Use and efficacy of fecal transplants for refractory Clostridia difficile

Report
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
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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
• 4th century Chinese Medicine
• Human fecal suspension by mouth for diarrhea related to food
poisoning
• 17th 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.
©2011 MFMER | slide-3
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.
©2011 MFMER | slide-4
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.
©2011 MFMER | slide-5
Cost-Effectiveness of FMT for Recurrent
Clostridium difficile Infection
• Cost-utility analysis of 4 strategies
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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.
©2011 MFMER | slide-6
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.
©2011 MFMER | slide-7
FMT in IBD: An Historical Perspective
• The year 1989: Kansas City
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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
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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.
©2011 MFMER | slide-8
FMT in IBD: The Data
• Case series of 6 patients with UC
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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.
©2011 MFMER | slide-9
2012 Systematic Review of FMT in IBD
Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.
©2011 MFMER | slide-10
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.
©2011 MFMER | slide-11
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.
©2011 MFMER | slide-12
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
©2011 MFMER | slide-13
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.
©2011 MFMER | slide-14
FMT for UC: The Backlash Continues
• 6 patients with UC
refractory to standard
therapy received FMT via
colonoscopy
Total Mayo Score Over the Course of the
Study
• All 6 had short-term
improvement in 1st 2 weeks
• 4 of 6 had increased stool
frequency by day 30
• No change in fecal
calprotectin or CRP
• No patients achieved
remission
Kump PK et al, Inflamm Bowel Dis 2013;19:2155-65.
©2011 MFMER | slide-15
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.
©2011 MFMER | slide-16
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.
©2011 MFMER | slide-17
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
Mayo Score at Week 6
• 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
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
©2011 MFMER | slide-19
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 2nd 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.
©2011 MFMER | slide-20
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
©2011 MFMER | slide-21
FMT in IBD Patients with Recurrent Clostridium
difficile Infection: Mayo (cont)
• After FMT, 92% noted clinical improvement in
symptoms and overall well-being
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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
©2011 MFMER | slide-22
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

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