Case History: Question - What`s New in Medicine
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Transcript Case History: Question - What`s New in Medicine
Antimicrobial Therapy
David H. Spach, MD
Professor of Medicine
Division of Infectious Diseases
University of Washington, Seattle
Use of Antimicrobials
• Treat Infections
• Cost
• Prevent Infections
• Resistance
Antibiotic Use and Resistance
Community Use
Hospital Use
Agricultural Use
Antibiotic Use and Resistance
Community Use
Hospital Use
Agricultural Use
2014 Most Prescribed Drugs
Infectious Diseases
36. Tamiflu
60. Zostavax
77. Truvada
84. Norvir
97. Atripla
Source: IMS National Prescription Audit, IMS Health.
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.
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.”
Source: IDSA. Clin Infect Dis. 2010:50:1081-3.
“ESKAPE” Pathogens
Enterococcus faecalis
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter species
Structure of Gram-Positive Bacteria
Penicillin Binding Proteins
DNA
Cell Membrane
Cell Wall
Structure of Gram-Negative Bacteria
Outer Membrane
Cell Wall
Periplasmic Space
Cell Membrane
Porin Channel
DNA
Antimicrobials: Site of Action
Cell Wall
Cytoplasm
Cell Membrane
DNA Inhibitor
23 S Ribosome
30S Ribosome
50S Ribosome
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): SSTI
Dalbavancin (Dalvance): SSTI
Oritavancin (Orbactiv): SSTI
Telavancin (Vibativ)
Telavancin: Mechanism of Action
Telavancin
Cell Wall Synthesis
DNA
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
Telavancin: Mechanism of Action (2)
Telavancin
Lipid II
(cell wall precursor)
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 q24
- 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.
Telavacin versus Vancomcyin for Complicated SSTI
ATLAS Trial
Study Design
Overall Success Rate*
Methods (N = 1867)
Regimens
- Telavancin: 10 mg/kg IV q24h
- Vancomycin: 1g IV q12h
100
Vancomycin
91
86
80
Patients%
- Two Phase 3 trials
- Randomized, double blind
- Patients with complicated SSTI
- Suspected or confirmed gram+
- N = 579 with MRSA
- Adults
Telavancin
60
40
20
0
All
*7-14 days after receipt of last antibiotic dose
Source: Stryjewski ME, et al. Clin Infect Dis. 2008;46:1683-93.
Telavacin versus Vancomcyin for HAP with Gram+
ATTAIN Trial
Study Design
Results
Methods (N = 1503)
Regimens (duration 7-21 days)
- Telavacin: 10 mg/kg IV q24h
- Vancomycin: 1g IV q12h
- Concomitant therapy for Gram- allowed
Vancomycin
100
82
81
80
Patients%
- Two Phase 3 trials
- Randomized, double blind
- Patients with HAP, including VAP
- Suspected or confirmed gram+
- Adults
Telavancin
60
40
22
20
17
0
Cure Rate
Source: Rubinstein E, et al. Clin Infect Dis. 2011;52:31-40.
Mortality
Ceftaroline (Teflaro)
Beta-Lactams: Mechanism of Action
Penicillin Binding Proteins
Ceftaroline
Transpeptidation
Carboxypeptidation
DNA
Cell Membrane
Cell Wall
Ceftaroline (Teflaro): Mechanism of Action
Altered Penicillin Binding Protein
PBP 2a
PBP 2a
DNA
Ceftaroline
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 SSTI
CANVAS 1 and 2
Study Design
Clinical Cure
Methods
Regimens (5-14 days)
Ceftaroline: 600 mg IV q12h
or
Vancomycin: 1g IV q12h +
Aztreonam: 1 g IV q12h
100
93
92
Vancomycin-Aztreonzam
93
94
80
Patients%
- Pooled analysis of 2 phase 3 trials
- Double-blind trial
- N = 1378 enrolled
- Complicated SSTI
Ceftaroline
60
40
20
0
All
Source: Corey GR, et al. Clin Infect Dis. 2012;56:641-50.
MRSA
Cetaroline vs. Ceftriaxone for CAP
Focus1 and 2
Study Design
Clinical Cure Rate
Methods
Regimens (5-14 days)
Ceftaroline: 600 mg IV q12h x 5-7d
or
Ceftriaxone: 1g IV q12h x 5-7d
Ceftriaxone
100
84
80
Patients%
- Pooled analysis of 2 phase 3 trials
- Double-blind trial
- N = 1228 enrolled
- Community acquired pneumonia
- Patients hospitalized
Ceftaroline
60
40
20
0
FOCUS 1: received 2 doses of clarithromycin on d1
Source: File TM, et al. Clin Infect Dis. 2010;51:1395-405.
