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Anita Olczak
Clostridium difficile infection
Katedra i Klinika Chorób Zakaźnych i Hepatologii
CM UMK
Wwykład sponsorowany przez BMS
C. difficile: microbiology
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Gram positive spore forming bacillus (rods)
Obligate anaerobe
Part of the GI Flora in
◦ 1-3% of healthy adult
◦ 70% of children < 12 months
Some strains produce toxins A & B
Toxins-producing strains cause C. diff Infection (CDI)
CDI ranges from mild, moderate, to severe and even fatal illness
C. difficile: microbiology
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A common cause of nosocomial antibiotic-associated diarrhea (AAD)
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Most common infectious cause of acute diarrheal illness in LTCFs
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The only nosocomial organism that is anaerobic and forms spores (survive
> 5 months and hard to destroy)
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Pathogenesis is mainly due to toxins production
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Infective dose is < 10 spores
Changing Epidemiology.
Current strange of C . difficile
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BI/NAP1/027, toxinotype III
 Historically uncommon – epidemic since 2000
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More resistant to fluoroquinolones
Produces extra toxin called binary toxin
More virulent
 Increased toxin A and B production
 Change in binding domain of toxin B  increase adherence to the
gut wall
 Increased sporulation  increase survival
• Causes more cases and more severe disease even at low risk populations
C. difficile: Transmission
C. difficile: Transmission
C. difficile: Transmission
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Fecal – oral route
◦ Contaminated hands of healthcare workers
◦ Contaminated environmental surfaces.
Person to person in hospitals and LTCFs
Reservoir:
◦ Human: colonized or infected persons
◦ Contaminated environment
C. diff spores can survive for up 5 months on environmental surfaces.
C. difficile: Pathogenesis
Antibiotic
therapy
Disruption of gut
flora
C. difficile
exposure
Toxin
production
C. difficile: Pathogenesis
Step 1- Ingestion
of spores
transmitted
from other patients
Step 2- Germination into
growing (vegetative) form
Step 3 -
Altered lower intestine
flora (due to antimicrobial use)
allows proliferation of C. difficile in
colon
Step 4 . Toxin B & A
production leads to colon damage
+/- pseudomembrane
C. Difficile infection: Risk factors
•Antimicrobial exposure
• Any and all antibiotics – including surgical prophylaxis
• Clindamycin – highest risk for original strain
• Fluoroquinolones – highest risk for NAP1 strain
• Sulfamethoxazole-trimethoprim prophylaxis has not been
associated with CDAD
• Reduced humoral response
• Acid suppressant agents
C. Difficile infection: Risk factors
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Exposure to antimicrobials (prior 2-3 months)
Exposure to healthcare (prior 2-3 months)
Prolonged hospitalization
Infection with toxogenic strains of C. difficile
Old age > 65 years
Severe underlying illness
Immunosuppression & HIV
Chemotherapy (immunosuppression & antibiotic-like activities)
Tube feeds and GI surgery
Exposure to gastric acid suppression meds ??
Antimicrobials Predisposing to CDI
Very commonly related
Less commonly related
Uncommonly related
Clindamycin
Ampicillin
Amoxicillin
Cephalosporins
Fluoroquinolons
Sulfa
Macrolides
Carbapenems
Other penicillins
Aminoglycosides
Rifampin
Tetracycline
Chloramphincol
 Among symptomatic patients with CDI:
• 96% received antimicrobials within the 14 days before onset
•100% received an antimicrobial within the previous 3 months
 20% of hospitalized patients are colonized with C. difficile
Acid suppression and CDAD
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Clostridium difficile spores are not killed by gastric acid
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BUT, vegetative forms which germinates spore form are killed by
gastric acid
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Clinical trials differ
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2 x higher incidence of CDAD with proton pump inhibitors
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Confounded by severity of disease and hospital length of stay
Cohen SH et al. IDSA Guidelines 2010,Dubberke ER et al. AJT 2009,Cunningham R et al. J Hosp Infect 2003,Dubberke ER et al. Clin
Infect Dis 200, Loo VG et al. NEJM 2005
Clinical manifestation
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Illness caused by toxin-producing strains of C. difficile ranges from
◦ Asymptomatic carriers = Colonized
◦ Mild or moderate diarrhea
◦ Pseudo membranous colitis that can be fatal
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A median time between exposure to onset of CDI symptoms is of 2–3 days
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Risk of developing CDI after exposure ranges between 5-10 days to 10
