Treatment Guideline Chart
Clostridioides (formerly Clostridium) difficile infection is commonly associated with antibiotic treatment and is one of the most common nosocomial infections.
Symptoms usually start on days 2-3 of antibiotic treatment, but may also occur up to 8-12 weeks after discontinuation of antibiotics.
Discontinuation of antibiotics may be the only measure needed for patients with only mild diarrhea, no fever, no abdominal pain nor a high WBC count.
Cessation of antibiotics allows for reconstitution of the normal colonic microflora and markedly reduces risk of recurrence.

Clostridioides%20difficile%20infection Treatment

Principles of Therapy

  • The first step in otherwise healthy patients is to stop the offending antibiotic as soon as possible
    • May be the only measure needed for patients with only mild diarrhea, no fever, no abdominal pain nor a high WBC count
    • Cessation of antibiotics allows for reconstitution of the normal colonic microflora and markedly reduces the risk of recurrence
  • Treatment for C difficile should be started if colitis is evident and diarrhea continues despite discontinuation of precipitating antibiotic
    • If with fulminant C difficile infection and clinical condition deteriorates despite antibiotic therapy, surgical treatment with total abdominal colectomy or a diverting loop ileostomy with colonic lavage is recommended 
  • Antibiotic therapy specific for C difficile should be given to the following:
    • Patients with severe diarrhea or colitis
    • Elderly patients
    • Patients with multiple concomitant illnesses
    • Patients in whom antibiotics cannot be discontinued
  • Empiric antibiotic therapy may be initiated in cases where there is a delay in laboratory confirmation or for patients with fulminant infection 
  • Oral route of administration is preferred because C difficile remains within the lumen of the colon and does not invade the mucosa
  • Other medications that also need to be stopped and avoided include laxatives (to decrease the risk of prolonged diarrhea), opiates and antidiarrheal/anti-peristaltic medications (because impaired intestinal motility can worsen toxin-mediated disease) and unnecessary proton pump inhibitors
  • Asymptomatic toxigenic C difficile colonization requires no treatment

Duration of Therapy

  • Antibiotics are generally given for 10-14 days
    • Normalization of stool consistency and frequency may take weeks after clinical response
  • Prolonged treatment may be necessary for patients with severe colitis or those with underlying gastrointestinal (GI) conditions



  • Recent data suggest that Vancomycin is superior to Metronidazole in all cases of C difficile infection
  • 1st-line agent for both non-severe and severe initial cases and for first recurrence in patients previously treated with Metronidazole
  • Oral Vancomycin is poorly absorbed from the intestines which results in high concentrations in the gut lumen along with fewer adverse effects
  • For fulminant cases, it may be given orally or via nasogastric tube with IV Metronidazole 
    • May be administered as retention enema in patients with ileus
  • IV Vancomycin has no effect on C difficile infection as it is not excreted into the colon


  • A treatment option for patients with both non-severe and severe initial cases, for first recurrence in patients previously treated with Vancomycin and for patients with multiple recurrences 
  • As effective as Vancomycin but with fewer secondary recurrences
    • May be given to patients at high risk for recurrence 
  • Has intestinal microbiota-sparing effect
  • May be considered if patient is allergic or intolerant to Vancomycin


  • No longer recommended as 1st-line agent due to data showing poor rates of initial cure (resolution of diarrhea after 10 days of treatment) and sustained cure (clinical cure and absence of recurrence within 1 month posttreatment)
  • Recommended only if patient is allergic or intolerant to or cannot afford Vancomycin or Fidaxomicin, or if Vancomycin or Fidaxomicin is unavailable 
  • Oral Metronidazole is an alternative agent for non-severe initial cases; IV Metronidazole is used in combination with oral and rectal Vancomycin for fulminant infection 
  • Not to be used in severe or recurrent infection
  • Avoid prolonged or repeated treatment courses due to risk of neurotoxicity 

Other Agents


  • As effective as Vancomycin but there is concern regarding the development of resistant enterococcal strains 

Bacitracin (Oral) 

