Clostridium difficile

Aka: Clostridium difficile, Pseudomembranous colitis, Pseudomembranous Enterocolitis

1. See Also
   1. Diarrhea
   2. Infectious Diarrhea
   3. Chronic Diarrhea
   4. Health Care-Associated Infection
2. Epidemiology
   1. Incidence: 84 cases per 100,000 persons in U.S. in 2005 (double 1996 Incidence)
   2. Mortality: 2.0 deaths per 100,000 persons in U.S. in 2006
      1. Quadruple 1999 mortality, 14,000 deaths annually in U.S.
   3. References
      1. Kelly (2008) N Engl J Med 359(18): 1932-40 [PubMed]
3. Pathophysiology
   1. Obligate, anaerobic, Gram Positive, spore-forming bacillus
      1. Causes Secretory Diarrhea via 2 toxins (A and B)
   2. New virulent epidemic strain: NAP1/B1/027
      1. Strain responsible for the 5 fold increase in C. difficile infections from 1999 to 2007
      2. Toxin A/B levels are >16 fold higher than other strains
      3. Produces binary toxin in addition to typical toxins A and B
      4. Higher rate of associated toxic Megacolon
      5. Highly Fluoroquinolone resistant
   3. Sequence of infection
      1. Normal colonic Bacteria disturbed (e.g. antibiotics)
      2. Exposure to C. difficile
         1. C. difficile is acquired in health care settings in 94% of cases
            1. However presentation is delayed until after hospitalization in 75% of cases
         2. C. difficile is commensal in only 3% of patients
         3. C. difficile survives in hospital room >40 days
         4. Colonization occurs in 7 to 26% of acute care facilities
         5. Colonization risk increases for each day of hospitalization
            1. Occurs in 50% of those hospitalized >4 weeks
         6. Colonization is community acquired in 41% of cases
            1. More common young, female with few comorbidities and less severe infection
            2. Occurs without antibiotic exposure frequently
            3. Khanna (2012) Am J Gastroenterol 107(1): 89-95 [PubMed]
      3. Colonization with Clostridium difficile
         1. Asymptomatic (carrier state)
            1. Asymptomatic patients account for >50% C. difficile colonization cases
         2. Symptomatic (typically symptoms start 3 days after exposure)
            1. Mild Diarrheal illness or
            2. Severe illness (Pseudomembranous colitis)
4. Risk Factors
   1. Highest risk patients
      1. Older patients over age 64 years old
         1. Risk of C. difficile infection increases 2% for each year over age 18 years old
      2. Debilitated patients
      3. Immunocompromised patients
      4. Cystic Fibrosis patients (high risk for fulminant infection)
   2. Acid suppression
      1. Proton Pump Inhibitors (e.g. Omeprazole)
         1. Highest risk as they raise gastric pH most significantly
      2. H2 Blockers (e.g. Ranitidine)
         1. Less risk than with Proton Pump Inhibitors
      3. Consider stopping indefinately following diagnosis of Clostridium difficile (due to higher risk of recurrence)
   3. Corticosteroid use
   4. Recent antibiotic use within last 3 months (especially last 7-10 days)
      1. General
         1. All antibiotics can cause C. difficile Diarrhea (even single dose perioperative antibiotics)
         2. Broad-spectrum agents are highest risk
         3. Risk increases with combination antibiotic regimens, frequent dosing and longer therapy duration
      2. Most common antibiotic causes
         1. Clindamycin
            1. ClindamycinOdds Ratio 16
            2. More common cause again since resurgence for MRSA management
         2. Fluoroquinolones (e.g. Ciprofloxacin, Levofloxacin)
            1. FluoroquinoloneOdds Ratio 5.5
            2. Emerging as very common cause
         3. Ampicillin or Amoxicillin (most common cause in United States)
         4. Broad-spectrum Cephalosporins
      3. Less common antibiotic causes
         1. Macrolides (e.g. Erythromycin, Azithromycin)
         2. Tetracycline 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. References
         1. Brown (2013) Antimicrob Agents Chemother 57(5): 2326-32 +PMID:23478961 [PubMed]
5. Symptoms
   1. Asymptomatic carrier state is common
   2. Megacolon may be present without Diarrhea
   3. 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 [PubMed]
      2. Characteristics
         1. Frequent, watery Bowel Movements to profuse Diarrhea up to 20-30 stools daily
         2. Mucus and occult blood often present
         3. Crampy Abdominal Pain
   4. Acute inflammatory symptoms (<50% of cases)
      1. Fever
      2. Abdominal Pain
      3. Melana and Hematochezia are uncommon (although occult blood in stool is more often present)
   5. Extraintestinal symptoms
      1. Asymmetric oligoarticular large joint Arthralgia
6. Labs: Diagnosis
   1. Indications: Screening
      1. At least 3 unformed stools in 24 hours (required)
      2. Antibiotic use in last 3 months
      3. Inflammatory Bowel Disease with acute exacerbation
   2. Contraindications to testing
      1. Formed stool (no Diarrhea)
      2. Recent Laxative use
