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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. Significant unmet medical need

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Staphylococcus aureus Bacteremia and Endocarditis

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  1. Staphylococcus aureus Bacteremia and Endocarditis Francis P. Tally, M.D. Senior Vice President and Chief Scientific Officer Cubist Pharmaceuticals, Inc.

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. Challenges to Studying Staphylococcus aureus Bacteremia/Endocarditis

  12. Diagnosis of enrolled patients by modified Duke criteria at baseline

  13. Overall Screening and Enrollment(as of October 8, 2004)

  14. 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

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