Approach

The main goal of treatment is to discontinue the implicated antimicrobial agent and begin appropriate therapy. All patients not already hospitalized should be admitted unless they have no systemic symptoms and no organ dysfunction, in which case they can be treated as outpatients.

Most recommendations in this section are based on the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines published in early 2018, with a focused update published in 2021.​[2]​​[78]​​ Guidelines from the American College of Gastroenterology (ACG) published in 2021 largely support these recommendations, although the ACG also recommends conventional fecal microbiota transplantation (FMT) as a second-line option in severe and fulminant disease (as well as for recurrent disease), and vancomycin as the preferred first-line treatment for treatment of the initial episode. While guidelines mostly align, particularly in their promotion of fidaxomicin as a first-line treatment, there are still some key differences.[83]​

It should be noted that the IDSA/SHEA and ACG guidelines were published before the approval of live biotherapeutic products (a type of fecal microbiota-based therapy). Therefore, these guidelines recommend conventional FMT as the sole option when fecal microbiota-based therapy is indicated. However, in practice there is a shift toward using live biotherapeutic products (where available) in place of conventional FMT. Guidelines from the American Gastroenterological Association (AGA) published in 2024 are the only guidelines that currently recommend live biotherapeutic products.​[84]

Infection prevention and control

Hospitalized patients with confirmed or suspected infection should be isolated in a private room with a dedicated toilet in order to reduce the risk of infection to other patients. In institutions where there are a limited number of private rooms, priority should be given to patients with stool incontinence. It is important to place patients with suspected infection on contact precautions before test results become available. Contact precautions should be continued for at least 48 hours after diarrhea has resolved, and until discharge if Clostridioides difficile infection rates remain high.[2]​​​[64]

Healthcare professionals should use gowns and gloves on entry to a room when caring for patients. Hand hygiene should be performed before and after patient contact and after removing gloves. Either soap and water, or an alcohol-based product, should be used. Patients should also be encouraged to wash their hands and shower to reduce spore burden on the skin. Disposable patient equipment is preferred if available (rectal thermometers are not recommended).[2]​​​

The World Health Organization provides guidelines on correct hand-washing technique. A structured washing technique was found to be more effective than an unstructured technique against C difficile.[63] WHO: guidelines on hand hygiene Opens in new window

Discontinue causative agent

At the first suggestion of diagnosis, the inciting antibiotic(s) should be discontinued as soon as possible.[2]​​ If antibiotics cannot be withdrawn, an agent less likely to cause C difficile infection should be substituted. In particular, ampicillin, cephalosporins, clindamycin, carbapenems, and fluoroquinolones should be avoided.[21][22]

Supportive care

Patients should be evaluated for fluid status initially, especially if they are hospitalized. If necessary, hydration and electrolyte replacement should be instituted. Use of antimotility agents, including opioids and loperamide, should be avoided, although there is no evidence to support this recommendation.

Initial episode: antibiotic therapy

Antibiotic therapy should be started empirically if there is likely to be a substantial delay (>48 hours) in laboratory confirmation or for fulminant infection. For other patients, antibiotic therapy may be started after diagnosis in order to limit the overuse of antibiotics. Recommended regimens are based on the severity of disease and whether the episode is an initial episode or a recurrence.

IDSA/SHEA recommends fidaxomicin as a first-line agent for an initial episode of C difficile infection, as it is more effective than vancomycin with respect to sustained clinical response. This recommendation is based on moderate-certainty evidence. Fidaxomicin may not be widely available and is more costly; therefore, vancomycin remains an acceptable alternative. Previously, oral metronidazole was the antibiotic of choice; however, it is now only recommended in settings where access to a first-line agent is limited.[2]​​​[78]

Initial episode: nonsevere

  • Supportive clinical data: leukocytosis with WBC count of ≤15,000 cells/mL and serum creatinine <1.5 mg/dL (<0.13 mmol/L)

  • First-line treatment: oral fidaxomicin for 10 days

  • Alternative treatment: oral vancomycin or metronidazole for 10 days

Initial episode: severe

  • Supportive clinical data: leukocytosis with WBC count of ≥15,000 cells/mL and serum creatinine >1.5 mg/dL (>0.13 mmol/L)

  • First-line treatment: oral fidaxomicin for 10 days

  • Alternative treatment: oral vancomycin for 10 days

Initial episode: fulminant (severe, complicated infection)

  • Supportive clinical data: hypotension, shock, ileus, or megacolon

  • First-line treatment: oral vancomycin (at a higher dose than the dose for nonfulminant infection). If ileus is present, rectal installation of vancomycin can be considered. Intravenous metronidazole should be given with oral or rectal vancomycin, particularly if ileus is present as this may impair delivery of oral vancomycin to the colon

  • Alternative treatments: tigecycline or immune globulins have been used in patients who are not responding to first-line treatments, but no controlled trials have been performed.

