©2016 MFMER | slide-1 One-Hit Wonders: A New Era of Antibiotics? Patrick Wieruszewski, PharmD PGY-1 Pharmacy Resident Pharmacy Grand Rounds November 1, 2016
©2016 MFMER | slide-1
One-Hit Wonders: A New Era of Antibiotics?
Patrick Wieruszewski, PharmD PGY-1 Pharmacy Resident
Pharmacy Grand Rounds November 1, 2016
©2016 MFMER | slide-2
Objectives
• Identify advantages and disadvantages of single-dose antibiotics
• Review the pharmacology of dalbavancin and oritavancin
• Discuss current evidence and the place in therapy of dalbavancin and oritavancin
©2016 MFMER | slide-3
Single-Dose Antimicrobials
• Route of administration
• Penicillin G benzathine IM for syphilis
• Pharmacokinetics
• Azithromycin for Chlamydia trachomatis
• Formulation
• Azithromycin microspheres for CAP
Workowski KA. Clin Infect Dis 2015;61(Suppl 8).
Abramowicz M et al. Med Lett Drugs Ther 2005;47(1218):78-80. CAP = Community-acquired pneumonia
©2016 MFMER | slide-4
Single-Dose Antimicrobials Advantages
• Patient adherence
• Potentially reduced resistance
• Potential cost reductions
• ↓ hospitalizations
• ↓ hospitalized complications
• No need for long-term venous catheters
• No therapeutic drug monitoring
Llor C et al. Int J Infect Dis 2013;17(3):e168-72.
Roberts KD et al. Pharmacotherapy 2015;35:935-48.
Crotty MP et al. J Clin Microbiol 2016;54:2225-32.
©2016 MFMER | slide-5
Single-Dose Antimicrobials Disadvantages
Roberts KD et al. Pharmacotherapy 2015;35:935-48.
Crotty MP et al. J Clin Microbiol 2016;54:2225-32.
May be lost to
follow up
Standardized dosing
Therapeutic drug
monitoring
Safety data
Antimicrobial stewardship
©2016 MFMER | slide-6
Dalbavancin and Oritavancin
One-Hit Wonders?
©2016 MFMER | slide-7
Question 1
• Dalbavancin and oritavancin have broad spectrum activity against gram positive and gram negative bacteria including multidrug resistant organisms
• True
• False
• I don’t know
©2016 MFMER | slide-8
Vancomycin
Dalbavancin
Oritavancin
1
1
3 Oritavancin
Dalbavancin
2 2 2 2
3
1 1
©2016 MFMER | slide-10
MSSA MRSA hVISA VISA VRSA DNSSA
Vancomycin ✓ ✓ V X X V
Dalbavancin ✓ ✓ ✓ V X ✓
Oritavancin ✓ ✓ ✓ ✓ ✓ ✓
MSSA = Methicillin-sensitive S. aureus
MRSA = Methicillin-resistant S. aureus
hVISA = heterovariant Vancomycin-intermediate S. aureus (MIC=1-4)
VISA = Vancomycin-intermediate S. aureus (MIC=8-16)
VRSA = Vancomycin-resistant S. aureus (MIC≥32)
DNSSA = Daptomycin non-susceptible S. aureus
V = variable
Brade KD et al. Infect Dis Ther 2016;5:1-15.
Smith JR et al. Infect Dis Ther 2015;4:245-58.
Spectrum of Activity Staphylococcus spp.
©2016 MFMER | slide-11
Spectrum of Activity Other organisms
Strep
spp.
VSE
VRE
G+
anaerobes
Gram
negatives
Vancomycin ✓ ✓ X ✓ X
Dalbavancin ✓ ✓ V ✓ X
Oritavancin ✓ ✓ ✓ ✓ X
VSE = Vancomycin-sensitive Enterococcus
VRE = Vancomycin-resistant Enterococcus
V = variable
Brade KD et al. Infect Dis Ther 2016;5:1-15.
Smith JR et al. Infect Dis Ther 2015;4:245-58.
