Clostridioides difficile Infection

Clostridioides difficile Infection

Learning Objectives

• Describe pathogenesis of Clostridioides difficile
• Identify risk factors for C. difficile and discuss strategies to mitigate risk
• Evaluate a patient presenting with symptoms consistent with C. difficile infection
• Recommend treatment and management strategies for patients presenting with C. difficile infection

Epidemiology

• Clostridioides difficile (C. difficile) is a bacterium that can cause life-threatening diarrhea, with infections occurring most often in people who have taken antibiotics for other conditions. It is the most common healthcare-associated infection.
• Threat level: Urgent
• Estimated cases in hospitalized patients in 2017: 223,900
• Estimated deaths in 2017: 12,800
• Estimated attributable healthcare costs in 2017: 1B
• Historically thought of as a nosocomial infection.
  • Hospital-onset C. difficile infection is a reportable condition (positive C. difficile test after 3 days of hospitalization).
• Rates are increasing in patients residing in the community in patients without significant healthcare exposure
• Previously known as Clostridium difficile

Pathogenesis

• Transmitted via the fecal-oral route
• Disruption of the intestinal microbiota is key
  • A healthy microbiome resists colonization with C. difficile
  • Disrupted microbiome allows C. difficile to colonize and proliferate
• Toxin production leads to manifestations of disease
  • Toxin A: enterotoxin – intestinal fluid secretion, mucosal injury and inflammation
  • Toxin B: cytotoxin – leads to mucosal injury
  • Not all strains produce toxin

Disease Initiation

1. Ingestion of C. difficile spores.
2. Susceptible microbiota due to impaired resistance to colonization (antibiotics, surgery, immunosuppression).
3. C. difficile toxin production.

Recovery

1. Restoration of microbiota to resist colonization.
2. Fecal transplant.

Patient Case

• Patient: TP, 79 yo male
• Chief Complaint: Admitted to the hospital with fevers found to be secondary to C. difficile colitis.
• PMH:
  • Pancreatic cancer diagnosed 6 months ago
  • Hypertension
  • CDI this past January
• PSH: Pancreatico-duodenectomy 4 months ago
• Current Medications:
  • Protonix 40 mg po daily
  • Lisinopril/HCTZ 20/12.5 mg po daily
  • Ciprofloxacin 250 mg po BID for E. coli UTI started 2 days ago
  • FOLFIRINOX: last cycle 14 days ago

Risk Factors: Prior Antibiotic Use

• One of the most identified risk factors for CDI
• Patients must have exposure to the organism
  • Colonization
  • Acquisition
• Risk of CDI is increased during antibiotic therapy and for several weeks to months after therapy cessation
• Studies have shown efforts to optimize antibiotic stewardship can reduce C. difficile rates

Influences on Antibiotic Risk

• Broad spectrum of antibiotic coverage
• Intrinsic activity against C. difficile
• Anaerobic activity
• Antibiotic resistance
• Administration of multiple antibiotics
• Prolonged duration of therapy
• Stimulation of toxin production

Antibiotics with Highest Risk of CDI

Risk Factors: Acid Suppressive Therapy

• Decreased acid preserves ingested organisms
• Proton pump inhibitors (PPIs) may alter intestinal microbiota
• PPIs may directly impair leukocyte activity

Association with CDI

Other Medications

• Chemotherapy
  • Antibiotic effects
  • Disruption of microbiota (mucositis, etc.)
  • Immunosuppression
• Antidepressants?

Co-morbidities

• Immunosuppression
• Inflammatory bowel disease
• Depression
• Renal impairment

Other Risk Factors

• Age
• Hypoalbuminemia
• Hospital admission in past 60 days
• Length of hospital admission
• Previous history of CDI
• Invasive procedures
  • Tube feeding
  • Mechanical ventilation
  • Gastrointestinal surgery

Patient Case (Revisited)

• Patient: TP, 79 yo male
• Chief Complaint: Admitted to the hospital with fevers found to be secondary to C. difficile colitis.
• PMH:
  • Pancreatic cancer diagnosed 6 months ago
  • Hypertension
  • CDI this past January
• PSH: Pancreatico-duodenectomy 4 months ago
• Current Medications:
  • Protonix 40 mg po daily
  • Lisinopril/HCTZ 20/12.5 mg po daily
  • Ciprofloxacin 250 mg po BID for E. coli UTI started 2 days ago
  • FOLFIRINOX: last cycle 14 days ago

Clinical Presentation

• Asymptomatic Colonization
• Symptomatic disease
  • Diarrhea: 3 or more unformed stools in 24 hours
  • Abdominal pain
  • Fever
  • Leukocytosis
  • Pseudomembranous colitis seen on colonoscopy (white and yellow plaques in colon)
  • Toxic megacolon