The ACG recommends vancomycin or fidaxomicin for the treatment of an initial episode of severe or nonsevere disease.[58]

Highest quality evidence indicates fidaxomicin is significantly better than vancomycin at achieving sustained symptomatic cure (defined as the number of patients with resolution of diarrhea minus the number of patients with recurrence or death) in adults with non-multiply recurrent infections. It is therefore considered a better treatment option than vancomycin in all patients except those with severe infections. Cure rates with metronidazole were significantly less compared to vancomycin and fidaxomicin. Furthermore, fidaxomicin is more effective at preventing recurrence compared with vancomycin.[85][86][87][88]​​​​

One Cochrane review found moderate-quality evidence to suggest that vancomycin is superior to metronidazole, and fidaxomicin is superior to vancomycin, for achieving symptomatic cure in patients with C difficile infection, although the difference in effectiveness is not too large. No firm conclusions could be made regarding the efficacy of antibiotic treatment in severe disease as most studies excluded these patients. No conclusions regarding the need for antibiotic treatment in patients with mild infection, beyond discontinuing the causative antibiotic, could be made due to the lack of no-treatment control studies in the review.[89] [ Cochrane Clinical Answers logo ]

Vancomycin or fidaxomicin are the preferred agents in patients with underlying inflammatory bowel disease. These patients also generally require hospitalization for aggressive management. The decision to cease or continue immunosuppressive agents in patients with inflammatory bowel disease during acute infection should be made on a case-by-case basis.[90] If treatment is stopped, observational data and expert opinion suggest that treatment can be restarted after 48 to 72 hours of targeted antibiotic therapy.[91]

While therapeutic drug monitoring is not usually recommended with the use of oral vancomycin, it may be considered on a case-by-case basis, particularly in high-risk situations where high blood levels are anticipated (e.g., renal impairment, combination oral and enteral therapy, severe disease, inflammatory bowel disease).[92]

Antibiotic resistance to C difficile has been reported rarely with fidaxomicin, vancomycin, metronidazole, and tigecycline.[93]

Nitazoxanide and fusidic acid may be effective for the treatment of an initial episode of C difficile infection, but have less supportive evidence. There is a lack of good-quality evidence to support the use of rifaximin, tigecycline, or bacitracin for treatment of an initial episode.[94][95]​​

Severe and fulminant disease: surgery

Surgery may be warranted in severe complicated or fulminant disease, or in patients who do not respond to antibiotic therapy.[2]​​​[3][96]​ Fulminant disease is underappreciated as a life-threatening disease because of a lack of awareness of its severity and its nonspecific clinical syndrome. Early diagnosis and treatment are essential for a good outcome, and early surgical intervention should be considered in patients who are unresponsive to medical therapy or who have rising white blood cell count or lactate level. The surgical procedure of choice is a subtotal colectomy with preservation of the rectum. Diverting loop ileostomy (with colonic lavage followed by antegrade vancomycin flushes) is an alternative approach.​[2]​​​[97] Both procedures have similar survival rates; however, loop ileostomy is associated with a lower risk of surgical site infections, and an increased rate of colonic preservation. Evidence is limited.​​​[98][99]​​

Severe and fulminant disease: conventional fecal microbiota transplantation

US guideline recommendations on conventional FMT (a type of fecal microbiota-based therapy) for severe and fulminant disease vary.

  • The ACG recommends considering conventional FMT in patients with severe and fulminant disease who are refractory to antibiotic therapy, in particular, when patients are deemed poor surgical candidates.[58] 

  • The AGA recommends conventional FMT for hospitalized patients with severe or fulminant disease who are refractory to antibiotic therapy.[84]

  • However, IDSA/SHEA do not currently recommend conventional FMT for these patients as yet.[2]​​ 

While key guidelines currently recommend conventional FMT, in practice there is a shift toward using live biotherapeutic products (where available) in place of conventional FMT. However, guidelines do not currently recommend live biotherapeutic products for patients with severe and fulminant disease, and they are not approved for this indication.

One meta-analysis of randomized controlled trials found that there was no statistically significant difference between medical therapy and conventional FMT in patients with primary infection.[100]

See Recurrent infection: conventional fecal microbiota transplantation section below for more information.