©2016 MFMER | slide-12
Kinetics & Dosing
Parameter Vancomycin Dalbavancin Oritavancin
Half-life (h) 4-6 346 245
Clearance (L/h) 4.06 0.0513 0.445
Volume of
distribution (L)
60.5 7-13 87.6
Protein binding (%) 55 93 85
Elimination Urine,
75% over 24h
Urine,
33% unchanged;
feces, 20%
Urine, < 5%;
feces, < 1%
Drug Interactions -- -- InH: 2C9, 2C19
InD: 3A4, 2D6
Typical dosing 15 mg/kg IV q12h
+ TDM
1000mg IV day 1,
500mg IV day 8
1200mg IV once
Renal adjustments Yes, dialyzable Yes, non-dialyzable No, non-dialyzable
Crotty MP et al. J Clin Microbiol 2016;54:2225-32.
InH = Inhibitor
InD = Inducer
TDM = Therapeutic drug monitoring
©2016 MFMER | slide-13
Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection (DISCOVER 1 & DISCOVER 2)
Boucher HW et al. N Eng J Med 2014;370(23):2169-79.
©2016 MFMER | slide-14
• Design
• International, multicenter, randomized, double-blind, double-dummy phase 3
• Intervention
• Dalbavancin 1gm IV on day 1 then 500mg IV on day 8
• Vancomycin 15 mg/kg IV q12h x 10-14 days
• Population
• ≥18 years of age
• Acute bacterial skin and skin-structure infection
• ≥ 1 systemic and ≥ 2 local signs of infection
• Requiring ≥ 3 days of IV antibiotics
Study Design and Treatment DISCOVER 1 & 2
Boucher HW et al. N Eng J Med 2014;370(23):2169-79.
©2016 MFMER | slide-15
• Primary Outcome
• Treatment success at 48-72 hours after drug initiation
• Cessation of spread of erythema
• Resolution of fever
• Secondary Outcomes
• Clinical response at end of therapy
• Safety Outcomes
• Adverse events
• Death
Efficacy and Safety Assessments DISCOVER 1 & 2
Boucher HW et al. N Eng J Med 2014;370(23):2169-79.
©2016 MFMER | slide-16
Treatment Success DISCOVER 1 & 2
Boucher HW et al. N Eng J Med 2014;370(23):2169-79.
82 78 80
83
77 80
0
20
40
60
80
100
DISCOVER 1 DISCOVER 2 Both Trials
% o
f p
ati
en
ts
Vancomycin
Dalbavancin
*Absolute difference (95% confidence interval)
1.5 (-4.6-7.9) -1.5 (-7.4-4.6) -0.1 (-4.5-4.2)
©2016 MFMER | slide-17
Secondary Endpoints DISCOVER 1 & 2
Boucher HW et al. N Eng J Med 2014;370(23):2169-79. MSSA = Methicillin-Susceptible S. aureus
MRSA = Methicillin-Resistant S. aureus
97 98 92
98 97 100
0
20
40
60
80
100
Staphylococcusaureus
MRSA Streptococcuspyogenes
% o
f p
ati
en
ts
Vancomycin
Dalbavancin
Investigator-assessed clinical response
MSSA
MRSA
Streptococcusspp.
©2016 MFMER | slide-18
• Strengths
• Study design
• Pooled analyses of both trials
• Sensitivity analyses with type of infection and pathogen
• Extended surveillance of adverse events
• Limitations
• Subjective assessment of clinical response
• Vancomycin fixed dosing and no TDM
• Adherence in a monitored clinical setting
• Low MRSA rates
Study Critique DISCOVER 1 & 2
Boucher HW et al. N Eng J Med 2014;370(23):2169-79. TDM = Therapeutic drug monitoring
©2016 MFMER | slide-19
A Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection
Dunne MW et al. Clin Infect Dis 2016;62(5):545-51.
©2016 MFMER | slide-20
Dunne MW et al. (2016)
• Dose-exploration study in ABSSSI
• 1500mg IV once
• 1000mg IV on day 1 then 500mg IV on day 8
• No differences in adverse events up to 28 days
ABSSSI = Acute bacterial skin and skin structure infection Dunne MW et al. Clin Infect Dis 2016;62(5):545-51.
81 84 84 85 84 85 85 85
0
20
40
60
80
100
48-72 hr 36-75 hr Day 14 Day 18
% o
f p
ati
en
ts
1-Dose
2-Dose
Treatment response Clinical success
©2016 MFMER | slide-21
Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections (SOLO I)
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Single-Dose Oritavancin Versus 7-10 Days of Vancomycin in the Treatment of Gram-Positive Acute Bacterial Skin and Skin Structure Infections (SOLO II)
Corey GR et al. Clin Infect Dis 2015;60(2):254-62.
