Transcript Use and efficacy of fecal transplants for refractory Clostridia difficile
Use and Efficacy of Fecal Transplant for Refractory Clostridium difficile in IBD Patients Edward V. Loftus, Jr., MD Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota
Division of GASTROENTEROLOGY & HEPATOLOGY ©2011 MFMER | slide-1
Loftus Disclosures (last 12 months)
•
Research support
• • • • • • • • • • • AbbVie UCB Bristol-Myers Squibb Shire Genentech Janssen Amgen Pfizer Takeda GlaxoSmithKline Robarts Clinical Trials •
Consultant
• AbbVie • UCB • Janssen • Takeda • Immune Pharmaceuticals • MedImmune • Celgene
History of Fecal Transplant
• 4 th • century Chinese Medicine Human fecal suspension by mouth for diarrhea related to food poisoning • 17 th • century Veterinary Medicine Transfauntation (transfer of cecal contents or fresh feces) from healthy horses to treat horses with diarrhea • WWII: “consumption of fresh warm camel feces has been recommended by Bedouins as remedy for bacterial dysentery; efficacy confirmed by German soldiers in North Africa” • 1958: Fecal enema for pseudomembranous colitis •
Micrococcus pyogenes
• 1983: Fecal enema for
C. difficile
infection • 1991 – 2014: Multiple reports of fecal transplant for
C.
Brandt L Gastrointest Endosc 2013 Aug;78(2):240-9.
difficile
Smits LP et al, Gastroenterology 2013;145:946-53.
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FMT for Recurrent Clostridium difficile Infection: Systematic Review and Meta-Analysis
• 11 studies, 273 patients • Pooled resolution rate, 89% • Trend that lower GI administration had higher resolution rate (91%) than UGI route (81%)
Kassam Z et al, Am J Gastroenterol 2013;108:500-8.
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Randomized Trial of FMT vs Vancomycin vs Vancomycin Plus Bowel Lavage for Recurrent Clostridium difficile Infection
• 43 patients with recurrent
C. difficile
infection • Initially planned 40 patients in each of 3 arms • Primary endpoint: cure of CDI without relapse within 10 wks • C diff tests at weeks 2, 3, 5, 10 • Interim analysis: study terminated early because efficacy already demonstrated • No serious adverse events
Van Nood E et al, N Engl J Med 2013;368:407-15.
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Cost-Effectiveness of FMT for Recurrent Clostridium difficile Infection
• Cost-utility analysis of 4 strategies • Metronidazole • • • Oral vancomycin Fidaxomicin FMT via colonoscopy • Modeled 2 additional recurrences • Most cost-effective approach was FMT via colonoscopy • Incremental cost-effectiveness ratio was $17,016 per QALY relative to oral vancomycin • FMT dominated metronidazole and fidaxomicin • In order for fidaxomicin to be cost-effective, cost would need to be less than $1359
Konijeti GG et al, Clin Infect Dis 2014;58:1507-14.
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Oral Capsulized Frozen FMT for Relapsing Clostridium difficile Infection
• 20 patients with recurrent CDI received capsulized frozen FMT from healthy volunteer donors • 70% resolution of diarrhea after single capsule-based FMT; after retreatment of non-responders overall response rate 90%
Youngster I et al, JAMA 2014;312:1772-8.
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FMT in IBD: An Historical Perspective
• The year 1989: Kansas City • • • • • A physician (J.D.B.) 7 years: Steroid refractory, active & severe UC Controlled with α-tocopherylquinone Large volume retention enemas with donor flora Symptom free for 6 months, off medications, normal endoscopy and no acute inflammation • The year 1989: Australia • 45/M with UC for 18 mo (pancolitis) and elevated LFTs • Refractory to sulfasalazine • • Received FMT and asymptomatic in days No recurrence at 3 months
Bennet D, Lancet 1989, Jan 21: 164.
Borody T, Med J Austr 1989; 150: 604.
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FMT in IBD: The Data
• Case series of 6 patients with UC • • • • 3 males, 3 females Age 25 – 53 years 2 had left sided colitis, 2 with pancolitis Disease duration < 5 years • FMT administered as retention enemas every 5 days • Symptoms improved in 1 week • Complete reversal achieved in all patients by 4 months
Borody T, J Clin Gastroenterol 2003;37(1):42 –47.
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2012 Systematic Review of FMT in IBD
Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.
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FMT in IBD: The Data
• 41 patients (20 males, 18 females, 3 unknown) • Age range: 11 - 78 years • 27 with UC • • 12 with Crohn’s 2 with indeterminate • Duration of follow-up: 2 weeks - 13 years • Disease duration: 18 months - >20 years • Variable extent of disease • Variable prior treatment for IBD • Most reports had donor screening protocols
Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.
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FMT in IBD: The Data
• 26 patients: FMT for treatment of IBD • Among 17 patients: • 13/17 ceased IBD medications within 6 weeks • 16 patients experienced symptom reduction / resolution within 4 months • 15 experienced complete resolution within a year • Among 24 patients: • 15 (63%) had no evidence of active disease 3 –36 months after FMT
Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.
