section name header

Info


A. Characteristicsnavigator

  1. C. difficile is a Gram positive anaerobic bacillus
  2. Cause of ~20% of cases of antibiotic associated diarrhea
  3. Major source of nosocomial diarrhea
  4. Causes most cases of pseudomembranous colitis
  5. Increased risk in patients on enteral tube feeding (especially post-pyloric feeding) [5]
  6. Typically moderate diarrhea with abdominal tenderness and cramping

B. Pathogenesisnavigator

  1. Probably a normal commensal organism in human gut
  2. Disruption of normal colonic bacteria with antibiotics leads to C. difficle overgrowth
  3. Release of C. difficile toxins causes colonic epithial cell damage and inflammation
  4. Spores from C. difficile are highly resistant to heat, acid and may survive for years
  5. Oral-fecal transfer is common
  6. Toxins
    1. Toxin A: 308K enterotoxin; causes fluid secretion, mucosal damage, inflammation
    2. Toxin B: 260K cytotoxin; non-toxic in animals
  7. Toxin A Mediated Diarrhea [6]
    1. Toxin A causes mast cell degranulation and release of inflammatory mediators
    2. Histamine, prostaglandins, and serotonin are released
    3. These stimulate submucosal vascular leakage, fluid secretion, mucosal inflammation
    4. Secretomotor reflexes are also stimulated
    5. Substance P and Calcitonin Gene Related Peptide (CGRP) also play a role in fluid leakage
    6. Antibody response to toxin A protects against recurrent C. difficile diarrhea [4]
  8. New strain of C. difficile with hyperproduction of toxins A and B leading to more severe disease has been isolated and is causing significant outbreaks [1,10]
  9. Toxin-gene variant strain with tolC deletion responsible for epidemic outbreaks of fluoroquinolone resistant C. difficile [13,14]
  10. C. difficile colonization (asymptomatic) appears to reduce subsequent diarrhea risk [7]
  11. Use of clindamycin increases resistance and risk of large diarrheal outbreaks [9]
  12. Use of gastric acid suppressive agents (H2-blockers or proton pump inhibitors) increases risk of community aquired C. difficile diarrhea 2.0-2.9X [3]

C. Antibiotics and C. difficilenavigator

  1. Frequent Induction
    1. Clindamycin
    2. Ampicillin and Amoxicillin
    3. Cephalosporins, primarily 2ND and 3RD generation
  2. Infrequent
    1. Tetracyclines, Erythromycin
    2. Sulfonamides, Trimethoprim
    3. Fluoroquinolones
    4. Chloramphenicol
  3. Rare or No Induction of C. difficile
    1. Aminoglycosides (iv)
    2. Metronidazole
    3. Vancomycin (iv or po)
  4. Toxic to C. difficile
    1. Metronidazole (po better than iv)
    2. Vancomycin (po only)
  5. Hospital wide restriction of clindamycin use leads to reduced C. difficile cases [11]
  6. Antibiotic associated hemorrhagic (bloody) diarrhea caused by Klebsiella oxytoca [16]

D. Diagnosisnavigator

  1. High Suspicion
    1. Presence of risk factors
    2. Sudden onset of explosive diarrhea in hospitalized patient
    3. New onset diarrhea often with high spiking fevers
    4. Sudden, marked leukocytosis with >10% immature neutrophils (leukemoid reaction)
    5. Any patient in hospital with unexplained leukocytosis [8]
  2. Risk Factors
    1. Frequent in older patients with long term hospitalizations on antibiotics
    2. Antibiotic use is almost always present, particularly cephalosporins, fluoroquinolones
    3. Colonization with C. difficle
    4. Increased risk in patients on tube feeding [5]
    5. Clindamycin resistant C. difficile associated with large hospital outbreaks [13]
    6. Emerging fluoroquinolone resistant C. difficile [13,14]
    7. Absence of these risk factors makes likelihood of diagnosis very low
  3. Stool
    1. Demonstration of organism or toxin in stool critical for diagnosis
    2. Culture (sensitivity >95%) or toxin assay (sensitivity ~70-80%)
    3. Testing for toxin on >1 stool sample may increase sensitivity
    4. Appearance often characteristic: Foul smelling, green-black and watery
  4. Pseudomembranous Colitis
    1. Diagnosis made by colonoscopy
    2. Type I: patchy epithelial necrosis, exudation of fluid and fibrin into colonic lumen
    3. Type II: Focus of epithelial ulceration with eruption of inflammation above ulcer
    4. Type III: diffuse epithelial necrosis and overlying pseudomembrane (mucin, fibrin, cells)
  5. Risk Factors in Patients with Diarrhea which suggest C. difficile [9]
    1. Onset of diarrhea >5 days after administration of antibioitics (1.4X risk)
    2. Hospital stay longer than 15 days (1.3X risk)
    3. Presence of fecal leukocytes by microscopy (2.4X risk) or lactoferrin assay (3.7X risk)
    4. Presence of semiformed (as opposed to watery) stools (2.3X risk)
    5. Cephalosporin use (2.4X risk)
  6. Antibody response to toxin A protects against recurrent C. difficile diarrhea [4]
  7. Laboratory Examination

