rifaximin for recurrent clostridium difficile infections
DESCRIPTION
An evaluation of the current literature supporting the use of Rifaximin for Recurrent Clostridium Difficile Infections.TRANSCRIPT
Rifaximin for Recurrent Clostridium Difficile
Infection (CDI)
Marti LarrivaPharmD Candidate
June 13, 2013
Patient Case Background Literature Summary & Conclusions Patient Case
Outline
Patient Case
Mr. J 68 y/o male PMH: HTN, HLD, A.
Fib., recurrent CDI Admitted for AMS
with acute respiratory failure due to HCAP for which he was treated with: meropenem and vancomycin
Developed C. diff. while in hospital and is being treated with vancomycin 125 mg PO x 14d, today is day 14 and his symptoms persist
4 previous C. diff episodes
Team considering rifaximin if symptoms do not improve
What is the role of rifaximin in the treatment
of recurrent clostridium difficile infection?
Clinical Question
Background
Clostridium DifficileRifaximinGuidelines
Background
Clostridium Difficile Gram positive spore-forming anaerobic bacilli
Antibiotics Associated with Normal Flora Disruption
Fluoroquinolones
Clindamycin
Penicillins (broad spectrum)
Cephalosporins (broad spectrum)
Figure 1: Pathogenesis of C. Diff. associated diarrhea (CDAD)
Risks for C. Diff. (aside from abx exposure)
Hospitalization Advanced age Severe illness Gastric acid suppression (PPIs) Recurrence: antibiotic use during treatment or
immediately post-treatment
Clostridium Difficile
Diagnosis
Moderate-severe diarrhea (≥ 3 episodes for 2 days) OR colitis PLUS Stool test positive for C. Diff. toxins Endoscopic or histologic findings of
pseudomembranous colitis
C. Diff. cont’d
Rifaximin
Mechanism Inhibition of bacterial RNA synthesis
Spectrum Broad: anaerobic or aerobic gram+ & -including: E. Coli, C. Difficile
Absorption 0.04%
Metabolism Excreted unchanged
Concentration in stool 8000 μg/g
FDA-approved use Traveler’s diarrheaHepatic encephalopathy prophylaxis
Non FDA-approved uses CDADHepatic encephalopathy treatmentSmall bowel bacterial overgrowth
Clin Infect Dis. 2006;42(4):541-7.
2010 SHEA/IDSA C. diff Guidelines:
Current CDI Guidelines
Severity Clinical picture Treatment S/Q
First episode (Mild/Mod) WBC <15,000 ORsCr < 1.5 x baseline
Metronidazole500 mg PO TID x 10-14 days
AI
First episode (Severe) WBC >15,000 ORsCr > 1.5 x baseline
Vancomycin 125 mg PO QID x 10-14 days
BI
First episode (Severe/Complicated)
Hypotension, shock, ileus, megacolon
Vancomycin 500 mg PO/NG QIDPLUSMetronidazole500 mg IV Q8H
CIII
First Recurrence … Same as first episode AII
Second Recurrence … Vancomycin in a tapered or pulsed regimen
BIIIS/Q = Strength of recommendation (A-C)/Quality of Evidence (I-III)
Infect Control Hosp Epidemiol. 2010;31(5):431-55.
Up to 29% of patients experience recurrence
after initial successful treatment of a first episode
Up to 45% of patients experience recurrence after treatment of first recurrence
Options for recurrence mentioned in text: Vancomycin taper Rifaximin Probiotic saccharomyces boulardii Fecal transplant
Guidelines continued
Literature
Randomized/Controlled Pilot (2011)- Garey et al.Retrospective (2012) – Mattila et al.
Case Series (2007-2009) – Johnson/Garey et al.
Design Randomized, double-blind, placebo-controlled, single center pilot
study
Inclusion >18 years old ≥2 unformed stools for two days OR > 6 stools in one day Treatment with PO vancomycin or metronidazole for 10-14 days
Exclusion History of chronic diarrheal disease History of more than 1 recurrence of C. Diff. Associated Diarrhea
(CDAD) Concomitant antidiarrheal, antimotility, or probiotics Severe C. diff colitis with surgery planned w/in 24h Required >14 days of standard therapy
Treatment Groups
Rifaximin 400 mg PO TID x 20 days OR
Identical placebo Note: both given immediately after receiving standard therapy
Garey et al.
