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Use of Antimicrobials

Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington, Seattle. Use of Antimicrobials. Cost Resistance. Treat Infections Prevent Infections. Antibiotic Use and Resistance. Community Use. Hospital Use. Agricultural Use.

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Use of Antimicrobials

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  1. Antimicrobial TherapyDavid H. Spach, MDProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle

  2. Use of Antimicrobials • Cost • Resistance • Treat Infections • Prevent Infections

  3. Antibiotic Use and Resistance Community Use Hospital Use Agricultural Use

  4. Antibiotic Use and Resistance Community Use Hospital Use Agricultural Use

  5. Antibiotic Resistance Antibiotic Development

  6. 2014 Most Prescribed Drugs Infectious Diseases36. Tamiflu60. Zostavax77. Truvada84. Norvir 97. Atripla Source: IMS National Prescription Audit, IMS Health.

  7. 2014 Most Profitable Drugs Infectious Diseases15. Atripla (HIV) 22. Truvada(HIV) 32. Solvaldi(Hepatitis C) 49. Prezista(HIV) 51. Isentress (HIV) 59. Reyataz(HIV) 71. Prevnar 13(Vaccine)75. Stribild(HIV) 81. Zyvox(Antibacterial)84. Complera(HIV) 87. Gardasil(Vaccine)88. Zostavax(Vaccine)93. Cubicin(Antibacterial)97. Viread (HIV) Source: IMS National Prescription Audit, IMS Health.

  8. Source: IDSA. Clin Infect Dis. 2010:50:1081-3.

  9. “Our audacious but noble aim is the creation of a sustainable global antibacterial drug R&D enterprise with the power in the short-term to develop 10 new, safe, and effective antibiotics by 2020.” Source: IDSA. Clin Infect Dis. 2010:50:1081-3.

  10. “ESKAPE” Pathogens • Enterococcus faecalis • Staphylococcus aureus • Klebsiellapneumoniae • Acinetobacterbaumannii • Pseudomonas aeruginosa • Enterobacter species

  11. Structure of Gram-Positive Bacteria Penicillin Binding Proteins DNA Cell Wall Cell Membrane

  12. Structure of Gram-Negative Bacteria Outer Membrane Cell Wall Periplasmic Space Cell Membrane DNA Porin Channel

  13. Antimicrobials: Site of Action Cell Wall Cytoplasm23 S Ribosome 30S Ribosome50S Ribosome Cell Membrane DNA Inhibitor

  14. Systemic Antibacterials: Recent FDA Approvals • 2009 -Telavancin(Vibativ): SSTI • 2010- Ceftaroline (Teflaro): SSTI, CAP • 2011- Fidaxomicin (Dificid): Clostridiumdifficile • 2013- Telavancin (Vibativ): HAP/VAP • 2014 Tedizolid (Sivextro): SSTIDalbavancin (Dalvance): SSTIOritavancin(Orbactiv): SSTI

  15. Telavancin (Vibativ)

  16. Telavancin: Mechanism of Action Telavancin Cell Wall Synthesis DNA

  17. Ligase Telavancin: Mechanism of Action (1) D-Ala D-Ala Tripeptide Intermediate D-Ala D-Ala Cell Wall Pentapeptide Precursor D-Ala D-Ala Telavancin

  18. Telavancin: Mechanism of Action (2) Telavancin Lipid II(cell wall precursor)

  19. Telavancin (Vibativ) • FDA Status: approved for SSTI 2009, HAP in 2013 • Clinical Indication: 1) complicated SSTI caused by gram-positive bacteria (MSSA, MRSA,S. pyogenes, S. agalactiae, S. anginosusgroup, E. faecalis)2) VAP and HAP caused by MSSA or MRSA • Mechanism: Lipoglycopeptidevancomycin semisynthetic derivative --inhibits cell wall synthesis and binds to membrane lipid II molecules • Dosing: 10 mg IV q24 hours • Dose Reduction: - For CrCl30-50: 7.5 mg/kg q24 - For CrCl10-30: 10 mg/kg q48 • Adverse Effects: nephrotoxicity, diarrhea, “red man”, foamy urine Source: Damodaron SE, Madhan S. J PharmacolPharmacother. 2011;2:135-7.

  20. Telavacin versus Vancomcyin for Complicated SSTIATLAS Trial Study Design Overall Success Rate* • Methods (N = 1867) - Two Phase 3 trials- Randomized, double blind - Patients with complicated SSTI- Suspected or confirmed gram+- N = 579 with MRSA- Adults • Regimens - Telavancin: 10 mg/kg IV q24h - Vancomycin: 1g IV q12h *7-14 days after receipt of last antibiotic dose Source: Stryjewski ME, et al. Clin Infect Dis. 2008;46:1683-93.

