What is the recommended antibiotic regimen for an adult patient with suspected or confirmed Clostridium difficile (C. difficile) infection, particularly those with severe symptoms or a history of recent antibiotic use, hospitalization, or other risk factors?

Antibiotic Treatment for Clostridioides difficile Infection

For initial C. difficile infection, fidaxomicin 200 mg twice daily for 10 days is the preferred first-line treatment, with vancomycin 125 mg four times daily for 10 days as an acceptable alternative; metronidazole should only be used for non-severe disease when the preferred agents are unavailable. 1

Initial Episode Treatment Algorithm

Preferred First-Line Therapy

• Fidaxomicin 200 mg orally twice daily for 10 days is the IDSA/SHEA preferred treatment for all initial CDI episodes, regardless of severity 1, 2
• Fidaxomicin demonstrates lower recurrence rates compared to vancomycin, though it is substantially more expensive 3, 4

Alternative First-Line Therapy

• Vancomycin 125 mg orally four times daily for 10 days remains an acceptable alternative for all initial episodes 1, 3
• This standard vancomycin dose (125 mg) is appropriate even for severe CDI—higher doses are NOT indicated unless the infection is fulminant 3

When Metronidazole Can Be Used

• Metronidazole 500 mg three times daily for 10-14 days should only be used for non-severe CDI when fidaxomicin and vancomycin are unavailable 1
• Non-severe disease is defined by WBC ≤15,000 cells/μL AND serum creatinine <1.5 mg/dL 1, 3
• Avoid prolonged or repeated metronidazole courses due to risk of cumulative and potentially irreversible neurotoxicity 4

Severe CDI (Non-Fulminant)

Disease Definition

• Severe CDI is characterized by WBC ≥15,000 cells/mL OR serum creatinine >1.5 mg/dL 3

Treatment Approach

• Use the same dosing as initial episodes: fidaxomicin 200 mg twice daily OR vancomycin 125 mg four times daily for 10 days 1, 3
• Do NOT escalate to vancomycin 500 mg for severe (non-fulminant) disease—the standard 125 mg dose is appropriate 3

Fulminant CDI

Disease Definition

• Fulminant CDI is defined by hypotension or shock, ileus, or megacolon 1, 3

Treatment Regimen

• Vancomycin 500 mg orally four times daily (or by nasogastric tube if unable to take orally) 1, 3
• PLUS intravenous metronidazole 500 mg every 8 hours administered concurrently 1, 3
• If ileus is present, consider adding rectal instillation of vancomycin 1

Recurrent CDI Management

First Recurrence

• Fidaxomicin 200 mg twice daily for 10 days (standard or extended pulsed regimen: twice daily for 5 days, then once every other day for 20 days) 1
• Alternative: Vancomycin in tapered and pulsed regimen (125 mg four times daily for 10-14 days, then twice daily for 7 days, once daily for 7 days, then every 2-3 days for 2-8 weeks) 1
• Consider bezlotoxumab 10 mg/kg IV once as adjunctive therapy during antibiotic administration, though use caution in patients with congestive heart failure 1

Second or Subsequent Recurrence

• Fidaxomicin (standard or extended regimen) OR tapered/pulsed vancomycin 1
• Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1
• Fecal microbiota transplantation (FMT) should be considered only after at least 2 recurrences (i.e., 3 total CDI episodes) with appropriate antibiotic treatment 1

Critical Management Principles

Discontinue Inciting Antibiotics

• Immediately discontinue the causative antibiotic if clinically feasible, as this significantly reduces recurrence risk 3, 4

Avoid Antimotility Agents

• Never use antiperistaltic agents (loperamide, diphenoxylate) or opiates in CDI patients, as they worsen outcomes and increase complications 3, 4
• The ESCMID explicitly recommends avoiding antiperistaltic agents (strong recommendation, moderate quality evidence) 4
• If metoclopramide is being used for other indications, consider temporarily discontinuing it during CDI treatment 4

Surgical Consultation

• Early surgical consultation is essential for fulminant cases, as colectomy may be life-saving in patients with toxic megacolon, perforation, or refractory shock 5

Important Clinical Caveats

• DIFICID (fidaxomicin) is only effective for C. difficile infection due to minimal systemic absorption and should not be used for other infections 2
• FMT carries FDA safety alerts regarding transmission of pathogenic organisms (including multidrug-resistant E. coli and potential SARS-CoV-2), with documented deaths; appropriate donor and specimen screening is mandatory 1
• Bezlotoxumab may be considered for patients at high risk for recurrence (age >65 years, immunocompromised, severe CDI on presentation), but implementation depends on available resources 1