Clostridioides difficile Infection, Including Pseudomembranous Colitis¶
Chapter 139 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 139
Key Clinical Points¶
- CDI is the most common healthcare-associated infection in the US (462,100 cases in 2017).
- Diagnosis requires diarrhea (≥3 unformed stools/24h for ≥2 days) plus detection of toxin A/B or toxigenic C. difficile.
- First-line treatment: Fidaxomicin (200 mg bid imes 10d) or Vancomycin (125 mg qid imes 10d).
- Metronidazole is recommended only for mild/moderate CDI if vancomycin/fidaxomicin unavailable.
- Fulminant CDI: Vancomycin (PO/NG) + Metronidazole (IV) + Rectal Vancomycin enema.
- Recurrent CDI: Fidaxomicin, Vancomycin taper-and-pulse, Rifaximin, or FMT.
- Bezlotoxumab reduces recurrent CDI risk in high-risk patients (>65 years, immunocompromised).
- Asymptomatic testing and 'tests of cure' are not recommended (50% remain colonized post-diarrhea).
- NAP1/BI/027 strain produces 16–23 imes more toxin and carries binary toxin CDT.
- Adynamic ileus with unexplained leukocytosis (≥15,000 WBC/μL) suggests unsuspected CDI.
1. DEFINITION & OVERVIEW¶
• Definition: Colonic infection acquired via antimicrobial use, disrupting normal microbiota.
• Key Features: ◦ Acquired in healthcare settings; most common hospital-acquired diarrheal illness. ◦ Caused by ingestion of C. difficile spores that germinate and secrete toxins (A/B) after microbiota disruption. ◦ Pseudomembranous colitis (PMC) is advanced CDI visible at endoscopy in \sim50% of cases with positive stool tests.
1.1 Microbiology & Classification¶
• C. difficile: Obligate anaerobe, gram-positive spore-forming bacillus. ◦ Spores persist on environmental surfaces and healthcare workers' hands. ◦ NAP1/BI/027 strain: Epidemic strain with 16–23 imes higher toxin production, binary toxin CDT, and fluoroquinolone resistance.
1.2 Toxin Production & Pathogenesis¶
• Toxigenic strains produce: ◦ Toxin A (enterotoxin) and Toxin B (cytotoxin): glucosylate Rho family GTPases, disrupting actin cytoskeleton. ◦ Binary toxin CDT: present in NAP1/BI/027 strain. ◦ Toxin B may be primary virulence factor (based on studies of isogenic mutants).
2. EPIDEMIOLOGY¶
• Trends: 462,100 US cases in 2017; 24% decrease (2011–2017) due to reduced healthcare-associated infections. • Community Spread: Community-associated rates now match healthcare-associated rates. • Historical Context: Epidemic NAP1/BI/027 strain drove early 2000s incidence surge.
2.1 Risk Factors¶
• Primary Driver: Antimicrobial use. ◦ Age >65 ◦ Prolonged hospitalization (>2 weeks: fecal colonization ≥20%). ◦ Gastrointestinal surgery, enteral feeding, proton pump inhibitors.
2.2 Strain Epidemiology¶
• NAP1/BI/027: Epidemic strain with 16–23 imes higher toxin production and binary toxin CDT. • Ribotype 106: (UK origin) currently the most common community-associated strain in the US.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Three essential events for CDI development: 1. Antimicrobial exposure → microbiota disruption. 2. Toxigenic C. difficile colonization. 3. Virulent strain, specific antimicrobials, or inadequate host immunity.
3.1 Host Immunity¶
• Immune Response: ◦ Serum IgG to toxin A/B correlates with protection against recurrence. ◦ Monoclonal antibodies (toxin A+B) reduce recurrence rates in trials. ◦ Antibody to toxin A alone is ineffective.
4. CLINICAL FEATURES¶
• General Manifestations: ◦ Diarrhea: soft/unformed/watery, non-bloody, characteristic odor. ◦ Systemic signs: Fever (28%), abdominal pain (22%), leukocytosis (50%). ◦ Adynamic ileus (20% of cases): May mask CDI with unexplained leukocytosis (≥15,000 WBC/μL).
4.1 Pseudomembranous Colitis (PMC)¶
• Pathology: Whitish-yellow plaques (1–2 mm) progressing to confluent pseudomembranes. ◦ Microscopy: necrotic leukocytes, fibrin, mucus, eroded epithelium with neutrophil infiltration. ◦ Note: 10% of cases have rectal sparing (see Figure 139-1).
4.2 Fulminant CDI¶
• Severe Presentation: Mimics acute surgical abdomen (ileus, toxic megacolon). ◦ Sepsis signs: hypotension, fever, tachycardia, leukocytosis (≥20,000 WBC/μL). ◦ Diagnostic Challenge: May occur when no diarrhea is present.
