Antimicrobial Therapy

David H. Spach, MDProfessor of Medicine

Division of Infectious DiseasesUniversity of Washington, Seattle

Use of Antimicrobials

• Treat Infections

• Prevent Infections

• Cost

• Resistance

Antibiotic Use and Resistance

Community Use

Hospital Use

Agricultural Use

Antibiotic Use and Resistance

Community Use

Hospital Use

Agricultural Use

Antibiotic Resistance

Antibiotic Development

Infectious Diseases

36. Tamiflu

60. Zostavax

77. Truvada

84. Norvir

97. Atripla

2014 Most Prescribed Drugs

Source: IMS National Prescription Audit, IMS Health.

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)

2014 Most Profitable Drugs

Source: IMS National Prescription Audit, IMS Health.

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

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

“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.”

“ESKAPE” Pathogens

· Enterococcus faecalis

· Staphylococcus aureus

· Klebsiella pneumoniae

· Acinetobacter baumannii

· Pseudomonas aeruginosa

· Enterobacter species

Structure of Gram-Positive Bacteria

Cell WallCell Membrane

Penicillin Binding Proteins

DNA

Structure of Gram-Negative Bacteria

Porin Channel

Outer Membrane

Cell Wall

Periplasmic Space

Cell MembraneDNA

Antimicrobials: Site of Action

Cell Wall

Cytoplasm 23 S Ribosome 30S Ribosome 50S Ribosome

DNA Inhibitor

Cell Membrane

Systemic Antibacterials: Recent FDA Approvals

· 2009 -Telavancin (Vibativ): SSTI

· 2010- Ceftaroline (Teflaro): SSTI, CAP

· 2011- Fidaxomicin (Dificid): Clostridium difficile

· 2013- Telavancin (Vibativ): HAP/VAP

· 2014 Tedizolid (Sivextro): SSTIDalbavancin (Dalvance): SSTIOritavancin (Orbactiv): SSTI

Telavancin (Vibativ)

Telavancin: Mechanism of Action

Cell Wall SynthesisTelavancin

DNA

Telavancin: Mechanism of Action (1)

Ligase

Tripeptide Intermediate

Cell Wall Pentapeptide Precursor

Telavancin

D-Ala D-Ala

D-AlaD-Ala

D-Ala D-Ala

Telavancin: Mechanism of Action (2)

Telavancin

Lipid II(cell wall precursor)

· 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 q24 - For CrCl 10-30: 10 mg/kg q48

· Adverse Effects: nephrotoxicity, diarrhea, “red man”, foamy urine

Telavancin (Vibativ)

Source: Damodaron SE, Madhan S. J Pharmacol Pharmacother. 2011;2:135-7.

Telavacin versus Vancomcyin for Complicated SSTIATLAS Trial

· 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

Study Design Overall Success Rate*

Source: Stryjewski ME, et al. Clin Infect Dis. 2008;46:1683-93.

All0

20

40

60

80

10091

86

Telavancin Vancomycin

Pa

tie

nts

%

*7-14 days after receipt of last antibiotic dose

Telavacin versus Vancomcyin for HAP with Gram+ATTAIN Trial

· 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

Study Design Results

Source: Rubinstein E, et al. Clin Infect Dis. 2011;52:31-40.

Cure Rate Mortality0

20

40

60

80

100

82

22

81

17

Telavancin Vancomycin

Pa

tie

nts

%

Ceftaroline (Teflaro)

Beta-Lactams: Mechanism of Action

Cell WallCell Membrane

Penicillin Binding Proteins

DNA

TranspeptidationCarboxypeptidation

Ceftaroline

Ceftaroline (Teflaro): Mechanism of Action

Altered Penicillin Binding Protein Ceftaroline

DNA

PBP 2a

PBP 2a

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.

Cetaroline for Complicated SSTICANVAS 1 and 2

· 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

Study Design Clinical Cure

Source: Corey GR, et al. Clin Infect Dis. 2012;56:641-50.

All MRSA0

20

40

60

80

10092 9393 94

Ceftaroline Vancomycin-Aztreonzam

Pa

tie

nts

%

Cetaroline vs. Ceftriaxone for CAPFocus1 and 2

· 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

Study Design Clinical Cure Rate

Source: File TM, et al. Clin Infect Dis. 2010;51:1395-405.