©2016 MFMER | slide-22
• Design
• International, multicenter, randomized, double-blind phase 3
• Intervention
• Oritavancin 1200 mg IV once
• Vancomycin 15 mg/kg IV q12h x 7-10 days
• Population
• ≥18 years of age
• Acute bacterial skin and skin-structure infection
• Thought/proven gram-positive causal pathogen
• Requiring ≥ 7 days of IV antibiotics
Study Design and Treatment SOLO I & SOLO II
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Corey GR et al. Clin Infect Dis 2015;60(2):254-62.
©2016 MFMER | slide-23
• Primary Outcome (ECE)
• Cessation of spreading/reduced size of lesion
• Absence of fever
• No rescue antibiotic administered
• Secondary Outcomes
• Clinical cure
• ≥20% reduction in lesion size at ECE
• Safety Outcomes
• Adverse events
Efficacy and Safety Assessments SOLO I & SOLO II
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Corey GR et al. Clin Infect Dis 2015;60(2):254-62. *ECE = Early clinical evaluation (48-72 hours after drug initiation)
©2016 MFMER | slide-24
Composite
79 83 82 80
0
20
40
60
80
100
SOLO I SOLO II
% o
f p
ati
en
ts
Vancomycin
Oritavancin
Primacy Outcome (non-inferiority) SOLO I & SOLO II
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Corey GR et al. Clin Infect Dis 2015;60(2):254-62.
80 81 80 83
0
20
40
60
80
100
SOLO I SOLO II
% o
f p
ati
en
ts
83 85 87 86
0
20
40
60
80
100
SOLO I SOLO II
% o
f p
ati
en
ts
Clinical cure Lesion reduction ≥ 20%
©2016 MFMER | slide-25
Microbiological Population SOLO I & SOLO II
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Corey GR et al. Clin Infect Dis 2015;60(2):254-62.
Staphylococcus aureus
MRSA
MSSA
Streptococcus species
S. anginosus group
S. pyogenes
-20 -15 -10 -5 0 5 10 15 20
At least one pathogen
Vancomycin better Oritavancin better
SOLO I
SOLO II
Difference
MRSA = Methicillin-Resistant S. aureus
MSSA = Methicillin-Sensitive S. aureus
©2016 MFMER | slide-26
• Strengths
• Study design
• Many subgroup analyses & confounder assessments
• Consistent baseline characteristics
• Extended surveillance of adverse events
• Limitations
• High drop out rates
• Unnecessary broad MRSA coverage
• No de-escalation with oritavancin
• “Clinical cure” as assessed by the investigator
Study Critique SOLO I & SOLO II
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Corey GR et al. Clin Infect Dis 2015;60(2):254-62.
©2016 MFMER | slide-27
Safety
Boucher HW et al. N Eng J Med 2014;370(23):2169-79.
Dunne MW et al. Clin Infect Dis 2016;62(5):545-51.
Corey GR et al. N Eng J Med 2014;370(23):2180-90.
Corey GR et al. Clin Infect Dis 2015;60(2):254-62.
• Possibly more serious anaphylactic reactions
• Dalbavancin
• Hypotension in phase 2 studies
• Oritavancin
• Infusion-related reactions
• Osteomyelitis
• Coagulation test abnormalities
©2016 MFMER | slide-28
Question 2
• 34 y/o M POD 8 s/p Whipple’s procedure is re-admitted for acute pulmonary embolism started on high intensity heparin infusion. He is also septic and there is concern for anastomotic leak. His surgical site appears dirty and is draining purulent fluid that is culture-confirmed MRSA. Which antibiotic(s) would you begin?