Recurrent infection

Recurrence rates have been reported to vary from 5% to 50%, although one study found at least one recurrence in 21% of healthcare-associated infections and 14% of community-associated infections.[6]​ Approximately 25% of patients treated with vancomycin for an initial episode experience at least one recurrent episode.[101][102]

Options for the management of recurrent infection include:

  • Antibiotic therapy

  • Fecal microbiota-based therapies

    • Conventional FMT

    • Live biotherapeutic products

  • Bezlotoxumab.

The optimal combination of these therapies for the management of recurrence is not well studied.

Recurrent infection: antibiotic therapy

IDSA/SHEA recommends that a first recurrence should be treated with the following antibiotic regimens:[2]​​​[78]

  • First-line treatment: a standard 10- or 20-day course of fidaxomicin

  • Alternative treatment: a prolonged tapered and pulsed-dose regimen of oral vancomycin, or a standard 10-day course of oral vancomycin (if metronidazole was used for the initial episode).

Subsequent recurrences may be treated with the following antibiotic regimens:[2]​​​[78]

  • A standard 10- or 20-day course of fidaxomicin.

  • A prolonged tapered and pulsed-dose regimen of oral vancomycin

  • A standard 10-day course of oral vancomycin followed by rifaximin for 20 days.

The ACG recommends a tapered and pulsed-dose regimen of oral vancomycin (after an initial course of fidaxomicin, vancomycin, or metronidazole) or fidaxomicin (after an initial course of vancomycin or metronidazole) for a first recurrence. Oral vancomycin may be considered for subsequent recurrences.[58]

Taper and pulsed-dose regimens of vancomycin were superior to taper alone and pulsed-dose alone regimens (resolution rates of 83% versus 68% and 54%, respectively) for recurrent infection. However, evidence is limited.[103]

Recurrent infection: bezlotoxumab

Bezlotoxumab is a human monoclonal antibody that binds to Clostridioides difficile toxin B. It has been approved to reduce the recurrence of C difficile infection in adults who are receiving antibacterial treatment for C difficile infection and who have a high risk of recurrence. It is not indicated for the treatment of C difficile infection and is not an antibacterial drug so must be used in combination with antibiotic therapy. Bezlotoxumab should be used under specialist guidance.

IDSA/SHEA recommends using bezlotoxumab alongside standard of care antibiotics for the prevention of recurrence in patients who have had a recurrent episode within the last 6 months, particularly those who are at high risk of recurrence (e.g., age ≥65 years, immunocompromised, severe disease on presentation) and provided logistics for intravenous administration is not an issue. This recommendation is based on very low certainty evidence.[78] The ACG also recommends considering bezlotoxumab for the prevention of recurrence in patients who are at high risk of recurrence.[58]​​

A single intravenous dose of bezlotoxumab (given in combination with standard antibiotic treatment) for primary or recurrent C difficile infection was associated with a 38% lower rate of recurrent infection compared with antibiotic treatment alone in 2 phase III trials. Sustained cure (no recurrent infection in 12 weeks) was achieved by 64% of patients compared with 54% of patients in the placebo group. The most common adverse effects were nausea and diarrhea, and the drug had a similar adverse effect profile to placebo.[104] One systematic review and meta-analysis of 13 studies (including two randomized controlled trials) found that bezlotoxumab significantly reduced the risk of recurrent C difficile infection compared with standard of care (15.8% vs. 28.9%, respectively).[105]​ Bezlotoxumab was no better at resolving recurrent infection compared with conventional FMT.​[106] Data on the use of bezlotoxumab when fidaxomicin is used as the standard of care antibiotic are limited.​[78]

In patients with a history of congestive heart failure, bezlotoxumab should be reserved for use when the benefits outweigh the risks. Heart failure was reported more commonly with bezlotoxumab compared to placebo in clinical trials, primarily in patients with underlying congestive heart failure.​[78]

Recurrent infection: conventional fecal microbiota transplantation

US guideline recommendations on conventional FMT (a type of fecal microbiota-based therapy) for recurrent infection vary.

  • IDSA/SHEA recommends conventional FMT as an option in patients with at least two recurrences and where antibiotic therapy has failed.[2]​​

  • However, the ACG recommends considering conventional FMT as a first-line option in patients experiencing their second or further recurrence of disease to prevent further recurrences.[58]

  • The AGA recommends fecal microbiota-based therapies (including conventional FMT) for immunocompetent patients with recurrent infection after the completion of standard-of-care antibiotic therapy. The AGA recommends conventional FMT specifically for mild to moderately immunocompromised patients, and recommends against the use of all fecal microbiota-based therapies in severely immunocompromised patients.[84]

The procedure involves implanting processed stool collected from a healthy donor into the intestinal tract of infected patients to correct intestinal dysbiosis. A short induction course of oral vancomycin may be used prior to conventional FMT to reduce C difficile burden in patients who are not receiving antibiotic therapy prior to planned FMT.[2]

Evidence supports the use of conventional FMT for recurrent infection.