5. DIFFERENTIAL DIAGNOSIS¶
• Clinical Context: Consider CDI in acute abdomen or sepsis cases with recent antimicrobial use (past 2 months). ◦ Note: Adynamic ileus may obscure diagnosis.
6. INVESTIGATIONS & DIAGNOSIS¶
- Clinical Presentation: Identify diarrhea ≥3 unformed stools/24h for ≥2 days.
- Laboratory Testing (Table 1): ◦ Stool culture: Most sensitive (++++); specificity of ++++ if the C. difficile isolate tests positive for toxin; turnaround time too slow for practical use. ◦ Cell culture cytotoxin test on stool: High specificity (++++), sensitivity (+++). ◦ Toxin EIA (A/B): Rapid results, but less sensitive than stool culture or cell culture cytotoxin test (sensitivity ++ to +++; specificity +++). ◦ GDH assay: More sensitive than toxin EIA (sensitivity +++ to ++++); requires confirmation. ◦ NAAT (PCR) for toxin A or B gene: Widely used in US; more sensitive than enzyme immunoassay; marked increase in CDI diagnoses when implemented (sensitivity ++++; specificity +++).
- Endoscopy: Rapid tool for suspected PMC; note that negative results do not exclude CDI.
6.1 Diagnostic Test Summary¶
Table 1 — Relative Sensitivity and Specificity of Diagnostic Tests for Clostridioides difficile Infection (CDI)
| TYPE OF TEST | RELATIVE SENSITIVITY | RELATIVE SPECIFICITY | COMMENT |
|---|---|---|---|
| Stool culture for C. difficile | ++++ | +++ | Most sensitive test; specificity of ++++ if toxin-positive; slow turnaround |
| Cell culture cytotoxin test on stool | +++ | ++++ | High specificity but not as sensitive as culture; slow turnaround |
| Enzyme immunoassay for toxins A and B in stool | ++ to +++ | +++ | Rapid results, less sensitive than culture or cell culture cytotoxin test |
| Enzyme immunoassay for C. difficile common antigen (GDH) | +++ to ++++ | +++ | More sensitive than toxin EIA; requires confirmation |
| Nucleic acid amplification tests (NAAT) | ++++ | +++ | Widely used in US; more sensitive than EIA; increased diagnoses when implemented |
| Colonoscopy/sigmoidoscopy | + | ++++ | Highly specific if pseudomembranes seen |
7. MANAGEMENT & TREATMENT¶
- Initial Actions: Discontinue antimicrobials if possible (15–23% respond).
- Primary Treatment (Table 2): ◦ Mild/Moderate: Fidaxomicin (200 mg bid imes 10d) OR Vancomycin (125 mg qid imes 10d). ◦ Severe: Fidaxomicin (200 mg bid imes 10d) OR Vancomycin (125 mg qid imes 10d). ◦ Metronidazole: Only if vancomycin/fidaxomicin unavailable; dose 500 mg tid imes 10–14 d.
- Fulminant CDI Treatment: ◦ Vancomycin (500 mg PO or via nasogastric tube) ◦ Metronidazole (500 mg IV q8h) ◦ Rectal instillation of vancomycin (500 mg in 100 mL of normal saline as a retention enema q6–8h).
- Recurrent CDI Management: ◦ Fidaxomicin (200 mg bid imes 10d OR 200 mg bid imes 5d followed by every other day imes 20 d). ◦ Vancomycin taper-and-pulse regimen. ◦ Rifaximin (400 mg bid imes 2 weeks). ◦ Fecal microbiota replacement therapy (FMRT) (Rebyota, Vowst) after appropriate antibiotic treatment.
- Adjunctive Therapy: ◦ Bezlotoxumab (10 mg/kg IV) for high-risk patients (age >65, immunocompromised, severe CDI).
