How is Clostridioides difficile infection classified by severity and what are the recommended treatments for mild‑to‑moderate, severe, fulminant, and recurrent disease?

Classification and Treatment of Clostridioides difficile Infection

Fidaxomicin 200 mg orally twice daily for 10 days is the preferred first-line treatment for all initial CDI episodes regardless of severity, with vancomycin 125 mg orally four times daily for 10 days as an acceptable alternative. 1, 2

Disease Classification by Severity

CDI severity is classified into four categories based on clinical and laboratory parameters:

Non-Severe CDI

• White blood cell count ≤15,000 cells/mL AND serum creatinine <1.5 mg/dL 1, 2

Severe CDI

• White blood cell count ≥15,000 cells/mL OR serum creatinine >1.5 mg/dL 1, 2

Fulminant (Severe-Complicated) CDI

• Hypotension or shock 1, 3
• Ileus or colonic distension 1, 3
• Toxic megacolon 1, 3
• May also present with serum albumin <30 g/L 3

Recurrent CDI

• Return of symptoms within 8 weeks after completion of treatment for a previous episode 1

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Treatment Algorithm

Initial Episode: Non-Severe or Severe CDI

The distinction between non-severe and severe disease does not change the initial antibiotic choice—both fidaxomicin and vancomycin are appropriate for either severity. 2

First-line options (in order of preference):

1. Fidaxomicin 200 mg orally twice daily for 10 days 1, 2

   • Provides superior sustained cure (≈77%) compared to vancomycin (≈63-68%) 2, 3
   • Markedly lower recurrence rates (13-17% vs 24-27% with vancomycin) 2, 3

2. Vancomycin 125 mg orally four times daily for 10 days 1, 2

   • Clinical cure rates of 81-92% 2, 3
   • Superior to metronidazole in severe disease (97% vs 76% cure rate) 1, 2

3. Metronidazole 500 mg orally three times daily for 10 days 1

   • Should only be used in resource-limited settings where vancomycin or fidaxomicin are unavailable 1, 2
   • Only appropriate for non-severe CDI 1, 2
   • Avoid repeated or prolonged courses due to cumulative, potentially irreversible neurotoxicity 2, 3

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Fulminant CDI

Vancomycin 500 mg orally (or via nasogastric tube) four times daily PLUS intravenous metronidazole 500 mg every 8 hours 1, 2, 3

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, 3

Critical pitfall: Intravenous vancomycin is ineffective for CDI because it is not excreted into the colon 2, 3

Surgical consultation:

• Should not be delayed in fulminant CDI 2
• Total abdominal colectomy with ileostomy is indicated for: perforation, refractory systemic inflammation despite antibiotic therapy, toxic megacolon, or severe ileus 1, 3
• Surgery should be performed early, before serum lactate exceeds critical thresholds (consider operating before lactate >5.0 mmol/L) 1, 3

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First Recurrence

Fidaxomicin 200 mg orally twice daily for 10 days is the preferred option 1, 2, 3

Alternative regimens:

1. Tapered-and-pulsed vancomycin regimen: 1, 2, 3

   • 125 mg four times daily for 10-14 days
   • Then 125 mg twice daily for 7 days
   • Then 125 mg once daily for 7 days
   • Then 125 mg every 2-3 days for 2-8 weeks

2. Extended-pulsed fidaxomicin: 2, 3

   • 200 mg twice daily for 5 days
   • Then 200 mg once every other day for 20 days

3. Standard vancomycin 125 mg four times daily for 10 days (if metronidazole was used for the initial episode) 1, 2

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Second and Subsequent Recurrences

Preferred options (in order):

1. Fidaxomicin (standard or extended-pulsed regimen) 2, 3

2. Tapered-and-pulsed vancomycin (as described above) 1, 2, 3

3. Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1, 2, 3

4. Fecal microbiota transplantation (FMT) is strongly recommended after at least two recurrences (three total CDI episodes) that have failed appropriate antibiotic therapy 1, 2, 3

   • Clinical trials report FMT resolution rates of 70-92% 1, 3
   • Randomized studies show 81% success with FMT versus 31% with vancomycin alone 3

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Adjunctive Therapy for High-Risk Patients

Bezlotoxumab 10 mg/kg intravenously as a single dose can be added to standard antibiotic therapy for patients at high risk of recurrence 2, 3

High-risk factors include:

• Age >65 years 2, 3
• Immunocompromised status 2, 3
• Severe CDI at presentation 2, 3
• Prior CDI episode 2, 3

Important safety warning: The FDA advises reserving bezlotoxumab for patients in whom the benefit outweighs the risk, particularly those with congestive heart failure 2, 3

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Critical Management Principles

• Discontinue the inciting antibiotic(s) as soon as possible to reduce recurrence risk 1, 2, 3
• Avoid antiperistaltic agents and opiates in all CDI patients 1, 2, 3
• Do not perform a "test of cure" after completing therapy 1, 2, 3
• Clinical improvement is usually evident within 3-5 days of initiating therapy; metronidazole may require up to 5 days 2, 3
• Monitor daily for stool frequency, consistency, and clinical parameters 2

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Common Pitfalls to Avoid

• Never use metronidazole for severe or fulminant CDI because cure rates are significantly lower (≈66% vs ≈79% for vancomycin) 2
• Never administer intravenous vancomycin for CDI as it does not reach the colon 2, 3
• Avoid repeated metronidazole courses due to neurotoxicity risk 2, 3
• Do not delay surgical consultation in patients with fulminant CDI 2, 3