  • Less effective than Vancomycin or Metronidazole
  • Given at 25,000 u PO 6 hourly x 10 days

Cholestyramine, Colestipol

  • Binds C difficile toxins
  • Results of studies have been variable
  • Binds Vancomycin and should therefore not be used concomitantly with this drug

Biologic Agents and Other Therapies

  • Include Ridinilazole, immunoglobulins, monoclonal antibodies (Actoxumab), bacteriophages and probiotics Saccharomyces boulardii, Lactobacillus spp and Bifidobacterium spp 
    • Probiotics appeared to be effective and safe with short-term use together with antibiotics in patients who are not severely debilitated or immunocompromised; may also be an effective adjunct in preventing recurrent infection
    • More studies are needed before these can be recommended

Treatment of Recurrent Infection

  • Mild recurrences often resolve spontaneously and do not require antibiotics
  • For first recurrence, drug previously given may be reused, eg oral Vancomycin or Fidaxomicin
  • For first recurrence in patients initially treated with Vancomycin or in second/subsequent recurrences, give Vancomycin in a tapered and/or pulse regimen
  • For recurrent fulminant disease (regardless if initial or second/subsequent recurrence), treatment is the same as the initial fulminant disease followed by a Vancomycin tapered regimen 
    • If first fulminant C difficile infection episode is not recurrent, complete treatment course without subsequent tapering if patient is improving; if with slow resolution of infection or significant abdominal findings, consider referring to an infectious disease specialist to extend treatment course for >14 days

Other Regimens

  • Vancomycin taper
    • 125 mg PO 6 hourly x 10-14 days, 12 hourly x 1 week, 24 hourly x 1 week, and then every 2 or 3 days x 2-8 weeks
    • Taper inhibits C difficile vegetative cells but preserves colonic flora
  • Vancomycin pulse therapy
    • 125 mg PO every 2 days or 500 mg PO every 3 days x 3 weeks
    • Used for the second recurrence of C difficile infection
  • Vancomycin 125 mg PO 6 hourly x 10 days followed by Rifaximin 400 mg PO 8 hourly x 20 days is a treatment option for patients with multiple recurrences
    • A case series had suggested that Fidaxomicin, instead of Rifaximin, may be given for 20 days 
  • Vancomycin 250-500 mg PO 6 hourly x 10 days followed by S boulardii 500 mg PO 12 hourly x 4 weeks 
  • Metronidazole 500 mg PO 6 hourly x 10 days followed by Cholestyramine 4 g PO 8 hourly + Lactobacillus 1 g PO 6 hourly x 4 weeks
  • Patients with >10 episodes of recurrent diarrhea may need long-term therapy


  • A human monoclonal antibody which binds to C difficile toxin B that is used to prevent recurrence in high-risk adults receiving antibacterial therapy for C difficile infection 
    • Risk of recurrent C difficile infection is decreased by approximately 40% when given during the first episode 
  • Not an antibacterial drug and thus should only be used in conjunction with C difficile infection antibacterial treatment 
    • May be administered at any time during the 10-14-day antibacterial treatment course

Fecal Microbiota Transplantation or Fecal Bacteriotherapy

  • An effective treatment for recurrent C difficile infection
  • A stool in a liquid suspension is transplanted in the patient’s GI tract
  • May be administered via a nasogastric tube, nasojejunal tube, upper endoscopy, colonoscopy, enema or encapsulated preparations 
  • It restores a healthier intestinal microbiota in patients with recurrent C difficile infection
  • Consider a fecal microbiota transplant in patients with at least 2 recurrences (3 episodes of C difficile infection) who have failed appropriate antibiotic therapy
    • Consult infectious disease and gastroenterology specialists for evaluation

Supportive Therapy

  • Administer fluids and electrolytes to rehydrate and maintain hydration
    • Please see Diarrhea in Adults - Infectious disease management chart for specific therapy
  • Diarrhea may resolve with conservative management in approximately 15-23% of otherwise healthy patients
  • Provide albumin supplementation to all patients with severe infection 
  • Aggressive resuscitation and invasive monitoring may be needed in patients with fulminant colitis
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