A. Characteristics
- C. difficile is a Gram positive anaerobic bacillus
- Cause of ~20% of cases of antibiotic associated diarrhea
- Major source of nosocomial diarrhea
- Causes most cases of pseudomembranous colitis
- Increased risk in patients on enteral tube feeding (especially post-pyloric feeding) [5]
- Typically moderate diarrhea with abdominal tenderness and cramping
B. Pathogenesis
- Probably a normal commensal organism in human gut
- Disruption of normal colonic bacteria with antibiotics leads to C. difficle overgrowth
- Release of C. difficile toxins causes colonic epithial cell damage and inflammation
- Spores from C. difficile are highly resistant to heat, acid and may survive for years
- Oral-fecal transfer is common
- Toxins
- Toxin A: 308K enterotoxin; causes fluid secretion, mucosal damage, inflammation
- Toxin B: 260K cytotoxin; non-toxic in animals
- Toxin A Mediated Diarrhea [6]
- Toxin A causes mast cell degranulation and release of inflammatory mediators
- Histamine, prostaglandins, and serotonin are released
- These stimulate submucosal vascular leakage, fluid secretion, mucosal inflammation
- Secretomotor reflexes are also stimulated
- Substance P and Calcitonin Gene Related Peptide (CGRP) also play a role in fluid leakage
- Antibody response to toxin A protects against recurrent C. difficile diarrhea [4]
- 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]
- Toxin-gene variant strain with tolC deletion responsible for epidemic outbreaks of fluoroquinolone resistant C. difficile [13,14]
- C. difficile colonization (asymptomatic) appears to reduce subsequent diarrhea risk [7]
- Use of clindamycin increases resistance and risk of large diarrheal outbreaks [9]
- 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. difficile
- Frequent Induction
- Clindamycin
- Ampicillin and Amoxicillin
- Cephalosporins, primarily 2ND and 3RD generation
- Infrequent
- Tetracyclines, Erythromycin
- Sulfonamides, Trimethoprim
- Fluoroquinolones
- Chloramphenicol
- Rare or No Induction of C. difficile
- Aminoglycosides (iv)
- Metronidazole
- Vancomycin (iv or po)
- Toxic to C. difficile
- Metronidazole (po better than iv)
- Vancomycin (po only)
- Hospital wide restriction of clindamycin use leads to reduced C. difficile cases [11]
- Antibiotic associated hemorrhagic (bloody) diarrhea caused by Klebsiella oxytoca [16]
D. Diagnosis
- High Suspicion
- Presence of risk factors
- Sudden onset of explosive diarrhea in hospitalized patient
- New onset diarrhea often with high spiking fevers
- Sudden, marked leukocytosis with >10% immature neutrophils (leukemoid reaction)
- Any patient in hospital with unexplained leukocytosis [8]
- Risk Factors
- Frequent in older patients with long term hospitalizations on antibiotics
- Antibiotic use is almost always present, particularly cephalosporins, fluoroquinolones
- Colonization with C. difficle
- Increased risk in patients on tube feeding [5]
- Clindamycin resistant C. difficile associated with large hospital outbreaks [13]
- Emerging fluoroquinolone resistant C. difficile [13,14]
- Absence of these risk factors makes likelihood of diagnosis very low
- Stool
- Demonstration of organism or toxin in stool critical for diagnosis
- Culture (sensitivity >95%) or toxin assay (sensitivity ~70-80%)
- Testing for toxin on >1 stool sample may increase sensitivity
- Appearance often characteristic: Foul smelling, green-black and watery
- Pseudomembranous Colitis
- Diagnosis made by colonoscopy
- Type I: patchy epithelial necrosis, exudation of fluid and fibrin into colonic lumen
- Type II: Focus of epithelial ulceration with eruption of inflammation above ulcer
- Type III: diffuse epithelial necrosis and overlying pseudomembrane (mucin, fibrin, cells)
- Risk Factors in Patients with Diarrhea which suggest C. difficile [9]
- Onset of diarrhea >5 days after administration of antibioitics (1.4X risk)
- Hospital stay longer than 15 days (1.3X risk)