• Dalbavancin
• Oritavancin
• Vancomycin + piperacillin/tazobactam
• Levofloxacin + gentamicin
©2016 MFMER | slide-29
Dalbavancin and Oritavancin
Outside of Acute Bacterial Skin and Skin Structure Infections
©2016 MFMER | slide-30
Dalbavancin Catheter-Related Bloodstream Infection
CoNS
MSSA
MRSA
E. faecalis
Open-label, randomized, controlled, phase 2 trial
Dalbavancin 1000mg IV day 1 then 500mg IV day 8
Vancomycin 1000mg IV q12h
Adults with signs of bacteremia possibly/definitely
associated with a catheter
50 50
79 87 87
96
0
20
40
60
80
100
Overall Clinical Microbiological
% o
f p
ati
en
ts
Vancomycin
Dalbavancin
Success at Test-of-Cure Visit
p<0.05
MRSA = Methicillin-Resistant S. aureus
MSSA = Methicillin-Sensitive S. aureus
CoNS = Coagulase-negative Staphylococcus
Raad I et al. Clin Infect Dis 2005;40(3):374-80.
©2016 MFMER | slide-31
0
2
4
6
8
10
12
0 200 400 600 800 1000
Bo
ne D
alb
avan
cin
(m
cg
/g)
Time (hr)
• Pharmacokinetic modeling of two Phase I studies
Dalbavancin Bone and Articular Tissue Infection
Dunne MW et al. Antimicrob Agents Chemother 2014;59(4):1849-55.
Observed
Predicted
Single 1000mg IV dose Day 14
Concentrations
Plasma* 15.3
Synovium† 15.9
Synovial fluid* 6.2
Bone† 4.1
Skin† 13.8
*mcg/mL †mcg/g
©2016 MFMER | slide-32
Dalbavancin Activity against Staphylococcal biofilms
• Minimum biofilm inhibitory concentration (MBIC)
• Minimum biofilm bactericidal concentration (MBBC)
Dalbavancin Vancomycin
MIC50 MIC90 MBIC50 MBIC90 MBBC50 MBBC90 MBBC50 MBBC90
MRSA 0.03 0.06 0.06 0.25 1 2 >128 >128
MSSA 0.03 0.06 0.06 0.12 1 2 >128 >128
MRSE 0.03 0.12 0.06 0.50 1 4 >128 >128
MSSE 0.03 0.12 0.03 0.25 1 4 128 >128
Fernandez J et al. Diagn Microbiol Infect Dis 2016;85:449-51.
Schmidt-Malan SM et al. Diagn Microbiol Infect Dis 2016;85:77-9. MRSE = Methicillin-resistant S. epidermidis
MSSE = Methicillin-sensitive S. epidermidis
MIC = Minimum inhibitory concentration
©2016 MFMER | slide-33
Two exploratory phase 2 multicenter, open-label, uncontrolled
studies
• 9/10 complete eradication of gram-positive pathogens from blood cultures
• No serious adverse effects
• 3 mg/kg then 2 mg/kg/day
• 4 mg/kg then 3 mg/kg/day
• 5 mg/kg then 4 mg/kg/day
Oritavancin Blood Stream Infection
Information provided by The Medicines Company for
Healthcare Professionals only. V01-11-0116
Dose escalation in gram-positive
bacteremia q24h for 7-10 days
Dose finding in subjects with S.
aureus bacteremia q24h for 10-14 days
• 5 mg/kg/day
• 6.5 mg/kg/day
• 8 mg/kg/day
• 10 mg/kg/day
Composite
Outcome Success
Clinical Cure
Bacteriologic
Eradication
5 mg/kg/day (n=6) 5 (83%) 5 (83%) 5 (83%)
6.5 mg/kg/day (n=7) 5 (71%) 5 (71%) 6 (86%)
8 mg/kg/day (n=24) 16 (67%) 17 (71%) 19 (79%)
10 mg/kg/day (n=20) 16 (80%) 16 (80%) 17 (85%)
Comparator (n=27) 19 (70%) 20 (74%) 21 (78%)
©2016 MFMER | slide-34
Enterococcus faecium
(Vancomycin-resistant)
Daptomycin 8 mg/kg
Bacteremia recurred @ 48 hours
Tigecycline added
8 weeks in, re-admitted
CVC infection Oral linezolid
x 2 weeks
5 months later VRE bacteremia Daptomycin +
tigecycline
Bacteremia recurred @ 72 hours
(Daptomycin-resistant)
Linezolid + tigecycline
Anorexia, nausea, ↑lactate, ↓platelets
Oritavancin 1200mg weekly
Antibiotic Initial Antibiotic Initial
Ampicillin 6 (R)* Daptomycin 4 (S)†
Vancomycin 6 (R)* Quinupristin/
dalfopristin
--
Tetracycline 6 (R)* Tigecycline 0.25†
Telavancin --
Linezolid 30 (S)*
Antibiotic 5 mo. Antibiotic 5 mo.
