Clostridium Difficile (C. diff)

Clostridium difficile Update 2015
Epidemiology and New Treatments including
Fecal Microbiota Transplantation
John Gray, MD, FACG, AGAF
The Presenter
• John Gray, MD, FACG, AGAF
• Gastroenterology Consultants
• Medical Director, Renown
Institute for Digestive and
Liver Care
• 775-852-4848
• [email protected]
Clostridium Difficile Infection
• First identified as primary cause of antibiotic associated
colitis 1978
• 14,000 deaths per year due to CDI
• Hospital acquired CDI increased doubled between 1999
and 2003
• Community acquired CDI 40% of cases
– Less likely to have antibiotic exposure (64% vs 94%)
• 31% of these had been on PPI
– 82% had some health care exposure (Hospital,
Nursing Office, physician or dental office
Background: Impact
Age-Adjusted Death Rate* for
Enterocolitis Due to C. difficile, 1999–2006
2.5
Rate
2.0
Male
Female
White
Black
Entire US population
1.5
1.0
0.5
0
1999 2000 2001 2002 2003 2004 2005 2006
Year
*Per 100,000 US standard population
Heron et al. Natl Vital Stat Rep 2009;57(14).
Available at http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf
Clostridium
Difficile Bacteria
• Clostridium difficile is an anaerobic gram-positive, sporeforming, toxin-producing bacillus first described in 1935
• “difficult clostridium”: hard to grow and culture on
conventional media
• Spore and vegetative forms
• Spores highly resistant to heat, alcohol, acid
• Toxin A (enterotoxin) and B (cytotoxin 10 X potency of A)
Background: Pathogenesis of CDI
1. Ingestion
of spores transmitted
from other patients
via the hands of healthcare
personnel and environment
3. Altered lower intestine flora
(due to antimicrobial use) allows
proliferation of
C. difficile in colon
2. Germination into
growing (vegetative)
form
Sunenshine et al. Cleve Clin J Med. 2006;73:187-97.
4. Toxin A & B Production
leads to colon damage
+/- pseudomembrane
Background: Epidemiology
Risk Factors
• Antimicrobial exposure
– Within 12 wks
• Acquisition of C. difficile
• Advanced age
• Underlying illness
• Immunosuppression
• Tube feeds
• ? Gastric acid
suppression
Main modifiable risk
factors
Background: Epidemiology
Current epidemic strain of C. difficile
• BI/NAP1/027, toxinotype III
• Historically uncommon – epidemic since 2000
• More resistant to fluoroquinolones
– Higher MICs compared to historic strains and current
non-BI/NAP1 strains
• More virulent
– Increased toxin A and B production
– Polymorphisms in binding domain of toxin B
– Increased sporulation
McDonald et al. N Engl J Med. 2005;353:2433-41.
Warny et al. Lancet. 2005;366:1079-84.
Stabler et al. J Med Micro. 2008;57:771–5.
Akerlund et al. J Clin Microbiol. 2008;46:1530–3.
CDI: Symptoms
• Carrier state:
– 20 % (hospitals)
– 50% (LTC facilities, infants ),
– 2% in healthy patients
•
•
•
•
•
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Diarrhea with colitis
Fever (15%), abdominal pain, high WBC
Rectal bleeding unusual
Pseudomembranous colitis
Toxic megacolon
Exacerbation of IBD
Pseudomembranous Colitis
CDI: Diagnosis
• PCR test for Toxin A and
B
– Highly sensitive and
specific
– Results in 1 hour
– Some false positives
• EIA for C. difficile GDH
• EIA for C. difficile toxins A
and B
• Cell culture cytotoxicity
assay
– Gold standard
• Selective anaerobic
culture
– Most sensitive
• Endoscopy
– PMC is
pathognomonic
CDI: Role of Colonoscopy
• High clinical suspicion for C. difficile with negative
laboratory assay(s)
• Prompt C. difficile diagnosis needed before laboratory
results can be obtained
• Failure of C. difficile infection to respond to antibiotic
therapy
• Atypical presentation with ileus or minimal diarrhea
CDI: Treatment of Initial Infection
• Discontinue any current antibiotics as soon as possible
• Metronidazole 500 tid (PO or IV) or 250 qid po x10-14
days
– Cost of 2 wks $214
• Vancomycin 125 mg qid x 10-14 days (PO only)
