recurrent C Diff infection: microbiome transplant helps

 A current JAMA letter to the editor (cdiff recurrent microbiome transplant jama2022 in dropbox, or doi:10.1001/jama.2022.16476) is a follow-up to the previous article in NEJM nine months earlier by the same research group (for the full earlier article, see cdiff SER-109 microbiome treatment for recurrent CDI nejm2022 in dropbox, or DOI: 10.1056/NEJMoa2106516, the ECOSPOR III trial). The former article reported C. diff recurrences up until 8 weeks after microbiome transplant, finding a 68% risk reduction independent of patient age or antibiotics received, and that most of the adverse effects were mild to moderate gastrointestinal ones, similar to that found with placebo

 

Details:

-- 182 patients who had at least three C difficile infection (CDI) episodes within 12 months were enrolled in the trial and randomized to four capsules daily of SER-109 for three days

-- all patients had a positive C. difficile test for toxin production, and symptom resolution after standard care antibiotics

-- mean age 66 (44% <65 years old), 60% female, 94% white

-- numbers of episodes of C diff infection: 3 in 60% of participants and at least 4 in 40%

-- prior C diff antibiotic regimens: 73% vancomycin, 27% fidaxomicin

--the current trial assessed outcomes through week 24 for the prespecified secondary endpoints of adverse events and durability of response, as well as time to recurrence of C. diff infections assessed at 4, 12, and 24 weeks

    -- a slew of potential treatment-emergent adverse events were documented through week 8; serious AEs and those of special interest (eg bacteremia, abscess, meningitis) were collected through week 24

 

Results:

-- among patients who experienced a C. difficile recurrence, timing to the recurrence was:

    -- by week 4: 65.1%

    -- between weeks 12 and 24: 6.3%

    -- more specific analysis found that the benefit from the medication started as early as 2 weeks and was durable through 24 weeks

-- cumulative recurrent CDI at 4, 8, 12 and 24 weeks were:

    -- week 4: SER-109 11.2% versus placebo 33.3%

        -- rate difference -22.1%, p<0.001; relative risk 65% decreased, RR 0.35 (0.19-0.67), p<0.001

    -- week 8: SER-109 12.4% versus placebo 39.8%

        -- rate difference - 27.4 , p<0.001; relative risk 68% decreased, RR 0.32 (0.18 -0.58), p<0.001

    -- week 12: SER-109 18% versus placebo 46.2%

        -- rate difference -28.3, p<0.001; relative risk 60% decreased, RR 0.40 (0.24-0.65) p<0.001

    -- week 24: SER-109 21.3% versus placebo 47.3%

        -- rate difference -26.0%, p<0.001; relative risk 54 % decreased, RR 0.46 (0.30- 0.73), p<0.001

 

-- the median time for recurrent CDI:

    -- SER-109: 3.3 weeks (interquartile range 0.6-23.4)

    -- placebo: 1.6 weeks (IQR 0.6-18.1)

       -- but the earliest recurrences occurred at day 4 after randomization, and 65% occurred within 4 weeks both in the placebo and SER-109 groups (this suggests that disrupted microbiome in C. diff infections is particularly sensitive to recurrent infections within days to a few weeks after the completion of the standard antibiotic treatment)

 

-- Adverse events AEs):

    -- serious AEs occurred in 15 patients in the SER-109 group and 19 in placebo, none considered drug-related

    -- AEs affecting >5% of the patients: abdominal distension, constipation, diarrhea, and UTIs were somewhat more common in the SER-109 group, and there were 3 serious UTIs in that group. all resolved

        -- though from the earlier NEJM study, it was notable that there were more overall gastrointestinal AEs in the placebo group, though this included symptoms related to recurrent CDIs:

            -- flatulence: 70% in SER-109 vs 76% placebo

            -- abdominal pain: in 51% vs 61%

            -- nausea: 18% vs 33%

            -- vomiting: 3% vs 11%

            -- diarrhea was about the same at 24% vs 22%, and constipation was worse with SER-109 (31% vs 24%) 

Commentary:

-- SER-109 is an investigational agent to improve gut microbiome health:

    -- clinical C diff infections are associated with adverse microbiota in the gut microbiome

    -- the antibiotics used to treat C. difficile may further distort the microbiota

    -- and, the major antibiotics used (vancomycin and fidaxomicin), are only 60-70% effective in reducing recurrent C diff infections, likely because they do not kill C. difficile spores which can then germinate into toxin-producing bacteria after treatment discontinuation

    -- prior studies have found that fecal transplants, through several different methods, are helpful in those with recurrent C. difficile infections, though the range of efficacy in multiple trials is quite variable using different healthy microbiota instilled in different ways (eg see http://gmodestmedblogs.blogspot.com/2014/11/more-tolerable-fecal-transplant-for.html )

        -- a small study done at Mass General found that microbiome transplant was effective utilizing oral capsules

        -- for a systematic review of the studies of fecal transplant done until 2015: see http://gmodestmedblogs.blogspot.com/2015/05/c-diff-and-fecal-transplant-systematic.html