  • One Cochrane review found that FMT likely leads to a large increase in the resolution of recurrent infection in immunocompetent adults compared to alternative treatments (e.g., antibiotics), based on moderate-certainty evidence. Conclusions could not be made regarding benefits or harms in immunocompromised patients due to a lack of data. FMT probably leads to a small decrease in the rates of serious adverse events (moderate-certainty evidence) and may decrease all-cause mortality (low-certainty evidence). However, an increased risk of these outcomes cannot be ruled out as the number of events was small.[107] [ Cochrane Clinical Answers logo ]

  • Randomized controlled trials have shown high success rates.[108][109][110]​ Meta-analyses have reported efficacy rates of 82.1% to 95.6%.[111][112]​ A prospective real-world analysis of a US FMT registry found that 90% of patients were considered cured (i.e., diarrhea had resolved without needing additional treatment) at 1-month follow-up. Of those cured at 1 month, 4% of patients experienced recurrence by 6 months.[113]​ However, FMT has been associated with lower cure rates in randomized trials compared with open-label and observational studies, and efficacy is higher for recurrent infection compared with refractory disease.[114]

  • FMT appears to be the optimum approach for the treatment of recurrent disease compared with antibiotics such as vancomycin or fidaxomicin or placebo.[115][116][117]​ A systematic review of randomized controlled trials found that there was moderate-quality evidence to indicate that FMT is more effective than vancomycin or placebo.[118] Another randomized controlled trial found that FMT (applied by colonoscopy or nasojejunal tube after 4 to 10 days of vancomycin) was superior to fidaxomicin or vancomycin in terms of clinical and microbiologic resolution or clinical resolution alone.[119]

  • Success of FMT may be improved by adequate bowel preparation at the time of FMT and optimizing antibiotic stewardship practices in the peri-FMT period. Nonmodifiable risk factors that increase the risk of treatment failure include advanced age, severe infection, inflammatory bowel disease, prior C difficile-related hospitalization, and inpatient status.[120]

The ACG recommends conventional FMT preferably through colonoscopy or oral capsules (or enema if other methods are unavailable), and suggest repeat FMT for patients experiencing a recurrence of CDI within 8 weeks of an initial FMT.[58]

  • Cure rates with FMT via colonoscopy are superior to FMT via enema and nasogastric tube, and comparable to FMT via oral capsules.[121]

  • Frozen or lyophilized FMT is as effective as fresh FMT in achieving resolution of diarrhea, and lower gastrointestinal delivery may be more effective than upper gastrointestinal delivery.[109][122][123][124]

  • Oral capsules are promising due to their ease of administration, and an overall efficacy of 82% has been reported with this method of delivery.[112]

Conventional ​FMT is generally well tolerated, but adverse effects may include fever, abdominal tenderness or discomfort, flatulence, nausea/vomiting, diarrhea/constipation, and infections.[125]

  • FMT-related adverse effects have been reported in 19% of patients undergoing FMT, and were generally considered to be mild to moderate and self-limiting. However, serious adverse effects, including infections and death, were reported in 1.4% of patients. All serious adverse effects were reported in patients with mucosal barrier injury.[126]

  • Patients who received FMT via colonoscopy experienced more adverse effects compared to patients who received FMT via enema or oral capsules.[127]

  • Long-term consequences are unknown.

Conventional FMT is recommended in patients with inflammatory bowel disease.

  • Earlier observational evidence suggested that FMT may be less effective at clearing C difficile infection in patients with inflammatory bowel disease.[128]​ However, one meta-analysis of cohort studies found no significant difference in cure rate after FMT in patients with C difficile infection with or without inflammatory bowel disease, but noted that further randomized controlled trials are necessary to validate its safety and efficacy in these patients.[129] Another meta-analysis found that FMT appears to be a highly effective therapy for preventing recurrent infection in these patients.[130]

  • The ACG recommends that FMT should be considered for recurrent infection in patients with inflammatory bowel disease.[58]

Conventional ​FMT may transmit pathogenic microorganisms leading to serious or life-threatening infections.

