1. Clostridium difficile Infection (CDI): Increasingly Severe and Rapidly Fatal Disease Requires High Certainty of Treatment Efficacy Dale N. Gerding, MD Associate Chief of Staff for Research Edward Hines Jr. Veterans Affairs Hospital Professor of Medicine (Infectious Diseases) Loyola University Chicago Stritch School of Medicine

2. Disclosures: DNG is a consultant for Genzyme, GOJO, Optimer, Salix, Merck, Cepheid, BD Genome, Schering-Plough and ViroPharma. His institution has research grants in his name from Genzyme, GOJO, Massachusetts Biological Laboratories, Optimer, and ViroPharma. He holds patents for the treatment and prevention of CDI with non-toxigenic Clostridium difficile (NTCD) licensed to ViroPharma. Views expressed are those of the presenter and do not necessarily reflect the views of the U.S. Department of Veterans Affairs, the major funding source for his research.

3. Clostridium difficile Infection (CDI) CDI rates of diarrhea and colitis have continued to increase in the United States since 2000. A common epidemic hypervirulent C. difficile strain continues to be reported from hospitals in an expanding list of states. More severe CDI with higher mortality and higher rates of colectomy, especially in the elderly, continues to be reported. Currently, non-absorbed oral agents that are locally active such as vancomycin and new investigational drugs are the most effective treatments available for severe CDI.

4. From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15 And unpublished CDC data 0 20 40 60 80 100 120 1996199719981999200020012002200320042005 Year Discharges per 100,000 population Any listed Primary Rates of CDI Nearly Tripled in U.S. Hospitals between 2000 and 2005

5. States with the Epidemic Strain of C. difficile Confirmed by CDC (N=37) Updated November 9, 2007 DC PR AK HI 37 States and DC confirmed by CDC

6. CDI Rates and Mortality Increase with Increased Patient Age Age (Years) CDI Rate per 1000 Admissions Attributable 30-Day Mortality Rate (%) <403.52.6 41-5011.21.2 51-6020.03.2 61-7024.45.1 71-8038.36.2 81-9054.510.2 >9074.414.0 Loo et al NEJM 2005;353:2442-9

7. Dilated Loops of Colon in a Patient with CDI

8. Fulminant CDI: Severe and Rapidly Fatal Disease Hospital Admission for Community Pneumonia CABG Surgery Diarrhea Onset 17,700 27,000 65,000  51 yo male underwent coronary artery bypass grafting and received cefazolin pre-surgery. Previous antibiotic Rx with gatifloxacin, piperacillin/tazobactam, ceftriaxone, and azithromycin.  Rapidly progressive 4-day course from diarrhea to shock and death. WBC elevated throughout course and rose precipitously near the time of death.

9. Abdominal CT Findings in Fulminant CDI Ascites Thickened Colonic Wall

10. Normal Colon Colon with PMC due to Clostridium difficile Infection Normal Colon and Pseudomembranous Colitis (PMC) as seen at Colonoscopy

11. Histological Appearance of Pseudomembranous Colitis (PMC) Pseudomembrane Mucosal Destruction and Inflammatory Response

12. Colon Autopsy Specimen of a Patient who Died of Severe CDI: Confluent PMC is Evident

13. Inflammatory Response to C. difficile Toxins alters GI Tract Physiology Toxin A is a potent enterotoxin (causes fluid loss) and a very active white blood cell attractant. Toxin B is a potent cell cytotoxin (kills cells) CDI patients commonly demonstrate an elevated White Blood Cell count Clin Infect Dis 2002;34:1585-92 Fecal Lactoferrin, Interleukin-1beta, and Inter-leukin-8 are elevated in patients with severe CDI. Clin Diagnostic Lab Immuno 1997;4:719-722 Cyclooxygenase (Cox)-2 expression and prostaglandins are elevated in the presence of Toxin A. JID 2001;184:648-52

14. Summary CDI is a severe inflammatory colonic disease with high mortality and morbidity, especially in the elderly. C. difficile Toxins A and B and the associated inflammation produced cause structural, functional, and biochemical changes in the GI tract of CDI patients that are poorly understood. Currently, no in vitro model has been developed for the C. difficile-infected GI tract and the best in vitro model to demonstrate bioequivalence in CDI is uncertain.

15. Summary (cont.) Given that vancomycin is currently the preferred treatment for severe CDI, we must have some clinical evidence of efficacy for generic agents prior to exposure of patients with life-threatening CDI to formulations that have never been given to humans. I suggest FDA openly discuss both the uncertainties inherent in any bioequivalence method proposed for CDI as well as the risks and benefits to patients associated with approving a bio-inequivalent formulation.