weeks
Cohen SH et al. IDSA Guidelines 2010,Dubberke ER et al. AJT 2009,Cunningham R et al. J Hosp Infect 2003,Dubberke ER et al. Clin
Infect Dis 200, Loo VG et al. NEJM 2005
Clinical manifestation
Typical presentation
• Watery diarrhea
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Up to 10-15 bowel movements
per day
Fever
Abdominal cramping,
discomfort
Unexplained leukocytosis
Atypical presentation
• Vitals: fever
• Physical exam: abdominal
pain/distension
• Lab values: leukocytosis >30,000
cells/mm3
• >50% transplant patients
• CT scan: severe colitis
Cohen SH et al. IDSA Guidelines 2010,Dubberke ER et al. AJT 2009,Cunningham R et al. J Hosp Infect 2003,Dubberke ER et al. Clin
Infect Dis 200, Loo VG et al. NEJM 2005
Symptoms of CDI
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Watery diarrhea
 > 3 unformed stools in 24 or fewer consecutive hours
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Loss of appetite
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Fever
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Nausea
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Abdominal pain and cramping
Diagnosis
• Up to 50% of hospitalized patients are colonized
• Only perform diagnostic tests if symptomatic
• CDAD is a clinical diagnosis
• Colonoscopy for the presence of pseudomembranes
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definitive diagnosis
• Test for C.difficile toxin in stool
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Cytotoxicity cell assay (Gold Standard)
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Expensive, 24 hour turn around time
ELISA
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Inexpensive, rapid turn around time
60-90% sensitive with a negative predictive value >95%
Repeat testing increases risk of false positive
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
Best strategy for C. difficile testing
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Testing should be performed only on diarrheal stool
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Testing asymptomatic patients is not indicated
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Testing for cure is not recommended
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
Best strategy for C. difficile testing
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For clinical use: two-step testing uses initially EIA detection
of GDH for screening followed by cytotoxicity assay or
toxigenic culture for confirmation
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Gold standard is stool culture followed by toxigenic culture
assay
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Toxin is very unstable, degrades at room temperature, and
undetectable within 2 hours (false negative results)
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
CDI Surveillance: Case definition
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Case definition
 Clinical: presence of diarrhea AND
 Laboratory: A stool test result positive for toxigenic C. diff or its toxins
OR colonoscopic / histopathologic findings demonstrating evidence of
pseudomembranes
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
CDI Surveillance: Case definition
Surveillance definitions of CDI by time of onset:
 Healthcare facility (HCF)-onset, HCF-associated CDI  Onset > 48 hrs of
admission
 Community-onset, HCF-associated CDI  Onset in the community or
within 48 hours of admission and within < 4 weeks of the last discharge
 Community-associated CDI  Onset in the community but within more
that 12 weeks of last discharge
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
Diagnosis
Test
Advantage
Disadvantage
• Detects toxin A or both A & B
• Rapid (same day)
Less sensitive 63-94%
Provides specific and sensitive results for
C. diff
67-100%
-Detect toxin B
-Technical expertise
-Expensive
-24-48 hours
Glutamate
Dehydrogenase
(GDH)
Rapid, sensitive, may prove useful as a
triage or screening tool
Not specific, toxin testing
required to
verify diagnosis
PCR
Rapid, sensitive, detects presence of toxin
gene
Expensive
Special equipment
Most sensitive test available when
performed appropriately
False-positive
results if isolate is not tested
for toxin
labor-intensive; requires 48–96
hours
Enzyme immunoassay (EIA)
Testing
Toxins
Organism ID
Tissue culture
cytotoxicity assay
Stool culture
Classifying Disease severity
Clinical Definition
Supportive Clinical Data
Initial episode, mild or moderate
WBC < 15,000 cells/mcL
OR
Scr < 1.5 x above baseline
Initial episode, severe
WBC > 15,000 cells/mcL
OR
Scr > 1.5 x above baseline
Initial episode, severe, complicated
Hypotension or shock, ileus, megacolon
Cohen SH et al. IDSA Guidelines 2010
Classifying Disease severity
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Dehydration
Electrolyte disturbances
Hypoalbuminemia
Toxic megacolon
Bowel perforation
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Sepsis
• Renal failure
• Total colectomy
