1. C-1 CUBICIN ® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis Anti-Infective Drugs Advisory Committee Meeting March 6, 2006

2. C-2 Staphylococcus aureus Bacteremia Henry F. Chambers, M.D. Professor of Medicine, UCSF Chief of Infectious Diseases San Francisco General Hospital

3. C-3 Case 1 38 y/o man, new CHF, alcoholic cardiomyopathy, Hct = 13 (normal 40-45) 38 y/o man, new CHF, alcoholic cardiomyopathy, Hct = 13 (normal 40-45) Given PRBCs, diuretics, afterload reducers Given PRBCs, diuretics, afterload reducers HD 6: upper + lower endoscopy HD 6: upper + lower endoscopy Post-procedure T = 39 o C, blood cultures taken Post-procedure T = 39 o C, blood cultures taken HD 7: afebrile but BC x2 = GPC in clusters; R forearm former IV site red, tender, indurated HD 7: afebrile but BC x2 = GPC in clusters; R forearm former IV site red, tender, indurated Vancomycin administered Vancomycin administered HD 8: BC isolate = MSSA; f/u BC sterile HD 8: BC isolate = MSSA; f/u BC sterile

4. C-4 Management Issues What is the risk of a poor outcome? What is the risk of a poor outcome? What antibiotic should be used? What antibiotic should be used? What is the duration of therapy? What is the duration of therapy?

5. C-5 Raad, CID 14:75, 1992 What is the risk of a poor outcome? Complications in catheter-associated SAB

6. C-6 StudyRateTypes Fowler, N = 314 (CID 40:695, 2005) 13% Endocarditis, arthritis, osteomyelitis Thomas, N= 276 (Int Med J 35:319, 2005) 9% death 6% early 4% late Endocarditis, arthritis, thrombosis, pneumonia, epidural asbcess Complication What is the risk of a poor outcome?

7. C-7 Independent Predictors of Complicated SAB Fowler, Arch Intern Med 163:2066, 2003

8. C-8 What is the risk of a poor outcome? 1 point each for skin findings, fever > 72h, community onset 4 points for positive blood culture @ 48-96h Fowler, Arch Intern Med 163:2066, 2003

9. C-9 Predictors of Poor Outcome for Staphylococcus aureus Bacteremia Septic shock Septic shock Persistent focus of infection Persistent focus of infection Secondary focus of infection Secondary focus of infection Prolonged bacteremia on therapy (>48-72h) Prolonged bacteremia on therapy (>48-72h) Elderly patient (age > 60 years) Elderly patient (age > 60 years) MRSA MRSA Use of vancomycin instead of a  -lactam Use of vancomycin instead of a  -lactam Duration of treatment < 10-14 days Duration of treatment < 10-14 days

10. C-10 Criteria for Antimicrobial Therapy of Staphylococcus aureus Bacteremia 1. Bactericidal activity 2. Non-toxic, well-tolerated 3. Parenteral administration, at least initially 4. Convenient dosing

11. C-11 What antibiotic should be used? Antimicrobial Therapy and Vaccines, 2 nd Ed., 2002, page 641 “If the focus of infection has been promptly removed with rapid documented resolution of the bacteremia (< 3 days), 2 weeks of antibiotic therapy with a penicillinase-resistant penicillin, first-generation cephalosporin, or glycopeptide is likely to be enough…..Under no circumstances should patients simply have the catheter removed without antibiotic treatment.”

12. C-12 What antibiotic should be used? Fowler, CID 27:478-86, 1998

13. C-13 RegimenProsCons Nafcillin or oxacillin 2 g q4h IV Highly effectivePoorly tolerated, inconvenient Cefazolin 2 g q8h IV EffectiveInconvenient Vancomycin 1 g q12h IV Well tolerated, convenient Less effective than  -lactams Dicloxacillin or cephalexin 1 g qid PO Convenient (oral) Unknown efficacy, GI side effects, qid dosing What antibiotic should be used?