        -- there is some interesting research on other approaches that avoid microbiome transplant, including the use of bacteriophages (see http://gmodestmedblogs.blogspot.com/2019/11/c-diff-increasing-and-using.html 

    -- there are also some newer meds coming around, such as bezlotoxumab, a humanized monoclonal antibody infusion, especially for those with recurrent CDI infections: eg see Wilcox MH, et al. NewEngl J Med 2017; 376: 305-317, or DOI: 10.1056/NEJMoa1602615

    -- other studies have found that within healthy microbiomes, spore-forming Firmicutes bacteria “modulate the production and consumption of metabolites that are important to host defense and colonization resistance” and “antibiotic-induced loss of beneficial Firmicutes bacteria leads to increases in primary bile-acid concentrations, which enables C. difficile spore germination and a cycle of recurrent disease”; it has been shown in other experiments that specific bile acid changes have been associated with adverse microbiota (quotes are from the NEJM article)

    -- SER-109 is an oral microbiome therapeutic with live, purified Firmicutes spores administered. In the above study there were four donors who had had an extensive health examination including personal and family medical history, laboratory screening, urinalysis, and viral/bacterial/parasite testing of blood and stool prior to stool donation, all donated prior to December 2019. Capsules of the material were produced according to regulated practices (including clearance of non-spore forming bacteria, fungi, parasites, and viruses); SER-109 included multiple classes of bacteria all from the phylum Firmicutes (see above), including one phylum of “Firmicutes novel class” (details in their table S3)

    -- as noted in the prior NEJM article, they found that the species of SER-109 (Firmicutes) were detected at week one post treatment and were associated with bile acid concentrations known to inhibit C. difficile spore germination

-- overall, it does remain surprising to me that microbiome transplants work. the gut has 39 trillion microbes. seems pretty striking that taking a few pills or having infusion of small amounts of healthy microbiome could effect change in the composition of the whole microbiome within one week (see their figure # in the NEJM article).  certainly those little microbes do have a way of reproducing rapidly, but the ability of a few introduced species to out-reproduce the prior microbiome seems to me to be pretty extraordinary....

 

Limitations:

-- there were very limited data on the patients with C diff infections, just that they had a mean age 66, 60% female, 94% white. Not so diverse...  Did they have community-acquired C diff? what were their risk factors? recognized ones include older age, antibiotic use (and varies by type, with clinda and fluorouinolones leading the pack, per https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903408/ ), cardiac disease, chronic kidney disease, inflammatory bowel disease, hospitalizations and long-term care facilities,  immunocompromise, obesity, cirrhosis; and there are some studies finding that use of PPIs is associated with increased C diff infections and recurrent CDI's  (see http://gmodestmedblogs.blogspot.com/2017/04/ppis-and-recurrent-c-diff-infections.html )

-- the above study made assumptions that would tend to skew the results away from a positive effect of the SER-109: all patients who left the study early, were lost to follow-up, or who died were included in the analysis as if they had a recurrent infection

-- although these stool specimens were from a small number (4) healthy adults with microbiomes not containing many known possible pathogens (ie, clearing non-spore forming bacteria, fungi, parasites, and viruses), there always remains the possibility that a novel microbe might miss detection and slowly take over the gut leading to a bad outcome years later, well after anyone is looking for adverse events.

-- and, of course, one potential limitation for us guys in primary care: they decided to change the name of the bacterium (as is the wont of those infectious disease types, who seem to live to make things confusing for us) from Clostridium difficile to Clostridioides difficile: at least it is still C difficile in either case for us, though the new name is a bit harder to say even after practicing it.....

so, this article brings up several issues:

-- C. difficile infections can be serious/life-threatening, and also be recurrent and very difficult to treat

-- probably the main way to avoid them is to keep a healthy microbiome, by eating healthy foods that support a healthy microbiome (including lots of veges, fiber, not much sugar: eg see http://gmodestmedblogs.blogspot.com/2017/10/mediterranean-diet-helps-nafld.html as well a more recent article on suggesting more specific stratification of people based on underlying issues/diseases  (https://www.sciencedirect.com/science/article/pii/S0271531720305017 ), exercise, and especially minimizing antibiotics...

    -- for many blogs on antibiotic overprescribing, see http://gmodestmedblogs.blogspot.com/search?q=antibiotic+overprescribing . though a large % of antibiotic usage is in industrial food animals (see http://gmodestmedblogs.blogspot.com/2018/04/antibiotic-overuse-in-animals-and.html ), which migrate through our food chain directly (the meat) and potentially indirectly (potentially through excrement of drug-resistant bugs making it into the water that irrigates plants...)

-- for those who have recurrent C diff infections, there may well be some benefit from manipulating the microbiome. The study on SER-109 is intriguing, not only because it was so successful, but that it was limited to replenishing one seemingly beneficial phyla of bacteria, Firmicutes.

    -- which raises the real possibility (i think) that researchers might be able to develop pure cultures of the aggregate of these bacteria in the right proportion (as in the stool samples collected in this study), but avoid the potential problem of a human-to-human microbiome transplant unknowingly also transporting a novel, unknown virus or other pathogen that might lead to bad outcomes. seems like that might well work.  we'll see....

geoff

 

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