• Death
Cohen SH et al. IDSA Guidelines 2010
Prevention
• Horizontal transmission (IDSA)
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Hand washing with soap and water
Contact precautions: gloves and gown
Clean areas with sporicidal agents
• Minimize risk factors
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
Prevention
Core
Supplemental
Gloves/gowns on room entry
Private room (preferred) or
cohort with dedicated commodes
Dedicated equipment
Maintain for duration of
diarrhea
Measure compliance
 Extend use of contact
precautions beyond duration
of diarrhea
 Presumptive isolation
 Universal glove use on units
with high CDI rates
 Intensify assessment of
compliance
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009
Prevention
http://www.medscape.org/viewarticle/558476
Treatment
 Stop or narrow antibiotics
 Metronidazole (PO, IV)
 Vancomycin (PO, PR)
 Fidaxomycin (PO)
 Alternatives
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IVIG
Rifaximin
Nitizoxanide
Metronidazole
Metronidazole Not FDA approved for CDAD
Mechanism: disrupts protein synthesis resulting in cell death in
anaerobic bacteria
 Dose: 500 mg PO Q8h, 500 mg IV Q6-8h
 Pharmacokinetics: rapidly absorbed
 Concentration in colon minima
 Use: effective for mild to moderate disease and first recurrence
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Adverse effects
Caution in liver failure
Higher risk for side effects as drug is hepatically metabolized
Neurotoxicity, primarily manifested as paraesthesias
Paraesthesias are more common with prolonged exposure
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vancomycine
 FDA approved for CDAD
 Mechanism: inhibits the growth of C.Difficile (bacteroistatic)
 Dose: 125 – 500 mg PO Q6h; 500 mg PR
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IV administration does not treat CDAD
Enema may lead to bacteremia from colonic flora
 Administration:
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Oral capsules (expensive)
IV product used orally (in hospital administration)
Retention enema
vancomycine
 Use: Initial episode of severe or complicated disease and for
recurrence
 Pharmacokinetics: poorly absorbed in gut
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Concentrates in colon
 Adverse effects
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Compromised gastrointestinal tract may result in systemic
absorption
Fidaxomicin
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FDA approved for CDAD in May 2011
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Mechanism: macrolide antibiotic
• Kills C.difficile (bactericidal)
• Postantibiotic effect
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Dose: 200 mg PO BID x 10 days
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Pharmacokinetics: poor absorption in gut
Fidaxomicin
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Use: treatment of C.difficile infections
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Non-inferior to oral vancomycin
• Lower rate of recurrence of non-NAP1 strain
• Less effect on normal colonic flora
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Adverse effects: Nausea, vomiting
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Minimal drug interactions
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Significant cost: $2800 for 10 day course, poorly covered by insurance
providers
Infectious Diseases Society of America
(IDSA) Guidelines
Clinical Definition
Recommended Treatment
Initial episode, mild or moderate
Metronidazole 500 mg PO Q8h x 10-14 days
Initial episode, severe
Vancomycin 125 mg PO Q6h x 10-14 days
Initial episode, complicated
Vancomycin 500 mg PO Q6h
PLUS
Metronidazole 500 mg IV Q8h
+/- Vancomycin 500 mg enema for ileus
First recurrence
Same as for initial episode
Second recurrence
Vancomycin taper or pulsed regimen
Cohen SH et al. IDSA guidelines 2010
Infectious Diseases Society of America
(IDSA) Guidelines
Cohen SH et al. IDSA guidelines 2010
Recurrence
• 6 – 25% of patients experience 1 episode of recurrence
• Definition: relapse of same infection or re-infection from
new strain
• Risk factors
• Age > 65
• Metronidazole (especially in patients > 65)
• Use of other antibiotics during or after initial treatment
• Impaired immune response to toxin A
Cohen SH et al. IDSA guidelines 2010
Treatment of Recurrence
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First recurrence: same as initial episode
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Second recurrence: vancomycin taper and/or pulse therapy
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Taper: slow taper over prolonged period of time
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Pulse: high dose given fewer times over a prolonged period
of time
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Avoid metronidazole for cumulative neurotoxicity
> 2 recurrences:
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Alternative therapy
Cohen SH et al. IDSA Guidelines 2010, Dubberke ER et al. AJT 2009