      3. Testing for cure in asymptomatic patients (following treatment of active infection) is NOT recommended
   3. One-Step Clostridium difficile testing
      1. Clostridium difficile PCR (preferred)
         1. Best test efficacy and recommended by American College Gastroenterology
         2. Increased risk of overdiagnosis of carrier state
      2. Clostridium difficile A and B toxin ELISA
         1. Will likely be replaced by PCR testing - in transition as of 2014 (see above)
         2. Preferred over Clostridium difficile culture, and widely available
         3. Test Sensitivity: 75-95%
         4. Test Specificity: 83-98%
         5. Available within 2 hours of obtaining sample
         6. Aldeen (2000) Diagn Microbiol Infect Dis 36(4): 211-3 [PubMed]
   4. Multi-step protocols
      1. Glutamate dehydrogenase antigen
         1. Highly sensitive and rapid assay for antigen produced by all C. difficile isolates
         2. Positive tests are then reflexed to PCR or ELISA testing (see above)
7. Labs: Other
   1. Hypoalbuminemia
   2. Complete Blood Count
      1. Leukocytosis variably present (<50% of cases)
      2. White Blood Cell Count may be greater than 20,000
      3. White Blood Cell Count greater than 30,000 is related to C. difficile in 25% of cases
8. Imaging: 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
9. Diagnostics
   1. 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
10. Differential Diagnosis
    1. Antibiotic intolerance (resolves off antibiotics)
    2. Infectious enteritis
       1. Acute Gastroenteritis
       2. Amebic dysentary
       3. Klebsiella oxytoca
          1. Like Clostridium difficile, causes Antibiotic-Associated Diarrhea, that may be hemorrhagic
          2. Improves after stopping antibiotics and NSAIDs
    3. Inflammatory Bowel Disease
    4. Ischemic Colitis
11. Evaluation: Severe Infection Criteria
    1. Severe infection criteria risk stratify management (e.g. Vancomycin selection for treatment)
    2. High risk patients of severe, fulminant disease (with 2 or more of the following risk factors)
       1. Age over 60 years old
       2. Temperature >38.3 C (100.9 F)
       3. Albumin <2.5 g/dl
       4. Leukocytosis with White Blood Cell Count >15,000/L
       5. Serum Creatinine >50% increase over baseline
       6. Pseudomembranous colitis on endoscopy
       7. Intensive care unit management
       8. Zar (2007) Clin Infect Dis 45(3): 302-7 [PubMed]
12. 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 and stop medications that could worsen condition
       1. Proton Pump Inhibitors
       2. Opioid
       3. Antidiarrheal agents
       4. Cholestyramine (Questran)
          1. Binds Vancomycin and Metronidazole in the Intestine lowering their efficacy against C. difficile
    4. Do not retest for toxin post-treatment if asymptomatic
       1. May be positive, but does not require treatment
13. Management: Adults
    1. Metronidazole
       1. Drug of choice for mild to moderate infection (WBC <15k, Creatinine <1.5 mg/dl) due to low cost
          1. However resistance is growing and may approach 30% in some regions
             1. IDSA is shifting to recommending oral Vancomycin as first-line in 2018
          2. Not recommended for c. difficile recurrence treatment
             1. If repeated after was used for prior management, neurotoxicity risk
       2. Dose
          1. Typical: 500 mg orally every 6-8 hours 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 or rectally
       2. Indications
          1. Drug of choice for severe C. difficile infection
             1. See severe infection criteria above
          2. Second line agent to Metronidazole
             1. Risk of promoting Vancomycin resistance
             2. Had been very expensive ($600-800 per course)
                1. Inexpensive if pharmacist compounds the intravenous form into oral formulation
                2. Firvanq oral Vancomycin solution is also available $125 per course
       3. Dose: 125-500 mg orally (or rectally) four times daily for 10-14 days (10 days is often sufficient)
          1. Use low dose (125 mg) in most patients
          2. Consider high dose (500 mg) in severe illness
             1. Studies suggest 125 mg four times daily is as effective as higher doses
          3. Extended course may be used for persistent Diarrhea
             1. See Vancomycin recurrence protocol below
    3. Fidaxomicin (Dificid)
       1. Advantages
          1. Narrow spectrum antibiotic (C. difficile, Staphylococcus, Enterococcus)
             1. Does not affect Gram Negative Bacteria including normal bowel flora
          2. High efficacy (90% cure rate, similar to Vancomycin)
          3. Lower C. difficile recurrence rates than with Vancomycin
          4. Minimal systemic absorption
       2. Disadvantages
          1. Very expensive ($3000 to $4000 for a 10 day course)
       3. Dose: 200 mg orally twice daily for 10 days
14. 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
