT by enema.

--if no improvement, on day 4 they received an additional dose. those not responding to the 2 doses were offered more doses or antibiotics

results:

--at 13 weeks, clinical resolution was 75.0% for those in the frozen FMT group and 70.3% in the fresh FMT groups (non-inferior, at p<0.001), 

--50% needed only one FMT for clinical resolution. another 23% needed 2, and another 10% needed 3-5 FMTs for clinical resolution.

--in the per-protocol group (those who received up to 2 same-modality FMTs, did not require antibiotics for c diff between the first 2 FMTs and did not get systemic antibiotics for intercurrent infections during the study), 178 patients overall (91 for frozen and 87 for fresh FMT), 62% had clinical resolution after 1 FMT and another 20% after 2 FMTs

--no difference in proportion of patients with adverse or serious adverse events. 70% had transient diarrhea, 10% abdominal cramps, <5% nausea in the 24 hours after FMT and 20% had constipation, 25% flatulence in the followup period. no difference if fresh or frozen

so, a few points:

--although this study tested and showed the non-inferiority of frozen FMT samples (which greatly improves the ability to really use this technique in practice, not relying on fresh samples), perhaps the main importance of this study is that FMT worked so well. in the per-protocol group, 85% had clinical response by 1 or 2 FMTs (73% by the modified intention-to-treat analysis). these numbers are quite similar to other FMT trials, including when FMT is done by colonoscopy or nasogastric tube.

--this group of patients were pretty sick. 51% were inpatients, 66% had moderate to severe c diff, 42% had the 027 ribotype strain, and 24 were immunocompromised. of note, those who were immunocompromised (mostly from malignancies or on immunosuppressants), 93% had clinical resolution and 5 of 6 who had inflammatory bowel disease responded

--the procedure to get the FMT was actually pretty simple: 100g of stool diluted with 300ml of bottled water, stirred with a sterile wooden spatula, then gauze was placed on top to strain off the solids, and the suspension was put in a 60cc syringe.  could be done at home...

--and the administration was really easy: an enema (could be done in a clinic), though for me there is some residual appeal for the pills

--as noted in prior blogs on the microbiome (see http://gmodestmedblogs.blogspot.com/search/label/microbiome ), there are very impressive data on microbiome changes and obesity, insulin resistance, diabetes, inflammatory bowel disease, atherosclerosis, asthma, celiac disease and perhaps even colon cancer, as well as the development of intestinal infections (eg: c diff, c jejuni) and the proliferation of antibiotic-resistant bacteria. though it would be really great to make fundamental changes that prevent at least some of the adverse microbiome changes (minimizing antibiotic use in humans and in agriculture, avoiding artificial sweeteners, eating a healthy diet and doing exercise, perhaps eating probiotics, etc), one wonders what the long-term effects of FMT used to fight c diff might be: would it alter these bad clinical outcomes by changing the gut microbiome? Are there potential negative long-term effects of FMT?

see http://gmodestmedblogs.blogspot.com/search/label/c%20difficile for some of the older emails/blogs on FMT. these include several of the earlier smaller studies (including the one where pills were used for the FMT with good success and no doubt better tolerability, and a more recent meta-analysis)