Rifaximin for Recurrent Clostridium Difficile Infections

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


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


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


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


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%) -


Rifaximin is a safe treatment for CDI with

reasonable effect and should be considered as an optional treatment for recurrent CDI.

Author’s Conclusions


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?


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?

Health & Medicine

Rifaximin for Recurrent Clostridium Difficile Infections