Clostridium difficile

Aka: Clostridium difficile, Pseudomembranous colitis

1. See Also
   1. Diarrhea
   2. Infectious Diarrhea
   3. Chronic Diarrhea
2. Epidemiology
   1. Dramatic increase in cases in last decade
3. Pathophysiology
   1. Anaerobic, Gram Positive, spore-forming bacillus
   2. New virulent strain: NAP1/B1/027
      1. Toxin A/B levels are >16 fold higher than other strains
      2. Produces binary toxin in addition to typical toxins A and B
      3. Higher rate of associated toxic Megacolon
   3. Sequence of infection
      1. Normal colonic bacteria disturbed (e.g. antibiotics)
      2. Exposure to C. difficile
         1. C. difficile is commensal in only 3% of patients
         2. C. difficile survives in hospital room >40 days
         3. Occurs in 50% of those hospitalized >4 weeks
      3. Colonization with Clostridium difficile
         1. Results in carrier state (asymptomatic) or
         2. Mild Diarrheal illness or
         3. Severe illness (Pseudomembranous colitis)
4. Risk Factors
   1. Highest risk patients
      1. Elderly
      2. Debilitated patients
      3. Immunocompromised patients
      4. Cystic Fibrosis patients (high risk for fulminant infection)
   2. Proton Pump Inhibitors (raise gastric pH)
      1. Consider stopping indefinately following diagnosis of Clostridium difficile (due to higher risk of recurrence)
   3. Corticosteroid use
   4. Recent antibiotic use
      1. General
         1. All antibiotics can cause C. difficile Diarrhea
         2. Broad-spectrum agents are highest risk
      2. Most common antibiotic causes
         1. Quinolones (e.g. Ciprofloxacin, Levofloxacin)
            1. Emerging as very common cause
         2. Ampicillin or Amoxicillin
         3. Cephalosporins
         4. Clindamycin
            1. Less common now due to decreased Clindamycin usage
      3. Less common antibiotic causes
         1. Macrolides (e.g. Erythromycin, Azithromycin)
         2. Tetracyclines antibiotics (e.g. Doxycycline)
         3. Sulfonamides (e.g. Bactrim)
         4. Trimethroprim
      4. Rare antibiotic causes
         1. Parenteral Aminoglycosides
         2. Metronidazole (used for treatment)
         3. Vancomycin (used for treatment)
5. Symptoms
   1. Asymptomatic carrier state is common
   2. Diarrhea (variably present)
      1. Timing
         1. Incubates for 2-7 days after colonization
         2. Most cases occur on days 4-9 of antibiotic course
         3. Onset <14 days after antibiotics in 96% of cases
         4. All cases occur within 3 months of antibiotics
         5. Olson (1994) Infect Control Hosp Epidemiol 15:371
      2. Characteristics
         1. Frequent, loose Bowel Movements
         2. Mucus and occult blood often present
         3. Crampy Abdominal Pain
      3. Associated findings
         1. Fever
         2. Asymmetric oligoarticular large joint arthralgia
6. Labs
   1. Complete Blood Count
      1. Leukocytosis variably present
7. Radiology: Abdominal XRay
   1. Dilated colon: >7 cm in greatest diameter
   2. Small Bowel dilation or air-fluid levels may be present
   3. Mucosal edema or thumbprinting may also be present
8. Diagnosis
   1. Clostridium difficile Toxin
   2. Endoscopy (Flexible Sigmoidoscopy or Colonoscopy)
      1. Not recommended in most cases
      2. May be indicated if diagnosis is unclear
      3. Findings: Mucosal lesions with pseudomembranes
9. Differential Diagnosis
   1. Antibiotic intolerance (resolves off antibiotics)
   2. Infectious enteritis
      1. Acute Gastroenteritis
      2. Amebic dysentary
   3. Inflammatory Bowel Disease
   4. Ischemic colitis
10. Management: General Measures
    1. Discontinue antibiotic
       1. Diarrhea resolves in up to 25% of cases with stopping
       2. If antibiotic required, choose one with lower risk
    2. Indications to start antibiotics immediately (empiric)