14. C-14 What is the duration of therapy? 7-10 or fewer days? – Associated with high relapse, complication rates 10-14 days? – Standard recommended duration 4-6 weeks? – For endocarditis, osteomyelitis, complicated SAB

15. C-15 What was done? PICC placed PICC placed Ceftriaxone 2g IV q24h for 14 days Ceftriaxone 2g IV q24h for 14 days Home infusion therapy arranged Home infusion therapy arranged

16. C-16 Case 2 44 y/o man, homeless, IVDU with fever and back pain, non-localizing exam 44 y/o man, homeless, IVDU with fever and back pain, non-localizing exam Vancomycin administered Vancomycin administered 3/3 BC positive MRSA 3/3 BC positive MRSA TTE negative, MRI spine negative TTE negative, MRI spine negative Fever persists during first week Fever persists during first week 1/3 BC + MRSA 72h after admission 1/3 BC + MRSA 72h after admission

17. C-17 Jensen, Arch Intern Med 162: 27, 2003 What is the risk of a poor outcome? Complications in community-onset SAB

18. C-18 Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

19. C-19 Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

20. C-20 Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

21. C-21 Independent Predictors of Complicated SAB Fowler, et al, Arch Intern Med 163:2066, 2003

22. C-22 What antibiotic should be used? RegimenProsCons Nafcillin or oxacillin 2 g q4h IV Highly effective Poorly tolerated, inconvenient Cefazolin 2 g q8h IV EffectiveInconvenient Vancomycin 1 g q12h IV Well tolerated, convenient Less effective than  -lactams Dicloxacillin or cephalexin 1 g qid PO Convenient (oral) Unknown efficacy, GI side effects, qid dosing

23. C-23 What was done? PICC placed PICC placed Methadone maintenance Methadone maintenance Vancomycin ~1g q12h IV for 6 weeks Vancomycin ~1g q12h IV for 6 weeks Trough serum concentrations of ~15  g/ml Trough serum concentrations of ~15  g/ml

24. C-24 What happened? Patient returned 3 mo later complaining of back pain Patient returned 3 mo later complaining of back pain Afebrile, normal exam Afebrile, normal exam Blood cultures negative Blood cultures negative MRI: T10-T11 osteomyelitis, discitis MRI: T10-T11 osteomyelitis, discitis Bone biopsy culture: MRSA Bone biopsy culture: MRSA

25. C-25 What was done? PICC placed PICC placed Methadone maintenance Methadone maintenance Vancomycin ~1g q12h IV for 6 weeks Vancomycin ~1g q12h IV for 6 weeks Trough serum concentrations or ~15  g/ml Trough serum concentrations or ~15  g/ml

26. C-26 Management Issues Is this a vancomcyin failure? Is this a vancomcyin failure? Is so, why did it fail? Is so, why did it fail? What is the risk of a poor outcome now? What is the risk of a poor outcome now? What antibiotic(s) should be used now? What antibiotic(s) should be used now? What is the duration of therapy? What is the duration of therapy?

27. C-27 “State of the Art” Treatment of Staphylococcus aureus Bacteremia Current armamentarium is inadequate for Current armamentarium is inadequate for – Out patient treatment – MRSA – Patients who fail or cannot tolerate therapy Physicians often must rely on Physicians often must rely on – Drugs not approved for treatment of complicated staphylococcal infections – Drugs of unknown or poorly documented efficacy – Second-line agents – Combinations of agents of uncertain benefit

28. C-28 CUBICIN ® (daptomycin for injection) for S. aureus Bacteremia Including Those With Known or Suspected Endocarditis David Mantus, Ph.D. Vice President, Regulatory Affairs Cubist Pharmaceuticals Adjunct Assistant Professor Massachusetts College of Pharmacy

29. C-29 Adjudication Committee Member and Affiliation Elias Abrutyn, M.D. Associate Provost and Associate Dean for Faculty Affairs, and Interim Chief, Infectious Disease Drexel University G. Ralph Corey, M.D. Professor of Internal Medicine & Infectious Disease Duke University Medical Center Sara Cosgrove, M.D. Assistant Professor, Dept of Medicine, Div of Infectious Disease Johns Hopkins University School of Medicine and Johns Hopkins Bloomberg School of Public Health Vance G. Fowler, M.D. Associate Professor of Medicine Duke University Medical Center Adolf W. Karchmer, M.D. Professor of Medicine, Chief, Division of Infectious Diseases Beth Israel Deaconess Medical Center