– Cost of 2 wks $1400
• 90-98% effective
• No need to repeat Toxin assay if patient asymptomatic
after treatment
– Can remain + for 6 wks after treatment
CDI: Severe Infection Diagnosis
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WBC > 15K
Cr > 1.5 x pre morbid Cr
Fever > 38.3
Albumen < 2.5
PMC
> 10 BM day
Severe Abdominal Pain
CDI: Severe Infection Treatment
• Vancomycin 125 mg (? 500 mg) qid po1st line choice
• Fidaxomycin 200 mg po bid if no response to
Vancomycin
• If Ileus add metronidazole 500 mg IV q 8 hours
– Consider rectal vancomycin retention enema
containing 500 mg in 100 mL of normal saline every 6
hours
• Surgery for toxic megacolon, necrotizing enterocolitis,
refractory disease
CDI: 1ST Recurrence
• 25 % of patients will have 1 recurrence
– 45-60 % will have additional recurrence
• Treat 1st recurrence similar to initial infection, however if
initial infection severe, treat with vancomycin
• ? Role of Fidaxomycin
– possibly lower risk of recurrence compared to
vancomycin (15 vs 25%)
– bacteriocidal, narrow antimicrobial spectrum
– cost $3296
CDI: 2ND recurrence
• 6 wk tapered course of
Vancomycin (Preferred)
– Cost $2200
Additional Recurrences
• Vancomycin follow by Rifaximin
• Fidaxomicin
• Fecal Microbiota Transplanation
– Experimental
– No randomized controlled studies
Fecal Microbiota Transplant
•
•
•
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Stool from healthy donor diluted, filtered, centrifuged
Donor can be healthy selected or patient selected, at Renown use a stool
bank from healthy donors
Method of Administration
– NGT
• Risk SIBO, vomiting, aspiration
• Inexpensive
– EGD
• Especially helpful if colon inflamed
• Risk SIBO
– Rectal Enema
• inexpensive
– Colonoscopy
90% successful in preventing recurrence
Long-Term Follow-Up of
Colonoscopic Fecal Microbiota
Transplant for Recurrent Clostridium difficile Infection
• 43 patients treated
• Donors:10 patient selected, 33 random donors
• Study results not affected by relationship between
donor and patient
• Cure rate 86 % after 1 treatment 95 % after 2
treatments
• Primary method of administration colonoscopy
• No major side effects
Khoruts et al, Am J Gastroenterol 2012; 107:761–767
Donor Testing
• Ab for HIV 1 and 2.
• Viral Hepatitis A IgM.
• Hepatitis B surface Ag and
core Ab.
• HCV Ab.
• RPR.
• Stool cultures for enteric
pathoges including
Salmonella, Shigella,
Yersinia, Campylobacter, E.
Coli O157:H7, MRSA, VRE
• Ova and parasites
examination.
• StoolGiardia,Cryptosporidium
and Helicobacter pylori
antigens.
• Clostridium difficile toxin B
PCR.
• Liver function tests including
alkaline phosphatase, AST,
ALT
Donor Screening (infection)
• Known HIV or Hepatitis B, C infection.
• Known exposure to HIV or viral hepatitis at any time.
• High risk behaviors including sex for drugs or money,
men who have sex with men, more than one sexual
partner in the preceding 12 months, history of
incarceration, any past use of intravenous drugs or
intranasal cocaine.
• Tattoo or body piercing within 12 months.
• Travel to areas of the world with increased risk of
travelerʼs diarrhea.
• Current communicable disease, e.g., upper respiratory
tract viral infection.
Donor Screening (other)
• History of irritable bowel syndrome, or any of the
associated symptoms,including frequent abdominal
cramps, excessive gas, bloating, abdominal distension,
fecal urgency, diarrhea or constipation.
• History of inflammatory bowel disease such as Crohnʼs
disease,ulcerative colitis, lymphocytic colitis.
• Chronic diarrhea.
• Chronic constipation or use of laxatives.
• History of gastrointestinal malignancy or known colon
polyposis.
Donor Screening (other)
• History of any abdominal surgery, e.g., gastric bypass,
intestinal resection, appendectomy, cholecystectomy,
etc.
• Use of probiotics or any other over the counter aids for
specific purposes of regulating digestion.
