C. difficile prevention & treatment Probiotics, antibiotics & fecal microbiota transplantation The scoop on therapeutic poop Monika Fischer, MD, MSCR Assistant Professor of Clinical Medicine
C. difficile prevention & treatment
Probiotics, antibiotics & fecal microbiota transplantationThe scoop on therapeutic poop
Monika Fischer, MD, MSCRAssistant Professor of Clinical Medicine
DisclosureDisclosure
No conflict of interest
Clostridium difficile infection Clostridium difficile infection (CDI)(CDI)
Traditional medical school fact: Clostridium difficile pseudomembranous colitis is a Clindamycin aftermath and highly treatable with metronidazole
C. difficile infection (CDI) associated with numerous other antibiotics and often resistant
to metronidazole
US rates hospital discharges with CDI doubled between 2000 and 2008
Increased need for ICU stay and prolonged antibiotic courses to clear infection
High colectomy rates (10%) High case mortality: 7500/year (10-fold increase
since 1999) Refractory disease in low risk populations
Beginning of 2000Epidemic strain of C. difficile
.
BI/NAP1/027BI/NAP1/027
Linked to widespread fluoroquinolone and cephalosporin use
High-level fluoroquinolone resistance “Hypervirulent” 18-fold more toxin A & B Binary toxin: Improved toxin-binding and
translocation into the cells
Poutanen SM et al. CMAJ. July 6,2004;171(1).
C. difficile infectious inoculum is 10 spores
Host factorsHost factors Age ≥ 65 year Immunosuppression
– recipients of organ transplants (3-11%), chemotherapy, corticosteroids, HIV, IBD, ESRD, ESLD
PPI use ≥ 3-fold Hospitalization, long-term care facilities
– After 1 week 13%, after 4 weeks > 50% colonization rate
Previous CDI
Prevention: infection controlPrevention: infection control
Early detection– High index of suspicion in patients with risk factors– Empiric therapy should be started regardless of
laboratory testing– Use of best diagnostic test for toxigenic C. diff.
with a rapid turn-around time (PCR)– Repeat stool testing is discouraged
• < 5% chance for positive test
Routine screening in hospitalized patients without diarrhea is not recommended
Hospital-based infection Hospital-based infection control programcontrol program
Antibiotic stewardship Contact precautions should be maintained
at a minimum until the resolution of the diarrhea
– Private rooms– Hand hygiene: soap (preferably 4%
chlorhexidine) & water. Alcohol based antiseptic does not kill C.diff spores!
– Barrier precautions (gloves & gowns)
Prevention: infection controlPrevention: infection control
Single use disposable equipment Environmental disinfection with10% bleach
(5,000 p.p.m. chlorine) for at least 10 minutes
Infection control “bundle” decreased CDI hospital rates by 33% (7.2/1000 to 4.8/1000)
Prevention: ProbioticsPrevention: Probiotics
Annals 2012 SER and Meta-analysis of 20 trials: Probiotics given for the duration of the antibiotic therapy or up to 2 weeks after reduced the incidence of CDI by 66%
No difference in outcome – Between species: Bifidobacterium, Lactobacillus,
Saccharomyces, or Streptococcus– Single species vs. mixture– Adults vs. children– Lower or higher doses (<10 billion CFU/d vs.≥10 billion
CFU/d)
Treatment: supportive careTreatment: supportive care
Any inciting antimicrobial agent should be discontinued
Maintain enteral nutrition Fluid resuscitation, electrolyte replacement DVT prophylaxis Anti-motility agents are allowed but only in
combination with medical therapy
Treatment: antibioticsTreatment: antibiotics
Patients with mild-to-moderate CDI should be treated with metronidazole 500 mg po tid for 10 days
Patients with severe CDI should be treated with vancomycin 125 mg po qid for 10 days
Failure to respond to metronidazole therapy within 5-7 days should prompt change to vancomycin
ACG guidelines 2013
Patients with ileostomy, Hartman’s Patients with ileostomy, Hartman’s pouch, or colon diversionpouch, or colon diversion
Vancomycin via enema should be included in the treatment
Oral vancomycin can’t reach the disconnected segments
Metronidazole as adjunctive therapy: colonic excretion is high across the inflamed mucosa but drops dramatically once mucosa starts to heal
CDI severityCDI severity
Mild-to-moderate: diarrhea ± any other sign/symptom - not meeting criteria for severe
Severe: serum albumin< 3g/dl plus one of the following
– WBC≥ 15,000– Abdominal tenderness
ACG guidelines 2013
Severe and complicated CDISevere and complicated CDI
Any of the following attributable to CDI:– Admission to ICU– Hypotension– T≥ 38.5 °C– Ileus or significant abdominal tenderness– Mental status changes– WBC ≥ 35,000 or ≤ 2,000– Serum lactate level > 2.2 mmol/L– End organ failure
ACG guidelines 2013
Severe and Complicated CDISevere and Complicated CDI
Vancomycin 500 mg po qid plus metronidazole 500 mg iv q 8 hrs, and vancomycin per rectum (500 mg in 500ml saline as enema) qid (patients with ileus)
Consult surgery: colectomy vs. loop ileostomy with lavage and vancomycin flushes
Fidaxomicin po and tigecycline iv. ((Fecal transplant?))
