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Clostridium difficile: 2012 Update. Julia B. Garcia-Diaz, MD, MSc Ochsner Clinic Foundation October 20 th , 2012. Case Presentation . 61 yo male was admitted to the hospital with the complain of bloody diarrhea

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clostridium difficile 2012 update
Clostridium difficile: 2012 Update

Julia B. Garcia-Diaz, MD, MSc

Ochsner Clinic Foundation

October 20th, 2012

case presentation
Case Presentation
  • 61 yo male was admitted to the hospital with the complain of bloody diarrhea
  • 4 days before admission, he was diagnosed with gastroenteritis (fever 39.5, diarrhea) and was given ciprofloxacin. In spite of taking the antibiotics, he continued to pass watery stool mixed with blood
  • Past history: liver disease with esophagealvarices for which band ligation was done twice & also pancytopenia due to hypersplenism
  • Stool: WBC 5-10/HPF, RBC 10-20/HPF.
  • Positive stool occult blood
  • Stool Clostridium difficile: positive
  • CBC
    • WBCs 2.1 x 103 /cm
    • Hemoglobin 10.8 gm/dl
    • Hematocrit 31.2
    • Platelet count 36,000
Phosphorus 2.9 mg/dl

Calcium of 8.2 mg/dl

Albumin 2.3 gm/dl

Alkaline phosphatase83 U/L

AST 21 U/L

ALT 18 U/L

GGT 18 U/L

Total Bilirubin 2.9 mg/dl

  • Direct1.8 mg/dl
  • BUN 27 mg/dl
  • Creatinine 0.7 mg/dl
  • Sodium 133 mEq/L
  • Potassium 3.3 Meq/L

Abdominal ultrasound showed shrunken cirrhotic liver measuring 12 cm

Gallbladder showed small stones.

The spleen was hugely enlarged measuring 19.98 x 7.77 cm

hospital course
Hospital Course
  • The patient was started on oral vancomycin 250mg q6h and metronidazole treatment 500mg q8h
  • 4 days later: the patient started complaining of severe abdominal pain and examination showed markedly distended abdomen with evidence of guarding and rigidity
  • A KUB was done and it showed marked distension of the colon reaching up to 9.5 cm in diameter
hospital course1
Hospital Course
  • A cecostomy tube was placed in to help in deflation of the colon followed by sigmoidoscopy or total colonoscopy.
hospital course2
Hospital Course
  • The patient had successful insertion of cecostomy tube and sigmoidoscopy was performed with improvement of the abdominal distension
hospital course3
Hospital Course
  • Rapid deterioration with hepatic coma and hepatorenal failure occurred.
  • 4 days later the patient died.
an epidemic toxin gene strain of clostridium difficile mcdonald lc nejm 2005 353 1433
  • Reported increase 2000-01 – 21%
  • Pittsburgh – 26 colectomies and 18 deaths

C. difficile appears to be causing more disease and more serious disease. Possible role of strain BI/NAP1

• Toxin A and B – high production

c l mcdonald dale gerding
C.L. McDonaldDale Gerding
  • 23 states and 5 countries
  • 2004: diagnosis (ICD-9) showed 25% increase over 2003
  • Average rate is 5-10/1000 discharges (US hospitals)
  • Guidelines (SHEA/IDSA): Spring ’07
  • Antibiotics: cephalosporinsand FQ
  • NAP-1 strain: reference lab CDC if epidemic in new area
  • Strain does not change management



Prospective study in 12 Quebec hospitals

• Risk factors

• Clinical features

• Strain types: PFGE, binary toxin, tcdC deletion

Main intervention:
    • Infection control
    • Single rooms, contact precautions, early detection and Rx, dedicated equipment, soap, household bleach and education
  • Antibiotic control 5-10% decrease
  • Toxin assay: cytotoxinat 24 hr
  • Treatment: metronidazolein ~ 80%
  • Rates in 12 hospitals consortium and region decrease >50%

