What is the treatment for Clostridioides difficile (C. diff) infection in an inpatient setting?

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From the Guidelines

Treating Clostridioides difficile (C. diff) infection in hospitalized patients requires prompt antimicrobial therapy based on disease severity, with oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days recommended for initial non-severe cases, as stated in the 2021 clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) 1.

Treatment Approach

For initial non-severe cases, the preferred treatment is fidaxomicin 200 mg given twice daily for 10 days, while an alternative treatment is vancomycin 125 mg given 4 times daily by mouth for 10 days.

  • For severe cases, the same regimens are used, though some clinicians may increase vancomycin to 500 mg four times daily.
  • For fulminant C. diff with hypotension, shock, or ileus, vancomycin 500 mg 4 times daily by mouth or by nasogastric tube is recommended, with consideration of adding rectal instillation of vancomycin if ileus is present, and intravenously administered metronidazole (500 mg every 8 hours) should be administered together with oral or rectal vancomycin, particularly if ileus is present.

Recurrent Infections

For recurrent infections, extended vancomycin tapers, fidaxomicin, or fecal microbiota transplantation may be considered, with the choice of treatment depending on the severity of the recurrence and the patient's underlying health status.

  • Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments, as stated in the 2024 AGA clinical practice guideline on fecal microbiota-based therapies for select gastrointestinal diseases 1.

Supportive Care and Infection Control

Supportive care is essential, including fluid resuscitation, electrolyte replacement, and avoiding antimotility agents and unnecessary antibiotics.

  • Infection control measures are crucial, including placing patients in contact isolation, using gloves and gowns when entering rooms, and practicing proper hand hygiene with soap and water, since alcohol-based sanitizers are less effective against C. diff spores.

Key Considerations

  • The treatment approach should be individualized based on the patient's specific clinical presentation and underlying health status.
  • The use of bezlotoxumab, a human monoclonal antibody that reduces recurrent CDI, may be considered in patients with CDI due to the 027 epidemic strain, in immunocompromised patients, and in patients with severe CDI, as stated in the 2020 proposal for a comprehensive approach to infections across the surgical pathway 1.

From the FDA Drug Label

DIFICID® is indicated in adult and pediatric patients aged 6 months and older for the treatment of C. difficile-associated diarrhea (CDAD). The recommended dosage for adults is one 200 mg DIFICID tablet orally twice daily for 10 days. The recommended dosage for pediatric patients weighing at least 12.5 kg and able to swallow tablets is one 200 mg DIFICID tablet administered orally twice daily for 10 days.

To treat C. difficile-associated diarrhea (CDAD) in adult inpatients, the recommended treatment is:

  • Fidaxomicin (PO): 200 mg orally twice daily for 10 days. For pediatric inpatients (6 months to less than 18 years of age), the recommended treatment is:
  • Fidaxomicin (PO):
    • For patients weighing at least 12.5 kg and able to swallow tablets: 200 mg orally twice daily for 10 days.
    • For patients unable to swallow tablets, use the oral suspension as recommended in the dosage table 2.

From the Research

Treatment Options for C. difficile Infection

  • Fidaxomicin, vancomycin, and metronidazole are commonly used antibiotics for the treatment of C. difficile infection (CDI) 3, 4, 5, 6, 7
  • Fidaxomicin has been shown to be effective in reducing recurrence, especially in high-risk patients 3, 7
  • Vancomycin is often used as a first-line therapy, and fidaxomicin is considered a good alternative, especially in patients at risk of relapse 4

Comparison of Treatment Outcomes

  • A study comparing fidaxomicin, metronidazole, and vancomycin found that fidaxomicin had increased odds of suffering another episode of C. difficile, and was inferior to metronidazole for recurrent CDI 6
  • Another study found that fidaxomicin was superior to metronidazole, vancomycin, or their combination for a sustained clinical response and in the prevention of recurrent CDI in the initial episode, first recurrence, and non-severe cases 7

Treatment of Recurrent CDI

  • Extended-pulsed fidaxomicin (EPFX) has been proposed as a salvage regimen for patients with multiple high-risk features, including advanced age, active malignancy, and prior treatment failures 3
  • Vancomycin combined with fecal microbiota transplantation remains the primary therapy for multiple recurrent CDI 4

Antibiotic Resistance

  • Resistance profile for C. difficile was found to be 4.07% for vancomycin and 3.49% for metronidazole in one study 6
  • Vancomycin resistance of C. difficile statistically decreased, whereas metronidazole resistance did not vary during the studied period 6

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Extended-pulsed Fidaxomicin Therapy for Recurrent Clostridioides difficile Infection After Standard Vancomycin and Fidaxomicin Failure: A Case Report.

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 2025

Research

Update of treatment algorithms for Clostridium difficile infection.

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2018

Research

Fidaxomicin versus metronidazole, vancomycin and their combination for initial episode, first recurrence and severe Clostridioides difficile infection - An observational cohort study.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2021

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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