stollman neil-the-clostridium-difficile-epidemic-and...

Neil H. Stollman, MD, FACG

The C. difficile Epidemic and the Immunocompromised Patient

(with particular attention to IBD)

Neil H. Stollman, MD, FACGChief, Division of Gastroenterology

Alta Bates Summit Medical Center, Oakland, CAAssociate Clinical Professor of Medicine

University of California San Francisco

OUTLINE• Treatment of C. difficile infection in general• Treatment of C. difficile infection with FMT• CDI in immunocompromised patient (more

common, more severe, harder to Rx)• Safety and efficacy of FMT in IC and IBD pts• Safety and efficacy of FMT to Rx IBD itself

ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology

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Current ACG Guidelines: Treatment• Stop offending Abx if possible, avoid anti-peristaltics• Empiric Rx appropriate when high suspicion• Metronidazole 500mg TID x10-14d (mild/moderate)

• Vancomycin 125mg QID x10-14d (severe disease, metronidazole intolerant, pregnant/breastfeeding, or failure to respond 5-7 days)

• No routine post-Rx testing (can stay positive)• Complicated disease: PO/PR vanco plus IV metro • Early surgical evaluation for critically ill patients

Am J Gastroenterol 2013; 108:478–498

Current Guidelines: Recurrent Disease

• Same Rx as prior, unless severe (vanco)• 2nd recurrence: taper/pulse regimen• ACG explicitly recommends ‘consideration of FMT’

after third recurrence and after taper


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Why FMT? It’s all about the biome, baby!

Reconstitution of a ‘more normal’ biome (whatever that turns out to be) is more logical than further biome

disruption with additional antibiotics

Diversity Matters:Decreased Microbial Diversity in CDI

Chang JY, et al, J Infect Dis. 2008; 197:435-8


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How to Rx?FMT routes of administration• Nasogastric or nasoduodenal tube

– Uncomfortable, ? risky– Requires radiology or EGD

• Retention enemas– Variable patient ability to tolerate

• Lower endoscopy– Enables examination of mucosa– More costly, sedation risks

• Encapsulation– Likely decreased procedure related risk & cost

Aas et al. 2003; Rubin et al 2012; Van Nood 2013; Silverman et al. 2010; Kassam et al 2012; Lee et al 2014;

FMT: DONOR STOOL ENGRAFTS

Khoruts A. J Clin Gastroenterol 2010


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Engraftment is durable (3 months)

Li SS, et al Science 2016; 352:586-9

FMT for CDI: open label data

• Open label retrospective case series (lower)– 77 (of 94 eligible) followed 3-68 months (mean 17)– Primary Cure rate: 91%– Secondary Cure rate: 98%

• All late recurrences occurred in setting of subsequent unrelated antibiotics

• No overt or acute AEs, although 4 patients developed auto-immune diseases later (ITP, Sjogrens, RA)

Brandt LJ et al. Am J Gastroenterol 2012 ; 107 : 1079 – 87 .


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FMT for CDI: First RCT• 43 patients with >1 recurrence

A) Vanco 500 mg QID x 14dB) Vanco 500 mg QID plus bowel lavageC) Vanco 500 mg QID x4-5 days, plus lavage and then

nasoduodenal infusion (donor pool); 2nd infusion (different donor) offered if failed (3 patients)

• Concerns: unblinded, small, terminated early after (unplanned) interim analysis when investigators become aware of treatment difference, and felt “unethical to continue”

van Nood E et al. N Engl J Med 2013 ; 368 : 407–15

FMT for CDI: Netherlands RCT

81.3 93.8 30.8 23.1

First Infusion Donor Feces(n=13)

Infusion of Donor FecesOverall (n=16)

Vancomycin (n=13) Vancomycin plus lavage(n=13)

Cure

d w

ithou

t rel

apse


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Most thought that the NEJM RCT signaled the ‘arrival’ of FMT, but actually, no……

The 1st TELEVISED fecal transplant performed on Grey’s Anatomy, 11/20/08

First US RDBPCT FMT (colonoscopy)

• 46 patients with multiply rCDI at 2 sites (RI & NY)– Excluded age >75 and immunocompromised

• Intervention: Fresh donor vs. autologous stool• Dosage: 20-100 (mean 64) grams stool/300 ml saline• Primary endpoint: No recurrence of diarrhea

requiring further anti-CDI therapy at 8 weeks

Kelly C, et al. Annals Int Med Aug 2016 Epub ahead of print


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Outcomes Varied by Study site

91% 90% 92%

63%

43%

90%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall Rhode Island New York

Cure with Donor FMT Cure with Placebo

P=0.024 P=0.019 P=0.89

Cochrane Review 2013

• 11 studies• 273 CDI patients • Overall cure 245 / 273

(89.7%)– Upper 82%– Lower: 91%– No reported AEs

Systematic Review 2015

• 2 RCTs, 21 case-series

• 516 patients (rCDI)

