Clostridioides (Clostridium) difficile in Adults

Last modified June 2023

Clostridioides difficile (C. difficile; previously called Clostridium difficile) is spore-forming, gram-positive, anaerobic bacteria that can lead to infections of the gastrointestinal tract. The FAQ below addresses common questions about C. difficile including risk factors, symptoms, prevention, and treatment.


What are the effects of C. diff?

  • C.diff can affect patients differently. Some patients may present as asymptomatic carriers (i.e., colonized with the bacteria) while others may have a potentially fatal infection.9
  • Symptoms of CDI commonly include:7
  • watery diarrhea (≥3 bowel movements/24 hours).
    • abdominal pain or tenderness.
    • decreased appetite and nausea.
    • fever.

How is Cdiff infection classified?

  • Severity of CDI is defined as:
    • non-severe: elevated white blood cell count, but still ≤15,000 cells/mL and serum creatinine <1.5 mg/dL (in Canada serum creatinine ≤1.5 x baseline).1,22
    • severe: elevated white blood cell count of at least 15,000 cells/mL or serum creatinine >1.5 mg/dL (in Canada serum creatinine >1.5 x baseline).14,22
    • fulminant (severe complicated in Canada): hypotension or shock, ileus, or megacolon.1,14,22
  • Recurrent CDI: new symptoms and laboratory confirmation AFTER a previous CDI in the past eight weeks.14,22
    • Risk factors include ≥65 years old, immunocompromised, severe CDI, and ribotype 027/078/244 infections.1
    • About 20% of patients will have an initial recurrence of CDI.14
    • Risk of recurrence, severity, and mortality increase with subsequent infections.14

What are risk factors for C. diff?

  • Antibiotics (because they suppress normal gut bacteria) are the most important modifiable risk factor for CDI.9
    • Use antibiotics appropriately, especially high-risk antibiotics (e.g., carbapenems; higher generation cephalosporins; clindamycin; fluoroquinolones).7
  • Chronic kidney disease (CKD) and end-stage kidney disease (ESKD).9,14
  • Gastrointestinal surgery or procedure, or inflammatory bowel disease.9,14
  • Increased age (e.g., ≥65 years old).14
  • Immunosuppression (e.g., cancer, human immunodeficiency virus, organ transplant).34
  • Recent hospitalization (within the past two months), or long-term care.14,38
  • Proton pump inhibitor use.39
  • Risk factors specific for community-acquired CDI include white race, cardiac disease, CKD, and IBD.14

What laboratory tests are used to identify C. diff?

  • Use a stool toxin test WITH either glutamate dehydrogenase (GDH) or nucleic acid amplification test (NAAT).14

Antigen detection (e.g., glutamate dehydrogenase [GDH]):7

  • rapid turn-around time (e.g., <1 hour).
  • Often combined with polymerase chain reaction (PCR) or toxigenic culture because it is non-specific (e.g., will be positive for carriers of non-toxigenic strains of C. diff9).

Molecular assays (PCR assays):7

  • sensitive and specific for toxin-producing C. diff (i.e., tests for the gene coding for C. diff toxin). Can be positive in patients with diarrhea due to another cause who are coincidentally colonized with C. diff, leading to overdiagnosis.

Stool culture:7

  • most sensitive of the C. diff tests, but has a slow turn-around time (e.g., 48 to 96 hours).
  • non-toxigenic cultures are associated with false positive results due to colonization with non-toxigenic strains.
    • Check to see if your lab has a toxigenic culture to minimize false positive results.
  • Labor intensive and requires an appropriate environment for growth of an anaerobic organism.

Toxin testing:7

  • Tissue culture cytotoxicity (detects toxin B only):
    • results typically available in 24 to 48 hours.
    • less sensitive than PCR or toxigenic culture.
  • Enzyme immunoassay: can detect both toxin A and toxin B. Some labs may offer a toxin B-only assay.
    • not as sensitive as culture cytotoxicity, PCR, or toxigenic cultures.

