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Staphylococcus aureus Bacteremia and Endocarditis. Francis P. Tally, M.D. Senior Vice President and Chief Scientific Officer Cubist Pharmaceuticals, Inc . Summary: Staphylococcus aureus Bacteremia. Significant unmet medical need

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staphylococcus aureus bacteremia and endocarditis

Staphylococcus aureus Bacteremia and Endocarditis

Francis P. Tally, M.D.

Senior Vice President and Chief Scientific Officer

Cubist Pharmaceuticals, Inc.

summary staphylococcus aureus bacteremia
Summary: Staphylococcus aureus Bacteremia
  • Significant unmet medical need
  • Heterogeneous population including endocarditis with different outcomes
  • Lack of a placebo effect
  • Difficult to study but possible
  • Traditional non-inferiority assessment may not be the best or only assessment of efficacy
high unmet medical need
High Unmet Medical Need
  • Staphylococcus aureus is a leading cause of bacteremia
  • Virulence leads to a high proportion of endocarditis (including on normal heart valves), metastatic infections, and/or death
  • Staphylococcus aureus bacteremia is both a cause and a result of endocarditis
  • Changing epidemiology is a therapeutic challenge
    • Growing resistance to beta-lactam antibiotics
    • Increasing tolerance to vancomycin
slide4
Proportion and Mortality of Coagulase-negative Staphylococcal and S. aureus Bacteremias (SCOPE Surveillance System)

Proportion of BSI*

crude mortality

Coagulase-negative staphylococci

S. aureus **

(n~4237)

(n~6566)

* Total 20,978 monomicrobial bacteremias

** 41% resistant to Methicillin

Wisplinghoff et al. CID 29:309-317, 2004

case fatality of staphylococcus aureus bacteremia n 122 in the pre antibiotic era
Case Fatality of Staphylococcus aureus Bacteremia (n=122) in the Pre-Antibiotic Era

33

total cases

Case Fatality = 82%

20

16

15

14

Number of patients

13

9

9

recovered

4

4

4

3

1

0 0

0

Age strata

Skinner & Keefer. Arch Int. Med 68:851-75, 1941

mortality of mssa vs mrsa bacteremia meta analysis
Mortality of MSSA vs. MRSA BacteremiaMeta-Analysis

RR=1.42

p<.001

N=3963

Cosgrove SE et al. Clin Infect Dis 36:53-59, 2003

vancomycin resistance an emerging problem

1996

2001

2002

1986

VRE 1

VISA 2

Vanco Heteroresistance3

VRSA 4

Vancomycin Resistance: An Emerging Problem

1 Murray. NEJM 342:710, 2000

2 Hiramatsu, K et al.  J. Antim. Chemo. 40:135-136, 1997

3 Fridkin SK. CID 32:108, 2001

4 MMWR 51:565-567, 2002

vancomycin efficacy and heteroresistance
Vancomycin: Efficacy and Heteroresistance

EFFICACY IN MSSA/MRSA

  • Vancomycin less effective versus nafcillin in MSSA bacteremia
    • Chang et al. Medicine 82, 2003
  • Vancomycin failure with MRSA endocarditis
    • Small & Chambers. AAC34:1227-1231, 1990

HETERORESISTANCE/TOLERANCE

  • Vancomycin heteroresistance associated with increased failure
    • Fridkin SK. CID 32:108, 2001
    • Lin & Chambers. AAC 47:3040, 2003
  • Increased vancomycin failures with MICs ≥ 1 μg/ml and/or tolerance
    • Sakoulas. JCM, 2004
slide9
Retrospective Analysis of Vancomycin Failure Associated with Vancomycin MIC in Patients with MRSA Bacteremia

MIC = Minimum Inhibitory Concentration

Source: Sakoulas et al.JCM, June 2004

phase 3 study of daptomycin in infective endocarditis bacteremia due to staphylococcus aureus
Phase 3 study of Daptomycin in Infective Endocarditis/Bacteremia due to Staphylococcus aureus
  • Multi-center (US & Western Europe)
  • Randomized
  • Open Label
  • Blinded external adjudication committee
  • Comparator-controlled
    • Semi-synthetic penicillins or vancomycin
  • Protocol Amendment of April 1, 2004 to include LIE
summary staphylococcus aureus bacteremia14
Summary: Staphylococcus aureus Bacteremia
  • Significant unmet medical need
  • Heterogeneous population including endocarditis with different outcomes
  • Lack of a placebo effect
  • Difficult to study but possible
  • Traditional non-inferiority assessment may not be the best or only assessment of efficacy