An evaluation of the current literature supporting the use of Rifaximin for Recurrent Clostridium Difficile Infections.

1. Marti Larriva
PharmD Candidate
June 13, 2013

2. 
 Patient Case
 Background
 Literature
 Summary & Conclusions
 Patient Case
Outline

3. 
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

4. 
 What is the role of rifaximin in the treatment of
recurrent clostridium difficile infection?
Clinical Question

5. 
Background
Clostridium Difficile
Rifaximin
Guidelines

6. 
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)

7. 
 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

8. 
 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

9. 
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 diarrhea
Hepatic encephalopathy prophylaxis
Non FDA-approved uses CDAD
Hepatic encephalopathy treatment
Small bowel bacterial overgrowth
Clin Infect Dis. 2006;42(4):541-7.

10.  2010 SHEA/IDSA C. diff Guidelines:
Current CDI Guidelines
Severity Clinical picture Treatment S/Q
First episode (Mild/Mod) WBC <15,000 OR
sCr < 1.5 x baseline
Metronidazole
500 mg PO TID x 10-14 days
AI
First episode (Severe) WBC >15,000 OR
sCr > 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 QID
PLUS
Metronidazole
500 mg IV Q8H
CIII
First Recurrence … Same as first episode AII
Second Recurrence … Vancomycin in a tapered or pulsed
regimen
BIII
S/Q = Strength of recommendation (A-C)/Quality of Evidence (I-III)
Infect Control Hosp Epidemiol. 2010;31(5):431-55.

11. 
 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

12. 
Literature
Randomized/Controlled Pilot (2011)- Garey et al.
Retrospective (2012) – Mattila et al.
Case Series (2007-2009) – Johnson/Garey et al.

13. 
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.

14. 
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 diarrhea
Rifaximin susceptibility of C. diff isolates
Drug related adverse effects
Garey et al cont’d
Garey et al. Antimicrob Chemother. 2011;66(12):2850-5.

15. 
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.

16. 
 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.

17. 
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.

18. 
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.

19. 
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.

20. 
 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.

21. 
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.

22. 
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)
Johnson
et al.
(2009)
6 patients 3-8 Rifaximin immediately post CDAD treatment
when the patient was asymptomatic:
Rifaximin 400 mg PO BID x 14 d
CDAD 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.)
Garey
et 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.

23. 
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.

24. 
 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

25. 
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

26. 
 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

27. 
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.

28. 
Questions?