  21. Telavacin versus Vancomcyin for HAP with Gram+ATTAIN Trial Study Design Results • Methods (N = 1503) - Two Phase 3 trials- Randomized, double blind - Patients with HAP, including VAP- Suspected or confirmed gram+- Adults • Regimens(duration 7-21 days)- Telavacin: 10 mg/kg IV q24h - Vancomycin: 1g IV q12h - Concomitant therapy for Gram- allowed Source: Rubinstein E, et al. Clin Infect Dis. 2011;52:31-40.

  22. Ceftaroline(Teflaro)

  23. Beta-Lactams: Mechanism of Action Penicillin Binding Proteins Ceftaroline TranspeptidationCarboxypeptidation DNA Cell Wall Cell Membrane

  24. Ceftaroline (Teflaro): Mechanism of Action Altered Penicillin Binding Protein Ceftaroline PBP 2a PBP 2a DNA

  25. Ceftaroline (Teflaro) • FDA Status: approved 2010 • Indication: SSTI, CAP • Class: Cephalosporin (“5th Generation”) • Mechanism: Inhibits cell wall synthesis (binds to PBP, including PBP2a) • Dose: 600 mg IV q12 hours • Activity: - Broad gram-positive activity: MSSA, MRSA, VISA, DRSP- Gram-negative: Enterobacteriaceae- Not active against Pseudomonas sp. or Proteus sp., or E. faecium • Adverse Effects: seroconversion to positive direct Coombs’ test Source: Saravolatz LD, et al. Clin Infect Dis. 2011;52:1156-63.

  26. Cetaroline for Complicated SSTICANVAS 1 and 2 Study Design Clinical Cure • Methods - Pooled analysis of 2 phase 3 trials - Double-blind trial - N = 1378 enrolled - Complicated SSTI • Regimens(5-14 days)Ceftaroline: 600 mg IV q12horVancomycin: 1g IV q12h + Aztreonam: 1 g IV q12h Source: Corey GR, et al. Clin Infect Dis. 2012;56:641-50.

  27. Cetaroline vs. Ceftriaxone for CAPFocus1 and 2 Study Design Clinical Cure Rate • Methods - Pooled analysis of 2 phase 3 trials - Double-blind trial - N = 1228 enrolled - Community acquired pneumonia - Patients hospitalized • Regimens(5-14 days)Ceftaroline: 600 mg IV q12hx 5-7dor Ceftriaxone: 1g IV q12h x 5-7d FOCUS 1: received 2 doses of clarithromycin on d1 Source: File TM, et al. Clin Infect Dis. 2010;51:1395-405.

  28. Tedizolid (Sivextro)

  29. Protein Synthesis 50 S Ribosome 30 S Ribosome 50S 23S fMet-tRNA 30S DNA 23S 70 S Initiation Complex

  30. Tedizolid(Zyvox): Mechanism of Action 50 S Ribosome Tedizolid 30 S Ribosome 50S 23S fMet-tRNA 30S DNA 23S 70 S Initiation Complex

  31. Tedizolid (Sivextro) • FDA Status: approved June 20, 2014 • Clinical Indication: approved for SSTI caused by susceptible bacteriaMSSA, MRSA, S. pyogenes, S. agalactiae, S. anginosusgroup, E. faecalis • Class: Oxazolidinone; binds to 23S rRNA of 50S subunit • Mechanism: Inhibits protein synthesis (blocks ribosomal initiation complex) • Dose: 200 mg IV or PO once daily • Adverse Effects: nausea, headache, diarrhea Source: Tedizolid Package Insert

  32. Tedizolid versus Linezolid for SSTI: Oral TherapyESTABLISH-1 Study Design (ESTABLISH-1) Early Clinical Response • Methods - Randomized, double blind, phase 3 trial - 81 study centers - N = 667 adults - Acute bacterial SSTI • Regimens - Tedizolid: 200 mg PO qd x 6d - Linezolid: 600 mg PO bid x 10 days Source: Prokocimer P, et al. JAMA. 2013;309:559-69.

  33. Tedizolid versus Linezolid for SSTI: IV/Oral TherapyESTABLISH-2 Study Design (ESTABLISH-2) Early Clinical Response • Methods - Randomized, double blind, phase 3 trial - 58 centers in 9 countries - N = 666 adults - Acute bacterial SSTI • Regimens* - Tedizolid: 200 mg IV/PO qd x 6d - Linezolid: 600 mg IV/PO bid x 10 days *required to receive IV therapy for minimum of 1 day, then could step down to PO Source: Moran GJ, et al. Lancet Infect Dis 2014;14:696-705.

