C-1 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

C-2 The Daptomycin Trial A 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

C-3 Lowy, NEJM S. aureus A Unique Organism

C-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.

C-5 The Daptomycin Trial A 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

C-6 The Daptomycin Trial A New Drug Approved for complicated skin infections Despite this 25% of daptomycin use is off-label for S. aureus bacteremia!

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

C-8 The Daptomycin Trial Bacteremia 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

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

C-10 The Daptomycin Trial Bacteremia and Endocarditis No randomized endocarditis trial for over 20 years: nafcillin vs nafcillin/gentamicin Korzeniowski et al Ann Int Med Imipenem approval for endocarditis based on 11 patients Medical Reviewer, FDA 1985

C-11 The Daptomycin Trial Bacteremia 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

C-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?

C-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

C-14 Adjudication Committee Final Diagnoses (ITT) LIE 8% RIE 14% cBAC 53% uBAC 25% LIE 8% RIE 16% cBAC 50% uBAC 27% Daptomycin Group N = 120 Comparator Group N = 115

C-15 Success at End of Therapy and Test of Cure (ITT) End of Therapy Test of Cure DaptomycinComparator % Success

C-16 MRSA - Success at TOC by Final Diagnosis (IEAC, ITT) Success Rate % /5 0/4

C-17 IEAC Reasons For Failure at TOC (ITT, > One Reason May Apply) Daptomycin N = 120 Comparator N = 115 Overall failure 67 (55.8%) 67 (58.3%) Persisting or relapsing S. aureus infection 19 (15.8%) 11 (9.6%) Clinical failure without persisting or relapsing S. aureus infection 4 (3.3%) 4 (3.5%) Discontinued due to adverse event 8 (6.7%) 17 (14.8%) Patient died 13 (10.8%) 13 (11.3%) Non-study antibiotics 20 (16.7%) 16 (13.9%) No blood culture drawn at TOC 9 (7.5%) 9 (7.5%) 12 (10.4%) Non-evaluable (e.g., withdrew consent, left AMA) 9 (7.5%) 9 (7.5%) 14 (12.2%)

C-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%

C-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

C-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

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

C-22 The Daptomycin Trial My Conclusions S. aureus infections are a serious and increasing problem Clinicians need a new treatment option Daptomycin provides us with that option