# Presentation: 573874

## 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

## 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.

**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.

## 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.**

## Rates of CDI Nearly Tripled in U.S. Hospitals 

- And unpublished CDC data

- Any listed
- Primary

- Rates of CDI Nearly Tripled in U.S. Hospitals
- between 2000 and 2005

## States with the Epidemic Strain of C. difficile Confirmed by CDC (N=37) Updated November 9, 2007

- 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**

**Notes:**
	Slide <number>
	Most recently, a number of outbreaks have been reported. According to a study led by investigators from the CDC and Hines VA Hospital, a previously uncommon strain of C. difficile has emerged and caused geographically dispersed outbreaks.1,2

	As of November 9, 2007, the epidemic NAP1 strain of C. difficile has been confirmed by the CDC in 37 states and Washington, DC. States with the NAP1 strain include: Arizona, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Indiana, Iowa, Kansas, Kentucky, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, Tennessee, Texas, Utah, Vermont, Virginia, Washington, and Wisconsin.2

McDonald LC, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-2441.
Centers for Disease Control and Prevention. Data and statistics about Clostridium difficile infections. www.cdc.gov/ncidod/dhqp/id_Cdiff_data.html. Accessed January 8, 2008.

## CDI Rates and Mortality Increase with Increased Patient Age

| Age (Years) | CDI Rate per 1000 Admissions | Attributable 30-Day Mortality Rate (%) |
| --- | --- | --- |
| <40 | 3.5 | 2.6 |
| 41-50 | 11.2 | 1.2 |
| 51-60 | 20.0 | 3.2 |
| 61-70 | 24.4 | 5.1 |
| 71-80 | 38.3 | 6.2 |
| 81-90 | 54.5 | 10.2 |
| >90 | 74.4 | 14.0 |

- Loo et al NEJM 2005;353:2442-9

## Dilated Loops of Colon in a Patient with CDI

**Dilated Loops of Colon in a Patient with CDI**

## 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.

## Abdominal CT Findings in Fulminant CDI

**Abdominal CT Findings in Fulminant CDI**

- Ascites

- Thickened Colonic Wall

## Normal Colon and Pseudomembranous Colitis (PMC) as seen at Colonoscopy

- Normal Colon

- Colon with PMC due to
*Clostridium difficile *Infection

**Normal Colon and Pseudomembranous Colitis (PMC) as seen at Colonoscopy**

## Histological Appearance of Pseudomembranous Colitis (PMC)

- Pseudomembrane

- Mucosal Destruction and Inflammatory Response

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

## 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-1*beta, *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

## 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.

## 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.