Plan. Background Antibiotics Antibodies Vaccine Probiotics and Fecal Microbiota Transplant (FMT) Binding resins. Plan

Transcription

1 I have no financial relationships with any commercial entity to disclose Medical Treatment of Recurrent and Refractory C. difficile Infection George Hylands Russell, MD, MS Background C. Difficile evolution Refractory/Recurrent CDI 1st causal link to Pseudomembranous colitis s 2000 J type Resistant To clinda outbreaks NAP1/B1/ Netherlands 078 INCREASING SEVERITY AND VIRULENCE Taken from NEJM 2008;359: based on work by Zar, et al. A comparison of vancomycin and metronidazole for the treatment of C. diff- associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45: Aslan S, Et al. Tretment of C. diff- associated disease: old therapies and new strategies. Lancet Infect Dis 2005; 5:

2 Hypervirulent Strain: NAP1/B1/027 Contains a binary toxin whose role is not understood (not infective without Toxin A/B) Homologous to iota toxin of C. perfringens? Synergism with toxin A/B Only 6% of other C. diff strains make binary toxin Overproduction of toxins A/B 2ary to deletion mutation in TcdC protein Resistance to fluroquinolones Competitive advantage in hospital OR for nosocomial CDI with fluoroquinolone use 3.9 (95% CI, 2.2 to 6.6) [Loo, V. NEJM 2005; 353:2442-9] Taken from NEJM 2008;359: based on work by Warny, et al.in:hecht,g, ed.microbial pathogenesis and the intestinal epithelial cell. Washington, D.C. ASM Press, 2003: Risk of Recurrence of CDI Risk of Recurrence of CDI Tied to failure to develop serum IgG antibodies after intial C. dif infection (and initial infection likely to initial lack of memory ab response) Tied to human mutation in IL-8 allele that increases IL-8 levels 125 patients with recurrent disease: mutation v no mutation = 17% to 39% of Infection Rate o (Jiang,et. Am J Gastroenterol 2006; 101:112.) Risk of recurrent infection increases with each treatment failure. (Jiang,et. Am J Gastroenterol 2006; 101:112.) Antibiotics The Perfect CDI drug High Level of Drug in Colon Little Systemic Absorption Little Effect on Microflora 2

3 Teicoplanin Promising Not available in USA 2 RPCT are in progress Rifamixin Negligible impact on gut flora C. diff can develop resistance commonly Initial data promising. Open label work promising. No RCT High Cost Nitazoxanide comparable to vancomycin (Musher, et al. Clin Infect Dis 2009; 48:41-6) High cost Only 1 very small RCT study Taken from NEJM 2008;359: based on work by Zar, et al. A comparison of vancomycin and metronidazole for the treatment of C. diff- associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302-7, Fidaxomicin (Dificid) No data to support combination antibiotic therapies, sequential antibiotic therapy, or triple antibiotic therapy though they are used for RCDI out of desparation Louis T, et al. Fidaxomicin vs. Vancomycin for C. difficile Infection. NEJM. 2011; 364: Taper and Pulse Data Antibodies Antibodies McFarland L, et al. Am J Gastroenterol 2002; 97:

4 IVIG IVIG First reported by Leung (J Pediatrics. 1991; 118: ) One study showed mortality rate of 57% No RCT s Perhaps for only seriously ill Will certainly be replaced by monoclonal antibodies Used (more and more rarely) to treat recurrent and severe CDI with mixed results. Generally not recommended Abourgergi MS, et al. Inravenous Immunoglobulin for the Treatment of C. difficile Inection: A Review. Dig Dis Sci 2011; 56: (Abourgergi MS, et al. Dig Dis Sci 2011; 56:19-26.) Monoclonal Antibodies Vaccine Lowy I, et al. NEJM 2010; 362: Vaccine Computer model shows cost-effectiveness of vaccine (Lee B, et al. Vaccine. 2010; 28: ) C difficile toxoid vaccine successful in treating recurrent C. diff (Giannasca P, et al. Vaccine. 2004; 22: and Souglioultzis S, et al. Gastroenterology 2005; 128: ) Sanofi- Aventis is currently sponsoring a phase II RCT of toxoid vaccine (clinicaltrials.gov NCT and NCT ) Probiotics/ Fecal Microbiota Transplant (FMT) 4