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FMT in IBD and C. difficile infection
• 15 patients received FMT for CDI • In 12 patients • 12/12: resolution of CDI • 11/12: marked reduction / complete resolution of diarrhea • FMT resulted in improved response to IBD medications in 6 patients
Anderson JL, Aliment Pharmacol Ther 2012; 36: 503-516
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FMT for UC: Variable Clinical, Serological, and Microbiological Response
• 5 pts with moderate to severe UC refractory to standard therapy, 3 days of FMT via NJT and enema • 1 pt had clinical response by wk 12, 2 pts had no change, and 2 worsened • All developed fever and elevated CRP immediately after FMT
Angelberger S et al, Am J Gastroenterol 2013;108:1620-30.
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FMT for UC: The Backlash Continues
• 6 patients with UC refractory to standard therapy received FMT via colonoscopy • All 6 had short-term improvement in 1 st 2 weeks • 4 of 6 had increased stool frequency by day 30 • No change in fecal calprotectin or CRP • No patients achieved remission Total Mayo Score Over the Course of the Study
Kump PK et al, Inflamm Bowel Dis 2013;19:2155-65.
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FMT for IBD: Systematic Review & Meta-Analysis 2014
• 18 studies (9 cohort, 8 case reports, 1 RCT), 122 patients (79 UC, 39 Crohn’s, 4 IBDU) • Overall response rate, 45% • 22% UC • 61% Crohn’s • Conclusion: safe, but effectiveness highly variable Overall response in cohort studies, 36.2%
Colman RJ & Rubin DT, J Crohns Colitis 2014 online early.
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FMT in IBD: Systematic Review
• 31 studies, 133 IBD patients • 43% had recurrent
C. difficile
infection • Resolution or reduction of symptoms in 80 patients (71%) • When an objective score was used, 62% partial or complete response • In those without
C. difficile
, 69% • Endoscopic improvement in 57%, but only in 20% when objective score was used • Fever and increased CRP not uncommon
Ianiro G et al, Medicine (Baltimore) 2014;93(19):e97.
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UC Patients Failed to Show Significant Improvement After FMT: Placebo-Controlled RCT
IBDQ at Week 6 • • Prospective, double blind RCT • 53 active UC patients (Mayo score ≥ 4 with endoscopic Mayo subscore ≥ 1) • Negative for
C. difficile
• 42% on steroids, 19% on immunomodulators, and 9% on biologics • 6 weeks of once-weekly fecal microbiota therapy delivered by retention enemas (n = 27) vs placebo delivered by water enemas (n=26) • Results • No difference in remission between groups at week 6 (assessed by Mayo score, IBDQ and EQ-5D) • No adverse events related to FMT Limitations • • Short duration (6 weeks) Small sample size Mayo Score at Week 6
Moayeddi P, et al. Gastroenterology 2014;146(5):S-159.
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FMT in IBD: Lessons from C. difficile studies
• IBD included Microscopic colitis • N=4 • Complete remission of diarrhea • No mention of IBD remission from FMT
Hamilton MJ, Am J Gastroenterol 2012; 107:761 –767
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•
FMT for Recurrent Clostridium difficile Infection in Immunocompromised Patients
Multicenter retrospective analysis of 80 pts with recurrent CDI who were immunosuppressed • Included 36 pts with IBD on immunosuppressants or biologics • Efficacy in IBD population: • 86% had resolution of CDI with first FMT • Overall cure rate (including 2 nd FMT), 94% • Safety: SAE in 15% within 12 wks post-FMT • 2 deaths, including one witnessed aspiration while sedated for scope to administer FMT • SAE rate for IBD patients similar (11%) • 5 IBD pts (14%) had disease flare post-FMT, and 3 UC pts underwent colectomy
Kelly CR et al, Am J Gastroenterol 2014;109:1065-71.
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FMT in IBD Patients with Recurrent Clostridium difficile infection: Mayo Rochester Experience (n=13)
• 7 Crohn’s, 6 UC • Median age, 27 years (range, 21-48) • Median IBD duration, 3 years (0.2-15) • Median 4 C diff infection episodes (1-12) • Median 5 failed treatment regimens (2-13) • 77% failed at least 2 drugs • 77% failed a prolonged vancomycin taper • IBD drugs included 5-ASA (6), biologics (6), IMM (3), steroids (5)
Khanna S et al, Am J Gastroenterol 2013;108(Suppl 1):S508
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FMT in IBD Patients with Recurrent Clostridium difficile Infection: Mayo (cont)
• After FMT, 92% noted clinical improvement in symptoms and overall well-being • 1 patient saw no improvement, was C diff positive • 6 patients had complete resolution • • 6 patients had partial resolution Median time to resolution was 2 days (1-14) • No patients stopped IBD therapies • In fact, 46% required escalation of IBD therapy at some point after FMT despite being C diff negative • Conclusion: Safe and effective for recurrent C. diff, but doesn’t appear to improve the course of IBD
Khanna S et al, Am J Gastroenterol 2013;108(Suppl 1):S508
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Conclusions
• Fecal microbial transplantation appears to be highly effective in eradicating recurrent
Clostridium difficile
infection • In the subset of IBD patients with recurrent CDI, FMT also appears to be highly effective and reasonably safe including in patients on immunomodulators and biologics • It is far from certain that FMT will be effective for the treatment of IBD itself in the absence of recurrent CDI • Placebo-controlled RCT of fecal enemas in UC was negative ©2011 MFMER | slide-23