• Established metabolic syndrome or any early features
suggestive of its emergence. Body mass index > 26
kg/m2, waste:hip ratio > 0.85 (male) and > 0.8 (female);
BP > 135 mmHg systolic and > 85 mmHg diastolic.
• Known systemic autoimmunity, e.g., connective tissue
disease, multiple sclerosis, etc.
Donor Screening (other)
• Known atopic diseases including asthma or eczema.
• Chronic pain syndromes including fibromyalgia, chronic
fatigue syndrome.
• Ongoing (even if intermittent) use of any prescribed
medications, including inhalers or topical creams and
ointments.
• Neurologic, neurodevelopmental, and
neurodegenerative disorders including autism,
Parkinsonʼs disease, etc.
Donor Screening (other)
• Presence of a skin rash, wheezing on auscultation,
lymphadenopathy, hepatomegaly or any stigmata of liver
disease, swollen or tender joints,’ muscle weakness,
abnormal neurological examination.
Benefits of Healthy Selected Donor
• Donor screening criteria can be highly selective to avoid
patients with those conditions possibly associated with
the microbiome
• Convenience
• Donor screening costs spread over many patients.
– 3 patients per donated specimen
– Screening labs done every 6 months
– Each stool tested for infectious agents
• Potential immediate availability for use during severe
refractory infection
Renown FMT Program
• Patients must have had an initial CDI and 2 recurrences
• Random highly selected donor (Stool Bank from National
Source)
• Frozen specimens kept for 1 year
• Administration via Colonoscopy or if felt not safe, EGD
into the duodenum
• May be given by EGD in severe fulminant PSM with ileus
not responding to usual therapy (while continuing usual
therapy)
• Protocol/Study approved by the Renown Institutional
Review Board
• Will track and report results
Patient Eligibility
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1 initial infection and 2 or more recurrent episodes of toxin positive mild to moderate
C. difficile infection including 1 relapse despite 6 week of pulsed/tapered vancomycin
Persistent symptomatic toxin positive C. difficile infection not responding to
conventional therapy (vancomycin) for at least 1 week.
Severe toxin positive C. difficile infection (hospitalized patient with fulminant C difficile
and illeus) will be treated at the treating physician’s discretion.
Although there are no absolute contraindications, Considerations for
Increased Risk of Adverse Events should be given to:
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Known history of immunosuppressive agents, including high dose corticosteroids, calcineurin inhibitors,
chemotherapy and anti-tumor medications.
Patients must have adequate liver function.
No history of HIV, bone marrow transplant within the last year, or any other cause
that would effect the immune system.
Renown FMT Protocol
• FMT is to prevent recurrence of CDI. The
initial infection must be completely treated
and the patients symptoms back to their
baseline prior to FMT.
• If CDI patient still having diarrhea and
cramping after treatment, additional testing
necessary to explain symptoms prior to
FMT
Renown FMT Protocol
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Patients should complete a 2 wk course of antibiotics after their last replapse
(preferable vancomycin or Fidaxomycin) prior to receiving FMT.
Stop current antibiotics 24-48 hours prior to transplant (Not in case of severe or
persistent colitis)
Clear liquid diet/bowel preparation 1 day prior
FMT via colonoscopy, or EGD if colonoscopy not felt safe
Obtain random biopsies throughout the colon to r/o microscopic colitis
Patient monitored by FMT physician/office staff 2,4,6 and 8 wks post FMT by phone
or office visit
– Office visits needed at least at 1-2 wks and 8 wks post FMT
– Follow up office visits should include objective assessment of patients symptoms
(diarrhea, abdominal pain or cramps, general well being) relative to their
baseline.
– Patients must be able to and commit to follow up in order to participate in the
study
C. Diff Toxin checked at 8 wks
Thank You
• John Gray, MD, FACG, AGAF
• Gastroenterology Consultants
• Medical Director, Renown
Institute for Digestive and
Liver Care
• 775-852-4848
• [email protected]
Additional Information
• Patient should be referred to a gastroenterologist.
• Questions from clinical staff and physicians can be
directed to Dr. Gray at 775-852-4848 or
[email protected].
• If you or someone you know if interested in being a fecal
donor, contact Shannon White, RN, at 775-982-5050 or
[email protected].