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Primary Care Corner with Geoffrey Modest MD: Probiotics in c diff

9 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent systematic review with a meta-analysis looked at 19 published studies on the efficacy of probiotics in preventing C. difficile infections (CDI) in inpatients put on antibiotics, finding benefit if given close to the 1st dose of antibiotics (see 10.1053/j.gastro.2017.02.003).

Details:

  • 6261 subjects were involved in these 19 studies
  • The studies were done in the USA, UK, Turkey, Canada, Norway, China, Italy, and Germany. Several different probiotic formulations were used, most with Lactobacillus species. The daily dose of probiotics varied dramatically from 4 to 900 colony forming units, most started the probiotics within the 1st 2 days of beginning the antibiotics, duration of probiotics varied from 14 days to 14 days after completion of the antibiotic course, and the age varied from those greater than 18 up to age 80 (weighted average 68 years). Commonly excluded groups were those who were pregnant, immunocompromised, required intensive care, had pre-existing GI disorders. The hospitals’ baseline incidence of CDI range from 1.5 to 7.4%
  • Overall 4 probiotic species were studied: Lactobacillus, Saccharomyces, Bifidobacterium, and Streptococcus.

Results:

  • The overall incidence of CDI in the probiotic cohort was 1.6% (54/3277); in the control group it was 3.9% (115/2984), with p<0.001.
  • The pooled relative risk of CDI was decreased 58% with probiotics, RR 0.42 (0.30-.57)
  • The number needed to treat was 43 patients to prevent one case of CDI
  • Meta-regression analysis showed that there was a significant decline in probiotic efficacy for each day in delay of starting probiotics after the 1st dose of antibiotic, with an 18% decrease for every day the probiotics were delayed (p=0.04)
    • Probiotics given within the 1st 2 days of starting antibiotics had a 68% risk reduction of CDI, RR 0.32 (0.22-0.48) than starting later, where there was a 30% reduction, RR 0.70 (0.40-1.23)
  • No adverse events attributable to probiotics (in general adverse events tended to be less in the probiotic group)
  • Overall quality of the evidence was high. The magnitude of efficacy was the same when analysis was limited only to the high qualities trials

Commentary:

  • CDI incidence has increased dramatically in the past 10 years, more than doubling and costing $4.8 billion, with attendant morbidity and mortality (more than 29,000 deaths in 2011). The standard treatment has approximately 20% treatment failure and around half of the patients have recurrence, especially those who are older.
  • Certain probiotics seem to colonize the gut well, despite concurrent use of antibiotics: specifically Lactobacillus and Bifidobacterium.
  • To me it is difficult to assess with certainty their conclusions about timing, given the inconsistency of the approach to treatment (huge variability in types and doses of probiotics), as well as the fact that the vast majority of studies treated early, within the first 2 days or so. However, it does make intuitive sense that if we are to protect the gut with probiotics, that should be done early, especially before there is a large overgrowth of C. difficile
  • The best guess of the authors, though not definitive, was at the most efficacious probiotics were: Lactobacillus, and Lactobacillus in combination with either Streptococcus or both Streptococcus and Bifidobacterium
  • A review of the individual studies found that they all found benefit from the probiotics, though for some of the individual studies these did not reach statistical significance.
  • A cost-benefit analysis done in the UK suggested that using a Lactobacillus probiotic in hospitalized patients over 65 on antibiotics would lead to a cost savings of over $500 per patient. Another study in Canada also suggested cost savings.
  • So, though current guidelines, for example from the American College of Gastroenterology, do not recommend the use of probiotics for the primary prevention of CDI, this meta-analysis is pretty convincing that they work with no evident adverse effects. And, I would think, should be strongly considered in outpatients put on broad-spectrum antibiotics (e.g. Ciprofloxacin).