ACG guidelines 2013
Special situationsSpecial situations Pregnancy and breastfeeding: Oral Vancomycin IBD
– All patients with IBD flare need testing for c.diff – empirical therapy
– Highest risk with corticosteroid use > 3-fold– Reduced dosing of corticosteroids – Immunosuppression can be maintained but
escalation should be avoided– Initiation of anti-TNF 72-hrs after starting therapy
for CDI
C. diff can cause enteritis and pouchitis!
Treatment of Recurrent CDITreatment of Recurrent CDI
Repeat metronidazole if the first epidose was treated with metronidazole
Treat with vancomycin pulse regimen for severe or if the first episode was treated with vanco
– Vancomycin 125 mg po qid for 10 days followed by 125 mg every 3 days for 10 doses
Consider FMT for the third recurrence
ACG guidelines 2013
Recurrent Recurrent C. difficile C. difficile infectioninfection
• 25% of patients have a recurrence after the initial treatment
• Patient with first recurrence have a 35-45% chance for second recurrence
• With subsequent recurrence: risk > 50%
• Antibiotics are not very helpful
Kelly and Lamont. NEJM 2008
After emergence of BI/NAP1/027 high failure After emergence of BI/NAP1/027 high failure rates with metronidazole and high recurrence rates with metronidazole and high recurrence rates with both metronidazole and rates with both metronidazole and vancomycinvancomycin
Aslam S. et al. Lancet Infec.Dis. 2005. 5:549-557 (pooled results from 25 studies)
FidaxomicinFidaxomicin
New bacteriocidal antibiotic Poorly absorbed narrow-spectrum
macrolide FDA approval for CDI in 2011
Fidaxomicin vs.Vancomycin Fidaxomicin vs.Vancomycin
Louie TJ. NEJM. 2011;364:422-31
Vancomycin Vancomycin vs.vs. fidaxomicin for fidaxomicin for the first recurrence of CDIthe first recurrence of CDI
20% recurrence
36% recurrence
Cornelly OA. Clin Infect Dis. 2012. 55: 154-61
The New Kid on the block: The New Kid on the block: StoolStool
FMT is placement of suspension of fresh stool harvested from healthy individual into the gastrointestinal tract of an individual with CDI
– Through standard colonoscopy– Rectal enema– NJ and NG tube
Alternative therapy, but by no means new…
A 1,700-year-old method
• 4th century China: human fecal suspension by mouth “yellow soup“ for food poisoning, severe diarrhea
Fecal transplantation in veterinary Fecal transplantation in veterinary medicine since the 17medicine since the 17thth century century
• Transfaunation
• Horses with diarrhea per rectum
• Cattle per os as rumen
Modern history of human fecal Modern history of human fecal transplantationtransplantation
1958 Ben Eiseman reported “miraculous cure” with FMT in 4 patients with fulminant pseudomembranous colitis
“re-establish the balance of nature” “immediate and dramatic” responses “this simple yet rational therapeutic method should
be given more extensive clinical evaluation”
Explosion of FMT case studies Explosion of FMT case studies since 2010since 2010
• > 500 cases reported with 92% success rate with the first treatment and up to 98% if a second infusion was necessary
• Longest follow up 17 months of 77 pts – zero recurrence without antibiotics (all recurrences related to antibiotic use 8/30)
• 97% of patients would undergo another FMT if needed• 57% voted for FMT as their preferred first treatment option
Brandt, L. ACG. 2012
• Duodenal infusion of donor feces after vancomycin for 4 days and bowel lavage
• Vancomycin therapy for 14 days
• Vancomycin therapy for 14 days plus bowel lavage on day 4-5
Nood et alNEJM.
Jan. 2013
13
15
NoodNEJM2013
Microbiota diversity increases after stool
transplant
Who should be treated with Who should be treated with FMT?FMT?
After 3 episodes or after failure of vancomycin pulse regimen (ACG guidelines)
L. Brandt recommendations:• First line therapy in severely ill patients• FMT may be preferred for the first episode of
CDI because antibiotic perturbs the microbiota and may lead to antibiotic resistance
Brandt, L. JCGE. 2011
Risks of FMTRisks of FMT
• Colonoscopic perforation• Transmission of infections and other
diseases
• Long-term risk? Increased incidence of autoimmune conditions: 4 out of 77 patients developed peripheral neuropathy, Sjӧgren syndrome, RA, ITP within median 17 months f/u
Brandt LJ. ACG. 2012;107:1079-1087
Donor selectionDonor selection
Intimate contacts, family members to mitigate risk of transmissible diseases
But, results with “standardized” or “universal” donors are similarly excellent with fresh or frozen/thawed preparations
Donor screeningDonor screening
Stool– Bacterial culture– Ova & parasites including Giardia,
Cryptosporidium, Cyclospora, Isospora– C.difficile– H. pylori
Blood– Hepatitis A, B, C– HIV 1/2– Syphilis
Donor selectionDonor selection
Exclusion criteria– IBD, IBS, functional diarrhea or constipation,
h/o GI malignancy – Antibiotic use within 3 months– Systemic chemotherapy or
immunosuppression within 1 year– Known HIV, hepatitis B and C, illicit drug use,
incarceration, tattoo/piercing within 6 months
Donor’s badgeDonor’s badge
Which route of administration Which route of administration is the best? is the best?