5 Probiotics for CDI Decreased diversity of gut flora after C. diff (Chang J. J Infect Dis. 2008; 197: ) Theoretically, RCDI thrives within a niche that is absent its natural constituent gut microflora Meta-analysis of RCT with probiotics for CDI show no reduction in recurrence (Macfarland, et al. Am J Gastroenterol. 2006; 101: and Pllai A, et al. Cochrane Database Syst Rev. 2008; CD ) Probably not particularly harmful but AE s reported Sepsis Endocardits Liver abscess S. boulardii fungemia Lactobacillus GG 1987: 5 adults in open label case series of multiply RCDI cured (Gorbach, et al. Lancet. 1987; 2:1519) Open label case series of 5 children with multiply RCDI improved with LGG for 2 weeks (Biller, et al. JPGN. 1995; 21:224-6) 2005: RCT shows no benefit for LGG in rates of RCDI after 39 days of follow-up (Lawrence, et al. J Med Microbiol. 2005; 54:905-6) Saccharomyces boulardii DBPRCT shows S. boulardii 500 mg PO BID for 4 weeks during and after anbtibiotisc for CDI decreased recurrence: 26.3% vs. 44.8% (p=0.02) [MacFarland, et al. JAMA 1994; 271: ] Refuted by follow-up DBPRCT that showed no difference with S. boulardii 1 g qd for 4 wks: 43.3% vs. 47.4% [Surawicz, et al. Clin Infect Dis 2000; 31: ] Non-toxigenic C. diff strains show promise Infection prevented in hamster model when colonized with nontoxigenic C. diff strain (Sambol S, et al. J Infectious Diseases 2002; 186: ) RCDI pts treated with non-toxigenic C. dif prevented further recurrences (Seal, et al. Eur J Clin Microbiol. 1987; 6: ) N=38, non-toxogenic vs placebo 2% vs 38% (p=.01). Ethical considerations because spores spread Offers herd immunity Fecal Microbiota Transplant The perfect probiotic Khoruts shows that pre-fmt, the RCDI patient lacks Bacteroides predominance that was present after FMT (Khoruts A, et al. J Clin Gastroenterology. 2010; 44: ) Grehan shows that transplanted microflora remain similar to donor even 24 weeks after FMT (Grehan, et al. J Clin Gastroenterology. 2010; 55: ) Up until fecal retention enema was used. Now NGT and colonoscopy also used. FMT (continued) Russell, et al. report index case of child with recurrent NAP1/B1/027 CDI tx by FMT (Pediatrics. 2010; 146: e ) Review of experience from literature from : 275 cases, 89% success rate (Brandt L, et al. J Clin Gastroenterology. 2011; 45: S ) Recent prospective American case series of 70 pts with RCDI (Mattila, et al. Gastoenterology 2012; 142: % of non NAP1/B1/027 cured 89% of NAP1/B1/027 (4 failures had pre-existing serious conditions) FAILURES: 4 patients who initially cured relapsed within 1 year and 50% successfully re-transplanted 5

6 FMT (continued) Routinely used after three recurrences (Bakken JS, et al. Treatment of RCDI with FMT. Clin Gastroenterol Hep; 2011: ) FECAL trial underway as RPCT (clinicaltrials.gov NCT ) Efficacy of 4 days vancomycin followed by FMT and then 14 days vanco FMT vs vanco taper Probiotics/ Fecal Microbiota Transplant (FMT) Binding resins Binding resins Effectiveness is used as an adjunct therapy Bind C. dif toxin and don t affect microflora Efficacy is 36% for colestipol to 68% cholestyramine (Leffler D. Gastroenterology. 2009; 136: ) Phase III trial of Tolevamer showed it was less effective than metronidazole and vancomycin so marketing ceased (Louie T, et al. Program Abstracts fo the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy ) Probiotic? 6