Clostridium Difficile Treatment and Prevention of - wi
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Transcript Clostridium Difficile Treatment and Prevention of - wi
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
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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