SER 1: colonoscopy and enema (required repeated infusions) with superior cure rate > 85% vs. 76% upper GI route
SER 2: colonoscopy superior 93% vs. 85% nasogastric tube
NasogastricNasoenteric tubeEGD
Quick ConvenientInexpensiveAvoid colonoscopy
Fecal enemas
Easy to administerCheapCan be performed at home
Via colonoscopy
Highest patient acceptance
Ability to assess disease severity and colonic mucosa
FMT via colonoscopy at IU
FMT at IU Hospital
Patient preps for colonoscopy Stops vancomycin 36-48 hrs before
FMT Fresh stool (not older than 6 hrs)
emulsified in the endo suite and infused into the terminal ileum or right colon
Patient receives Imodium and observed for 2-3 hrs.
Environmental cleaning at home CPT code 44705
Bakken J, Borody T, Brandt L et al.
Treating Clostridium difficile Infection With Fecal Microbiota Transplantation.
Clinical Gastroenterology and
Hepatology, December 2011, 9(12):1044-
1049.
Why and how does FMT work?Why and how does FMT work?
Borody, T. J. &
Khoruts, A. (2011)Nat. Rev. Gastroen
terol. Hepatol.
Mechanism of actionMechanism of action
FMT is introduction of a complete, stable community of gut-organisms to repair or replace the disrupted native microbiota
Reestablishment of the host defense against C. difficile
Engraftment of the donor microbiota is durable
Bacterial fingerprints of the donor and Bacterial fingerprints of the donor and recipient stool before and after FMTrecipient stool before and after FMT
Khoruts A. J Clin Gastroenterol. 2010;44:354-360
Donor Day 0; Patient Day 14; Patient Day 33
Probiotics in the treatment and Probiotics in the treatment and recurrence prophylaxis of CDIrecurrence prophylaxis of CDI
Limited evidence for adjunct probiotics to reduce risk of recurrence
S. boulardii showed efficacy in few trials reducing recurrence rate to 35% vs. 65% but only in patients on high dose vancomycin
Why probiotics don’t work? – Insufficient CFU count– Not the right species or mixture – Wrong media (milk) to culture probiotics
Lawley et al. PLOS 2012
1. Mice treated with Clindamycin for 7 days2. Infected with C. difficile BI/NAP1/027 from
hospitalized patients3. Mice developed severe colitis4. Dysbiosis
• Reduced diversity • Reduced Bacteriodetes and Firmicutes• Increased opportunistic pathogens (Klebsiella,
E. coli, Proteus mirabilis, Enterococcus faecalis) • Up-regulated pro-inflammatory genes
Animal experiment – murine model of C. difficile colitis
5. Mice treated with vancomycin
• Suppression of C. difficile shedding
6. Relapse upon cessation of therapy
7. FMT using healthy mice stool per os
Durable suppression of C. difficile shedding for several months resolve disease and contagiousness
Lawley PLOS 2012
Targeted bacteriotherapyTargeted bacteriotherapy
Instead of stool from healthy mice
A mixture of six phylogenetically diverse bacterial species including obligate and facultative anaerobes Bacteriodetes and Firmicutes cured CDI in mice with severe colitis infected with BI/NAP1/027
Lawley, T. 2012
Stool substitute to Stool substitute to ‘rePOOPulate’ the gut‘rePOOPulate’ the gut
• Made from purified intestinal bacterial cultures derived from a healthy donor after recovering 33 isolates using “Robogut”
Petrof, EO. Microbiome
2013.
Future ?Future ?
Custom designed pill of selected micro-organisms to restore the balance of the microbiota or correct a deficiency of a specific commensal organism curing a disease or reversing a metabolic condition
Summary of FMT Summary of FMT
• FMT is a simple, acceptable and currently the most efficacious treatment for recurrent CDI--- may play a role in the treatment of variety of GI and non-GI diseases
• FMT via the upper tract seems to be less efficacious than via the lower tract
• Long-term safety remains unknown
• The Future… “Artificial stool” or targeted bacteriotherapy
ReferencesReferences
Surawicz, Ch. Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficle infections. AJG. 2013
Johnston, B. Probiotics for the prevention of Clostridium Difficile-Associated Diarrhea. Annals. 2012
Van Nood, E. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. NEJM. 2013
ReferencesReferences Brandt, L. Intestinal Microbiota and the Role
of Fecal Microbiota Transplant in the Treatment of C. difficile Infection. AJG. 2013
Bakken, J. Treating Clostridium difficile Infection with Fecal Microbiota Transplantation (the Fecal Microbiota Transplantation Workgroup). CGH. 2011
Brandt, L. An overview of fecal microbiota transplantation. Gastrointest. Endosc. 2013