Ampicillin 6 (R)* Daptomycin 6 (R)†
Vancomycin 6 (R)* Quinupristin/
dalfopristin
1.5 (I)†
Tetracycline 6 (R)* Tigecycline 0.25†
Telavancin 0.19† Oritavancin 0.5†
Linezolid 31 (S)*
Oritavancin 78 y/o M w/ bioprosthetic aortic valve endocarditis
*Kirby Bauer disk diffusion (mm) †Minimum inhibitory concentration (mcg/mL)
VRE = Vancomycin-resistant Enterococcus
CVC = Central venous catheter Johnson JA et al. Open Forum Infect Dis 2015;2(4):ofv156.
©2016 MFMER | slide-35
Antibiotic 8 mo. Antibiotic 8 mo.
Ampicillin 6 (R)* Daptomycin 4 (S)†
Vancomycin 6 (R)* Quinupristin/
dalfopristin
--
Tetracycline 6 (R)* Tigecycline 0.094†
Telavancin 32† Oritavancin 0.5†
Linezolid 35 (R)*
Oritavancin 78 y/o M w/ bioprosthetic aortic valve
Completed 7 weeks of
Oritavancin
8 days later VRE
bacteremia Oritavancin
1200mg twice weekly
Bacteremia recurred @
2 weeks AVR/MVR + Linezolid + Tigecycline
Post-operatively anorexia, nausea,
↑lactate Oritavancin
1200mg twice weekly
10 weeks later LFT
abnormalities Oritavancin
stopped
7 months: LFTs returned normal
17 months: blood cultures clear
Test Value
Alanine aminotransferase 84 U/L
Aspartate aminotransferase 77 U/L
Alkaline phosphatase 333 U/L
AVR = aortic valve replacement
MVR = mitral valve replacement
LFT = Liver function test
Johnson JA et al. Open Forum Infect Dis 2015;2(4):ofv156.
*Kirby Bauer disk diffusion (mm) †Minimum inhibitory concentration (mcg/mL)
VRE = Vancomycin-resistant Enterococcus
©2016 MFMER | slide-36
Antimicrobial Stewardship Considerations
• Streamlining therapy
• Potential overuse
• Hypersensitivity reactions
• Avoidance of costly inpatient stays and CVC placement for long-term antibiotics
• High acquisition cost
CVC = Central venous catheter
©2016 MFMER | slide-37
Vancomycin 1500mg q12h
x 14 days $121.80
Oritavancin 1200mg $2,704
Dalbavancin 1500mg $4,176
©2016 MFMER | slide-38
Ongoing Clinical Trials
• Dalbavancin
• Safety and efficacy in adults with osteomyelitis
• Adults with community-acquired bacterial pneumonia*
• Children with ABSSSI, osteomyelitis
• Oritavancin
• PK and safety of co-administration with warfarin
• Safety in children with bacterial infections
https://clinicaltrials.gov/ct2/show/NCT02685033
https://clinicaltrials.gov/ct2/show/NCT02269644
https://clinicaltrials.gov/ct2/show/NCT02814916
https://clinicaltrials.gov/ct2/show/NCT02134301
https://clinicaltrials.gov/ct2/show/NCT02340988 *Withdrawn prior to enrollment
©2016 MFMER | slide-39
Question 3
• In the event a patient experiences anaphylaxis to oritavancin, he/she should be emergently taken to dialysis
• True
• False
©2016 MFMER | slide-40
Conclusion
• Dalbavancin and oritavancin are novel lipoglycopeptides with ultra-long half-lives allowing them to be given in a single dose with similar efficacy in ABSSSIs compared to vancomycin
• Dalbavancin and oritavancin have the potential to reduce costly inpatient hospital stays in patients requiring intravenous antibiotics
• Though non-formulary at Mayo Clinic, dalbavancin and oritavancin are currently being explored for use against resistant gram positive organisms and more severe infections such as endocarditis and osteomyelitis
©2016 MFMER | slide-41
Questions & Discussion