Clostridioides difficile

Background

Microbiology

• Spore-forming, anaerobic, Gram-positive bacillus

Risk factors

• Antibiotic exposure, typically broad-spectrum antibiotics especially those with anaerobic coverage12
  • Highest risk oral options are clindamycin, fluoroquinolones (especially with NAP1 strain), cephalosporins, monobactams, and carbapenems
  • Lowest risk oral options are tetracyclines and penicillins
  • Highest risk IV options are cefipime, imipenem, and piperacillin-tazobactam; possibly also other carbapenems, third-generation cephalosporins, and lincosamides34
• PPI use
• Chemotherapy
• Hematopoietic stem cell transplantation
• C. difficile carrier on screening (about 40 times more likely to get disease when exposed to antibiotics)3

Pathophysiology

• Two toxins
  • Toxin A (enterotoxin) causes intestinal secretion and mucosal damage
  • Toxin B (cytotoxin) is a virulence factor
• Virulence depends on strain (e.g. NAP1 quite virulent with high risk of severe disease and relapse)
• Spores can persist in GI tract up to 2 to 8 weeks despite treatment

Clinical Manifestations

• Profuse watery diarrhea
• When following antibiotics:
  • Risk is highest within two weeks of starting antibiotics until 1 week after stopping antibiotics
  • Risk increases with the duration of antibiotics
  • Risk depends on the antibiotic used1
    • High risk: clindamycin, fluoroquinolones, and non-penicillin β-lactams (i.e. cephalosporins, monobactams, and carbapenems)
    • Low risk: macrolides, trimethoprim-sulfamethoxazole, and penicillins
    • No risk: tetracyclines

Severity

Severity	Definition5
Mild	WBC ≤15 AND creatinine ≤1.5 x baseline
Severe, uncomplicated	WBC >15 OR creatinine >1.5 x baseline OR hypoalbuminemia
Severe, complicated	Hypotension OR shock OR ileus OR megacolon

Children

• Asymptomatic carriage is common in infants (37% at 1 month, decreasing to adult levels of 3-5% by 3 years) 6
  • Thought to be related to a lack of the binding target of C. difficile toxin
• Clinical disease is rare before 12 to 24 months of age

Diagnosis

• Usually done with either nucleic acid testing for the toxin gene, or with an EIA test for GDH and toxin A/B enzyme

Test	Sensitivity	Specificity
GDH immunoassay	94-96%	92-95%
Toxin A/B enzyme immunoassay	58-83%	99%
Parallel GDH and toxin A/B immunoassay	58-82%	99.5%
Toxin B PCR	91-96%	96-98%

Management

Severity	First-line5	Alternatives
Initial episode
Mild to moderate	Vancomycin 125 mg po QID for 10-14 days	Fidaxomicin 200 mg po BID for 10 days Metronidazole 500 mg po TID for 10-14 days
Severe, uncomplicated	Vancomycin 125 mg po QID for 10-14 days Fidaxomicin 200 mg po BID for 10 days
Severe, complicated	Vancomycin 125-500 mg po QID for 10-14 days plus metronidazole 500 mg IV q8h	Fidaxomicin 200 mg po BID for 10 days plus metronidazole 500 mg IV q8h Consider rectal vancomycin if ileus
Recurrent episode
First recurrence, mild to moderate	Vancomycin 125 mg po QID for 14 days	Fidaxomicin 200 mg po BID for 10 days
First recurrence, severe, uncomplicated	Vancomycin 125 mg po QID for 14 days Fidaxomicin 200 mg po BID for 10 days
Second or subsequent recurrence	Vancomycin as prolonged tapered or pulsed regimen	Consider fecal microbiota tranplantation after vancomycin

• For rectal vancomycin, add 500 mg to 100 mL normal saline and give as retention enema every 6 hours
• A sample vancomycin taper: 125 mg po QID for 14 days, then 125 mg po TID for 7 days, then 125 mg po BID for 7 days, then 125 mg po daily for 7 days, then 125 mg po q2-3d for 2 to 8 weeks

Fulminant Infection

• Standard medical treatment is oral vancomycin and intravenous metronidazole
• May need colectomy as life-saving treatment, particularly for perforation or toxic megacolon
• No clear data supporting high-dose vancomycin, even in severe CDAD7
• Fidaxomicin can be considered8
• Tigecycline has been considered but likely ineffective9

Tapered-Pulsed Fidaxomicin

• Case series suggest it may be helpful, though recurrence rate still up to 40%10
• Fidaxomicin 200 mg once daily for 7 days followed by 200 mg fidaxomicin every other day for the remaining 13 doses

Antimobility Agents

• Once the diarrhea is being treated, there is little evidence of harm with antimobility agents11

Prevention

Probiotics

• Insufficient evidence to recommend for or against

Primary Prophylaxis

• Prophylaxis with oral vancomycin 125 mg PO daily continued until 5 days after end of systemic antimicrobials may be beneficial in preventing CDAD in high-risk patients12
  • Included patients with age≥70 years or who were hospitalized in the past 90 days

Secondary Prophylaxis

• Oral vancomycin is occasionally used as secondary prophylaxis after a recent (within 3 to 12 months) episode of CDAD
• Per the IDSA guidelines, there is insufficient evidence to recommend for or against

Further Reading

• AMMI treatment practice guidelines for Clostridium difficile infection 2018
• Clostridioides difficile: diagnosis and treatments. BMJ. 2019;366:l4609. doi: 10.1136/bmj.l46091