Garey et al. Antimicrob Chemother. 2011;66(12):2850-5.
Primary Outcome Incidence of recurrent diarrhea 3 months post treatment:
Recurrent CDI = diarrhea & + toxin test after initial resolution
Self-reported diarrhea (w/o + toxin test)
Secondary Outcomes Time to recurrent diarrheaRifaximin susceptibility of C. diff isolatesDrug related adverse effects
Garey et al cont’d
Garey et al. Antimicrob Chemother. 2011;66(12):2850-5.
Rifaximin (n=33)
Placebo(n=35)
P value
Recurrent Diarrhea 7 (21%) 17 (49%) 0.018
CDI Recurrence 5 (15%) 11 (31%) 0.11
Self Reported diarrhea
2 (6%) 6 (17%) 0.15
Adverse Drug Events 2 (6%) 1 (3%) -
Results
Garey et al. Antimicrob Chemother. 2011;66(12):2850-5.
Use of rifaximin after standard antibiotic
treatment for CDI may decrease rates of recurrent diarrhea.
Larger sample size will be needed to detect a difference in CDI recurrence.
More research needs to be done to compare Rifaximin to other available regimens to treat recurrence (fidaxomicin, monoclonal antibodies to C. diff. toxins)
Author’s Conclusions
Garey et al. Antimicrob Chemother. 2011;66(12):2850-5.
Analysis
Strengths
Randomized, placebo-controlled
Intention-to-treat analysis performed
Limitations Small sample size
Not powered to see a difference in diarrhea due to CDI
No patients with more than 1 recurrence
Adherence to therapy not monitored
Funded by a research grant from Salix pharmaceuticals, manufacturer of Rifaximin
Garey et al. Antimicrob Chemother. 2011;66(12):2850-5.
Mattila et al.
Design Single center retrospective chart review
Inclusion Patients treated with rifaximin for recurrent CDI from March 2007 to December 2011 at Helsinki University Central Hospital (Finland)
Exclusion None
Treatment Rifaximin 400mg PO BID x 14 days(25 patients) Preceded by vancomycin 125 mg PO QID x 14 days(3 patients) Preceded by metronidazole 400 mg PO TID x 14 days(1 patient) Preceded by vancomycin taper x 6 weeks(2 patients) Instead: rifaximin 400 mg BID x 28 days only
Mattila et al. Aliment Pharmacol Ther. 2013;37(1):122-8.
Matilla et al. cont’d.
Patient Population
Average C. diff + stool tests = 3.5 (range: 1-6)Average metronidazole/vancomycin treatments = 4.3 (range: 2-12)
Primary Outcome
CDI Recurrence 2 years post treatment
Secondary Outcome
Rifampin MIC predictive for rifaximin susceptibility
No Recurrence Recurrence P value
Number of patients
17 (53%) 15 (47%) -
Mattila et al. Aliment Pharmacol Ther. 2013;37(1):122-8.
Rifaximin is a safe treatment for CDI with
reasonable effect and should be considered as an optional treatment for recurrent CDI.
Author’s Conclusions
Mattila et al. Aliment Pharmacol Ther. 2013;37(1):122-8.
Analysis
Strengths
Varied patient population
High recurrence and previous treatment rates
Long duration of follow up
Limitations
Retrospective Not randomized Single Center Finland - differing
isolates and susceptibilities?
Mattila et al. Aliment Pharmacol Ther. 2013;37(1):122-8.
