Clostridium difficile infec&on. Time to wake up and smell the..., um, nevermind. OK, next slide please. Bruce Dalton, BScPhm. PharmD. declara&ons No financial disclosures Personal acquaintance, co- worker, collaborator of author of studies to be discussed (fidaxomicin) 1
objec&ves Pathophysiology, disease course and treatment per guidelines Epidemiology Probio&cs Stool transplant New drugs The intes&nal microbiome Pathophysiology & Disease Course Alteration of GI flora (antibiotics +/-) Reduced immune competence Contact/colonization with pathogenic strain(s) Clostridium difficile associated diarrhea (CDAD) Mild moderate Diarrhea, abd cramps No fever, new signs of infection Severe Elderly + Diarrhea, abd cramps Fever, biochemical perturbations, incr WBC Fulminant, Complicated Ileus,Toxic megacolon, perforation 2
Mild moderate Diarrhea, abd cramps No fever, new signs of infection Severe Elderly + Diarrhea, abd cramps Fever, biochemical perturbations, incr WBC Fulminant, Complicated Ileus,Toxic megacolon, perforation Stop inducing antibiotics Metronidazole po 10-14 days Vancomycin po 10-14 days 20-30% 1. Surgical Emergency! -colectomy? 2. Systemic antibacterials for intra-abdominal infection 3. Vancomycin po/pr Metronidazole IV Recurrence > 2 episodes Vancomycin - taper 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). Infection control and hospital epidemiology, May 2010, vol. 31, no. 5 431-455 epidemiology Incidence & Surveillance Strain types & clinical significance Emerging pathogenic strains 3
Canadian Nosocomial Infec&on Surveillance Program Alberta Jan Mar 2013 Cases/ 10000 pt days Quebec epidemic 2004-5 rate ~13 CNISP 2010-11 rate = 6.3 cases/10,000 pt days Near benchmark rate in Alberta Contributory or primary cause of death 50-100/yr 4
Strains of Clostridium difficile Why do we care? Changing epidemiology Risk factors and precipitants Reservoir and transmission Challenges Clinical diagnosis by toxin or PCR Culture, typing is extra work/expense Where does C diff come from? Janezic, BMC Micro 2012 5
Pathogenic Strains of Clostridium difficile NAP (North American Pulsovar)1 /027 Pulse field gel electrophoresis Nosocomial outbreaks Quebec, NE US & Europe circa 2004-6 Negative control of toxin expressiondefective in NAP1 Warny et al, Lancet 2005 6
New Pathogenic Strain Clostridium difficile NAP 7/8 078 Reservoir in agricultural animals? Swine & cadle - >80% prevalence (of C diff posi&ve animals) Transmissible to humans through food Community associated CDI? hypervirulent tcdc dele&on 2004-2008 Canadian Nosocomial Surveillance Program (CNISP) - Emerg Inf Dis 2010. 0.5% of strains in 2005 1.6% of strains in 2008 Not systematically collected samples 552 samples tested for Clostridium difficile 2.4% posi&ve (13) 027 & 078 strains (3) 7
Metronidazole Resistance 1 pa&ent mul&ple metronidazole courses for Clostridium difficile resistance elements similar to metronidazole resistant H. pylori and B. fragilis Spain 2002 6.3% resistance Obvious treatment implica&ons but also: Tes&ng VRE probio&cs Probio&cs why they are different? Systema&c Review of Probio&cs efficacy for Preven&on Fecal transplant 8
probio&cs Natural product Millions of genera&ons of industrial- level fermen&ng Pharmaceu&cal product Not pure 9
Other pharmaceu&cals 1. What is the standard vancomycin potency (% of labeled quan&ty, USP)? a) 99.99% b) 99.9% c) 99% d) 90% 2. How many dis&nct molecules does pure Gentamicin USP, contain? a) 1 b) 3 c) 5 d) 7 probio&cs Natural product Millions of genera&ons of industrial- level fermen&ng Pharmaceu&cal product Not pure Food product Not a macronutrient 10
Year Ohland C & MacNaughton WK. Am J Physiol Gastrointes Liver Phys. 2010. 298: G807-G819 11
Ohland C & MacNaughton WK. Am J Physiol Gastrointes Liver Phys. 2010. 298: G807-G819 12
Anesthesiology, 2013 13
Primary preven&on in pa&ents taking an&bio&cs Hospitalized and ambulatory Clostridium difficile associated diarrhea (23 studies): Diarrhea & Stool posi&ve RR 0.36 (95% CI; 0.26-0.51) Median risk reduc&on 22/1000 = nnt ~50 14
Clostridium difficile infec&on (13 studies): Stool toxin posi&ve (+/- diarrhea) NS?? Meta analysis An&bio&c Associated Diarrhea 25 studies RR=0.60 (95% CI = 0.49-0.72) Do we care? 15
