1. Is Vancomycin Obsolete for Treating Serious Staphylococcal Infections? Part I Edward L. Goodman, MD, FACP, FIDSA, FSHEA August 26, 2009

2. Outline Case presentation Are vancomycin failures increasing? –Persistence of bacteremia –Metastatic foci of infection –Longer duration of fever Vancomycin for MSSA MIC creep of MRSA Pharmacodynamics of antibiotics: AUIC Consensus Guidelines 2009 Alternatives to vancomycin –Daptomycin –Linezolid –Tigecycline –Ceftobiprole?

3. Case Presentation MR #1283989 57 yo diabetic man admitted THD 2/08 with testicular pain and swelling Required intubation, tracheostomy and was found to have MRSA in trach secretions 2/6/08 7/19/08 readmitted with recurrent scrotal pain and swelling –2/2 blood cultures drawn 7/9/08 had MRSA with vancomycin MIC of 2, daptomycin MIC 1. –Could not do TEE due to obesity –Received vancomycin 7/19 till 8/18 (30 days)

4. Case Continued Readmit 9/8/08 with 2/2 blood cultures growing MRSA, Vanc MIC 2, dapto MIC 1 –Vancomcyin 9/10-913/08; then daptomycin (MIC 1) 9/14-10/15 (31 days) Readmit 1/27/09 with hip abscess –1/30/09 hip abscess drained: MRSA Vanc MIC 2 –Treated with daptomycin MIC 2 Hospitalized for unrelated problems 7/09 –ASC in ICU 7/10/09 still positive for MRSA!

5. Microbiology and Pharmacokinetics Date 2/6/087/19/089/9/081/30/09 Source TrachBC 2/2 Hip abscess Culture MRSA Vanc MIC 2 MRSA MIC 2 MRSA MIC 2 MRSA MIC 2 Vanc Levels Trough 11.2-22 Trough 21.3-24.8 Trough 17.7

6. Comments Clearly received adequate dose and duration of vancomycin –Yet relapsed within 3 weeks of a prolonged course This scenario is not new, but seems to be increasing in frequency Has MRSA become resistant to vancomycin? –MIC of 2 is within the susceptible range defined by Clinical and Laboratory Standards Institute CLSI (sensitive =16)

7. How Does Vancomycin Compare to Beta Lactams for MSSA? Chang et al. Staphylococcus aureus Bacteremia. 2003 Medicine;82:333- 339.

8. Stryjewski et al. Clin Inf Dis 2007;44:190-196

10. Does Resistance in MSSA Explain Vancomycin’s Failure? (Stryjewski et al)

11. Are there other explanations? (Stryjewski et al)

12. We Accept that Vancomycin is Inferior to Anti-staphylococcal Beta Lactams! What about MRSA? –Until recently we had no other choices. –Vancomycin is cheap, relatively safe, easy to give. –But is it effective? –What factors explain its apparent increasing failures?

13. MIC Creep Mohr JF, Murray BE. Point: Vancomycin is Not Obsolete for the Treatment of Infections Caused by MRSA. Clin Inf Dis 2007;44:1536

14. Pharmocodynamics: Dosing for Efficacy Blood Level Time Peak MIC Trough

15. Parameters of antibacterial efficacy Time above MIC (non concentration killing) - beta lactams, macrolides, clindamycin, glycopeptides 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin Peak/MIC (concentration dependent killing) - aminoglycosides, fluoroquinolones, daptomycin

16. Rybak MJ. The Pharmacokinetic and Pharmacodynamic Properties of Vancomycin. Clin Inf Dis 2006;42:S35-39

17. Rybak et al. Vancomycin Therapeutic Guidelines. Clin Inf Dis 2009;49:325

18. Rybak MJ. The Pharmacokinetic and Pharmacodynamic Properties of Vancomycin. Clin Inf Dis 2006;42:S35-39

19. Rybak et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm 2009;66;82-98

21. Take Home Messages Rybak et al. Vancomycin Therapeutic Guidelines. Clin Inf Dis 2009;49:325

22. Take Home Messages

23. Take Home cont’d

25. Key Take Home Message

28. Alternatives to Vancomycin for Less Serious MRSA Infections Skin and Soft Tissue –Trimethoprim-sulfa (TMP/SMX) –Doxycyline/minocycline –Clindamycin if no inducible resistance –NOT LEVOFLOXACIN! Urinary Tract Infections (always rule out bacteremia before Rx) –TMP/SMX –Not doxycycline or minocycline or linezolid Not adequate urinary concentration Plain tetracycline if susceptible (94%) –Perhaps, fluoroquinolones if susceptible in vitro

29. Alternatives to Vancomycin for Serious MRSA Infections Daptomycin Linezolid Tigecycline (not for bacteremia) Ceftobiprole (not yet FDA approved) COME BACK 9/16/09 FOR PART II and HEAR MORE ABOUT THE ALTERNATIVES TO VANCOMYCIN!

30. References Chang F et al. Staphylococcus aureus Bacteremia. Medicine 2003;82:333-339. Deresinski S. Counterpoint: Vancomycin and Staphylococcus aureus – An Antibiotic Enters Obsolescence. Clin Inf Dis 2007;44:1543-1548 Mohr JF and Murray BE. Point: Vancomycin Is Not Obsolete for the Treatment of Infection Caused by Methicillin-Resistant Staphylococcus aureus. Clin Inf Disd 2007;44:1536-1542. Moise-Broder PA et al. Accessory Gene Regulator Group II Polymorphism in MRSA. Clin Inf Dis 2004;38:1700-1705 Rybak MJ et al. Vancomycin Therapeutic Guidelines: A Summary of Consensus Recommendations. Clin Inf Dis 2009;49:325-327. Rybak MJ et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review. Am J Health-Syst Pharm 2009;66:82-98. Rybak MJ. The Pharmacokinetic and Pharmacodynamic Properties of Vancomycin. Clin Inf Dis 2006:42:S35-39. Stryjewski ME et al. Use of Vancomycin or First-Generation Cephalosporins for the Treatment of Hemodialysis-Dependent Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia. Clin Inf Dis 2007; 44:190-196.