30. C-30 Christopher H. Cabell, M.D., M.H.S., F.A.C.C. Assistant Professor of Medicine Division of Cardiology Duke University School of Medicine Henry F. “Chip” Chambers, M.D. Professor of Medicine University of California - San Francisco Chief, Division of Infectious Diseases San Francisco General Hospital George Drusano, M.D. Professor of Medicine and Pharmacology Albany Medical College Co-director Ordway Research Institute Donald Levine, M.D. Professor of Medicine Chief, General/Internal Medicine Wayne State University Albert Sheldon, Jr., Ph.D. President Antibiotic and Antiseptic Consultants, Inc. Experts Available for Questions and Answers

31. C-31 What is Daptomycin? Cyclic lipopeptide natural product Cyclic lipopeptide natural product Approved (IV, 4 mg/kg q24h) for complicated skin and skin structure infections, including MRSA Approved (IV, 4 mg/kg q24h) for complicated skin and skin structure infections, including MRSA – US 2003 – Israel 2004 – Argentina2005 – EU2006

32. C-32 Post-licensure Experience 150,000+ patients treated 150,000+ patients treated – No new toxicities – ~1/3 of doses delivered in outpatient setting Potency vs. S. aureus maintained Potency vs. S. aureus maintained – Microbiologic surveillance studies demonstrate > 99.9% of isolates are daptomycin susceptible ~25% of use is for bacteremia (off-label) ~25% of use is for bacteremia (off-label) – ~50% of this use at the 4 mg/kg dose approved for skin, NOT the 6 mg/kg dose studied in S. aureus bacteremia

33. C-33 Rationale for Daptomycin in S. aureus Bacteremia and Endocarditis Rapidly bactericidal in vitro and in vivo Rapidly bactericidal in vitro and in vivo Potency against MRSA and MSSA Potency against MRSA and MSSA Proven clinical efficacy in skin (MRSA and MSSA) Proven clinical efficacy in skin (MRSA and MSSA) Proven efficacy in animal models of S. aureus endocarditis at 6 mg/kg human equivalent dose Proven efficacy in animal models of S. aureus endocarditis at 6 mg/kg human equivalent dose Potential for outpatient treatment Potential for outpatient treatment – Monotherapy – Once-daily

34. C-34 Continuous Dialogue with FDA on Development Study design (2001-2002) Study design (2001-2002) – Open-label – Comparators – Enrollment of all patients with S. aureus – Data Safety Monitoring Board Study assessments and analyses (2004-2005) Study assessments and analyses (2004-2005) – Adjudication Committee – Primary endpoints – Statistical Analysis Plan agreed upon prior to unblinding Study results (2005) Study results (2005) – sNDA filed – Priority review granted

35. C-35 S. aureus Bacteremia and Endocarditis Supplemental Indication and Dose Proposed Indication Proposed Indication – Staphylococcus aureus bacteremia (SAB) including those with known or suspected endocarditis (SAIE) caused by methicillin-susceptible and methicillin-resistant strains Proposed Dose Proposed Dose – 6 mg/kg monotherapy administered as a 30-minute intravenous (IV) infusion once per day for a minimum duration of 2 to 6 weeks, depending on the clinical condition

36. C-36 Agenda G. Ralph Corey, M.D. Professor of Internal Medicine & Infectious Disease Duke University Medical Center Conclusions Gloria Vigliani, M.D. V.P. Medical Strategy Cubist Pharmaceuticals Safety Jeff Alder, Ph.D. V.P. Drug Discovery & Evaluation Cubist Pharmaceuticals Microbiology Helen Boucher, M.D. Assistant Professor of Medicine Dir. Infectious Diseases Fellowship Program Div. of Infectious Diseases and Geographic Medicine Tufts University-NEMC Efficacy David Mantus, Ph.D. V.P. Regulatory Affairs Cubist Pharmaceuticals Introduction

37. C-37 Overall Findings Daptomycin 6 mg/kg once daily: Effective in the treatment of S. aureus bacteremia and endocarditis Effective in the treatment of S. aureus bacteremia and endocarditis – Response higher in MRSA Well tolerated for extended treatment durations Well tolerated for extended treatment durations Less nephrotoxic than standard-of-care agents Less nephrotoxic than standard-of-care agents Provides a much needed option for treatment of patients with S. aureus bacteremia including those with known or suspected endocarditis Provides a much needed option for treatment of patients with S. aureus bacteremia including those with known or suspected endocarditis