Diagnosis

• Clinical presentation – helps distinguish between colonization and disease
• Laboratory stewardship – should only test symptomatic patients (3 or more stools per day and not on laxatives)
• Laboratory tests
  • Stool culture
  • Nucleic acid amplification test (NAAT)
  • Glutamate dehydrogenase (GDH)
  • Toxin enzyme immunoassay (EIA)
  • 2-step tests
    • GDH/EIA
    • NAAT/EIA

C. difficile NAAT

• Detects genetic material that codes for toxin production
• Does NOT detect the presence of actual toxin
• Cannot distinguish active infection from colonization
• Highly sensitive and specific
• Can detect genetic material weeks to months after infection – do NOT test for cure

Glutamate Dehydrogenase

• Enzyme produced by C. difficile (both toxin producing and NON-toxin producing strains)
• High sensitivity, lower specificity
• Good negative predictive value
• Often used as part of a 2-step test

Toxin EIA

• Typically detects the presence of Toxin A
  • May miss strains that only produce Toxin B
• Low sensitivity
• General consensus is that this test should not be used alone as it may miss diagnosis

2-step Tests

• GDH/EIA
  • If GDH negative – done
  • If GDH positive – will test EIA
    • If EIA positive, may do confirmatory NAAT test
• NAAT/EIA
  • If NAAT negative – done
  • If NAAT positive – will test EIA
    • No confirmatory test done

Definitions for Severity

• Severe C. difficile
  • Leukocytosis > 15 \times 10^3 cells/mL
  • Serum creatinine > 1.5$$ mg/dL
• Fulminant C. difficile
  • Hypotension or shock
  • Ileus
  • Megacolon

Management – Non-Pharmacologic

• Fluid intake to prevent (or treat) dehydration
• Infection prevention
  • Use soap and water to wash hands
  • Clean with bleach or other sporicidal agent
  • If inpatient – contact precautions

Treatment – Initial Episode (Adults)

Treatment – First Recurrence (Adults)

Preferred Therapy

• Preferred therapy: fidaxomicin
  • Standard regimen: 200 mg PO BID for 10 days
  • Pulsed regimen: 200 mg PO BID for 5 days, followed by 200 mg PO every other day for 20 days

Alternative Therapy

• Vancomycin PO in a tapered and pulsed regimen
  • Taper: decreasing doses
  • Pulse: administering doses, then a pause
  • Example regimen: vancomycin 125 mg PO four times daily for 10-14 days, BID for 7 days, daily for 7 days, then every 2-3 days for 2-8 weeks
• Vancomycin 125 mg PO four times daily for 10 days
  • ONLY if metronidazole used for initial therapy

Treatment – Second (or more) Recurrences (Adult)

• Any of the following
  • Fidaxomicin PO standard regimen
  • Fidaxomicin PO pulsed regimen
  • Vancomycin PO taper and pulse
  • Vancomycin 125 mg PO four times daily for 10 days followed by rifaximin chaser (400 mg PO three times daily for 20 days)
  • Fecal microbiota transplant

Treatment – Initial Episode and First Recurrence (Pediatrics)

*Do not exceed maximum adult dose

Treatment – Second (or more) Recurrences (Pediatrics)

• Any of the following
  • Vancomycin PO taper and pulse
  • Vancomycin 10 mg/kg/dose PO four times daily for 10 days followed by rifaximin for 20 days
    • Vancomycin - Do not exceed 500 mg
    • Rifaximin – no dosing recommendations for kids under 12 years of age
  • Fecal microbiota transplant

C. difficile Prevention

• Two FDA-approved fecal microbiota formulations indicated for prevention of subsequent recurrence of C. difficile (NOT active treatment)
  • Rebyota – 150 mL PR x1 dose, given 24-72 hours after antibiotic treatment for C. difficile has completed
  • Vowst – 4 capsules PO daily x3 days, started 2-4 days after antibiotic treatment for C. difficile has completed
    • Requires bowel prep prior to administration

Clostridioides difficile Bundles

• Ensure appropriate antibiotic treatment for C. difficile infection
• Stop or de-escalate antibiotics that are not treating C. difficile
• Stop or de-escalate acid suppressive therapy (proton pump inhibitors or H2-receptor antagonists)
• Stop antiperistaltics/antidiarrheal agents
• Stop laxatives if able

Controversial Treatments

• Probiotics – insufficient evidence to support use for treatment or prevention
• Immune globulin – has been used for severe, fulminant infection but no controlled trials support use
• Tigecycline - has been used for severe, fulminant infection but no controlled trials support use

Monitoring Response

• Stool frequency
  • May take up to 5-7 days of effective antimicrobial therapy before stool frequency decreases
• Fluid status
• Serum creatinine
• White blood cell count
• Temperature
• Vital signs