FOCUS 1: received 2 doses of clarithromycin on d1 Series10

20

40

60

80

100

8478

Ceftaroline Ceftriaxone

Pa

tie

nts

%

Tedizolid (Sivextro)

Protein Synthesis

50S

fMet-tRNA

50 S Ribosome

30S

30 S Ribosome

DNA

23S

70 S Initiation Complex

23S

Tedizolid (Zyvox): Mechanism of Action

50S

fMet-tRNA

50 S Ribosome

30S

70 S Initiation Complex

30 S Ribosome

DNA23S

Tedizolid

23S

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

Tedizolid versus Linezolid for SSTI: Oral TherapyESTABLISH-1

· 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

Study Design (ESTABLISH-1) Early Clinical Response

Source: Prokocimer P, et al. JAMA. 2013;309:559-69.

Series10

20

40

60

80

100

80 79

Tedizolid Linezolid

Pa

tie

nts

%

· 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

Study Design (ESTABLISH-2) Early Clinical Response

Source: Moran GJ, et al. Lancet Infect Dis 2014;14:696-705.

Series10

20

40

60

80

100

85 83

Tedizolid Linezolid

Pa

tie

nts

%*required to receive IV therapy for minimum of 1 day, then could step down to PO

Tedizolid versus Linezolid for SSTI: IV/Oral TherapyESTABLISH-2

Dalbavancin (Dalvance)

Dalbavancin (Dalvance): Mechanism of Action

DalbavancinCell Wall Synthesis

DNA

Dimer

Dimer

Dimer

· 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

Dalbavancin (Dalvance)

Source: Dalbavancin Package Insert

Dalbavancin versus Vancomycin for SSTIDISCOVER 1 and DISCOVER 2

· 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

Study Design Clinical Response to Therapy

Source: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7.

*DISCOVER 1 and DISCOVER 2

1° End Point 2° End Point 0

20

40

60

80

100

80

91

80

92

Dalbavancin Vancomycin-Linezolid

Pa

tie

nts

%

1° End Point = Success rate at 48 to 72 hours 2° End Point = Success rate at end of therapy

· 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

How is Dalbavancin Different from Vancomycin

Source: Guskey MT, et al. Pharmacotherapy. 2010;30:80-94.

Catheter-Related Bloodstream InfectionsDalbavancin versus Vancomycin

· 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

Study Design Overall Success Rate

Source: Raad I, et al. Clin Infect Dis 2005;40:374-80.

INVESTIGATIONAL-Dalbavancin not FDA approved for treatment of bloodstream infections

Series10

20

40

60

80

10087

50

Dalbavancin Vancomycin

Pa

tie

nts

%

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

Oritavancin (Orbactiv)

Oritavancin versus Vancomycin for SSTISOLO-I

· 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

Study Design (ESTABLISH-1) Investigator-Assessed Clinical Cure

Source: Corey R, et al. N Engl J Med. 2013;370:2180-90.

Series10

20

40

60

80

100

80 80

Oritavancin Vancomcyin

Pa

tie

nts

%

Fidaxomicin (Dificid)

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

Treatment Arms

Clostridium difficile : Fidaxomicin vs VancomycinStudy Design

From: Louie TJ, et al. N Engl J Med. 2011;364:422-31.

Study Design

Protocol

- N = 629 enrolled (548 evaluated)

- Double-blind, prospective, randomized trial

- Phase 3 trial

- Conducted from 2006-2008

- Age: 16 years and older

- Acute symptoms of C. diff and +stool toxin

- Randomized to fidaxomicin or vancomycin

Fidaxomicin200 mg PO BID X 10 days

Vancomycin125 mg PO QID x 10 days

Clostridium difficile: Fidaxomicin vs VancomycinResults

From: Louie TJ, et al. N Engl J Med. 2011;364:422-31.

Clinical Cure* Recurrence^0

20

40

60

80

10088.2

15.4

85.8

25.3

Fidaxomicin

Vancomycin

Pat

ien

ts %

Clinical Cure = resolution of symptoms and no need for further therapyRecurrence = diarrhea and positive stool test within 4 weeks after treatment

P < 0.005

Treatment of Gram-Negative Infections

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

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.”

Source: Centers for Disease Control and Prevention (CDC)

· 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

Conclusions