How does colonization differ from infection?

  • Colonization:7 no clinical symptoms, tests positive for C. diff and/or associated toxins.
  • Infection:7 symptoms present, tests positive for C. diff and/or associated toxins.
  • C. diff colonization is more common than infection.7
  • Avoid eradication confirmation testing after CDI treatment; many patients remain colonized after successful treatment.14,22

What strategies should be used to prevent the spread of C. diff?

  • Antimicrobial stewardship programs are critical to limit inappropriate prescribing of antibiotics.9
    • Ensure clindamycin, fluoroquinolones, and cephalosporin are used only when appropriate, and that they are discontinued when no longer necessary.9
  • Routinely use proper hand hygiene.9
    • Soap/water is preferred over alcohol-based hand sanitizer (washing physically washes away spores; alcohol does not inactivate them):9,33
      • during an outbreak.
      • after direct contact with stool or an area that has likely been contaminated with stool.
  • Use contact precautions until 48 hours after diarrhea has resolved.9,33
    • Use private rooms for hospitalized patients infected with C. diff, when possible.9,33
    • Wear gloves and gown (in most cases) when entering the patient’s room.9,33
    • Use disposable or patient-dedicated equipment, when possible, to limit exposure (e.g., blood pressure cuff).1
    • Clean reusable equipment with an appropriate sporicidal disinfectant (e.g., 2% glutaraldehyde) before using with other patients.9,13 Choose a product that will not harm the equipment.13 Follow label directions specific to C. diff.29
  • There are insufficient data to recommend empiric contact precautions when patients with a history of CDI are hospitalized.36

What are the treatment options for a FIRST EPISODE of nonsevere or severe C. diff?

Drug

Dose

When to Use

Costa

Vancomycin

125 mg PO QID x 10 days1,14
(10-14 days [Canada])22
(at least 14 days in patients with IBD14)

Non-severe or severe cases1,14,22 (preferred option for severe cases per ACG)14

See row “What are the available options for oral vancomycin?” for cost.

Fidaxomicin

200 mg PO BID x 10 days1,14

Non-severe or severe cases1,14 (preferred over vancomycin per IDSA1)

U.S.: ~$4,698
Canada: ~$2,050

Metronidazole

500 mg PO TID x 10-14 days1,14
(30 mg/kg/day divided QID x 10-14 days; max 500 mg/dose [Canada]22)

Alternative to vancomycin or fidaxomicin for non-severe cases1,14,22

U.S.: ~$15
Canada: ~$10 (may be <$5 using the 250 mg tablets)


How do treatment options for FIRST episode C. diff infections compare?

  • Pooled data (all severities) show ten days of oral vancomycin is more effective than oral metronidazole, NNT ~10 [Evidence Level B-2].9
    • Improved efficacy with vancomycin may be due to success rates in more severe cases.22
  • Vancomycin and fidaxomicin provide similar clinical cure (resolution of diarrhea maintained for at least two days after the end of treatment), adverse events, and impact on mortality in adults treated for severe CDI.1,27
    • However, fidaxomicin seems to be slightly better at reducing the risk of recurrence (NNT ~ 10).1,27
  • Guidelines differ slightly on preferred antibiotics.1,14,22
    • Any one of the three antibiotics may be appropriate to treat initial non-severe CDI.14
    • Even though vancomycin is less expensive than fidaxomicin, fidaxomicin might be more cost-effective due to potential for less recurrence, depending on the actual fidaxomicin price.28
  • Though standard practice based on clinical trials is to use ten days of therapy, up to 14 days can be used for patients with a delayed response.9 Extended durations are more commonly needed with metronidazole.9

What are the treatment options for patients with FULMINANT C. diff infections?