Prior blogs:

http://blogs.bmj.com/ebm/2014/12/03/primary-care-corner-with-geoffrey-modest-md-probiotics-in-irritable-bowel-syndrome/ is a blog on the efficacy of probiotics in irritable bowel syndrome

http://blogs.bmj.com/ebm/category/microbiome/ has a slew of blogs on the microbiome

http://blogs.bmj.com/ebm/category/clostridium-difficile/ has many blogs C. diff

and, http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ has many on antimicrobial resistance

Primary Care Corner with Geoffrey Modest MD: Refractory C diff and Frozen Fecal Transplant

10 Feb, 16 | by EBM

By Dr. Geoffrey Modest

JAMA just had an article comparing frozen vs. fresh fecal microbiota transplantation (FMT) for patients with recurrent C difficile infections (see 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 (e.g., 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://blogs.bmj.com/ebm/category/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 (e.g.: 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://blogs.bmj.com/ebm/category/clostridium-difficile/ 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)

Primary Care Corner with Geoffrey Modest MD: C. diff and fecal transplant, a systematic review

10 Jun, 15 | by EBM

By: Dr. Geoffrey Modest

There was a systematic review of fecal microbiota transplantation (FMT) for Clostridium difficile infections in the Annals of Internal Medicine recently (see 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 here for some prior studies and comments on FMT for C diff, and here 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 here). 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.

 

Primary Care Corner with Geoffrey Modest MD: More tolerable fecal transplant for resistant c diff infections

30 Jan, 15 | by EBM

By: Dr. Geoffrey Modest

So, yet another positive but small fecal transplant study for relapsing c diff infection, this time using (more tolerable/acceptable) oral capsules. On the ever recurrent microbiome theme, the point of these fecal transplants is to re-establish a healthy microbiome directly, as opposed to decimating the diseased microbiome with aggressive antibiotics (vanco, metronidazole). In this open-labeled study, 20 patients (median age 64.5, range 11-89) with at least 3 episodes of mild-to-moderate c diff infections who had failed 6-8 week tapers with vanco (with or without other antibiotic, including metronidazole or the very expensive fidaxomicin) or at least 2 severe episodes of c diff requiring hospitalization were given 15 capsules of frozen fecal microbiota transplant (FMT) from an unrelated donor for 2 consecutive days and followed up to 6 months (see doi:10.1001/jama.2014.13875​). Stool was harvested (if that is the correct term) from 4 healthy volunteers. Mean capsule storage was 113 days at -80 C. Results:

–Resolution of diarrhea in 14 of the 20 (70%, with CI 47-85%) after a single treatment with FMT
–The 6 nonresponders were retreated: 4 had resolution (i.e., total of 90%). nonresponders were defined as no change in diarrhea after 72 hours, retested and found positive for c diff.
–Effect pretty quick: daily number of bowel movements decreased from 5 the day prior to FMT, to 2 at day 3 and 1 at 8 weeks, with attendant increases in self-ranked health status
–Interesting that 9 of the patients (who all failed antibiotic therapy) had received the new and likely more powerful fidaxomicin​, and 6 resolved after only 1 treatment with FMT
–No serious adverse effects, no vomiting and only mild abdominal cramping and bloating in 6 patients.

So, FMT seems to work in this difficult, non-responsive group of patients with relapsing c diff infections. Although we need confirmation from both larger studies and studies done at different institutions, it all seems pretty promising and reflects a significant ideological shift: we should certainly do everything we can to decrease microbiome destruction (in this case, largely by avoiding unnecessary antibiotics and using as narrow-spectrum as possible — for example, using trimethoprim/sulfa instead of cipro for simple UTIs), and once the microbiome is disrupted, restore it with a healthy one instead of hitting it with more antibiotics (in fact, the antibiotics used seem to have increasing failure rates, now 30% for first occurrences and 60% for treatment failures!!). one advantage of this study is that FMT is scalable: does not require fresh stool from healthy donors which has to be screened (and is only good for 6 hours), limited availability, etc., and it uses stool from unrelated donors/healthy volunteers (some prior studies used related donors, which might even be worse, as we learned with blood donations: the chance of transmitting infection was actually higher with related donors, who were likely reticent to mention their own exposures).

Primary Care Corner with Geoffrey Modest MD: C. Diff

4 Jul, 14 | by EBM

there have been a couple of articles 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 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 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. blog from 2012:

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

–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 BifidobacteriumLactobacillus,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.

geoff

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