What s New for Clostridium difficile 2013 John Lynch MD MPH Harborview Medical Center University of Washington
Pathogenic Mechanisms of Diarrhea Toxins: Preformed: S aureus, C perfringens, B cereus Formed in the intestine by ingested bacteria: Stimulate intestinal secretion: V cholerae, enterotoxigenic E coli Cytotoxins: C difficile, Shigella, enterohemorrhagic E coli Invasion: Shigella, Salmonella, Campylobacter, Yersinia Disruption of enterocytes leading to decreased absoprtion: Giardia, Cryptosporidium Fred Buckner MD
Antibiotic-associated Diarrhea DDx Osmotic Diarrhea C difficile infection Antibiotics alter colonic microflora (dysbiosis) Impaired carbohydrate fermentation C difficile colonizes bowel Increased osmotic concentration in colonic lumen Osmotic diarrhea (80%) adapted from UpToDate 2007 Organism grows and releases toxin Toxin mediated diarrhea and colitis (20%)
How Much of a Problem? 1996 2000 2003 2004 98,0000 178,0000 cases 31/100,000 61/100,000 discharges 1.2% case fatality 2.3% McDonald Emerg Infect Dis 2006
Discharge rate for Clostridium difficile infection from US short-stay hospitals by age [22]. Lessa F C et al. Clin Infect Dis. 2012;55:S65-S70 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012.
Incidence of Clostridium difficile infection per 1000 hospitalizations by age (Healthcare Utilization Project Kids and Inpatient Database, United States, 1997 2006). Lessa F C et al. Clin Infect Dis. 2012;55:S65-S70 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012.
How Much of a Problem? 3,000,000 cases per year $3,200,000 per year
Community-acquired CDAD ~20% of CDI is community associated (20-50/100,000) CDC, 8 EIP surveillance sites, 2009-2011 984 patients with community-associated CDI 35.9% did not receive antibiotics* 18% had no outpatient healthcare exposure 40.7% had low-level outpatient healthcare exposure No healthcare exposure: higher exposure to infants under 1 year and household members with CDI Trend towards more PPI use among those w/o abx exposure Chitnis JAMA Internal Med 2013
Biology of C difficile Obligate anaerobic, Gram-positive, sporeforming rod Difficult to isolate due to slow growth compared to other clostridia(1), resistant to high temps and 70% ethanol Vegetative (replicating) and spore (dormant, transmissible) phases 1. Hall and O Toole
Biology of C difficile Toxin A and Toxin B TcdA is an enterotoxin, historically assoc with virulence TcdB is a cytotoxin assoc with outbreaks of severe disease Binary toxin in 6% - 12.5% of strains, disrupts cell cytoskeleton Surface proteins for adherence to epithelial cells stimulate inflammation, upregulated by ampicillin and clindamycin 1. Hall and O Toole
Hypervirulent C difficile Strains NAP1/ribotype 027 Associated mortality up to 6.9% Associated with outbreaks, age >65 and fluoroquinolone use Increased toxin production Binary toxin?