Voluntary laboratory reports of C. difficile positive faecal specimens:

England, Wales and Northern Ireland* 1990 - 2011

the first case
The First Case
  • 22 year old female, patient of Dr. William Osler
  • “A miserable, emaciated creature in a wretched physical condition.”
  • Underwent surgical resection of a gastric tumor on August 26, 1892
  • Postoperatively developed diarrhea that became progressively more severe
  • Died on post op day 15

“Diphtheritic membrane”

history cont d
History Cont’d

A fatal case of pseudomembranous colitis in 1948 was linked to streptomycin use, led to reexamination of the 1892 case

“Myriads of gram positive cocci” found- Staphylococcus aureus postulated as cause

Studies in 1950’s and 60’s document an association but did not prove causation

  • Clostridium difficile was first described in 1935, but its association with disease was not identified until 1978.
  • An anaerobic, spore forming gram positive rod; first described as a member of the normal flora of healthy infants in 1935
  • Due to the difficulty in cultivating the organism, it was originally called Bacillus difficilis
  • Given its current name 3 years later
toxin production
Toxin Production
  • 5-25% of strains do not produce toxins and don’t cause disease
  • Toxin A
    • 308 kdenterotoxin and cytotoxin
    • Chemoattractant for neutrophils
    • Activator for macrophages and mast cells
  • Toxin B
    • 269 kd potent cytotoxin
    • Disrupts the actin cytoskeleton
    • Found to be a potent necrotizing enterotoxin
    • Probably acts synergistically with toxin A
  • The most common recognized cause of nosocomial diarrhea
  • Incidence and severity increasing:
    • A new strain has been identified that carries and additional toxin (iota toxin)
    • C. difficile acquiring resistance to more antimicrobials
  • Frequency varies by institution
  • Results in 3.6 excess hospital days, cost of $3,700/pt
  • Readmissions for CDAD cost $128,000 per hospital per year
  • Conservative estimate of US cost per year $1.1 billion
acquisition of the organism
Acquisition of the Organism
  • In healthy adults intestinal carriage rates of toxigenicC. difficile are 5% or less
  • Carriage in healthy adults thought to be transient
  • High prevalence in newborns- up to 60-70%- all asymptomatic
  • In hospitalized patients colonization begins upon admission in patients given antimicrobials
    • 13-20% within the first week
    • 50% in patients hospitalized for more than 4 weeks
  • Even relatively minute amounts of antimicrobials can predispose to colonization
pathogenesis of infection
Pathogenesis of Infection
  • Three critical events necessary for CDAD
    • Disruption of the normal colonic microflora by antimicrobials or other means
    • Ingestion by the patient of a toxigenic strain of C. difficile and its arrival intact in the lower GI tract
    • One or more additional requirements for developing invasive disease
      • Advancing age
      • Severe underlying disease of any kind
      • Prolonged hospital stays
      • Manipulation of the GI tract (NG tubes, enemas, surgery, motility altering drugs)
      • Acid neutralizing drugs
medications associated with c difficile
Medications Associated with C. difficile
  • Most common antimicrobials
    • Clindamycin
    • Ampicillin/amoxicillin
    • Cephalosporins
    • Fluoroquinolones
  • Infrequent- Tetracyclines, macrolides, TMP/SMX
  • Rare or never- IV aminoglycosides, metronidazole, vancomycin, bacitracin
  • Chemotherapeutics with antibacterial activities
    • Ifosfamide, carboplatinetoposide 8% incidence
    • Others Mtx, 5FU, doxorubicin, cyclophosphamide
  • Bowel preparation regimens
clinical disease spectrum
Clinical Disease Spectrum
  • Asymptomatic colonization 2-5 or more X more common than clinical illness of any type
  • Mild diarrhea, minimal discomfort
  • Typical CDAD:
    • Crampy abdominal pain
    • Profuse diarrhea with mucoid, greenish watery stool with a characteristic odor
    • Low grade fever and leukocytosis
  • More severe disease with high fever, marked leukocytosis

Disruption of protective

colonic flora (AB or AN)

Colonization with toxigenic C. difficile

by fecal-oral transmission

Toxin A and B production

A/B: Cytoskeletal damage, loss of tight junctions.

