1. Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients
Katelyn R Richards, PharmD
University of Wisconsin Hospital and Clinics
PGY-2 Solid Organ Transplant Pharmacy Resident

2. Objectives
Compare and contrast Clostridium difficile associated disease (CDAD) in solid organ transplant recipients with the general population
Evaluate guideline recommendations for pharmacologic therapy
Describe the role of probiotics
Explain secondary prevention of CDAD
No conflicts of interest to disclose

3. Clostridium difficile
Spore-forming, anaerobic, gram-positive bacillus
Toxin producing – A & B
Inflammatory diarrhea, colonic mucosal injury
Pseudomembranous colitis
Less common in immunosuppressed patients
Fecal-oral route of transmission
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

5. History of New Strain Higher incidence of CDAD
North American PFGE type 1 (NAP1)
PFGE: pulsed-field gel electrophoresis
More virulent
Higher severity of disease
Incidence is more highly related to fluoroquinolone use then previous existing strain
Not necessarily drug resistant
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

6. Epidemiology Incidence in hospitalized patients: 1-2%
Incidence in transplant recipients
Liver: 3 – 7%
Kidney: 3.5 – 16%
Kidney-pancreas: 1.5 – 7.8%
Heart: 15%
Lung: 7 – 31%
Highest incidence within first 3 months
40% risk if inpatient for >4 weeks
20-30% of ABX-associated diarrhea
Incidence not typically significantly higher than other surgical patients
highest incidence within the first three months due to more frequent antimicrobial exposure intense immunosuppression and increased exposure to the healthcare setting
Incidence is increasing
Risk increases with prolonged length of stay: Up to 40% after 4 weeks
7 - 26% adult inpatients are colonized
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

7. Risk Factors Antimicrobial exposure Reduced humoral response
Any and all antibiotics – including surgical prophylaxis
Clindamycin – highest risk for original strain
Fluoroquinolones – highest risk for NAP1 strain
Sulfamethoxazole-trimethoprim prophylaxis has not been associated with CDAD
Reduced humoral response
Acid suppressant agents
Antimicrobial exposure – suppresses normal flora of GI tract providing a niche for c.diff to flourish; broadspectrum and prolonged use inc risk
Gastric acid kills vegetative forms of c.diff; PPI may disturb GI flora and allow C.difficile more easily colonize the bowel
Clinda and FQ due to resistance patterns of each strain
Dubberke ER et al. AJT 2009

8. Risk Factors Age >65 Severe underlying disease Uremia Surgery
Nasogastric or endotracheal tube
Prolonged hospitalization
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

9. Acid Suppression and CDAD Debate
Clostridium difficile spores are not killed by gastric acid
BUT, vegetative forms which germinates spore form are killed by gastric acid
Clinical trials differ
2 x higher incidence of CDAD with proton pump inhibitors
Confounded by severity of disease and hospital length of stay
Highly debatable
Not expected to affect pathogenesis of infection but
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009 Cunningham R et al. J Hosp Infect 2003
Dubberke ER et al. Clin Infect Dis 2007
Loo VG et al. NEJM 2005

10. Clinical Manifestations
Typical presentation
Watery diarrhea
Up to bowel movements per day
Fever
Abdominal cramping, discomfort
Unexplained leukocytosis
Atypical presentation
Vitals: fever
Physical exam: abdominal pain/distension
Lab values: leukocytosis >30,000 cells/mm3
>50% transplant patients
CT scan: severe colitis
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

11. Diagnosis Up to 50% of hospitalized patients are colonized
Only perform diagnostic tests if symptomatic
CDAD is a clinical diagnosis
Colonoscopy for the presence of pseudomembranes
definitive diagnosis
Test for C.difficile toxin in stool
Cytotoxicity cell assay (Gold Standard)
Expensive, 24 hour turn around time
ELISA
Inexpensive, rapid turn around time
60-90% sensitive with a negative predictive value >95%
Repeat testing increases risk of false positive
After negative toxin test, only test again based on clinical suspicion of disease; PCRs are newly available: advantage = enhanced sensitivity compared to ELISA but MUCH more expensive
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

