c diff: FMT, probiotics

there have been a couple of articles recently dealing with c. diff infections.

1. recent one from Mass General Hosp on use of fecal microbiota transplant (FMT) in patients with relapsing c diff infections (see cdiff fecal tx clin inf dz 2014 in dropbox, or DOI: 10.1093/cid/ciu135). the problem is that standard medical therapy (metronidazole or vanco) leads to recurrent c diff in 30% treated for a first episode. and, if 2 or more recurrences, there are diminishing returns: >60% have relapses. in this study, the fecal transplant was from screened, healthy volunteers, frozen and administered to 20 patients either through a nasogastric tube (10 patients) or colonoscope (10 patients). primary endpoint was resolution of diarrhea without relapse after 8 weeks. also looked at patient-reported health score. not an RCT (no placebo group). results:

    --baseline: patients (average age 50) with median of 4 relapses (5 antibiotic treatment failures) --[ie, even without control group, these patients are very unlikely to respond to yet another antibiotic course]

    --resolution in 14/20 (70%) patients after single FMT: 8/10 with colonoscopic transplant, 6/10 with nasogastric tube transplant.

    --5 patients retreated, 4 cured: resolution increased to total of 90% after a second FMT (patients were offered retreatment by nasogastric tube or colonoscopy -- all requested the NG tube)

    --self-ranked health score improved significantly with treatment

    --no signif adverse events

so, non-randomized study, though remarkably likely that further antibiotic therapy would be unsuccessful or to get spontaneous resolution, and had 90% cure rate, with efficacy as good with the less invasive NG tube administration technique!!!

2. an observational study of 12,026 patients at cleveland clinic between 2008-2012 who were at high risk of developing c diff -- age over 55 and put on a broad-spectrum antibiotic (eg piperacillin-tazobactam, or cipro, with cipro being used 90% of the time) and a gastric acid suppressant (PPI or H2-blocker) -- they compared those who happened to be on metronidazole for 1-3 days for  a non-c diff indication before being put on the broad-specturm antibiotics (n=811) vs not on metronid beforehand (n=11,215) (see cdiff prevention metronid clin gastro 2014 in dropbox, or doi.org/10.1016/j.cgh.2014.02.040). logistic regression done to control for patient demographics and comorbidities. results:

    --c diff developed in 11 patients on metronidazole (1.4%) vs 728 not on metronid (6.5%), finding an 80% reduction of c diff (adjusted odds ratio of 0.21). there was an incremental benefit in older patients

3. reprinted blog from 2012:

annals of internal medicine with recent meta-analysis of use of different probiotics in preventing c. diff infections (see cdiff probiotics metaanal annals 2012, or doi: 10.7326/0003-4819-157-12-201212180-00563 in dropbox).

--background:  c diff infections becoming more frequent and more severe over time.  more than 300K hospitalized pts in the US are affected every year.

--presumed reason is that antibiotics (esp broad-spectrum) disturb normal GI flora. probiotics should reinoculate gut with good bugs and thereby inhibit pathogen adhesion, colonization and invasion of the mucosa

--this meta-anal looked at 20 RCTs with 3800 pts, adults and kids.

--Probiotics used in the trials included Bifidobacterium, Lactobacillus,Saccharomyces, and Streptococcus species.  in most studies these were given for the duration of the antibiotic regimen

--results: decreased c diff infections by 66%!!!  and, fewer adverse effects in the probiotic group vs placebo (9.3% vs 12.6%)!!

--results similar in kids and adults, and with different probiotic species (details in their Table 1)

--their conclusion:  Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD (that is, cdiff assoc diarrhea, defined as antibiotic-related diarrhea with a positive c diff test)  without an increase in clinically important adverse events

so, these 3 studies raise some issues

    --in terms of c diff treatment, esp in those with relapsing infections, the use of fecal transplants is pretty impressive in this small study.  it raises the recurrent theme (at least in my blogs...) that the microbiome of the gut is really important and disturbances, whether they be antibiotics or red meat, can lead to bad outcomes. using fecal transplants from screened healthy volunteers is one approach, and the nasogastric approach seems more tolerable. using probiotics is another approach which should be tested, esp given the study on prevention of c diff. it is inherently more appealing to me to try re-establishing a healthy microbiome than adding an antibiotic (eg, metronidazole), since the antibiotic can also lead to resistance (it is disturbing that there is increasing resistance of H Pylori to metronidazole, which seems to track with metronidazole use for non H pylori indications. a bit like HIV, in that you need more than one antibiotic to cure H pylori, and using metronidazole as a single agent for a different application (eg treating bacterial vaginosis) might lead to resistance if there is an underlying infection with H Pylori.) there is the issue that most people get probiotics in health food/vitamin stores. these are not regulated, as with FDA, so what they say on the label is not necessarily accurate.