1. Antimicrobial Therapy. David H
Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington, Seattle 1

2. Use of Antimicrobials Treat Infections Prevent Infections Cost
Resistance 1

3. Antibiotic Use and Resistance
Community Use
Hospital Use
Agricultural Use 1

4. Antibiotic Use and Resistance
Community Use
Hospital Use
Agricultural Use 1

5. Antibiotic Resistance
Antibiotic Development 1

6. 2014 Most Prescribed Drugs
Infectious Diseases 36. Tamiflu 60. Zostavax 77. Truvada 84. Norvir
97. Atripla
Source: IMS National Prescription Audit, IMS Health. 1

7. 2014 Most Profitable Drugs
Infectious Diseases 15. 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. 1

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: 1

10. Enterococcus faecalis Staphylococcus aureus Klebsiella pneumoniae
“ESKAPE” Pathogens
Enterococcus faecalis
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter species 1

11. Structure of Gram-Positive Bacteria
Penicillin Binding Proteins
DNA
Cell Wall
Cell Membrane 1

12. Structure of Gram-Negative Bacteria
Outer Membrane
Cell Wall
Periplasmic Space
Cell Membrane
DNA
Porin Channel 1

13. Antimicrobials: Site of Action
Cell Wall
Cytoplasm 23 S Ribosome 30S Ribosome 50S Ribosome
Cell Membrane
DNA Inhibitor 1

14. Systemic Antibacterials: Recent FDA Approvals
Telavancin (Vibativ): SSTI
Ceftaroline (Teflaro): SSTI, CAP
Fidaxomicin (Dificid): Clostridium difficile
Telavancin (Vibativ): HAP/VAP
Tedizolid (Sivextro): SSTI Dalbavancin (Dalvance): SSTI Oritavancin (Orbactiv): SSTI 1

15. Telavancin (Vibativ) 1

16. Telavancin: Mechanism of Action
Cell Wall Synthesis
DNA 1

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

18. Telavancin: Mechanism of Action (2)
Lipid II (cell wall precursor) 1

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. anginosus group, E. faecalis) 2) VAP and HAP caused by MSSA or MRSA
Mechanism: Lipoglycopeptide vancomycin semisynthetic derivative -- inhibits cell wall synthesis and binds to membrane lipid II molecules
Dosing: 10 mg IV q24 hours
Dose Reduction: - For CrCl 30-50: 7.5 mg/kg q For CrCl 10-30: 10 mg/kg q48
Adverse Effects: nephrotoxicity, diarrhea, “red man”, foamy urine
Source: Damodaron SE, Madhan S. J Pharmacol Pharmacother. 2011;2:135-7. 1

20. Telavacin versus Vancomcyin for Complicated SSTI ATLAS 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: 1

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. 1

22. Ceftaroline (Teflaro)1

23. Beta-Lactams: Mechanism of Action
Penicillin Binding Proteins
Ceftaroline
Transpeptidation Carboxypeptidation
DNA
Cell Wall
Cell Membrane 1

24. Ceftaroline (Teflaro): Mechanism of Action
Altered Penicillin Binding Protein
Ceftaroline
PBP 2a
PBP 2a
DNA 1

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: 1

26. Cetaroline for Complicated SSTI CANVAS 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 q12h or Vancomycin: 1g IV q12h Aztreonam: 1 g IV q12h
Source: Corey GR, et al. Clin Infect Dis. 2012;56: 1

27. Cetaroline vs. Ceftriaxone for CAP Focus1 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 q12h x 5-7d or 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: 1

28. Tedizolid (Sivextro) 1

29. Protein Synthesis 50 S Ribosome 30 S Ribosome fMet-tRNA DNA
70 S Initiation Complex 1

30. Tedizolid (Zyvox): Mechanism of Action
50 S Ribosome
Tedizolid
30 S Ribosome
50S
fMet-tRNA
23S
30S
DNA
23S
70 S Initiation Complex 1

31. Tedizolid (Sivextro) FDA Status: approved June 20, 2014
Clinical Indication: approved for SSTI caused by susceptible bacteria MSSA, MRSA, S. pyogenes, S. agalactiae, S. anginosus group, 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 1

32. Tedizolid versus Linezolid for SSTI: Oral Therapy ESTABLISH-1
Study Design (ESTABLISH-1)
Early Clinical Response
Methods - Randomized, double blind, phase 3 trial 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: 1

33. Tedizolid versus Linezolid for SSTI: IV/Oral Therapy ESTABLISH-2
Study Design (ESTABLISH-2)
Early Clinical Response
Methods - Randomized, double blind, phase 3 trial 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: 1

34. Dalbavancin (Dalvance)1

35. Dalbavancin (Dalvance): Mechanism of Action
Cell Wall Synthesis
Dimer
Dimer
DNA
Dimer 1

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. anginosus group)
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 1

37. Dalbavancin versus Vancomycin for SSTI DISCOVER 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 d Vancomycin IV for ≥3 days, then oral linezolid 600 mg bid to complete 10-14d
*DISCOVER 1 and DISCOVER 2
1° End Point = Success rate at 48 to 72 hours 2° End Point = Success rate at end of therapy
Source: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7. 1

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. 1

39. Catheter-Related Bloodstream Infections Dalbavancin versus Vancomycin
INVESTIGATIONAL-Dalbavancin not FDA approved for treatment of bloodstream infections
Catheter-Related Bloodstream Infections Dalbavancin 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: Raad I, et al. Clin Infect Dis 2005;40: 1

40. Oritavancin (Orbactiv)1

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 Enterococcus faecalis)
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 1

42. Oritavancin versus Vancomycin for SSTI SOLO-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 Vancomycin: 1g IV q12h x 7-10 days
Source: Corey R, et al. N Engl J Med. 2013;370: 1

43. Fidaxomicin (Dificid)1

44. Fidaxomicin (Dificid)
FDA Status: Approved in May 2011
Indication: Clostridium difficile-associated diarrhea
Class: macrocyclic antibiotic
Mechanism: inhibits RNA polymerase and transcription
Dose: 200 mg bid x 10 days
In vitro C. difficile activity: 8x more active than vancomycin
Absorption: Minimal oral absorption
Adverse Effects: nausea, vomiting, abdominal pain 1

45. Clostridium difficile : Fidaxomicin vs Vancomycin Study Design
Protocol - N = 629 enrolled (548 evaluated) - Double-blind, prospective, randomized trial - Phase 3 trial - Conducted from Age: 16 years and older - Acute symptoms of C. diff and +stool toxin - Randomized to fidaxomicin or vancomycin
Treatment Arms
Fidaxomicin 200 mg PO BID X 10 days
Vancomycin 125 mg PO QID x 10 days
From: Louie TJ, et al. N Engl J Med. 2011;364: 1

46. Clostridium difficile: Fidaxomicin vs Vancomycin Results
P <
Clinical Cure = resolution of symptoms and no need for further therapy Recurrence = diarrhea and positive stool test within 4 weeks after treatment
From: Louie TJ, et al. N Engl J Med. 2011;364: 1

47. Treatment of Gram-Negative Infections1

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

49. “Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive.”
Source: Boucher HW, et al. Clin Infect Dis. 2013:56: 1

50. Source: Centers for Disease Control and Prevention (CDC)1

51. Conclusions Antibiotic development has dramatically fallen off
Antibiotics are lower priority for pharmaceutical development
Most recently approved antibiotics are for Gram+ infections
New antibiotics with favorable dosing characteristics
Huge need for antibiotics for multi-resistant gram negative pathogens 1