What is the treatment for Clostridium difficile infection (CDI)?

Treatment of Clostridium difficile Infection

For initial CDI, treat non-severe disease with oral vancomycin 125 mg four times daily for 10 days, and severe disease with the same vancomycin regimen; metronidazole is now considered less preferred even for non-severe cases. 1, 2

Disease Severity Classification

Determining disease severity is the critical first step that dictates your entire treatment approach.

• Non-severe CDI is characterized by stool frequency <4 times daily, no signs of severe colitis, and white blood cell count <15 × 10⁹/L 3

• Severe CDI is defined by one or more of the following: temperature >38.5°C, hemodynamic instability, leukocyte count >15×10⁹/L, serum creatinine rise >50% above baseline, elevated serum lactate, pseudomembranous colitis on endoscopy, or colonic wall thickening on imaging 1, 4

• Fulminant CDI presents with hypotension, shock, ileus, or megacolon 1

Initial Episode Treatment Algorithm

Non-Severe CDI (Oral Therapy Possible)

• First-line: Vancomycin 125 mg orally four times daily for 10 days 1, 2
• Alternative (less preferred): Metronidazole 500 mg orally three times daily for 10 days 3, 1
• Alternative for high recurrence risk: Fidaxomicin 200 mg orally twice daily for 10 days 1

The shift away from metronidazole as first-line therapy reflects emerging evidence of reduced response rates and higher recurrence rates compared to vancomycin 5, 6. While older ESCMID guidelines from 2009 recommended metronidazole for non-severe disease 3, more recent American College of Gastroenterology recommendations favor vancomycin for both non-severe and severe CDI 1.

Severe CDI (Oral Therapy Possible)

• First-line: Vancomycin 125 mg orally four times daily for 10 days 3, 1, 2
• Alternative: Fidaxomicin 200 mg orally twice daily for 10 days, especially for patients at high risk of recurrence 1

Severe CDI (Oral Therapy Impossible)

• Metronidazole 500 mg intravenously three times daily for 10 days PLUS intracolonic vancomycin 500 mg in 100 mL normal saline every 4-12 hours as retention enema AND/OR vancomycin 500 mg four times daily by nasogastric tube 3, 4

Fulminant CDI

• Oral vancomycin 500 mg four times daily for 10 days PLUS intravenous metronidazole 500 mg every 8 hours 1
• If ileus is present, add rectal vancomycin 500 mg in 100 mL normal saline every 6 hours as retention enema 1

Recurrent CDI Treatment Algorithm

Recurrence is defined as increased stool frequency for two consecutive days with looser stools or new signs of severe colitis, plus microbiological evidence of toxin-producing C. difficile after initial treatment response. 3

First Recurrence

• Treat based on severity using the same algorithm as initial episode 1
• Consider fidaxomicin 200 mg twice daily for 10 days or vancomycin in a tapered and pulsed regimen 1

Second and Subsequent Recurrences

• Vancomycin 125 mg orally four times daily for at least 10 days, followed by a tapered and pulsed regimen (e.g., decreasing daily dose by 125 mg every 3 days, then 125 mg every 3 days for 3 weeks) 3, 1
• Fecal microbiota transplantation should be considered for multiple recurrences that have failed appropriate antibiotic treatments 1, 5

The recurrence rate after standard therapy ranges from 18-25%, and after two recurrences, the risk exceeds 50% 3, 6. Fidaxomicin has demonstrated superior efficacy in preventing recurrence compared to vancomycin, particularly in patients receiving concomitant antibiotics 7.

Surgical Management

Colectomy should be performed before the patient deteriorates to the point of no return—ideally before serum lactate exceeds 5.0 mmol/L. 3, 1

Indications for Surgery:

• Perforation of the colon 3, 1
• Systemic inflammation and deteriorating clinical condition not responding to antibiotic therapy 3, 1
• Toxic megacolon 3, 1
• Severe ileus 3, 1

Critical Adjunctive Measures

• Discontinue the inciting antibiotic immediately if possible 3, 1, 4
• Avoid antiperistaltic agents and opiates as they can worsen colitis and increase complications 3, 4
• Discontinue unnecessary proton pump inhibitors in patients at high risk for CDI 1
• Use soap and water for hand hygiene, not alcohol-based sanitizers, as alcohol is ineffective against C. difficile spores 1

Common Pitfalls and Caveats

• Concomitant antibiotic use during CDI treatment is associated with lower cure rates (84.4% vs 92.6%), extended time to resolution (97 vs 54 hours), and higher recurrence rates 7. When concomitant antibiotics are unavoidable, fidaxomicin demonstrates superior efficacy over vancomycin 7.

• Nephrotoxicity occurs in 5% of patients treated with oral vancomycin, typically appearing within one week after treatment completion (median day 16), and is more common in patients >65 years of age (6% vs 3%) 2

• Mild CDI (stool frequency <4 times daily, clearly induced by antibiotics) may be treated by stopping the inducing antibiotic alone, but patients must be observed closely for clinical deterioration and started on therapy immediately if this occurs 3

• Treatment duration may need to be extended beyond 10 days in patients with delayed response to therapy 1

• Teicoplanin 100 mg twice daily can replace oral vancomycin if available 3, 4