       1. Older patients
       2. Multiple comorbid conditions
       3. Antibiotics can not be discontinued
       4. Severe disease
          1. Persistent Diarrhea
          2. Dysentary (fever, Leukocytosis)
    3. Avoid medications that could worsen condition
       1. Proton Pump Inhibitors
       2. Opioid
       3. Antidiarrheal agents
    4. Do not retest for toxin post-treatment if asymptomatic
       1. May be positive, but does not require treatment
11. Management: Adults
    1. Metronidazole
       1. Drug of choice due to low cost and high risk
          1. However resistance is growing and may approach 30% in some regions
       2. Dose
          1. Typical: 500 mg orally three times daily for 10-14 days
          2. Lower dose: 250 mg orally q6 hours for 10-14 days
          3. Parenteral dose: 500 mg IV q8 hours for 10-14 days
    2. Vancomycin
       1. Precaution: Only effective for C. Difficile if dosed orally
       2. Indications
          1. Patients at high risk of fulminant disease
          2. Second line agent to Metronidazole
             1. Risk of promoting Vancomycin resistance
             2. Very expensive ($800 per course)
                1. Inexpensive if pharmacist compounds the intravenous form into oral formulation
       3. Dose: 125-500 mg PO qid for 10-14 days
          1. Use low dose (125 mg) in most patients
          2. Use high dose (500 mg) in severe illness
12. Management: Child
    1. Mild to Moderate disease: Metronidazole (Flagyl)
       1. Metronidazole 7 mg/kg (maximum 500 mg) tid for 7 days
    2. Severe disease: Vancomycin
       1. Vancomycin 5 mg/kg (maximum 125 mg) q6 hours x7 days
13. Management: Recurrence
    1. Recurrence risk doubles with each episode
       1. Initial recurrence risk is 20%
       2. After third episode, recurrence is virtually assured
    2. Vancomycin taper
       1. Starting dose 125 mg every 6 hours for 1 week
       2. Taper to 125 mg every 12 hours for 1 week
       3. Taper to 125 mg daily for 1 week
       4. Taper to 125 mg every other day for 1 week
       5. Taper to 125 mg every third day for 2 weeks
    3. Probiotics (e.g. Florastor)
       1. Saccharomyces boulardii (avoid if immunocompromised)
          1. Dose 250 mg PO bid to tid for 1 month
          2. Has also been used with Vancomycin 500 mg PO qid
    4. Fecal transfer
       1. Healthy donor (e.g. spouse) with normal fecal flora
       2. Sample typically introduced via rectal enema
       3. Small volume fecal amount (25 grams) sufficient to reestablish normal flora
14. Management: Fulminant disease (high mortality rate)
    1. Metronidazole IV 500 mg every 8 hours and
    2. Vancomycin 500 mg PO qid and
    3. Vancomycin enema 500 mg in 100 cc NS q6 hours
       1. Delivered by foley in rectum, 30 cc balloon
       2. Balloon inflated for 60 minutes after dose
15. Prognosis: Findings of improvement (assess on day 5)
    1. Fever resolves within first 2 days
    2. Diarrhea resolves within first 4 days
16. Complications
    1. Toxic Megacolon
    2. Bowel perforation
    3. Dehydration or electrolyte abnormality
17. Prevention
    1. Avoid Proton Pump Inhibitors unless absolutely indicated
    2. Avoid broad-spectrum antibiotic use
    3. Probiotics may be considered in recurrent cases
    4. Prevent Clostridium difficile spore spread
       1. Spores are resistant to Alcohol, antibiotics and antiseptics
       2. Practice good hygiene
          1. Hand washing
          2. Disinfect surfaces
             1. Bleach
             2. Alkaline glutaraldehyde
             3. Ethylene oxide
18. References
    1. Suntharam (2006) First 24 hours, Park Nicollet Lecture
    2. Jabbar (2003) Prim Care 30(1):63-80
    3. Kyne (2001) Gastroenterol Clin North Am 30(3):753-77
    4. Hookman (2009) World J Gastroenterol 15(13): 1554-80
    5. Schroeder (2005) Am Fam Physician 71(5):921-8