12. Classifying Disease Severity
Clinical Definition
Supportive Clinical Data
Initial episode, mild or moderate
WBC < 15,000 cells/mcL OR
Scr < 1.5 x above baseline
Initial episode, severe
WBC > 15,000 cells/mcL
Scr > 1.5 x above baseline
Initial episode, severe, complicated
Hypotension or shock, ileus, megacolon
Cohen SH et al. IDSA Guidelines 2010

13. Complications Dehydration Electrolyte disturbances Hypoalbuminemia
Toxic megacolon
Bowel perforation
Sepsis
Renal failure
Total colectomy
Death
toxic megacolon is a rapid dilation of lg intestine within 1 to few days leading to perforation, sepsis, death
Total colectomy more
Cohen SH et al. IDSA Guidelines 2010

14. Prevention Horizontal transmission (IDSA) Minimize risk factors
Hand washing with soap and water
Contact precautions: gloves and gown
Clean areas with sporicidal agents
Minimize risk factors
The key to treatment is prevention since c.diff is highly contagious
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

15. Contact Precautions

16. Treatment Stop or narrow antibiotics Metronidazole (PO, IV)
Vancomycin (PO, PR)
Fidaxomycin (PO)
Alternatives
IVIG
Rifaximin
Nitizoxanide

17. Metronidazole (Flagyl®)
Not FDA approved for CDAD
Mechanism: disrupts protein synthesis resulting in cell death in anaerobic bacteria
Dose: 500 mg PO Q8h, 500 mg IV Q6-8h
Pharmacokinetics: rapidly absorbed
Concentration in colon minimal
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

18. Metronidazole (Flagyl®)
Use: effective for mild to moderate disease and first recurrence
Adverse effects
Caution in liver failure
Higher risk for side effects as drug is hepatically metabolized
Neurotoxicity, primarily manifested as paraesthesias
Paraesthesias are more common with prolonged exposure
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

19. Vancomycin (Vancocin®)
FDA approved for CDAD
Mechanism: inhibits the growth of C.Difficile (bacteroistatic)
Dose: 125 – 500 mg PO Q6h; 500 mg PR
IV administration does not treat CDAD
Enema may lead to bacteremia from colonic flora
Administration:
Oral capsules (expensive)
IV product used orally (in hospital administration)
Retention enema
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

20. Vancomycin (Vancocin®)
Use: Initial episode of severe or complicated disease and for recurrence
Pharmacokinetics: poorly absorbed in gut
Concentrates in colon
Adverse effects
Compromised gastrointestinal tract may result in systemic absorption
No drug interactions
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

21. Fidaxomicin (Dificid®)
FDA approved for CDAD in May 2011
Mechanism: macrolide antibiotic
Kills C.difficile (bactericidal)
Postantibiotic effect
Dose: 200 mg PO BID x 10 days
Pharmacokinetics: poor absorption in gut
Louie TJ et al. NEJM 2011

22. Fidaxomicin (Dificid®)
Use: treatment of C.difficile infections
Non-inferior to oral vancomycin
Lower rate of recurrence of non-NAP1 strain
Less effect on normal colonic flora
Adverse effects: Nausea, vomiting
Minimal drug interactions
Significant cost: $2800 for 10 day course, poorly covered by insurance providers
Louie TJ et al. NEJM 2011

23. Surgical Intervention
May be required in complicated or refractory cases
Total colectomy
3% in immunocompetent
13% in solid organ transplant recipients
May represent more severe disease
May reduce mortality if taken to the OR within 48 hours of medical therapy failure, bowel perforation or multi-organ failure
but these the bias to take these patients back to the OR quicker
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

24. Recurrence 6 – 25% of patients experience 1 episode of recurrence
Definition: relapse of same infection or re-infection from new strain
Risk factors
Age > 65
Metronidazole (especially in patients > 65)
Use of other antibiotics during or after initial treatment
Impaired immune response to toxin A
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

25. Treatment of Recurrence
First recurrence: same as initial episode
Second recurrence: vancomycin taper and/or pulse therapy
Taper: slow taper over prolonged period of time
Pulse: high dose given fewer times over a prolonged period of time
Avoid metronidazole for cumulative neurotoxicity
>2 recurrences:
Alternative therapy
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009

