Darren S. Bryan, MD
James R. Yon, MD
image BASICS
  • Clostridium difficile is a gram-positive, spore-forming anaerobic bacillus that releases toxins to produce clinical disease.
  • Infection caused by C. difficile is frequently associated with antibiotic use, hospitalization, and age.
  • Severity of infection can range from diarrhea to pancolitis, perforation, and death.
  • System(s) affected: gastrointestinal
  • Synonyms(s): C. difficile-associated disease or diarrhea (CDAD); C. difficile colitis; C. difficile
  • C. difficile infection is among the most common causes of hospital-acquired infection. The incidence appears to be rising (1).
  • There are approximately 15 new cases per 1,000 clinical discharges. Higher with increased age (2)
  • Rates of complications associated with C. difficile such as treatment failure and recurrence are also increasing (1).
  • C. difficile causes ˜25% of all cases of antibiotic-associated diarrhea
  • Prevalence of community-acquired C. difficile infection is increasing. Up to 40% of patients will require hospitalization (2).
  • C. difficile is present as a commensurate organism in 2-5% of the adult U.S. population.
  • C. difficile are motile bacteria existing in vegetative and spore forms. Spores can survive for months in harsh conditions and outside of the body.
  • Spread by fecal-oral contact. Acid-resistant spores pass through stomach, and reside predominantly in the colon.
  • Colonic colonization causes disruptions in barrier functions of the normal microbiome (2).
  • C. difficile is noninvasive. Toxins are produced that mediate disease:
    • Toxins A (enterotoxin) and B (cytotoxin) attract neutrophils and monocytes, degrading colonic epithelial cells, and causing clinical disease.
  • BI/NAP1/027 strain of C. difficile has been shown to produce a much more virulent form of disease, with increased endotoxin concentrations. It is associated with increased rates of colectomy and death.
No known genetic factors
  • Host risk factors
    • Age >65 years
    • Hospitalization or stay in long-term health care facility. The length of stay is directly correlated with the risk for C. difficile infection.
    • Comorbidities, including inflammatory bowel disease, immunosuppression, tube feeding, chronic liver disease, and end-stage renal disease
    • Previous C. difficile infection
  • Factors that disrupt normal colonic microbiota:
    • Exposure to almost all antibiotics (including perioperative prophylaxis) is associated with an increased risk for C. difficile infection.
    • Most commonly implicated antibiotics include: ampicillin, amoxicillin, clindamycin, cephalosporins, and fluoroquinolones
  • Recurrence from prior infection
    • Recurrence rates approximately 20% after initial episode. More likely to have recurrence with each additional episode (2)
  • Patients who have had colectomy for C. difficile infection can have colonization of the ileum. Community-acquired C. difficile infections (no overnight admission in >12 weeks) are more frequent in patients without other risk factors (younger, no recent antibiotic exposure).
Geriatric Considerations
C. difficile is the most common cause of acute diarrheal illness in long-term care facilities. Elderly patients also commonly have multiple other risk factors (comorbid disease, antibiotic exposure, medication use).
Pediatric Considerations
  • Neonates have a higher rate of C. difficile colonization (25-80%) but are generally less symptomatic than adults (possibly due to immature toxin receptors)
  • Frequently serve as carrier for symptomatic infection in adults
  • A comprehensive infection control program decreases the incidence of C. difficile infection.
  • 2010 Society for Healthcare Epidemiology of America (SHEA)/Infectious Diseases Society of America (IDS) guidelines:
    • For health care workers, patients, and visitors:
      • Contact precautions, including gloves and gowns, on entry to room
      • Alcohol-based hand sanitizers not effective. Hand hygiene with soap and water before and after patient interaction
      • Accommodate patients with C. difficile infection in private rooms, if possible.
    • Environmental cleaning and disinfection
      • Disinfection with hypochlorite solution or other spore-killing solutions
      • Identification and reduction of environmental sources of C. difficile, including the use of nondisposable rectal thermometers
    • Antimicrobial use restrictions
      • Minimize the frequency and duration of antibiotic therapy.
Pseudomembranous colitis, toxic megacolon, sepsis, colonic perforation
Physical exam findings range from mild abdominal pain to peritoneal findings and shock:
  • Mild or moderate disease: mild lower abdominal pain, often cramping pain
  • Severe disease: fever, nausea/vomiting, dehydration
  • Severe, complicated disease: shock, peritonitis, ileus
  • Antibiotic-associated diarrhea
  • Inflammatory bowel disease
  • Enteric infections
  • Food poisoning
  • SHEA/IDSA guidelines (2)
    • Mild or moderate disease: leukocytosis with white blood cell (WBC) count <15,000 cells/&mgr;L and a serum creatinine level <1.5× the premorbid level
    • Severe, uncomplicated disease: leukocytosis with WBC count > 15,000 cells/&mgr;L or a serum creatinine level >1.5× the premorbid level
    • Severe, complicated disease: markers of severe infection include hypotension, sepsis, markedly elevated WBC count, and bandemia
      • Other signs seen on imaging include obstruction, perforation, toxic megacolon, and colonic wall thickening
Initial Tests (lab, imaging)
  • Polymerase chain reaction (PCR)-based testing is preferred for C. difficile. Rapid, highly sensitive, and hightly specific (2)[B]
  • Alternative to PCR: screening and confirmatory testing. C. difficile common antigen tests: Tests for glutamate dehydrogenase (GDH), found in both toxic and nontoxic strains of C. difficile (sensitivity, 85-95%; specificity, 89-99%).
  • Confirmatory: enzyme immunoassay for toxins (A/B or A); rapid results, inexpensive, easy to use (sensitivity 63-94%)
  • Stool culture is the most sensitive test; however, non-toxin-producing strains also detected.