Studies repor&ng ADR 26 studies RR =0.80 (95% CI, 0.68-0.96) ie lower in probio&c grp vs placebo Common ADR: Abd cramping, nausea, fever, flatulence, taste disturbance Serious ADR: 4 studies non adributable to probio&c Systemic Review Conclusions CDAD more important endpoint than CDI Probio&cs overall moderately effec&ve in preven&on. AAD, ADR favour use of probio&cs Do not use in immune compromised 16
Relapsed CDAD pa&ents (median 3 relapses) Randomized to: 1. Vancomycin 500 mg po qid x 5days, then colonoscopy prep, then NJ stool transplant 2. Vancomycin 500 mg po qid x 14 days 3. Vancomycin 500 mg po qid x 14 days and colonoscopy prep on day 4 or 5 Stool transplant (cont d) Primary outcome: cure without relapse 10 wks Planned 40 pts per group (120) Results Study terminated auer 41 pts at planned interim analysis 17
Stool Transplant Summary Effec&ve for recurrence treatment and preven&on Limited number of centres/physicians will do it Safety issues: transmission of pathogens Op&mal technique unknown new therapeu&c strategies for CDI Fidaxomicin Rifaximin 18
First macrocyclic an&bio&c Fidaxomicin No systemic absorp&on AKA: lipiarmycin, lipiarmicin, lipiarmycin A3, tiacumicin B, clostomicin B1, OPT-80 Compared to healthy volunteers CDAD pts had 100-1000x lower bacteria at start of study Vanco treated pa&ents had further 100-10,000x lower bacteria counts up to day 28 Fidaxomicin bacteria counts were NS from beginning of study 19
Fidaxomicin Louie et al. Fidaxomicin vs Vancomycin for CDAD. NEJM 2011 DB, RCT mul¢re (67, N. America) Adults with primary episode CDI Excl. Toxic megacolon etc. Non- inferiority, per protocol & mitt analysis Primary outcome: clinical cure at 10 days non- inferiority margin of 10% NAP1/027 strain 23.6 vs 24.4 % NS 20
Cost data ~$2200/ bodle of 20 tabs (1 course), $220/day Vancomycin 125mg caps po qid = $32/day Metronidazole 500 mg po qid = 32/day Cost effec&veness vs vanco on basis of readmission costs (US data) Fidaxomicin summary Non- inferior for cure vs vancomycin Less recurrence for non- NAP1/027 strains Less collateral damage if cost/coverage issues equal?vre induc&on No evidence for improved efficacy in mul&ple recurrence pa&ents 21
Rifaximin Garey et al. JAC 2011 CDAD pa&ents treated with vancomycin/ metronidazole for 10-14 days 20 days rifaximin (400 mg po &d) or placebo (double blind) Primary outcome 90 day recurrence of diarrhea CDAD or non CDAD N=68, recurrent diarrhea in 49% vs 21% (p=0.018), nnt =4 Health Canada (SAP) or manufacturer will not release 22
Summary Alteration of GI flora (antibiotics +/-) Reduced immune competence Contact/colonization with pathogenic strain(s) Consider probiotics if not severely immune compromised Clostridium difficile associated diarrhea (CDAD) Mild moderate Diarrhea, abd cramps No fever, new signs of infection Severe Elderly + Diarrhea, abd cramps Fever, biochemical perturbations, incr WBC Fulminant Toxic megacolon, perforation Mild moderate Diarrhea, abd cramps No fever, new signs of infection Severe Elderly +Diarrhea, abd cramps Fever, biochemical perturbations, incr WBC Fulminant Toxic megacolon, perforation Stop inducing antibiotics Metronidazole po 10-14 days Vancomycin po 10-14 days or fidaxomicin if NAP 1/027 uncommon 20-30% 1. Surgical Emergency! -colectomy? 2. Systemic antibacterials for intra-abdominal infection 3. Vancomycin po/pr Metronidazole IV Recurrence > 2 episodes Rifaximin or Vancomycin - taper > 4 episodes Stool transplant 23
The Gut Microbiome The Human Microbiome Project (NIH, 2008) Goal: to characterize the microorganisms associated with human health and disease 5 body sites of emphasis: gut, oral, skin, female GU tract & respiratory tract Analy&c Method(s): 16S rrna sequencing 24
HMP author list 25
~300 healthy individuals to represent human species OTU = operational taxonomic units ~ spiecies 26
Enterotypes Implica&ons of gut micrbiome research GI (& other) cancers Cardiovascular disease Inflammatory bowel disease Obesity Diabetes 27
Nitazoxanide Metronidazole analogue Unclear if metronidazole resistance = nitazoxanide resistance RCT Clin Inf Dis 2006 n= 142 Metronidazole 10 days Nitazoxanide 7 days Nitazoxanide 10 days EOT response 82.4% 90% 88.9% NS 31 day response 57.6% 65.8% 74.3% NS 28