26. Alternative Therapies
Intravenous immune globulin (IVIG)
Rifaximin
Nitizoxanide
Fecal transplant

27. IVIG Not FDA approved for CDAD Mechanism: Antitoxin antibodies
Dose: 150 – 400 mg/kg
Use in combination with other antibiotic therapy
Efficacy controversial
Expensive
Not recommended by the American Society of Transplantation
Based on case studies and retrospective data
Dubberke ER et al. AJT 2009
Cohen SH et al. IDSA guidelines 2010

28. Rifaximin Not FDA approved for CDAD
Mechanism: inhibits bacterial RNA synthesis (bacteriostatic)
Used following vancomycin therapy
Dose: mg PO 2-3 times/day x 14d
High risk for development of C.difficile resistance
Effectiveness depends on the minimum inhibitory concentration (MIC)
Expensive
Use is based on recent uncontrolled case series
Johnson S et al. Clin Infect Dis 2007
Cohen SH et al. IDSA guidelines 2010

29. Nitizoxanide Not FDA approved for CDAD
Mechanism: interferes with aerobic metabolism of bacteria and protozoa
Dose: 500 mg PO Q12h x 10 days
Recent prospective, double-blind, randomized controlled trial suggests non-inferiority to vancomycin
Small sample size
Musher DM et al. Clin Infect Dis. 2009

30. Fecal Transplant Restore indigenous fecal flora Factors to consider:
Disruption of flora is a risk factor for C.difficile
Factors to consider:
Screen donor for transmissible agents
Logistic issues (timing, collection, processing)
Transplant typically done via nasogastric tube or enema
Limited availability but high success rates
Cohen SH et al. IDSA guidelines 2010

31. Infectious Diseases Society of America (IDSA) Guidelines
Clinical Definition
Recommended Treatment
Initial episode, mild or moderate
Metronidazole 500 mg PO Q8h x days
Initial episode, severe
Vancomycin 125 mg PO Q6h x days
Initial episode, complicated
Vancomycin 500 mg PO Q6h
PLUS
Metronidazole 500 mg IV Q8h
+/- Vancomycin 500 mg enema for ileus
First recurrence
Same as for initial episode
Second recurrence
Vancomycin taper or pulsed regimen
Cohen SH et al. IDSA guidelines 2010

32. American Society of Transplantation Guidelines
Dubberke ER et al. AJT 2009

33. Where dose fidaxomicin fit?
Non-inferior to vancomycin
Similar recurrence rate to vancomycin
Except non-NAP1 strains
Both products have minimal adverse effects
Fidaxomicin significantly more expensive
Clinical practice:
Typically used after vancomycin has failed
Louie TJ et al. NEJM 2011

34. Role of Probiotics
Small randomized trial showed reduced the risk of C.difficile with yogurt
Lactobacillus casei, bulgaricus, and Streptococcus thermophilus
Excluded patients on high-risk antibiotics
Not recommended for primary prevention
Risk of bacteremia
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
Hickson M et al. BMJ 2007

35. Secondary Prevention
If antibiotics are needed during C.difficile treatment:
Continue C.difficile treatment for the duration of the antibiotic regimen (and usually beyond course for anywhere from 3-10 days)
If prolonged, switch to vancomycin to avoid metronidazole toxicities
If broad-spectrum antibiotics are needed after C.difficile treatment is complete:
No empiric treatment of C.difficile without symptoms
Dubberke ER et al. AJT 2009
Cohen SH et al. IDSA guidelines 2010

36. References
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):
Dubberke ER, Riddle DJ, AST Infectious Disease Community of Practice. Clostridium difficile in solid organ transplant recipients. Am J Transpl 2009;9(s4):S35-S40.
Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoae. J Hosp Infect 2003;54:
Dubberke ER, Reske KA, Olsen YY, et al. Clostridium difficile-associated disease in a setting of endemicity: identification of novel risk factors. Clin Infect Dis 2007;45:
Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353:
Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:
Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44:
Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomized double blind placebo controlled trial. BMJ 2007;335:80

37. Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients
Katelyn R Richards, PharmD
University of Wisconsin Hospital and Clinics
PGY-2 Solid Organ Transplant Pharmacy Resident