Author (year)
Population
Number previous recurrences
Treatment Recurrences (time span)
Johnson et al.(2007)
8 patients 4-8 Rifaximin immediately post CDAD treatment when the patient was asymptomatic:(6) Rifaximin 400 mg PO BID x 14d(1) Rifaximin 200 mg PO TID x 14d(1) Rifaximin 200 mg PO BID x 14d
1 (233 days)
Johnsonet al.(2009)
6 patients 3-8 Rifaximin immediately post CDAD treatment when the patient was asymptomatic:Rifaximin 400 mg PO BID x 14 dCDAD treatment varied:(5) Symptomatic on vanco taper -> started vancomycin 125 mg PO QID until asymptomatic -> rifaximin(1) Symptomatic on vanco & s. boulardii x 1 month. Tx stopped and switched -> rifaximin
2 (4-25 mo.)
Gareyet al.(2009)
6 patients 1-4 (6) CDAD recurrence unresponsive to first line therapy, started on:Rifaximin 400mg PO TID x 14 days, then rifaximin 200 mg PO TID x 14 days
0 (54-398 days)*
Case Series
* 1 patient died due to other comorbidities
Garey et al. J Clin Gastroenterol. 2009;43(1):91-3.
Johnson et al. Clin Infect Dis. 2007;44(6):846-8. Johnson et al. Anaerobe. 2009;15(6):290-1.
Analysis
Strengths
Multiple recurrences Varying pre-
treatment regimens
Limitations
Not randomized Not placebo
controlled Small sample size
Garey et al. J Clin Gastroenterol. 2009;43(1):91-3.
Johnson et al. Clin Infect Dis. 2007;44(6):846-8. Johnson et al. Anaerobe. 2009;15(6):290-1.
Rifaximin may be effective in reducing the rate of
recurrent diarrhea when used as a chaser. Small prospective pilot study demonstrated benefit Retrospective showed not much benefit in recurrence Case series demonstrated potential benefit multiple
recurrences Larger studies are needed to confirm safety and efficacy
Dose: Rifaximin 400mg PO TID x 20 days Cost: ~$275 per course
Generally well tolerated and does not require renal dosing, fairly low risk with possible benefit.
Summary & Conclusions
Patient Case
Mr. J 68 y/o male PMH: recurrent CDI (4
previous epidodes) HCAP treated with
meropenem/vanco C. diff; vancomycin 125 mg
PO x 14d Today is day 14 and his
symptoms persist. Team considering rifaximin
if symptoms do not improve.
ID was consulted and they recommended a Vancomycin taper for this patient: Vancomycin 125 mg PO BID x 1
week Vancomycin 125 mg PO QD x 1
week Vancomycin 125 mg PO QOD x 1
week Vancomycin 125 mg PO every third
day x 1 week
Unclear if Mr. J was a candidate for Rifaximin:
2 options: Tx after 14 days, or treat after Vanco taper
Randomized/controlled study showing benefit No patients with >1 recurrence No patients with treatment patients requiring > 14
days of standard therapy Retrospective study/case reports
Multiple recurrences Varying treatment regimens including vanco taper
and tx of symptomatic patients. Resolution symptoms and no recurrence in a majority
of patients
Patient Case
References
1. Adachi JA, DuPont HL. Rifaximin: A novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis. 2006;42(4):541-7.
2. Brigidi P, Swennen E, Rizzello F et al. Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis. J Chemother. 2002;14(3):290-5.
3. Carman RJ, Boone JH, Grover H et al. In vivo selection of rifamycin-resistant clostridium difficile during rifaximin therapy. Antimicrob Agents Chemother. 2012;56(11):6019-20.
4. 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):431-55.
5. Garey KW, Ghantoji SS, Shah DN et al. A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with clostridium difficile infection. J Antimicrob Chemother. 2011;66(12):2850-5.
6. Garey KW, Jiang ZD, Bellard A et al. Rifaximin in treatment of recurrent clostridium difficile-associated diarrhea: An uncontrolled pilot study. J Clin Gastroenterol. 2009;43(1):91-3.
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(6):846-8.
8. Johnson S, Schriever C, Patel U et al. Rifaximin redux: Treatment of recurrent clostridium difficile infections with rifaximin immediately post-vancomycin treatment. Anaerobe. 2009;15(6):290-1.
9. Mattila E, Arkkila P, Mattila PS et al. Rifaximin in the treatment of recurrent clostridium difficile infection. Aliment Pharmacol Ther. 2013;37(1):122-8.
Questions?