  • Fluid resuscitation and higher doses of vancomycin are recommended for fulminant cases of C. diff:1,14,22
    • Vancomycin 500 mg QID PO or via nasogastric tube.1 The ACG guidelines recommend 500 mg QID for the first 48 to 72 hours. If clinical improvement is seen, reduce vancomycin doses to 125 mg QID x 10 more days.14
      • Consider rectal administration every six hours in patients unable to take things orally or with an ileus.1,14
        • For rectal administration mix vancomycin in 500 mL of sterile 0.9% sodium chloride injection and administer as a retention enema for about one to two hours.8,37
      • Monitoring of serum vancomycin concentrations can be considered to rule out drug accumulation.9
        • Despite lack of good oral absorption, serum vancomycin levels may be seen with higher doses, especially in patients with long durations of therapy, impaired kidney function, or impaired intestinal wall integrity.9
    • Add metronidazole 500 mg every 8 hours IV to vancomycin, especially if ileus present.1,14,22,37
  • For patients with refractory cases, surgery may be necessary, especially for severely ill patients (e.g., white blood cell count ≥25,000, lactate level ≥5 mmol/L).9 Options include:9,14,23
    • subtotal colectomy.
    • total colectomy with an end ileostomy and a stapled rectal stump.
    • diverting loop ileostomy with/without colonic lavage and intraluminal vancomycin flushes.
  • Consider FMT for patients with refractory, severe and fulminant CDI, especially those that are not good surgical candidates.14

How does use of other antibiotics affect the treatment of C. diff?

  • Data are conflicting on how concomitant antibiotic use DURING C. diff treatment impacts risk of recurrence.10,42 Fidaxomicin may be more effective than vancomycin in patients receiving concomitant antibiotics for other infections in regard to initial response and risk of recurrence.42
  • Antibiotic use AFTER CDI treatment may increase recurrence risk, especially within ≤4 weeks of completing CDI treatment.15
  • There are not enough data to recommend changes to C. diff antibiotic regimens for patients requiring concomitant antibiotic therapy or additional antibiotics after completing treatment for C. diff.9
  • There are limited data on prophylaxis against C. diff in patients requiring antibiotics to reduce recurrence.9,14
  • Prophylactic vancomycin or fidaxomicin in patients receiving systemic antibiotic therapy is controversial.9,15
    • Specific prophylaxis doses have not been well established but may include:9,40
      • vancomycin 125 mg PO once daily or BID.
      • Fidaxomicin 200 mg PO once daily.
  • Considerations when determining whether or not to provide prophylaxis might include:9
    • time since most recent CDI treatment.
    • number and severity of previous C. diff infections.
    • overall health status/frailty of the patient.

What are the available options for oral vancomycin?

  • Oral options and approximate cost for vancomycin 125 mg QID x 10 days:
    • capsules:a ~$368 (US) or ~$225 (Canada).
    • oral solution using reconstituted powder for injection:a~$65 (US) or ~$550 (Canada).
      • This oral solution is known to be poorly tolerated due to the bitter and unpleasant taste.19,20
      • Follow your facility’s protocol to prepare and dispense oral vancomycin solution made from the powder for injection (note simplified instructions are also found in the vancomycin injection product labeling).
    • commercially available oral solution (e.g., Firvanq [US only]):a~$150.
      • Offers a potentially more palatable (and possibly cost-effective) alternative to existing formulations.

What are the treatment options for a FIRST RECURRENT EPISODE of C. diff?

Drug

Dose

When to Use

Vancomycin

Tapered/pulsed regimen (e.g., 125 mg PO QID x 10-14 days, then 125 mg BID x 7 days, then 125 mg once daily x 7 days, then 125 mg every 2 to 3 days x 2-8 weeks)1,22

Alternative to fidaxomicin per IDSA and ACG1,14

  • May be preferred over fidaxomicin due to cost.

