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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
- 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?
Editor's Notes
- Can lead to complications like pseudomembranous colitis, ileus, or toxic megacolon. Broad spectrum antibiotics contribute to the loss of normal flora in the colon. The increased number of broad spectrum antibiotics and the increased duration of use increase the risk of associated C. diff infection.
- There are other factors besides antibiotics that increase the risk of getting C. diff, for example, hospitalization increases exposure to spores.
- 16 X higher toxin A and 23 X higher toxin BEpidemic-associated strainBI/NAP1/027More virulentIncreased toxin A and B productionBinary toxin productionIncreased resistance to FQ
- Despite the broad spectrum nature of Rifaximin, studies have shown that it does not detrimentally effect the normal gastrointestinal flora. More soluble in bile than in aqueous fluid, which may effect it’s efficacy in the colon. Rifaximin resistance > 32 ug/mLhttp://cid.oxfordjournals.org/content/42/4/541.long#ref-25
- This is the treatment guideline table pulled straight from the 2010 IDSA guidelines. Treatment is generally stratified based upon severity of infection and some elements of the clinical picture. Generally, the recommendations for the first episode of C. diff are based on high quality evidence like well designed randomized controlled trials. However, when you get into complicated cases or multiple recurrences the quality of the evidence and strength of the recommendations tend to decline. For recurrent C. diff the IDSA recommends tapered Vancomycin, but this is supported by moderate evidence and expert opinion. Strength of recommendationA Good evidence to support a recommendation for or against useB Moderate evidence to support a recommendation for or against useC Poor evidence to support a recommendationQuality of evidenceI Evidence from at least 1 properly randomized, controlled trialII Evidence from at least 1 well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than 1 center), from multiple time-series, or fromdramatic results from uncontrolled experimentsIII Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, orreports of expert committeesVancomycin taper = Vancomycin 125mg PO QID x 10-14d, then 125mg PO BID x 7 days, then125 mg PO QD x 1 week, then 125mg PO QOD x 2-8 weeksComplete ileus = Vancomycin 500mg q6h enema
- Since the guidelines were published there have been a few more studies looking at the option of Rifaximin.
- Other exclusions include: allergy to rifamycins, positive pregnancy test or breastfeeding.Garey et al was a randomized, double blind placebo controlled pilot study that looked at the use of Rifaximin in adults with c diff diarrhea after treatment with a standard course of vancomycin or metronidazole for 10-14 days. Our patient, Mr. J would have been excluded from this study because he had more than one recurrence and possibly needs treatment longer than 14 days. The regimen tested was either Rifaximin 400mg PO TID for 20 days or identical placebo.
- Overall 79 patients were enrolled in the study, but 11 patients were excluded prior to receiving study medication because they needed >14 days standard therapy OR were lost to follow up prior to starting study medications. Overall 68 patients received study medication, but 5 dropped out because they were no longer interested in receiving study medication, they were still included in the intention to treat analysis. Patients who received Rifaximin were more likely to be Black or Hispanic, otherwise baseline characteristics were similar among the groups. ADEs – placebo = rash; Rifaximin = nausea and pruitisNNT = 3.6NNH = 33
- Predicted needed 240 patients enrolled to see a 50% difference between the groups with alpha = 0.05 and beta = 20%. Limited budget and drug supply only allowed 80 patient enrollment.
- Mattila et al was a retrospective chart review that looked at the use of rifaximin for recurrent episodes of C. diff at a single center in Finland. Patients were treated with the BID regimen of Rifaximin listed here after treatment with varying regimens most commonly vancomycin 125 mg PO QID x 14 days.
- Patients in this study had high rates of recurrence and previous treatments. Authors looked at C. diff recurrence post treatment and in vitro resistance to rifampin.
- Several case series have been done by Johnson et al and Garey et al. Generally the case series were small, but had patients with several recurrences who had gone through multiple courses of treatment prior to Rifaximin. Several different treatment regimens were used with differing preceding therapies. Some of the details are listed here. Overall there were only a few recurrences during the follow upJohnson et al. 2007mean follow up of 233 days1 with relapse responded to a second course of rifaximinJohnson et al. 2009 2 failed during Rifaximin therapy. 1 patient was treated with a repeat course of rifaximin, but failed again, her MIC to Rifaximin was > 256 which is considered resistant, she had been treated with rifampin + vanco in a previous regimen (Vanco + S. boulardii x 1 mo) 1 other patient also had recurrence on rifaximin, but did not have a resistant MIC, she was restarted on Vancomycin for 8 months, had a trial off with CDI recurrence and was on vanco daily at the end of the follow up period without any recurrenceGarey et al. 2009 5/6 patients had complete resolution within 4-17 days with no recurrence during follow up 54-398 days post treatment. 1 patient died from other comorbidities.