- Presence of fecal leukocytes by microscopy (2.4X risk) or lactoferrin assay (3.7X risk)
- Presence of semiformed (as opposed to watery) stools (2.3X risk)
- Cephalosporin use (2.4X risk)
- Antibody response to toxin A protects against recurrent C. difficile diarrhea [4]
- Laboratory Examination
E. Arthritis and C. difficile [11]
- Arthritis associated with C. difficle has been reported in small number of cases
- Usually occurs 1-2 weeks after onset of enteric infection
- Causes an asymmetric polyarthritis which may be migratory
- Synovial fluid shows WBC 2-70K/µL, mainly neutrophils
- About 60% of patients are positive for HLA-B27
- Treat with antibiotics and glucocorticoids or NSAIDs, ± sulfasalazine
- Usually the arthritis is self limited with treatment
F. Treatment [1,15]
- Stop offending antibiotic(s) [12]
- Restrict use of clindamycin, certain 2nd and 3rd generation cephalosporins
- Aggressive replacement of fluid and electrolytes as needed
- Effective Antibiotic Treatment [15]
- Metronidazole: 500mg po tid x 10 days increasingly second line
- Vancomycin oral (Vancocin®): 125-500mg po qid x 10 days increasingly first line
- Increasing metronidazole resistance necessitates vancomycin first line
- Vancomycin first line recommended if WBC >20K/µL or other severe symptoms
- Metronidazole IV 500mg q8 hours ± vancomycin oral for very severe symptoms or shock
- Nitazoxanide (Alinia®) has good activity against C. difficile (10mg/kg bid oral)
- Rifaximin (Xifaxan®): non-absorbed antibiotic, 200mg tid x 10 days
- Tolevamer: oral investigational toxin binding polymer, similar efficacy to vancomycin
- Failure to respond to antibiotic treatment should prompt:
- Evaluation of compliance
- Search for alternative diagnosis
- Assessment for ileus or toxic megacolon
- Probiotic Agents [4,15,17]
- Yogurt / other active cultures po to replace bowel flora
- Lactobacillus in yogurt may help prevent antibiotic associated diarrhea
- Saccharomyces boulardii may help reduce incidence of C. difficile diarrhea
- May also reduce duration of symptoms and severity of disease
- Controlled trials shows modest efficacy
- Relapsing Infection [1,15]
- Occurs in ~20% of cases
- Recurrence typically occurs 3-21 days after discontinuing antibiotics
- Most relapses respond to another 10 day course of antibiotics
- In general, vancomycin 125-500mg po qid is used
- Treatment for 4-6 weeks may be successful, with tapering after 10 days
- Intravenous immune globulin (IVIg) has been successful in small studies
- Fecal transplantation has been used successfully (aestethically unappealing)
- Probiotics (Saccharomyces bouldardii or lactobacillus strain) - competition
- Cholestyramine (Questran®)
- Binds to C. difficile toxin and may improve symptoms
- Dose is cholestyramine 4gm po tid
- Cholestyramine also binds po vancomycin (stagger agents when used together)
- Enemas with stool or enteric flora are not recommended
References
- Bartlett JG. 2006. Ann Intern Med. 145(10):758
- Musher DM and Musher BL. 2004. NEJM. 351(23):2417
- Dial S, Delaney JA, Barkun AN, Suissa S. 2005. JAMA. 294(23):2989
- Kyne L, Warny M, Qamar A, Kelly CP. 2001. Lancet. 357(9251):189
- Bliss DZ, Johnson S, Savik K, et al. 1998. Ann Intern Med. 129(12):1012
- Goyal RK and Hirano I. 1996. NEJM. 334(17):1106
- Shim JK, Johnson S, Samore MH, et al. 1998. Lancet. 351(9103):633
- Wanahita A, Goldsmith EA, Marino GJ, Musher DM. 2003. Am J Med. 115(7):543
- Johnson S, Samore MH, Farrow KA, et al. 1999. NEJM. 341(22):1645
- Warny M, Pepin J, Fang A, et al. 2005. Lancet. 366(9491):1079
- Schmerling RH and Caliendo AM. 1998. NEJM. 338(25):1830 (Case Record)
- Climo MW, Israel DS, Wong ES, et al. 1998. Ann Intern Med. 128(12):989
- McDonald LC, Killgore GE, Thompson A, et al. 2005. NEJM. 353(23):2433
- Loo VG, Poirier L, Miller MA, et al. 2005. NEJM. 353(23):2442
- Treatment of Clostridium Difficile. 2006. Med Let. 48(1247):89
- Hogenauer C, Langner C, Beubler E, et al. 2006. NEJM. 355(23):2418
- Probiotics. 2007. Med Let. 49(1267):66