Risk Factors for CDAD Infection Older age: increases 2% every year after 18yo Antibiotic use PPI use More often NAP1 strains Colonization Hospitalization Chemotherapy PPI/H2-blockers Loo NEJM 2011
Unnecessary Antibiotic Use Shaughnessy ICHE 2012
Reasons for Antibiotic Use Shaughnessy ICHE 2012
Environmental Risks for CDAD Shaughnessy ICHE 2011
Shaughnessy ICHE 2011
C difficile Testing Enzyme immunoassay rapid, low cost, simple Sensitivity 60%-80% PCR for toxin B gene Sensitivity 98.8% Specificity 90.8% When hospitals switch to PCR, 2-fold increase in rates and case load Belmares SHEA 2011 Meeting
C difficile Treatment- Drugs Metronidazole Vancomycin Fidaxomicin Nitazoxanide Since 2000, failure rates increased from 2.5% to >18%, and >60% after multiple recurrences
Crook CID 2012
C difficile and Recurrence Most patients respond to therapy 15% to 30% recur Of those who recur 40% have a 2 nd recurrence Of those with 2 recurrences, 65% have a 3 rd
Risks for Relapse based on EMR Hebert ICHE 2013
C difficile Prevention Stop antibiotic therapy if possible Probiotics
C difficile and Probiotics Johnston Ann Intern Med 2012: moderate quality evidence from 13 trials suggests there is a large reduction in CDAD and few adverse effects Goldenberg Cochrane Review 2013: 23 RCTs support moderate quality evidence that probiotics are safe and effective for preventing C difficile-associated diarrhea
Fecal Microbiota Transplantation Transfaunation, Fabricius Aquapendente in the 17 th Century 1958, Eiseman treated 4 patients with pseudomembranous colitis
Fecal Microbiota Transplantation Fecal retention enemas common till 1989 NG tube in 1991 Colonoscopy in 2000 Self-administered enemas in 2010 ~325 reported cases worldwide, ¾ by colonoscopy or retention enema
Van Nood NEJM 2013
Fecal Microbiota Transplantation One systemic review: 317 patients, 8 countries, 27 case series/reports Overall cure rate of 92% One long-term follow-up study 5 US centers (including HMC) F/U 3-68 months 74% had resolution of diarrhea in <4 days 82% had resolution with 5 days, 17% had improvement 91% had primary cure, 98% secondary cure, 1 death of unk etiology while in hospice care Brandt Am J Gastro 2012 Gough CID 2011
Pre-FMT patient data Brandt Am J Gastro 2012
FMT: Nuts and Bolts Donors: no abx x 3m, no chemo, no HIV,HBV,HCV, ID, high risk behaviors, illicit drugs, incarceration, endemic diarrhea exposure, IBS, IBD, Giardia, cryptosporidium Pt abx till day -2 or -3, donor stool collected collected and used within 8hrs Dose: 6 tablespoons to entire donation (300-700cc) depending on institution All via colonoscopy into various parts of colon from terminal ileum to rectum Gough CID 2011
Post-FMT patient data Brandt Am J Gastro 2012
After FMT 53% of patients stated they would prefer FMT as 1 st treatment option with another recurrence 4 pts did not report improvement in abdominal pain after FMT Fatigue: 42% resolved, 51% improved, took avg of 4 weeks 4 pts w/ recurrence responded to vancomycin or nitazoxanide, 2 had successful 2 nd FMT 2 pts reported improvement in allergic sinusitis and arthritis 4 pts reported new conditions: peripheral neuropathy, Sjogren disease, ITP and RA
Stool Substitute Transplant Therapy Two patients infected with hyper-virulent C difficile (ribotype 078) with recurrent disease RePOOPulate = 62 anaerobic bacterial isolates from a 41 yo woman Purified isolates sequenced and underwent drug susceptibility testing 33 isolates representing commensals were used for the substitute 100ml via colonoscopy Petrof Microbiome 2013
Suggested Indications Recurrent or relapsing CDI defined as: at least 3 episodes of mild to moderate CDI and failure of 6 to 8 weeks of vancomycin with or without an alternative antibiotic (such as rifaximin or nitazoxanide) Fecal Microbiotia Transplantation Workgroup
54 year old man with DM in the hospital for tx of pneumonia x 5 days, now with diarrhea, WBC 26K, lactate of 4, hypotensive and has a tender belly. Imaging:
54 year old man with DM in the hospital for tx of pneumonia x 5 days, now with diarrhea, WBC 26K, lactate of 4, hypotensive and has a tender belly. Options?
Indications for Operative Management Neal Ann Surgery 2011
Surgery Surgical intervention in up to 20% of cases (?) Post-operative mortality 35% to 80% Traditional: subtotal colectomy with resection based on visual exam + end ileostomy New approach? Markelov Am Surg 2011
Diverting Loop Ileostomy and Colonic Lavage Neal Ann Surgery 2011 1. Diverting loop ileostomy 2. Colonic lavage with PEG 3. Antegrade vancomycin enemas x 10 days
Demographics and Outcomes Neal Ann Surgery 2011
A Systems Approach to Prevention Bundle at Rhode Island Hospital Infection control plan based on risk assessment Monitor hospital-wide morbidity and mortality associated with CDAD Switch to PCR-based testing Enhanced environmental cleaning Standardized CDAD treatment plan 2006-12/1000 discharges, 52 deaths 2012-3.6/1000 discharges, 19 deaths Mermel Jt Comm J Qual Patient Saf 2013