Clostridium difficile Infection (CDI): Increasingly Severe and Rapidly Fatal Disease Requires High Certainty of Treatment Efficacy Dale N. Gerding, MD.

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.

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.

From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15And unpublished CDC data

0

20

40

60

80

100

120

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Year

Dis

char

ges

per

100,

000

popu

latio

n

Any listedPrimary

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

DC

PRAK

HI

37 States and DC confirmed by CDC

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

Fulminant CDI: Severe and Rapidly Fatal Disease

Hospital Admission for Community Pneumonia CABG Surgery

Diarrhea Onset

17,70027,000

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

Ascites

Thickened Colonic Wall

Normal ColonColon 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-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

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.