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The Daptomycin Trial A Bad Bug

Staphylococcus aureus Bacteremia and Endocarditis: A Bad Bug and A New Drug G. Ralph Corey M.D. Professor of Internal Medicine and Infectious Diseases Duke University Medical Center Durham, North Carolina. The Daptomycin Trial A Bad Bug. Background “Bad Bugs - No Drugs”*

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The Daptomycin Trial A Bad Bug

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  1. Staphylococcus aureus Bacteremia and Endocarditis: A Bad Bug and A New DrugG. Ralph Corey M.D.Professor of Internal Medicine and Infectious DiseasesDuke University Medical CenterDurham, North Carolina

  2. The Daptomycin TrialA Bad Bug • Background “Bad Bugs - No Drugs”* S. aureus is no. 1 villain • Staphylococcus aureus • Unique organism • Increasing in frequency • Increasing in complexity • Increasing resistance • New options for therapy are badly needed *Talbot et al. CID. 2006.

  3. S. aureusA Unique Organism Lowy, NEJM 1998.

  4. S. aureus Bacteremia Is a Bad Disease: Prospectively Identified Patients at DUMC • 12-week mortality: 24% • Metastatic infections: 34% • Endocarditis: 12.2% • Relapse: 10% S. aureus = D. V.

  5. The Daptomycin TrialA Bad Bug • Background • “Bad Bugs - No Drugs”* • Staphylococcus aureus • Unique organism • Increasing in frequency • Increasing in complexity • Increasing resistance • New options for therapy are badly needed *Talbot et al. CID. 2006.

  6. The Daptomycin TrialA New Drug • Approved for complicated skin infections Despite this • 25% of daptomycin use is off-label forS. aureus bacteremia!

  7. The Daptomycin TrialBacteremia and Endocarditis • Daptomycin being “tested” in patients with S. aureus bacteremia by clinicians • A structured bacteremia trial needed but there were difficulties

  8. The Daptomycin TrialBacteremia and Endocarditis • Lack of indication for SAB • FDA guidance focuses on catheter-related blood stream infections (1999) - multiple organisms • No successful CR-BSI trial since this guidance Raad et al. CID 2005

  9. The Daptomycin TrialBacteremia and Endocarditis Focus on catheter-related infection ignores: • S. aureus is unique • Infection category undefined on enrollment • Origin of bacteremia NOT predictive of outcomeFowler et al. Archives 2003 • 40% of endocarditis is health care associated Fowler et al. JAMA 2005

  10. The Daptomycin TrialBacteremia and Endocarditis • No randomized endocarditis trial for over 20 years: nafcillin vs nafcillin/gentamicin Korzeniowski et al Ann Int Med. 1982 • Imipenem approval for endocarditis based on 11 patientsMedical Reviewer, FDA 1985

  11. The Daptomycin TrialBacteremia and Endocarditis Challenges • Design • Enrollment • Long f/u of difficult population in an open-label trial = lower than expected success rates • Inter-observer variability in echo readings • Consistency in outcome determination

  12. Daptomycin Trial Bacteremia and Endocarditis • These trials require vigilant clinicians • Is back pain from the hospital bed or new vertebral osteomyelitis? • Experienced teams needed to address difficult surgical decisions • When should a heart valve be replaced?

  13. Daptomycin Trial Bacteremia and Endocarditis • Given all these difficulties impressive that anyone would undertake a SAB/endocarditis trial • Fortunately the FDA provided significant support and guidance

  14. Daptomycin GroupN = 120 Comparator GroupN = 115 LIE8% LIE8% RIE16% RIE14% uBAC27% uBAC25% cBAC50% cBAC53% Adjudication Committee Final Diagnoses (ITT)

  15. 70 61.7 60.9 60 Daptomycin Comparator 50 44.2 41.7 40 % Success 30 70 115 53 120 48 115 74 120 20 10 0 End of Therapy Test of Cure Success at End of Therapy and Test of Cure (ITT)

  16. MRSA - Success at TOC by Final Diagnosis (IEAC, ITT) Success Rate % 3 6 4 8 20 45 6 10 5 11 14 43 6 22 10 22 0/4 0/5

  17. IEAC Reasons For Failure at TOC (ITT, > One Reason May Apply)

  18. The Daptomycin Trial Strengths • Well designed by the best endocarditis experts in the world in conjunction with the FDA • Wisely ignored the source of bacteremia as inclusion criteria - S. aureus unique 12-week mortality: 24% Metastatic complications: 34% Endocarditis: 12.2% Relapse: 10%

  19. The Daptomycin Trial Strengths • Wide variety of patients – results generalizable – new antibiotic must take on all comers • Combination therapy in comparator group sets the highest outcome bar • Core echocardiography laboratory essential • A blinded Independent External Adjudication Committee established

  20. Daptomycin Trial Outcome • Daptomycin at 6 mg/kg daily is safe and effective in the treatment of S. aureus bacteremia and endocarditis • Daptomycin is statistically non-inferior to comparator therapies and numerically better for MRSA

  21. The Daptomycin TrialOther Important Findings • Persistent S. aureus bacteremia - inadequate “surgical” intervention • Persistent infection can lead to decreased susceptibility

  22. The Daptomycin TrialMy Conclusions • S. aureus infections are a serious and increasing problem • Clinicians need a new treatment option • Daptomycin provides us with that option

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