Note: Every two- to three-day doses at the end of the taper are considered “pulses” with a goal allowing spores to germinate between doses (so that the resulting bacteria can be killed with the next dose), while allowing restoration of the normal flora.16

125 mg PO QID x 10 days (x 14 days [Canada])1,22

Option if metronidazole used for first episode of CDI per IDSA1

One of the preferred options for severe cases (Canada)22

Fidaxomicin

200 mg PO BID x 10 days1,14,22

Preferred option per IDSA and ACG1,14

  • Use may be limited due to cost.
  • May consider over vancomycin in hospitalized patients at high-risk for recurrence (e.g., older age, more severe illness).11,41

One of the preferred options for severe cases (Canada)22

Preferred if the first episode was treated with vancomycin or metronidazole.10

200 mg PO BID x 5 days, then 200 mg PO every other day x 20 days1

Preferred option per IDSA1

Metronidazole

500 mg PO TID x 10-14 days22

Per Canadian guidelines: only for non-severe cases AND if vancomycin or fidaxomicin can NOT be used.22


What is the role of bezlotoxumab in C. diff?

  • Bezlotoxumab (Zinplava [US only]) is a monoclonal antibody that binds to C. diff toxin B (10 mg/kg IV over one hour x one dose [cost: ~$3,800]) used with the standard antibiotics to reduce C. diff recurrence.30,a
    • Requires a 0.2 to 5 micron in-line or add-on filter for administration.30
    • Common adverse effects include headache, fever, and nausea.30
  • Consider adding bezlotoxumab to antibiotic therapy for patients with a CDI recurrence.1,14
    • Adding bezlotoxumab to C. diff antibiotic therapy may reduce the risk of recurrent CDI in adults with an initial or recurrent CDI compared to standard antibiotic therapy (NNT ~ 10 over 12 weeks) [Evidence Level A-1].18 Bezlotoxumab appears more beneficial (NNT ~ 6) when added to C. diff antibiotics in patients with multiple risk factors for recurrence [Evidence Level B-3].1
    • Per IDSA can also consider for initial CDI in patients at high risk for recurrence (e.g., age >65, patients who are immunocompromised, presenting initially with severe CDI).
    • Note there are limited data with combined use of bezlotoxumab with fidaxomicin.1
    • Use with caution in patients with heart failure.1 Heart failure symptoms and death were reported more often in patients with underlying heart failure treated with bezlotoxumab compared to placebo.8
    • Data are not available to assess safety and efficacy when combined with fecal transplantation.18

What are the treatment options for ADDITIONAL RECURRENT EPISODES of C. diff?

  • Antibiotic options for treatment of subsequent recurrent episodes of CDI include the following:
    • Vancomycin using a tapered/pulsed regimen (see “Treatment options for a first recurrent episode of C. diff” for dosing regimen).1,22
    • Vancomycin 125 mg PO QID x 10 days followed by rifaximin (Xifaxan [US]) 400 mg TID x 20 days (rifaximin cost:a ~$1,230 [US], only available as 550 mg strength in Canada as Zaxine).1
      • Note there are concerns about resistance rates of 30% to 50% with rifaximin, and ACG guidelines suggest additional studies to evaluate costs and benefits.14
    • Fidaxomicin 200 mg PO BID x 10 days or 200 mg PO BID x 5 days, then 200 mg PO every other day x 20 days.1
  • FMT (see below).
  • Consider suppressive oral vancomycin (e.g., 125 mg PO once daily) in patients with recurrent CDI who:14
    • are not candidates for FMT.
    • relapse after FMT.
    • require frequent antibiotic courses to treat C. diff.

What is the role of fecal transplant in the treatment of C. diff?