  • A systematic review of 303 immunocompromised patients found no difference between rates of serious adverse effects in immunocompromised and immunocompetent patients who undergo FMT.[131] However, the Food and Drug Administration (FDA) has warned that FMT may transmit multidrug-resistant organisms, leading to serious or life-threatening infections, particularly in patients who are immunocompromised. This follows two cases of immunocompromised adults who received FMT and developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. One of the patients died.[132]

  • The FDA recommends that healthcare providers consider the potential risk of transmission of pathogenic bacteria by FMT products, including enteropathogenic Escherichia coli (EPEC) and Shiga toxin-producing Escherichia coli (STEC), and the resultant serious adverse reactions that may occur.[133]

  • The FDA has warned that clinical use of FMT has the potential to transmit the SARS-CoV-2 virus and the monkeypox virus, and that additional precautions are required for stool donated after certain dates for each virus.[134][135]​​

  • A prospective cohort study found that patients who undergo FMT compared with those taking antibiotics had a decreased risk of bloodstream infection.[136]​​

  • Fecal products may also contain food allergens.

Safety concerns and the lack of large-scale availability are barriers to the widespread use of conventional FMT. Its use has decreased in recent years for various reasons, including:

  • The increasingly recognized risk of pathogen transmission

  • The coronavirus disease 2019 (COVID-19) pandemic

  • Regulatory agency requirements associated with using material from stool banks (e.g., requirement for an Investigational New Drug application in the US)

  • The availability of approved live biotherapeutic products (see below).

It should be noted that the IDSA/SHEA and ACG guidelines were published before the approval of live biotherapeutic products. Therefore, they recommend conventional FMT as the sole option when fecal microbiota-based therapy is indicated. However, in practice, there is a shift toward using live biotherapeutic products (where available) in place of conventional FMT.

Further research on this treatment is required as key components of FMT interventions are poorly reported.[137]

Recurrent infection: live biotherapeutic products

Live biotherapeutic products are another type of fecal microbiota-based therapy. These products have become commercially available in recent years and are being used in place of conventional FMT in some centers. These products have better standardized safety and efficacy data compared with conventional FMT. Live biotherapeutic products are either derived directly from human stool or contain a defined microbial component isolated from human stool and processed for manufacture ex vivo. The composition, formulation, and dose of products may differ.[138][139]

​The FDA has approved two donor-derived products for the prevention of recurrence of C difficile infection in patients ages ≥18 years.

  • Fecal microbiota live (known commercially as Rebyota® in the US) is a liquid rectal administration that is given as a single rectal dose (via retention enema) after antibiotic treatment. No bowel preparation is required.

  • Fecal microbiota spores live (known commercially as Vowst® in the US) is an oral capsule product given orally for 3 days after antibiotic treatment and bowel preparation. It is composed of spores rather than an isolated consortium of bacteria.

  • Other proprietary products may be available in other countries.

Live biotherapeutic products have numerous advantages over conventional FMT.[138][139]

  • Manufactured under a standardized process that includes donor and pathogen screening, good manufacturing practices, and rigorous clinical trials.

  • Less risk of containing known infectious pathogens due additional steps taken during the manufacturing process.

  • Can be prescribed by any healthcare provider, not just gastroenterology or infectious diseases specialists.

  • Simpler modes of delivery (e.g., oral products can be taken at home).

Live biotherapeutic products are not included in guidelines from IDSA/SHEA or the ACG as these guidelines were published before their availability. However, they are included in guidelines published by the AGA in 2024.

  • The AGA recommends the use of fecal microbiota-based therapies (including live biotherapeutic products) in immunocompetent patients with recurrent infection after the completion of standard-of-care antibiotic therapy. There is insufficient evidence to recommend live biotherapeutic products in immunocompromised patients.[84]

Evidence for live biotherapeutic products is limited.

  • Fecal microbiota live (Rebyota®) was studied in a randomized, double-blind phase 3 trial. Statistical modeling showed that 70% of participants remained free of recurrence at 8 weeks after treatment compared to 58% with placebo.[140]

  • Fecal microbiota spores live (Vowst®) was studied in a double-blind, placebo-controlled phase 2b/3 trial. Recurrence was significantly lower at 8 weeks after treatment compared to placebo (12% vs. 40%, respectively).[141]

  • ​The most common adverse effects were mild to moderate gastrointestinal adverse effects. While no major safety issues were reported, postmarketing surveillance is ongoing. Donor-derived products may contain food allergens. However, no cases of food allergen events have been reported as yet.[138]

  • No head-to-head trials or comparative studies with conventional FMT or bezlotoxumab have been published.[138]

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