  34. Dalbavancin (Dalvance)

  35. Dalbavancin (Dalvance): Mechanism of Action Dalbavancin Cell Wall Synthesis Dimer Dimer DNA Dimer

  36. Dalbavancin (Dalvance) • FDA Status: approved May 23, 2014 • Clinical Indication: approved for SSTI caused by gram-positive bacteria(MSSA, MRSA, S. pyogenes, S. agalactiae, S. anginosusgroup) • Mechanism: Lipoglycopeptide that inhibits cell wall synthesis • 2 Dose Regimen: 1000 mg IV followed 1 week later by 500 mg IV • Dose Reduction: - Regular hemodialysis: no dose change- For CrCl < 30 ml/min and no hemodialysis: 750 mg then 375 mg • Adverse Effects: nausea, headache, diarrhea Source: Dalbavancin Package Insert

  37. Dalbavancin versus Vancomycinfor SSTIDISCOVER 1 and DISCOVER 2 Study Design Clinical Response to Therapy • Methods - Pooled analysis of 2 phase 3 trials* - Randomized trials - N = 659 adults - Acute bacterial SSTI • Regimens - Dalbavancin 1000 mg d1, 500 mg d8 - Vancomycin IV for ≥3 days, then oral linezolid 600 mg bid to complete 10-14d 1° End Point = Success rate at 48 to 72 hours 2° End Point = Success rate at end of therapy *DISCOVER 1 and DISCOVER 2 Source: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7.

  38. How is Dalbavancin Different from Vancomycin • Mechanism of Action- Improved PBP binding due to hydrophobic side chain- More stable binding due to formation of dalbavancin dimers • Dalbavancin bactericidal and vancomycin bacteriostatic • Differences in dosing and dose reductions Source: Guskey MT, et al. Pharmacotherapy. 2010;30:80-94.

  39. INVESTIGATIONAL-Dalbavancin not FDA approved for treatment of bloodstream infections Catheter-Related Bloodstream InfectionsDalbavancin versus Vancomycin Study Design Overall Success Rate • Methods (N 75) - Phase 2, randomized, controlled - Patients with catheter-related BSI - Randomized, open-labeled - Catheter-related BSI cause by Gram+- Catheters removed for MSSA & MRSA - MRSA identified in 51% of patients • Regimens - Dalbavancin: 1.0 g IV d1; 0.5 g IV d8 - Vancomycin: 1g bid IV x 14d Source: RaadI, et al. Clin Infect Dis 2005;40:374-80.

  40. Oritavancin(Orbactiv)

  41. Oritavancin(Orbactiv) • FDA Status: approved August 6, 2014 • Clinical Indication: approved for acute SSTI caused by gram-positive bacteria (MSSA, MRSA, various streptococcal species, and Enterococcusfaecalis) • Mechanism: Lipoglycopeptide with multiple mechanisms: inhibits transglycolation, inhibits transpeptidation, and disrupts cell membranes • Single Dose Regimen: 1200 mg IV (infused over 3 hours) • Dose Reduction: - Mild or moderate renal impairment: no dose change- Severe renal impairment or hemodialysis: unknown • Adverse Effects: nausea, headache, diarrhea, vomiting

  42. Oritavancinversus Vancomycin for SSTISOLO-I Study Design (ESTABLISH-1) Investigator-Assessed Clinical Cure • Methods - Randomized, double blind, phase 3 trial - N = 954 adults - Acute bacterial SSTI • Regimens - Oritavancin: 1200 mg IV x 1 - Vancomycin: 1g IV q12h x 7-10 days Source: Corey R, et al. N Engl J Med. 2013;370:2180-90.

  43. Fidaxomicin (Dificid)

  44. Fidaxomicin (Dificid) • FDA Status: Approved in May 2011 • Indication: Clostridiumdifficile-associated diarrhea • Class: macrocyclic antibiotic • Mechanism: inhibits RNA polymerase and transcription • Dose: 200 mg bid x 10 days • In vitro C. difficileactivity: 8x more active than vancomycin • Absorption: Minimal oral absorption • Adverse Effects: nausea, vomiting, abdominal pain

  45. Clostridiumdifficile : FidaxomicinvsVancomycinStudy Design Fidaxomicin200 mg PO BID X 10 days Vancomycin125 mg PO QID x 10 days From: Louie TJ, et al. N Engl J Med. 2011;364:422-31.

  46. Clostridiumdifficile: FidaxomicinvsVancomycinResults P < 0.005 Clinical Cure = resolution of symptoms and no need for further therapyRecurrence = diarrhea and positive stool test within 4 weeks after treatment From: Louie TJ, et al. N Engl J Med. 2011;364:422-31.

  47. Treatment of Gram-Negative Infections

  48. Source: Boucher HW, et al. Clin Infect Dis. 2013:56:1685-94.

  49. Source: Boucher HW, et al. Clin Infect Dis. 2013:56:1685-94. • “Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive.”

  50. Source: Centers for Disease Control and Prevention (CDC)

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