Rifaximin for Recurrent Clostridium Difficile Infections

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

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Rifaximin for Recurrent Clostridium Difficile Infections

  1. 1. Marti Larriva PharmD Candidate June 13, 2013
  2. 2.   Patient Case  Background  Literature  Summary & Conclusions  Patient Case Outline
  3. 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. 4.   What is the role of rifaximin in the treatment of recurrent clostridium difficile infection? Clinical Question
  5. 5.  Background Clostridium Difficile Rifaximin Guidelines
  6. 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. 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. 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. 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. 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. 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. 12.  Literature Randomized/Controlled Pilot (2011)- Garey et al. Retrospective (2012) – Mattila et al. Case Series (2007-2009) – Johnson/Garey et al.
  13. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 28.  Questions?

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