E. Arthritis and C. difficile [11] navigator

  1. Arthritis associated with C. difficle has been reported in small number of cases
  2. Usually occurs 1-2 weeks after onset of enteric infection
  3. Causes an asymmetric polyarthritis which may be migratory
  4. Synovial fluid shows WBC 2-70K/µL, mainly neutrophils
  5. About 60% of patients are positive for HLA-B27
  6. Treat with antibiotics and glucocorticoids or NSAIDs, ± sulfasalazine
  7. Usually the arthritis is self limited with treatment

F. Treatment [1,15]navigator

  1. Stop offending antibiotic(s) [12]
  2. Restrict use of clindamycin, certain 2nd and 3rd generation cephalosporins
  3. Aggressive replacement of fluid and electrolytes as needed
  4. Effective Antibiotic Treatment [15]
    1. Metronidazole: 500mg po tid x 10 days increasingly second line
    2. Vancomycin oral (Vancocin®): 125-500mg po qid x 10 days increasingly first line
    3. Increasing metronidazole resistance necessitates vancomycin first line
    4. Vancomycin first line recommended if WBC >20K/µL or other severe symptoms
    5. Metronidazole IV 500mg q8 hours ± vancomycin oral for very severe symptoms or shock
    6. Nitazoxanide (Alinia®) has good activity against C. difficile (10mg/kg bid oral)
    7. Rifaximin (Xifaxan®): non-absorbed antibiotic, 200mg tid x 10 days
    8. Tolevamer: oral investigational toxin binding polymer, similar efficacy to vancomycin
  5. Failure to respond to antibiotic treatment should prompt:
    1. Evaluation of compliance
    2. Search for alternative diagnosis
    3. Assessment for ileus or toxic megacolon
  6. Probiotic Agents [4,15,17]
    1. Yogurt / other active cultures po to replace bowel flora
    2. Lactobacillus in yogurt may help prevent antibiotic associated diarrhea
    3. Saccharomyces boulardii may help reduce incidence of C. difficile diarrhea
    4. May also reduce duration of symptoms and severity of disease
    5. Controlled trials shows modest efficacy
  7. Relapsing Infection [1,15]
    1. Occurs in ~20% of cases
    2. Recurrence typically occurs 3-21 days after discontinuing antibiotics
    3. Most relapses respond to another 10 day course of antibiotics
    4. In general, vancomycin 125-500mg po qid is used
    5. Treatment for 4-6 weeks may be successful, with tapering after 10 days
    6. Intravenous immune globulin (IVIg) has been successful in small studies
    7. Fecal transplantation has been used successfully (aestethically unappealing)
    8. Probiotics (Saccharomyces bouldardii or lactobacillus strain) - competition
  8. Cholestyramine (Questran®)
    1. Binds to C. difficile toxin and may improve symptoms
    2. Dose is cholestyramine 4gm po tid
    3. Cholestyramine also binds po vancomycin (stagger agents when used together)
  9. Enemas with stool or enteric flora are not recommended

References navigator

  1. Bartlett JG. 2006. Ann Intern Med. 145(10):758 abstract
  2. Musher DM and Musher BL. 2004. NEJM. 351(23):2417 abstract
  3. Dial S, Delaney JA, Barkun AN, Suissa S. 2005. JAMA. 294(23):2989 abstract
  4. Kyne L, Warny M, Qamar A, Kelly CP. 2001. Lancet. 357(9251):189 abstract
  5. Bliss DZ, Johnson S, Savik K, et al. 1998. Ann Intern Med. 129(12):1012 abstract
  6. Goyal RK and Hirano I. 1996. NEJM. 334(17):1106 abstract
  7. Shim JK, Johnson S, Samore MH, et al. 1998. Lancet. 351(9103):633 abstract
  8. Wanahita A, Goldsmith EA, Marino GJ, Musher DM. 2003. Am J Med. 115(7):543 abstract
  9. Johnson S, Samore MH, Farrow KA, et al. 1999. NEJM. 341(22):1645 abstract
  10. Warny M, Pepin J, Fang A, et al. 2005. Lancet. 366(9491):1079 abstract
  11. Schmerling RH and Caliendo AM. 1998. NEJM. 338(25):1830 (Case Record)
  12. Climo MW, Israel DS, Wong ES, et al. 1998. Ann Intern Med. 128(12):989 abstract
  13. McDonald LC, Killgore GE, Thompson A, et al. 2005. NEJM. 353(23):2433 abstract
  14. Loo VG, Poirier L, Miller MA, et al. 2005. NEJM. 353(23):2442 abstract
  15. Treatment of Clostridium Difficile. 2006. Med Let. 48(1247):89 abstract
  16. Hogenauer C, Langner C, Beubler E, et al. 2006. NEJM. 355(23):2418 abstract
  17. Probiotics. 2007. Med Let. 49(1267):66 abstract