• Overall cure 85% – Upper: 77%– Colon: 90%– Enema: 78%– ‘Few short term AEs’

Kassam Z et al. Am J Gastroenterol 2013;108(4):500-508. Drekonja et al. Ann Intern Med 2015;162:630-638


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OpenBiome: open-label data• Non profit stool bank, used by 700+ centers (50

states) and over 15K patients since 2012. • Data on >2000 FMTs 1/2014 – 4/2016• Overall MD-reported cure rate: 84%• FMT by colonoscopy: 86% clinical cure rate • FMT by upper route: 74% clinical cure rate (n=200)

Obrien K, Kassam Z et al. DDW 2016 / IDSA 2016

FMT Safety: still TBD…..• Risk of infection

– Peritonitis, bacteremia (E coli, Proteus, Klebsiella, Listeria)– Norovirus, CMV following home FM

• Risks related to the procedure and administration– Perforation, sedation-related complications– Regurgitation of feces after 500mL slurry via ND tube– Fatal aspiration pneumonia (150 ml in duodenum via

enteroscope) – Bilateral aspiration pneumonia (200 ml via NJtube for IBD)

• Case reports: Rheumatoid Arthritis, ITP, Sjogren’sSyndrome, microscopic colitis, lymphoma, obesity

• IBD flares, increased CRPAas J, et al. Clinical Infectious Diseases 2003; Angelberger S, et al. Am J Gastroenterol 2013Schwartz et al, Am J Gastroenterol 2013Hohmann EL. NEJM 2014

Brandt, et al. Amer J Gastroenterol 2012; 107Ziud H, Advances in IBD 2014Alang N, Open Forum Infect Dis 2015 Agrawal M, et al. J Clin Gastroenterol 2016Baxter M, Clin Inf Dis 2015Van Nood et al. NEJM 2013Vermeire SJ, Crohn’s Colitis 2016Van Beurden, DDW 2016


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FMT: Clinical trials• C. difficile infection (38)• Crohn’s (5)• Ulcerative Colitis (15)• Pouchitis (3)• IBD (9)• IBS (6)• Constipation (4)• NAFLD/NASH (3)• PSC • Intestinal pseudo-obstruction

• Obesity/metabolic syndrome (5) • HIV• DM-II (2)• Pancreatitis (2)• Hepatitis B• MRSA enterocolitis• Drug-resistant organisms (4)• Hepatic encephalopathy (2)• Post-stem cell transplant (2)• Autologous FMT (preventative)

Clinicaltrials.gov 06/02/2016

FMT for CDI in Immunocompromised Hosts: case series data

• 16 centers; 80 IC patients treated with FMT for CDI– IBD, solid organ transplant, oncologic condition, HIV/AIDs, other condition

• 78% cure after single FMT; 89% overall cure• 12 (15%) SAEs, No infections related to FMT

– 10 hospitalizations– 2 deaths

• Aspiration during colonoscopy (pt with advanced esophageal cancer)• Another had pneumonia before and after FMT

Kelly CR et al. Am J Gastroenterol 2014; 109:1065-1071


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FMT for CDI in Immunocompromised Hosts: Meta-analysis

• 50 studies, 381 patients• Immunosuppressant meds (75%), solid organ

transplant (25%), cancer (13%), HIV (2%)– 87% resolution of CDI with 1 FMT (90% w/ 2)– Deaths: 2– Bacteremia: 5– FMT-related hospitalization: 14

Shogbesan O et al. ACG 2016, poster #879

• FMT for C. difficile in IBD: multicenter, retrospective

– 67 IBD patients (52% Crohn’s and 46% UC) in 8 centers– Initial FMT successful in 79%– IBD activity

• Improved post FMT in 37%• Worsened post FMT in 9%

– No SAEs attributed to FMT

FMT for CDI in IBD patients specifically

Fischer M, et al. Inflamm Bowel Dis 2016; 22:2402


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FMT as Rx of IBD? Is dysbiosis pathogenic? Dysbiosis??

EnvironmentalFactors

Immune Dysregulation

GeneticPredisposition IBD

Dysbiosis in IBD

• Reduced diversity c/w healthy subjects

– Increased Proteobacteria– Decreased Bacteroidetes

• Increased pro-inflammatory and entero-adherent bacteria– Bacterial invasion of mucosa

• Is this cause or consequence?

