Treatment Approaches for C. difficile Infection by Severity

Defining Disease Severity

The Infectious Diseases Society of America recommends defining non-severe CDI as a white blood cell count ≤15,000 cells/mL AND serum creatinine <1.5 mg/dL 1
The American Medical Association suggests that diarrhea without systemic signs of severe infection is characteristic of non-severe CDI 2
Severe CDI is defined as a white blood cell count ≥15,000 cells/mL OR serum creatinine ≥1.5 mg/dL, according to the Infectious Diseases Society of America 1
The European Society of Clinical Microbiology and Infectious Diseases notes that severe CDI may include marked leukocytosis, elevated creatinine (>50% above baseline), or decreased albumin (<30 g/L) 3, 4

The Infectious Diseases Society of America recommends oral vancomycin 125 mg four times daily for 10 days as a first-line treatment for non-severe CDI, with strong recommendation and high quality evidence 1
The Infectious Diseases Society of America also recommends fidaxomicin 200 mg twice daily for 10 days as a first-line treatment for non-severe CDI, with strong recommendation and high quality evidence 1
For severe CDI, the Infectious Diseases Society of America recommends oral vancomycin 125 mg four times daily for 10 days, with strong recommendation and high quality evidence 1
The European Society of Clinical Microbiology and Infectious Diseases suggests that vancomycin demonstrated a 97% cure rate versus 76% for metronidazole in severe disease 5

The American Medical Association recommends stopping precipitating antibiotics immediately if clinically feasible 2, 6
The European Society of Clinical Microbiology and Infectious Diseases advises avoiding antiperistaltic agents and opiates, as they worsen outcomes 3, 7, 8
The Infectious Diseases Society of America suggests assessing clinical response by 72 hours and escalating therapy if no improvement 9
Treatment response may require 3-5 days, according to the American Medical Association 2, 6

The 2018 IDSA/SHEA guidelines recommend vancomycin 125 mg four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days as first-line treatment for initial CDI, with strong recommendation and high quality evidence. 10, 11
Metronidazole should only be used in settings where access to vancomycin or fidaxomicin is limited, and only for non-severe disease (WBC ≤15,000 cells/mL AND creatinine <1.5 mg/dL). 12, 11

The standard duration for metronidazole is 10 days at a dose of 500 mg orally three times daily. 12, 11
Some patients treated with metronidazole may have delayed response to treatment, and clinicians should consider extending treatment duration to 14 days in those circumstances. 10, 13

Repeated or prolonged courses of metronidazole must be avoided due to risk of cumulative and potentially irreversible neurotoxicity (strong recommendation, moderate quality of evidence). 12, 11
This neurotoxicity risk is particularly concerning in elderly patients who may require longer treatment courses or experience recurrence. 12

For severe disease (WBC ≥15,000 cells/mL OR creatinine ≥1.5 mg/dL), metronidazole should NOT be used; vancomycin 125 mg four times daily for 10 days is required. 10, 11
For fulminant disease (hypotension, shock, ileus, megacolon), IV metronidazole 500 mg every 8 hours is added to high-dose oral vancomycin (500 mg four times daily), not used as monotherapy. 10, 12, 11

Do not use "test of cure" after completing CDI treatment; testing should only be performed in symptomatic patients. 14
If the patient shows no improvement by day 3-5, do not continue metronidazole for the full 10 days—escalate to vancomycin. 14