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
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
Clostridium difficile
 Spore-forming, anaerobic, gram-
positive bacillus
 Toxin producing – A & B
 Inflammatory diarrhea, colonic mucosal
injury
 Pseudomembranous colitis
http://textbookofbacteriology.net/normalflora_3.html

Less common in immunosuppressed
patients
 Fecal-oral route of transmission
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
http://www.humenhealth.com/clostridium-difficile-infection
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
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
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
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
Risk Factors
 Antimicrobial exposure




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
Dubberke ER et al. AJT 2009
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
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
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
Clinical Manifestations
Typical presentation
 Watery diarrhea

Up to 10-15 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
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
http://emedicine.medscape.com/article/226645-overview
60-90% sensitive with a negative predictive value >95%
Repeat testing increases risk of false positive
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
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
OR
Scr > 1.5 x above baseline
Initial episode, severe,
complicated
Hypotension or shock, ileus,
megacolon
Cohen SH et al. IDSA Guidelines 2010
Complications





Dehydration
Electrolyte disturbances
Hypoalbuminemia
Toxic megacolon
Bowel perforation

Sepsis
 Renal failure
 Total colectomy
 Death
http://www.hopkinsgi.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Cat_ID=AF793A59-B736-42CB9E1F-E79D2B9FC358&GDL_Disease_ID=2A4995B2-DFA5-4954-B770F1F5BAFED033
Cohen SH et al. IDSA Guidelines 2010
Prevention
 Horizontal transmission (IDSA)



Hand washing with soap and water
Contact precautions: gloves and gown
Clean areas with sporicidal agents
 Minimize risk factors
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
Contact Precautions
http://www.medscape.org/viewarticle/558476
Treatment
 Stop or narrow antibiotics
 Metronidazole (PO, IV)
 Vancomycin (PO, PR)
 Fidaxomycin (PO)
 Alternatives



IVIG
Rifaximin
Nitizoxanide
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
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
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)
Cohen SH et al. IDSA Guidelines 2010
Retention enema
Dubberke ER et al. AJT 2009
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
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
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
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
http://www.idse.net/ViewArticle.asp
x?d=Bacterial+Infections+/+MRSA&
d_id=211&i=June+2011&i_id=733&
a_id=17269
 Significant cost: $2800 for 10 day course, poorly
covered by insurance providers
Louie TJ et al. NEJM 2011
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
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
Recurrence
 6 – 25% of patients experience 1 episode of
recurrence
 Definition: relapse of same infection or reinfection 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
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
Alternative Therapies
 Intravenous immune globulin (IVIG)
 Rifaximin
 Nitizoxanide
 Fecal transplant
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
Dubberke ER et al. AJT 2009
Cohen SH et al. IDSA guidelines 2010
Rifaximin
 Not FDA approved for CDAD
 Mechanism: inhibits bacterial RNA synthesis
(bacteriostatic)
 Used following vancomycin therapy
 Dose: 200-400 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
Johnson S et al. Clin Infect Dis 2007
Cohen SH et al. IDSA guidelines 2010
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
Fecal Transplant
 Restore indigenous fecal flora

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
Infectious Diseases Society of
America (IDSA) Guidelines
Clinical Definition
Recommended Treatment
Initial episode, mild or
moderate
Metronidazole 500 mg PO Q8h x 1014 days
Initial episode, severe
Vancomycin 125 mg PO Q6h x 10-14
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
American Society of
Transplantation Guidelines
Dubberke ER et al. AJT 2009
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
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
http://www.parade.com/health/2009/09/20-good-bacteria-probiotics.html
Cohen SH et al. IDSA Guidelines 2010
Dubberke ER et al. AJT 2009
Hickson M et al. BMJ 2007
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
References
1.
2.
3.
4.
5.
6.
7.
8.
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):431-455.
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;54:243-245.
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;45:1543-1549
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;353:2442-2449.
Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium
difficile infection. N Engl J Med 2011;364:422-431.
Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficileassociated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect
Dis 2007;44:846-848
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
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