  • FMT is recommended for patients who have three or more C. diff episodes despite treatment or possibly for any case of severe, refractory C. diff when antibiotics don’t work at all.1,14,22,35
    • Canadian guidelines specify using FMT after a vancomycin pulse/taper for the second recurrence.22
  • Healthy donors who are screened (e.g., for infectious diseases [COVID-19, HIV, etc], autoimmune diseases [US], recent antibiotics, diarrhea, cancer) provide samples to stool banks to prep fecal transplants.12 However, there are FDA alerts regarding the safety of FMT and the risk of potential transmission of pathogenic organisms (e.g., enteropathogenic Escherichia coli [EPEC] and Shigatoxin-producing Escherichia coli [STEC], SARS-CoV-2).6,43,44
  • FMT is considered investigational.31,43
  • Rebyota is an FDA-approved fecal microbiota enema sourced from screened and tested donors for preventing recurrent C. diff in adults.32 It is administered in a clinic and requires ultracold storage.32
    • Rebyota leads to resolution of C. diff within two months for one of every 8 patients.32
    • Antibiotics should be completed 24 to 72 hours prior and avoided for eight weeks after.32
    • The most common adverse effects are abdominal pain or distension, diarrhea, nausea, and gas.32
  • Vowst is an FDA-approved oral fecal microbiota product sourced from screened and tested donors and treated with ethanol and filtration to make a suspension of desirable spores. It is indicated for preventing recurrent C. diff in adults. It can be stored at room temperature and self-administered.47
    • Vowst leads to resolution of C. diff within two months for one of every four patients.47
    • The dose is four capsules once daily on an empty stomach for three days.47
    • Antibiotics should be completed two to four days prior to starting Vowst.47 Patients will prep with 296 mL of magnesium citrate or 250 mL of polyethylene glycol solution at least eight hours prior to the first dose.47
    • The most common adverse effects are abdominal distension, fatigue, constipation, chills, and diarrhea.47

What is the role of probiotics and C. diff?

  • Routine use of probiotics to prevent CDI is not recommended.9,10,14,22
  • Preliminary data show probiotics may reduce the risk of a first-episode of C. diff, but studies are needed to confirm optimal dose and duration of therapy (Lactobacillus [e.g., Culturelle, Bio-K+], Saccharomyces boulardii [e.g., Florastor]).4,5,25,46
  • Some data support the use of probiotics to prevent recurrence in patients at high-risk or those with a history of C. diff (e.g., Saccharomyces boulardii [may be more effective in children than in adults]).2-5,26,45 For patients who wish to try:
    • Recommend Saccharomyces boulardii (e.g., Florastor) 20 billion colony-forming units daily, divided BID, for four weeks starting within two days of initiating antibiotics for C. diff.2,3

How should patients be educated to prevent the spread of C. diff at home?

  • Wash hands with soap and water, especially:17,21
    • after using the toilet.
    • after touching dirty surfaces.
    • before eating or handling/preparing food.
  • Avoid sharing personal care items (e.g., bath towels, razors, toothbrushes).21
  • Advise visitors to wash their hands before they leave.17
  • Clean commonly touched surfaces, including in the bathroom and kitchen, with an appropriate solution or wipes (e.g., 1:10 bleach solution, 1 part bleach mixed with 9 parts water, Clorox Healthcare Bleach Germicidal Wipes).17,21,24
  • Try to designate one bathroom that only the person infected with C. diff uses.17

Footnotes

  1. Pricing is wholesale acquisition cost (WAC), for generic when available. US medication pricing by Elsevier, accessed January 2023.

Abbreviations

ACG = American College of Gastroenterology; BID = twice daily; CDI = C. difficile infection (previously referred to as C. difficile-associated diarrhea or CDAD); EPA = Environmental Protection Agency; FMT = fecal microbiota transplantation; IBD = inflammatory bowel disease; IDSA = Infectious Diseases Society of America; IV = intravenous; NNT = number needed to treat; PO = orally; TID = three times daily; QID = four times daily.


Levels of Evidence

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]


References

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Cite this document as follows: Clinical ResourceClostridioides (Clostridium) difficile in Adults. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber’s Letter. February 2023. [390229]

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