A: Mucosal injury, inflammation, fluid secretion.

Colitis andDiarrhea

  • Endoscopy (pseudomembranous colitis)
  • Culture
  • Cell culture cytotoxin test
  • EIA toxin test
  • PCR toxin gene detection
  • Endoscopy looking for pseudomembranes
    • Quick, and specific
    • Pseudomembrane formation usually starts on the right side
    • Pseudomembrane formation a late manifestation
  • Culture
    • Takes several days
    • Need cytotoxic assay of organism after culture
  • Immunoassays
eia toxin tests
EIA toxin tests
  • Can detect toxin A, toxin B, or both
  • Rapid, cheap, and specific
  • Less sensitive than cytotoxin test
  • Toxin A tests will miss rare C. difficile isolates that produce toxin B only (Toxin A-negative, toxin B-positive outbreak, Winnipeg, 1998)
  • General principles
    • Whenever possible withdraw the offending antibiotic
    • Be patient; some improvement seen in first 2 days but mean time until resolution of diarrhea is 2-4 days
    • Don’t call them nonresponders until 6 days of therapy
    • Treat for 10 days
    • Avoid antiperistaltic agents
    • No role for test of cure assays
  • MIC 90of 0.4 ug/ml vs. C. difficile
  • 98% cure rate documented
  • Well absorbed in the upper GI tract: in healthy volunteers fecal concentration of drug low to undetectable
  • Bactericidal fecal concentrations achieved in the stool of patients with CDAD: fecal concentrations decrease as diarrhea improves
    • Drug secreted directly across inflamed mucosa
    • Decreased intestinal transit time with diarrhea decreases absorption

MIC 90of 1.6 ug/ml

Fecal concentrations of 2,000 to 5,000 ug/ml with po drug

Cure rates 98-100%

Second line therapy due to concerns of selecting for vancomycin resistant Enterococcus (VRE)

No drug in GI tract when given IV

Can be given by enema


A Comparison of Vancomycin and Metronidazole

for the Treatment of Clostridium difficile–Associated

Diarrhea, Stratified by Disease Severity

Zar et al. Clinical Infectious Diseases 2007; 45:302–7

treatment of multiple relapses
Treatment of Multiple Relapses

No controlled studies, lots of anecdotes and “personal favorite” regimens

Tapering courses of vancomycin or metronidazole

Vancomycin plus rifampin

Rifaximin chasers

Yogurt or other Lactobacillus preparations

Saccharomycesboulardii plus antibiotics

Intravenous immune globulin

Cholestyramine with or without antimicrobials

  • Indications for surgery:
    • fulminant disease
    • colonic perforation
    • toxic megacolon
    • failure of medical therapy
  • The role of intracolonicvancomycin in severe C. difficile–associated pancolitis can be an alternative to surgery or as a bridge to surgery in severely ill patients
infection control issues
Infection Control Issues
  • Two main approaches
    • Efforts directed at preventing horizontal spread including barrier methods, environmental cleaning
    • Efforts to minimize the possibility that organism exposure will result in a clinical infection, using antimicrobial restriction and limiting overall use of antimicrobials
barrier methods
Barrier Methods

Contact isolation including private room for all patients with diarrhea until C. difficile has been ruled out

When should they come out of isolation? Since many healthy persons and persons without diarrhea who are in hospitals carry C. difficile in their intestinal tract there is no rationale for continuing isolation for patients who no longer have diarrhea, or to test them for carriage once the diarrhea has ceased


Environmental Cleaning

Bleach is the single most effective agent for spore killing

Handwashing between all patient encounters

Switch to alcohol based foams: is it contributing to C. difficile transmission?