C diff

Diagnosis and Treatment of C.difficil per Natasha Bagdasarian et al. Published in JAMA 2019.

Systematic review of 116 included studies between 1978 and 2014.

DIAGNOSIS

• Laboratory testing cannot always distinguish between asymptomatic colonization and active infection.

Diagnostic criteria

• Diarrhea
• Positive stool test for toxigenic C. diff or toxins or visualization of pseudomembranous colitis

Diagnostic approaches

• Gold Standard: Toxigenic Culture (TC) and/or Cell Cytotoxicity Assay (CCA)
  • Anaerobic culture for 24-48 hrs followed by colony selection and culture with human cells to test for cell cytotoxicity which takes an additional 24-48 hours.
  • Time consuming and difficult, up to 5 days
  • Detects a little as 3 picograms of toxin
• Stool antigen looks for Glutamate dehydrogenase (GDH) via ELISA (EIA)
  • Does not distinguish between toxigenic and non-toxigenic strains
  • Half of C. diff isolates are non-toxigenic
• PCR / NAAT
  • Detects tcdA/tcdB genes, mRNA for the toxins
  • Detects presence of toxigenic strains of C. diff
  • mRNA doesn't necessarily imply active infection
• EIA / ELISA
  • Detects toxin in stool
  • Low sensitivity (0.73-0.87)
• Multistep algorithms, there are dozens
  • EIA for GDH / Toxin A/B
    • Both positive = C. diff
    • Both negative = NO C. diff
    • Mixed results, use PCR for tcdB as tiebreaker
  • Toxin EIA 1 (Meridian), higher PPV, lower NPV
  • Toxin EIA 2 (TechLab), lower PPV, higher NPV
  • Highest NPV (99.8%) GDH EIA + NAAT
  • Highest PPV (93.5%) Toxin EIA 1 + NAAT

TREATMENT

First line treatment

• PO Vancomycin (78.5% success rate, 25,3% recurrence rate)
• PO Metronidazole (66,3% success rate, 47% recurrence rate), recent strains have higher MIC

Disease stratification

• WBC (15), Cr (1.5% baseline), recurrence, hypotension, ileus, megacolon
• Mild = Metronidazole, preferred for cost and non-inferiority in mild disease
• Severe/Complicated = Vancomycin
• Recurrent = Metro or Vanco for first recurrence, Vanco for subsequent

Newer treatments

• Fidazomicin (87.7% success rate vs. 86.8% for vanco, 15.4% recurrence rate)
  • Expensive
• Fecal microbiota transplant (83-94% success rate for recurrent COL).
  • Fecal microbiota transplantation restores gut microbiota diversity, with the instillation of donor stool into the gastrointestinal tract of an infected patient.
  • This procedure has had good clinical response without reports of adverse events, for refractory or recurrent CDI.
  • The first systematic review was published in 2011 and included 317 patients with recurrent CDI treated with fecal microbiota transplantation via enema, nasojejunal-tube/gastroscope or colonoscopy.
  • Clinical resolution occurred in 92% of patients (89% after a single treatment), without serious adverse effects.
  • A recent review of 536 patients reported a 27% clinical response rate.
  • A randomized trial of fecal microbiota transplantation demonstrated symptom resolution in 94% of patients who received vancomycin for 5 days followed by either one or two treatments with fecal microbiota transplantation, versus 31% in those receiving vancomycin alone for 14 days, and 23% for those receiving vanconycin for 14 days plus bowel lavage. This study was stopped early after interim analyses demonstrated superiority of fecal microbiota transplantation, Among 18 patients in the other treatment groups who received subsequent fecal microbiota transplantation 83% had symptom resolution