clostridium difficile treatment and prevention of recurrence in transplant recipients katelyn r...
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Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients
Katelyn R Richards, PharmDUniversity 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
Less common in immunosuppressed patients
Fecal-oral route of transmission
Cohen SH et al. IDSA Guidelines 2010Dubberke ER et al. AJT 2009
http://textbookofbacteriology.net/normalflora_3.html
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 2010Dubberke 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 2010Dubberke 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 2010Dubberke 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 2010Dubberke ER et al. AJT 2009
Cunningham R et al. J Hosp Infect 2003Dubberke 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 2010Dubberke 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 60-90% sensitive with a negative predictive value >95% Repeat testing increases risk of false positive
http://emedicine.medscape.com/article/226645-overview
Cohen SH et al. IDSA Guidelines 2010Dubberke 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
Cohen SH et al. IDSA Guidelines 2010
http://www.hopkins-gi.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Cat_ID=AF793A59-B736-42CB-9E1F-
E79D2B9FC358&GDL_Disease_ID=2A4995B2-DFA5-4954-B770-F1F5BAFED033
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 2010Dubberke 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 2010Dubberke 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 2010Dubberke 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) Retention enema
Cohen SH et al. IDSA Guidelines 2010Dubberke 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 2010Dubberke 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
Significant cost: $2800 for 10 day course, poorly covered by insurance providers
Louie TJ et al. NEJM 2011
http://www.idse.net/ViewArticle.aspx?d=Bacterial+Infections+/+MRSA&d_id=211&i=June+2011&i_id=733&a_id=17269
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 2010Dubberke ER et al. AJT 2009
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 2010Dubberke 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 2010Dubberke 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 2009Cohen 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 2007Cohen 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 10-14 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
Cohen SH et al. IDSA Guidelines 2010Dubberke ER et al. AJT 2009
Hickson M et al. BMJ 2007http://www.parade.com/health/2009/09/20-good-bacteria-probiotics.html
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 2009Cohen SH et al. IDSA guidelines 2010
References1. 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.
2. 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.
3. 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.
4. 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
5. 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.
6. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-431.
7. 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;44:846-848
8. 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, PharmDUniversity of Wisconsin Hospital and Clinics
PGY-2 Solid Organ Transplant Pharmacy Resident