  • Repeat testing during the same episode of diarrhea is not recommended. Stool carriage persists for 3 to 6 weeks after successful treatment (2)[A].
Diagnostic Procedures/Other
  • Endoscopy can be used to evaluate for pseudomembranes and exclude other conditions
    • While not all patients with C. difficile infection have pseudomembranes, their presence is pathognomonic for C. difficile.
  • Flexible sigmoidoscopy may miss 15-20% of pseudomembranes present in the proximal colon.
  • Colonoscopy evaluates the entire colon: used when diagnosis is in doubt or severity demands rapid diagnosis
  • Plain films may show thumbprinting and colonic distension.
  • CT may show mucosal wall thickening, thickened colonic wall, and pericolonic inflammation.
Test Interpretation
Pseudomembranes consist of inflammatory and cellular debris that forms visible exudates that can obscure the underlying mucosa. These exudates have a yellow to grayish color.

  • Avoid antimotility agents and opiates.
  • Avoid indiscriminate use of antibiotics.
  • Proton pump inhibitors associated with recurrent infection, however have not shown to be causal
  • Discontinue offending antibiotic, if possible.
First Line
  • Mild or moderate infection (3)[A]
    • Oral metronidazole is the drug of choice for mild to moderate C. difficile infection:
      • 500 mg PO TID for 10 to 14 days
      • If patient is unable to take oral medications, then intravenous (IV) metronidazole or intraluminal vancomycin can be used.
  • Severe infection (3)[A]
    • Enteral vancomycin is 1st-line therapy in patients with severe or fulminant C. difficile infection:
      • 125 mg PO QID for 10 to 14 days
      • Vancomycin retention enema if unable to take PO, or if there is evidence of poor gastrointestinal motility
  • Severe, complicated infection—consider surgical and critical care consultation (3)[A]
    • Vancomycin: 500 mg PO QID and metronidazole 500 mg PO TID
  • 1st recurrence
    • Treat the same as 1st episode
  • 2nd recurrence
    • Vancomycin taper and/or pulse: vancomycin 125 mg PO QID for 10 to 14 days, then 125 mg PO BID for 7 days, then 125 mg PO once daily for 7 days, then 125 mg PO every 2 to 3 days for 2 to 8 weeks:
      • Pulse dosing every 2 to 3 days allows spores to germinate and then be killed.
Second Line
  • Vancomycin: indicated for patients who cannot tolerate or have failed metronidazole therapy and for those who are pregnant
  • Fidaxomicin is another option 200 mg PO BID. Similar cure rates to vancomycin and lower recurrence rates, however can be cost prohibitive.
  • Fidaxomicin rapidly kills C. difficile whereas vancomycin inhibits growth. Fidaxomicin has a narrow antimicrobial spectrum and helps preserve normal anaerobic flora.
  • Fecal transplant: stool from healthy, screened donor. Administered via either rectal or oral route. Highly effective treatment for recurrent infections (>90% cure rate) when offending antibiotic stopped. Recipient gut flora have been transformed in as few as 3 days following fecal transplantation (4)[A].
  • Most patients improve with conservative management and oral antibiotics.
  • Patients with severe fulminant colitis develop paralytic ileus, leading to distention (megacolon), and potential perforation.
  • Severe lower quadrant abdominal pain or signs of hemodynamic instability in the setting of known infection should prompt surgical and critical care consultation.
  • Adjunctive therapy with intravenous immunoglobulin (IVIG) has shown initial promise, but more data are required before routine clinical use.
  • Probiotics have an (strain-specific) inhibitory effect on C. difficile and may play a role in prevention.
  • Other investigational treatment options:
    • New antibiotics (Rifalazil, Tolevamer, and Ramoplanin)
    • Monoclonal antibodies to directly modulate the effects of toxins
    • Vaccine form of C. difficile antitoxin antibody
Admission Criteria/Initial Stabilization
  • Hypovolemia
  • Inability to keep up with enteric losses
  • Hematochezia
  • Electrolyte disturbances
IV Fluids
To maintain volume status
Discharge Criteria
  • Decreased diarrhea severity and frequency
  • Tolerating oral diet and medications
  • Do not repeat testing for toxins, as they may shed for weeks following an acute infection.
Many patients can be treated as outpatients.
Patient Monitoring
  • Relapses of colitis occur in 15-30%
  • Relapses typically occur 2 to 10 days after discontinuing antibiotics.
Regular diet or NPO if severe and surgical evaluation required
Educate patients about C. difficile transmission, the importance of hand washing, and the appropriate use of antibiotics.
  • Most patients improve with conservative management and oral antibiotics.
  • 1-3% of patients develop severe/fulminant colitis requiring emergency colectomy.
1. Khanna S, Pardi DS. Clostridium difficile infection: management strategies for a difficult disease. Therap Adv Gastroenterol. 2014;7(2):72-86.
2. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539-1548.
3. Debast SB, Bauer MP, Kuijper EJ; European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1-26.
4. Shankar V, Hamilton MJ, Khoruts A, et al. Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation. Microbiome. 2014;2:13.
Additional Reading
  • Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
  • Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508.
  • McCollum DL, Rodriguez JM. Detection, treatment, and prevention of Clostridium difficile infection. Clin Gastroenterol Hepatol. 2012;10(6):581-592.
A04.7 Enterocolitis due to Clostridium difficile
Clinical Pearls
  • C. difficile is spread by fecal-oral contact.
  • Alcohol-based hand sanitizers are ineffective against C. difficile. Wash hands with soap and water.
  • Testing and treatment of asymptomatic patients is not recommended.
  • PCR is the preferred initial test.
  • Patients may shed organism or toxin for weeks after treatment. Repeat toxin assays following treatment are not helpful.
  • Metronidazole remains the drug of choice for mild to moderate disease.