7.1 Treatment Regimens¶
Table 2 — Recommendations for the Treatment of Clostridioides difficile Infection (CDI)
| CLINICAL SETTING | TREATMENT(S) | COMMENTS |
|---|---|---|
| Initial episode, mild to moderate | Fidaxomicin (200 mg bid imes 10 d) or alternatively Oral vancomycin (125 mg qid imes 10 d) | Metronidazole is less effective; use only if vancomycin/fidaxomicin not available. |
| Initial episode, severe | Vancomycin (125 mg qid imes 10 d) or Fidaxomicin (200 mg bid imes 10 d) | |
| Fulminant | Vancomycin (500 mg PO/NG) + Metronidazole (500 mg IV q8h) + Rectal vancomycin enema (500 mg in 100 mL NS, q6–8h) | Defined as severe CDI with hypotension, shock, ileus, or toxic megacolon. Duration may be >2 weeks. |
| Multiple recurrences | Vancomycin taper-and-pulse; Fidaxomicin (200 mg bid imes 10d OR 200 mg bid imes 5d followed by every other day imes 20 d); Rifaximin (400 mg bid imes 2 weeks); FMRT | FMRT (Rebyota, Vowst) only after appropriate antibiotic treatment. |
| Adjunctive | Bezlotoxumab 10 mg/kg given IV | For high-risk patients. |
8. PROGNOSIS & COMPLICATIONS¶
• Recurrence: 15–30% of treated patients experience recurrence. ◦ Recurrent CDI carries 11% risk of serious complications (shock, megacolon, perforation, colectomy, death within 30 days). • Surgical Intervention: Surgical colectomy for refractory cases of fulminant CDI.
9. SPECIAL CONSIDERATIONS¶
• Proton Pump Inhibitors: Modest risk factor if not on antibiotics. • Neonatal: Common colonization but disease is rare. • FMT: Now FDA-approved (Rebyota/Vowst) for recurrent CDI.
10. KEY PEARLS & CLINICAL TRAPS¶
• Avoid 'tests of cure': Not predictive of recurrence; 50% remain colonized post-diarrhea. • Clinical Trap: Adynamic ileus + leukocytosis (≥15,000 WBC/μL) → suspect CDI. • Surgical Mimic: Fulminant CDI may present without diarrhea (mimics surgical abdomen).
Reference Tables¶
TABLE 139-1 Relative Sensitivity and Specificity of Diagnostic Tests for Clostridioides difficile Infection¶
Harrison's 22e, p.1084
| TYPE OF TEST | RELATIVE SENSITIVITYa | RELATIVE SPECIFICITYa | COMMENT |
|---|---|---|---|
| Stool culture for C. difficile | ++++ | +++ | Most sensitive test; specificity of ++++ if the C. difficile isolate tests positive for toxin; turnaround time too slow for practical use |
| +++ | ++++ | ||
| Enzyme immunoassay for toxins A and B in stool |
++ to +++ | +++ | With clinical data, is diagnostic of CDI; rapid results, but not as sensitive as stool culture or cell culture cytotoxin test |
| +++ to ++++ | +++ | ||
| Nucleic acid amplification tests for C. difficile toxin A or B gene in stool |
++++ | +++ | Detects toxigenic C. difficile in stool; widely used in United States for clinical testing; more sensitive than enzyme immunoassay toxin testing; marked increase in CDI diagnoses when implemented |
| + | ++++ |
TABLE 139-2 Recommendations for the Treatment of Clostridioides difficile Infection¶
Harrison's 22e, p.1085
| CLINICAL SETTING | TREATMENT(S) | COMMENTS |
|---|---|---|
| Initial episode, mild to moderate |
Fidaxomicin (200 mg bid × 10 d) or alternatively Oral vancomycin (125 mg qid × 10 d) |
Oral metronidazole is less effective than the other options and may necessitate a longer treatment course for response. Metronidazole (500 mg tid × 10–14 d) is recommended only if vancomycin or fidaxomicin is not readily accessible and for mild to moderate disease only. |
| Oral vancomycin (125 mg qid × 10 d) or alternatively Fidaxomicin (200 mg bid × 10 d) |
||
| Initial episode, fulminant | Vancomycin (500 mg PO or via nasogastric tube) plus metronidazole (500 mg IV q8h) plus consider Rectal instillation of vancomycin (500 mg in 100 mL of normal saline as a retention enema q6–8h) |
Fulminant CDI is defined as severe CDI with the addition of hypotension, shock, ileus, or toxic megacolon. The duration of treatment may need to be >2 weeks and is dictated by response. |
| Fidaxomicin (200 mg bid × 10 d) or Oral vancomycin (125 mg qid × 10 d) or Oral vancomycin followed by a taper-and-pulse regimena |
||
| Multiple recurrences | Oral vancomycin treatment followed by a taper-and-pulse regimen or Fidaxomicin (200 mg bid × 10 d or 200 mg bid × 5 d followed by every other day × 20 d) or Vancomycin (125 mg qid × 10 d), then stop vancomycin and start rifaximin (400 mg bid × 2 weeks) or Fecal microbiota replacement therapy (FMRT) |
It is recommended that FMRT by fecal microbiota (Rebyota, live-jslm) given by enema or fecal microbiota spores (Vowst, live-brpk) given orally be considered only after appropriate antibiotic treatment for recurrent CDI. |
| Bezlotoxumab 10 mg/kg given IV |