Transcript C. difficile - Lafayette Medical Education Foundation

C. difficile prevention & treatment
Probiotics, antibiotics
& fecal microbiota transplantation
The scoop on therapeutic poop
Monika Fischer, MD, MSCR
Assistant Professor of Clinical Medicine
Disclosure
 No conflict of interest
Clostridium difficile infection
(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
Beginning of 2000
Epidemic strain of C. difficile
 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
.
BI/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
C. difficile infectious inoculum is 10 spores
Poutanen SM et al. CMAJ. July 6,2004;171(1).
Host 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 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
control 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 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: 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 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: 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
pouch, 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 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 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 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.
ACG guidelines 2013
 ((Fecal transplant?))
Special 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 CDI
ACG guidelines 2013
 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
Recurrent C. difficile infection
• 25% of patients have a recurrence after
the initial treatment
• Patient with first recurrence have a 3545% 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
rates with metronidazole and high recurrence
rates with both metronidazole and vancomycin
Aslam S. et al. Lancet Infec.Dis. 2005. 5:549-557
(pooled results from 25 studies)
Fidaxomicin
 New bacteriocidal antibiotic
 Poorly absorbed narrow-spectrum
macrolide
 FDA approval for CDI in 2011
Fidaxomicin vs.Vancomycin
Louie TJ. NEJM. 2011;364:422-31
Vancomycin vs. fidaxomicin for
the first recurrence of CDI
20%
recurrence
36%
recurrence
Cornelly OA. Clin Infect Dis. 2012. 55: 154-61
The New Kid on the block:
Stool
 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
medicine since the 17th century
• Transfaunation
• Horses with diarrhea per rectum
• Cattle per os as rumen
Modern history of human fecal
transplantation
 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
since 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 • Vancomycin •
of donor feces after
therapy for 14
vancomycin for 4
days
days and bowel
lavage
Vancomycin therapy
for 14 days plus
bowel lavage on day
4-5
15
13
Nood et al
NEJM.
Jan. 2013
Microbiota diversity
increases after stool
transplant
Nood
NEJM
2013
Who should be treated with
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 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 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 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 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 badge
Which route of administration
is the best?
Nasogastric
Nasoenteric tube
EGD
Fecal enemas
Via colonoscopy
Easy to administer
Highest patient
Cheap
acceptance
Quick
Can be performed at
Convenient
home
Ability to assess
Inexpensive
disease severity
Avoid colonoscopy
and colonic
mucosa
 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
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):10441049.
Why and how does FMT work?
Borody,
T. J. &
Khoruts,
A. (2011)
Nat. Rev.
Gastroen
terol.
Hepatol.
Mechanism 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
recipient 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
recurrence 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
Animal experiment –
murine model of C. difficile colitis
1. Mice treated with Clindamycin for 7 days
2. Infected with C. difficile BI/NAP1/027 from
hospitalized patients
3. Mice developed severe colitis
4. Dysbiosis
• Reduced diversity
• Reduced Bacteriodetes and Firmicutes
• Increased opportunistic pathogens (Klebsiella,
E. coli, Proteus mirabilis, Enterococcus faecalis)
• Up-regulated pro-inflammatory genes
Lawley et al. PLOS 2012
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 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
‘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 ?
 Custom designed pill of selected microorganisms 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
• 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
References
 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
References
 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