78
Tedizolid (Sivextro)
Protein Synthesis
50 S Ribosome
30 S Ribosome
50S
fMet-tRNA
23S
30S
23S
70 S Initiation Complex
DNA
Tedizolid (Zyvox): Mechanism of Action
50 S Ribosome
Tedizolid
30 S Ribosome
50S
fMet-tRNA
23S
30S
DNA
23S
70 S Initiation Complex
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 Therapy
ESTABLISH-1
Study Design (ESTABLISH-1)
Early Clinical Response
Methods
Tedizolid
100
- Randomized, double blind, phase 3 trial
- 81 study centers
- Acute bacterial SSTI
Regimens
- Tedizolid: 200 mg PO qd x 6d
80
Patients%
- N = 667 adults
Linezolid
60
40
20
- Linezolid: 600 mg PO bid x 10 days
0
Source: Prokocimer P, et al. JAMA. 2013;309:559-69.
80
79
Tedizolid versus Linezolid for SSTI: IV/Oral Therapy
ESTABLISH-2
Study Design (ESTABLISH-2)
Early Clinical Response
Methods
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
Linezolid
100
85
80
Patients%
- Randomized, double blind, phase 3 trial
- 58 centers in 9 countries
- N = 666 adults
- Acute bacterial SSTI
Tedizolid
60
40
20
0
Source: Moran GJ, et al. Lancet Infect Dis 2014;14:696-705.
83
Dalbavancin (Dalvance)
Dalbavancin (Dalvance): Mechanism of Action
Dalbavancin
Cell Wall Synthesis
Dimer
Dimer
DNA
Dimer
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
Dalbavancin versus Vancomycin for SSTI
DISCOVER 1 and DISCOVER 2
Study Design
Clinical Response to Therapy
Methods
Regimens
- Dalbavancin 1000 mg d1, 500 mg d8
- Vancomycin IV for ≥3 days, then oral
linezolid 600 mg bid to complete 10-14d
100
80
Patients%
- Pooled analysis of 2 phase 3 trials*
- Randomized trials
- N = 659 adults
- Acute bacterial SSTI
Dalbavancin
Vancomycin-Linezolid
91
80
92
80
60
40
20
0
1° End Point
*DISCOVER 1 and DISCOVER 2
2° End Point
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.
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.
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)
Regimens
- Dalbavancin: 1.0 g IV d1; 0.5 g IV d8
- Vancomycin: 1g bid IV x 14d
Vancomycin
100
87
80
Patients%
- 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
Dalbavancin
60
40
20
0
Source: Raad I, et al. Clin Infect Dis 2005;40:374-80.
50
Oritavancin (Orbactiv)
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 versus Vancomycin for SSTI
SOLO-I
Study Design (ESTABLISH-1)
Investigator-Assessed Clinical Cure
Methods
Oritavancin
100
- Randomized, double blind, phase 3 trial
- N = 954 adults
Regimens
- Oritavancin: 1200 mg IV x 1
- Vancomycin: 1g IV q12h x 7-10 days
80
Patients%
- Acute bacterial SSTI
Vancomcyin
60
40
20
0
Source: Corey R, et al. N Engl J Med. 2013;370:2180-90.
80
80
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
Clostridium difficile : Fidaxomicin vs Vancomycin
Study Design
Study Design
Treatment Arms
Protocol
- N = 629 enrolled (548 evaluated)
- Double-blind, prospective, randomized trial
Fidaxomicin
200 mg PO BID X 10 days
- 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
From: Louie TJ, et al. N Engl J Med. 2011;364:422-31.
Vancomycin
125 mg PO QID x 10 days
Clostridium difficile: Fidaxomicin vs Vancomycin
Results
100
88.2
Fidaxomicin
85.8
Patients %
80
Vancomycin
60
40
25.3
15.4
20
P < 0.005
0
Clinical Cure*
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;364:422-31.
Recurrence^
Treatment of Gram-Negative Infections
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: Boucher HW, et al. Clin Infect Dis. 2013:56:1685-94.
Source: Centers for Disease Control and Prevention (CDC)
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