Sellon RK et al. Infect Immun 1998, Anderson JL et al. Alimen Pharmacol Ther 2012Nagalingam NA & Lynch SV. Inflamm Bowel Dis 2012; Xavier RJ, et al Nature 2007; Ott SJ, et al. Gut 2004


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Microbiome-based Rx in IBD: not a new idea

• Diversion of fecal stream (Crohn’s)

• Antibiotics are sometimes beneficial.– Colonic or fistulizing Crohn’s disease or pouchitis

• Efficacy of probiotics in pouchitis or active disease– VSL #3 & E. coli Nissle 1917 for UC

Singh R. Clin Microbiol Inf 2014; Ghouri YA. Clin Exp Gastroenterol. 2014; Mennigen R. Gastroenterol Res Pract 2015; Lopez J. Gastroenterol and Hepatol 2016

IBD patient willingness to undergo FMT

0%

20%

40%

60%

80%

100%

No

Unsure

Yes

Self-reported disease severity and willingness to undergo FMT

Kahn S. Inflamm Bowel Dis 2013

24%

34%

5%2%

11%

19%

5%Proof of safety

Demonstration of efficacy

Side effects of currentmedicationsPerception that it is morenaturalPhysician recommended

Would consider ifconventional therapies failTo avoid taking pills


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FMT in IBD: Evidence from Cohort StudiesAuthor IBD

typePopulation n. FMT Method Response

Kunde S. et al (2013) UC Pediatric 9 Enema 7/9 (78%) response and 3/9 (33%) remission at one week; 6/9 (67%) maintained response at 1 month

Suskind et al (2014) CD Pediatric 9 NG 8 achieved clinical remission (CR) and 1 improved

Zhang et al (2013) CD Adult 16 Gastroscope 12 achieved CR

Kump PK. et al (2013) UC Adult 6 Colonoscopy 2 improved; None achieved CR though microbiota shifted to resemble donor

Angelberger S. et al (2013) UC Adult 5 NJ + enema Positive clinical response in one patient whose microbiota had been effectively augmented by FMT. 2 worsened

Damman et al (2014) UC Adult 7 Colonoscopy 1 deteriorated, 4 no improvement, 2 clinical remission

Vaughn et al (2014) CD Adult 9 Colonoscopy 4 CR, 2 improved, 3 showed no improvement

Vermeire S. et al. (2012) CD Adult 4 NJ infusion No significant clinical or endoscopic improvement at 8 weeks

Landy et al. (2013) UC Adult 5 NG No patient had improvement, no change in immunological parameters

Moayyedi, et al. Rossen, et al.

Study design DBRCT (1:1) DBRCT (1:1)

Study population Adults, mild to moderate UC Adults, mild to moderate UC

Sample size calculation 130 80Randomized/completed 75/70 50/37Donor stool Volunteers, fresh or frozen Volunteers, freshPlacebo Water Autologous stool

Primary endpoint Remission: Mayo score ≤ 2 andendoscopic score of 0 at week 7.

Remission: activity score ≤ 2 and ≥ 1 point decrease in Mayo score at week 12.

Route of delivery Retention enema Naso-duodenal tube

Dose schedule Weekly for 6 weeks 2 doses (0 and 3 weeks)

Subjects achieving primary endpoint (remission)

9/38 (24%) FMT vs. 2/37 (5%) controls (p=0.03)

7/23 (30%) FMT vs. 5/25 (20%) controls (p=0.51)

Moayyedi et al Gastroenterology 2015; 149: 102-109. Rossen et al Gastroenterology 2015; 149; 110-118

FMT in IBD: Evidence from PRCTs


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Why the Conflicting Results?• Treatment Protocol

– Number of infusions (6 vs 2); upper vs. lower route– “Donor B” effect (Donor B: remission in 7/18 (39%), Donors A/C/D/E/F

remission in 2/20 (10%) (P=0.06). • Both stopped early due to futility

– Treatment effect smaller than anticipated (larger study positive)– Greater delta between FMT vs. controls

• Microbiome analysis in both– Showed increased diversity after FMT in responders. – Remission associated with specific changes…Signal?

FOCUS Trial• Randomized, double blind, placebo controlled• 3 centers (Australia); 81 patients• Adults with mild to moderate UC >3 months duration

– Any extent except distal proctitis– Excluded patients receiving anti/probiotics, anti-TNF or any biologic

• Intensive, multi-donor FMT, initially via colonoscopy, then 5 enemas/week x 8 weeks at home

Paramsothy S, et al. DDW 2016


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0

20

40

60

80

100

FMT Placebo

11/41 3/40

27%

8%

p = 0.02

Primary Outcome week 8Steroid free clinical remission AND Endoscopic remission or response

No difference in AEs between armsColitis worsened in 2 pts FMT, 1 PBO

FMT for CDI, immunocompromised, IBD: much work remains

• Is FMT safe (probably) and effective (yes) to Rx CDI in IC and IBD?• Is FMT safe (probably) and effective (TBD) to Rx IBD itself?

• Who is the ideal recipient?– Genotype specific?– Phenotype?: Pouchitis, Proctitis, ileal Crohn’s, Post-operative prophylaxis, remission – Microbiome profile specific?

• Who / what is the ideal donor? And best “dose”, delivery mode?– Infusion schedule– Induction vs. maintenance– Specific donors (‘superdonors’?) with specific beneficial bacterial profiles?


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