How should Clostridioides difficile infection be treated, including first‑line therapy for mild‑to‑moderate and severe disease and management of recurrences?

Treatment of Clostridioides difficile Infection

For initial CDI episodes, fidaxomicin 200 mg orally twice daily for 10 days is the preferred first-line treatment, with vancomycin 125 mg orally four times daily for 10 days as an acceptable alternative; metronidazole should only be used in resource-limited settings where neither agent is available. 1, 2

Initial Episode Treatment Algorithm

Preferred First-Line Therapy

• Fidaxomicin 200 mg orally twice daily for 10 days is the preferred treatment for all initial CDI episodes regardless of severity 1, 2, 3
• Fidaxomicin demonstrates superior sustained cure rates (77% vs 63-68% for vancomycin) due to significantly lower recurrence rates (13-17% vs 24-27% for vancomycin) 1
• The distinction between non-severe and severe disease does not change the initial antibiotic choice—both fidaxomicin and vancomycin are appropriate for either severity 1, 2

Alternative First-Line Therapy

• Vancomycin 125 mg orally four times daily for 10 days remains an acceptable alternative with proven efficacy (81-92% clinical cure rates) 1, 4
• Vancomycin demonstrated superior cure rates compared to metronidazole in severe CDI (97% vs 76% in intention-to-treat analysis) 1, 2

Metronidazole: Limited Role Only

• Metronidazole 500 mg orally three times daily for 10-14 days should only be used for non-severe CDI in resource-limited settings where vancomycin or fidaxomicin are unavailable 1, 2
• Non-severe disease is defined as: WBC ≤15,000 cells/μL AND serum creatinine <1.5 mg/dL 1, 2
• Avoid repeated or prolonged metronidazole courses due to risk of cumulative and potentially irreversible neurotoxicity 2, 5

Fulminant/Life-Threatening CDI

Definition and Recognition

• Fulminant CDI is defined by: hypotension or shock, ileus, or megacolon 1
• Additional markers include: WBC >15,000 cells/μL, serum creatinine ≥1.5 mg/dL, or albumin <30 g/L 1

Treatment Regimen

• Vancomycin 500 mg orally or via nasogastric tube four times daily PLUS intravenous metronidazole 500 mg every 8 hours 1, 2
• If ileus is present, add vancomycin 500 mg in 100 mL normal saline per rectum every 4-12 hours as a retention enema 1, 2
• Intravenous vancomycin has no effect on CDI since it is not excreted into the colon 1, 2
• Vancomycin can be administered via nasogastric tube or trans-stoma in surgical patients with ileostomy or colonic diversion 1, 2

First Recurrence Treatment

Preferred Approach

• Fidaxomicin 200 mg orally twice daily for 10 days is the preferred option for first recurrence 1, 2
• Alternative extended-pulsed fidaxomicin regimen: 200 mg twice daily for 5 days, then once every other day for 20 days 1
• Fidaxomicin reduced recurrence after first recurrence from 35.5% with vancomycin to 19.7% (absolute difference -15.8%, p=0.045) 6

Alternative Approaches

• Vancomycin tapered and pulsed regimen: 125 mg four times daily for 10-14 days, then twice daily for 7 days, then once daily for 7 days, then every 2-3 days for 2-8 weeks 1, 2
• Standard vancomycin 125 mg four times daily for 10 days if metronidazole was used for the initial episode 1

Adjunctive Therapy

• Bezlotoxumab 10 mg/kg intravenously once during administration of standard antibiotic therapy may be considered for patients with risk factors for recurrence 1
• Risk factors include: age >65 years, immunocompromised status, severe CDI on presentation, or history of prior CDI 1
• Caution: FDA warns that bezlotoxumab should be reserved for use when benefit outweighs risk in patients with congestive heart failure 1

Second and Subsequent Recurrences

Antibiotic Options

• Fidaxomicin 200 mg twice daily for 10 days OR extended-pulsed regimen (twice daily for 5 days, then once every other day for 20 days) 1
• Extended-pulsed fidaxomicin achieved 70% sustained cure vs 59% with vancomycin (p=0.030) in patients ≥60 years 7
• Vancomycin tapered and pulsed regimen as described above 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 is strongly recommended after at least 2 recurrences (i.e., 3 CDI episodes) that have failed appropriate antibiotic treatments 1, 2
• FMT demonstrated 81% resolution rate compared to 31% with vancomycin alone in one randomized trial 1

Critical Management Principles

Essential Actions

• Discontinue the inciting antibiotic agent(s) as soon as possible to reduce recurrence risk 2, 5
• Avoid antiperistaltic agents and opiates in all patients with CDI 1, 2
• Do not perform a "test of cure" after treatment completion 1, 2

Concomitant Antibiotic Use

• Use of concomitant antibiotics during CDI treatment was associated with lower cure rates (84.4% vs 92.6%, p<0.001) and extended time to resolution (97 vs 54 hours, p<0.001) 8
• When concomitant antibiotics are necessary, fidaxomicin achieved 90.0% cure vs 79.4% for vancomycin (p=0.04) 8
• Fidaxomicin reduced recurrence by 12.3% compared to vancomycin when concomitant antibiotics were used (16.9% vs 29.2%, p=0.048) 8

Treatment Response Monitoring

• Clinical response typically requires 3-5 days after starting therapy, with metronidazole potentially taking up to 5 days 1, 2
• Median time to resolution of diarrhea was 4-5 days with vancomycin in clinical trials 4
• Evaluate treatment response daily by assessing stool frequency, consistency, and clinical parameters 2

Common Pitfalls to Avoid

• Do not use metronidazole for severe CDI due to significantly inferior cure rates (66% vs 79% for vancomycin in intention-to-treat analysis) 1
• Do not use repeated courses of metronidazole due to neurotoxicity risk 2, 5
• Do not administer intravenous vancomycin for CDI treatment as it is not excreted into the colon 1, 2
• Do not delay surgical consultation in fulminant cases; surgery should be performed before serum lactate exceeds critical thresholds 1, 2