15. Management: Recurrence
    1. Recurrence risk doubles with each episode
       1. Initial recurrence risk is 20-30% (typically within 2 months)
       2. After third episode, recurrence is virtually assured
    2. Recurrence risk factors
       1. Prolonged antibiotic use
       2. Prolonged hospitalization course
       3. Diverticulosis
       4. Multiple comorbid illnesses
       5. Elderly patients
       6. Immunocompromised
    3. Management
       1. Vancomycin is preferred antibiotic for recurrence management
       2. Metronidazole is not recommended for recurrence due to neurotoxicity risk
    4. Vancomycin taper
       1. Start 125 mg orally four times daily for 10-14 days,
       2. Then 125 mg orally twice daily for 7 days
       3. Then 125 mg orally daily for 7 days
       4. Then 125 mg orally once every 2-3 days for up to 8 weeks
    5. Probiotics
       1. Precautions
          1. Avoid if immunocompromised (risk of Septicemia)
          2. Take Probiotics 2 hours after antibiotic dose
       2. Saccharomyces boulardii
          1. Dose 250 mg PO bid to tid for 1 month
          2. Has also been used with Vancomycin 500 mg PO qid
       3. Lactobacillus (Culturelle)
    6. Fecal transfer (Stool transplant, fecal bacteriotherapy, intestinal microbiota transplant)
       1. Healthy donor (e.g. spouse) with normal fecal flora
       2. Sample typically introduced via Nasogastric Tube or similar
       3. Small volume fecal amount (25 grams) sufficient to reestablish normal flora
       4. Long term cure rates approach 92%
       5. Gough (2011) Clin Infect Dis 53(10): 994-1002 [PubMed]
       6. Brandt (2012) Am J Gastroenterol 107(7): 1079-87 [PubMed]
16. Management: Fulminant disease (high mortality rate)
    1. Indications
       1. Intractable colitis, toxic Megacolon or bowel perforation
       2. Severe Leukocytosis (e.g. White Blood Cell Count to 30,000)
       3. Serum Lactate >5
       4. Multi-system organ failure or other shock-like state
    2. Management
       1. Metronidazole IV 500 mg every 8 hours AND
       2. Vancomycin 500 orally four times daily 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
       4. Colectomy may be indicated in the most severe diseases
17. Prognosis
    1. Findings of improvement (assess on day 5)
       1. Fever resolves within first 2 days
       2. Diarrhea resolves within first 4 days
    2. Recurrence rates
       1. After episode 1: Recurrence in up to 25%
       2. After episode 2: Recurrence in up to 65%
18. Complications
    1. Toxic Megacolon
    2. Bowel perforation
    3. Dehydration
    4. Electrolyte abnormality
19. Prevention
    1. Avoid Proton Pump Inhibitors (or other acid suppression such as H2 Blocker use) unless absolutely indicated
    2. Antibiotic Stewardship
       1. Avoid broad-spectrum antibiotic use if possible
          1. Narrow antibiotic spectrum based on ongoing findings such as culture results
       2. Use antibiotics only when indicated, and no longer than the necessary duration
    3. Probiotic Indications
       1. Recurrent C. difficile (see above)
       2. Concurrent use with antibiotics (start while patients hospitalized)
          1. Dosing
             1. Start within 1-2 days of antibiotic initiation
             2. Continue for 5 days beyond antibiotic course
             3. Take 2 hours after each antibiotic dose
          2. Probiotic species appear to be equally effective
             1. Saccharomyces boulardii (e.g. Florastor)
             2. Lactobacillus (e.g. Culturelle)
          3. Multiple studies demonstrate significant reduction in C. difficile infection following antibiotic use
          4. Hempel (2012) JAMA 307(18): 1959-69 [PubMed]
          5. Hickson (2007) BMJ 335(7610): 80 [PubMed]
          6. Gao (2010) Am J Gastroenterol 105(7): 1636-41 [PubMed]
    4. Prevent Clostridium difficile spore spread
       1. Spores are resistant to Alcohol, antibiotics and antiseptics
          1. Chlorhexidine and soap are effective
       2. Contact Isolation of patient
          1. Use personal protective gear including hand hygiene, gowns and gloves
       3. Practice good hygiene
          1. Hand washing with soap and water
          2. Hand sanitizers (e.g hand gels) are not effective against Clostridium difficile
          3. Disinfect surfaces and equipment with sporicidal disinfectants
             1. Bleach
             2. Alkaline glutaraldehyde
             3. Ethylene oxide
20. References
    1. (2018) Presc Lett 25(4)
    2. Majoewsky (2012) EM:RAP C3 2(4): 3
    3. Suntharam (2006) First 24 hours, Park Nicollet Lecture
    4. Hsu (2014) Am Fam Physician 90(6): 377-82 [PubMed]
    5. Jabbar (2003) Prim Care 30(1):63-80 [PubMed]
    6. Kyne (2001) Gastroenterol Clin North Am 30(3):753-77 [PubMed]
    7. Hookman (2009) World J Gastroenterol 15(13): 1554-80 [PubMed]
    8. Schroeder (2005) Am Fam Physician 71(5):921-8 [PubMed]
    9. Winslow (2014) Am Fam Physician 89(6): 437-42 [PubMed]