OHSUWhat’s Up with Long- Acting Antibiotics Daily Dose of Stewardship

DATE: SEPTEMBER 27, 2019 PRESENTED BY: AMBER STREIFEL, PHARMD, BCPS Objectives

• Describe dalbavancin and oritavancin activity, dosing, and adverse effects

• Discuss use of long-acting antimicrobials in OHSUcomplicated infections • Illustrate potential scenarios for appropriate use

2 Pipeline

• 42 new antibiotics in clinical development • 1 in 5 antibiotics that enter Phase 1 trials will be OHSUapproved

Dalbavancin & oritavancin

http://sitn.hms.harvard.edu 3www.pewtrusts.org Dalbavancin & Oritavancin • Lipoglycopeptide antibiotics similar in structure to vancomycin • Approved for treatment of skin and soft tissue infection OHSU• Extended half-life

4 Spectrum of Activity Active against gram positive species – Methicillin-resistant S. aureus and S. epidermidis – Streptococcus sp – Enterococcus sp

Oritavancin – Vancomycin-resistant E. faecalis and E. faecium OHSU– Vancomycin-intermediate and vancomycin-resistant S. aureus

5 Dalbavancin vs Oritavancin

Dalbavancin Oritavancin

Standard Dose 1500 mg 1200 mg

Infusion Time 30 minutes 3 hours

Drug Interactions None known Artificial increase in anticoagulant monitoring OHSUparameters Spectrum Similar to + VRE, VISA, VRSA vancomycin

6 Dosing Dalbavancin

1000 mg x1, then 500 mg weekly OR 1500 mg

OHSU• Renal adjustment – CrCL < 30 mL/min • Hepatic impairment – No adjustment recommended

7 Dosing in Complicated Infections

1500 mg x2

OHSUvs.

1000 mg x1, 500 mg weekly

8 Dunne MW et al. AAC 2015; 59(4):1849-55 Clinical Evidence

. Skin & Soft Tissue: DISCOVER Trials . Catheter related bloodstream infections

dalbavancin non-inferior to standard of OHSUcare antibiotics

Boucher HW et al. NEJM 2014 370(23): 2169-79 9 Raad I, et al. CID 2005;40:374-80. Osteomyelitis

• Randomized, open-label trial • 1500 mg x2 vs standard of care for 4-6 weeks OHSU• First episode of osteomyelitis

10 Rappo U et al. OFID 2018 Complicated Bacteremia & Endocarditis

• Case series of 27 patients with infective endocarditis • Clinical success rate of 92.6% • 24 of the 27 initiated dalbavancin after OHSUclearance of blood cultures

• Randomized clinical trial?

11 Tobudic S et al. CID 2018; 67(5):795-8. Pulmonary Infections

• Phase 1 study: • Single dose of dalbavancin 1500 mg • Epithelial lining fluid concentration- 36%

• Exceeded MIC90 of S. aureus > 7 days

• Clinical outcomes? OHSU• Single case report – unclear outcome

12Rappo U et al. AAC 2019 Barber KE et al. J Pharmacol Pharmacother 2017 Gaps in the Literature

• CNS infections • Methicillin-susceptible Staph aureus – Clinical efficacy vs β-lactams? • Clinical outcomes for more complicated OHSUinfections?

13 Safety

• Most common adverse effects – Infusion reaction < 2% – Gastrointestinal < 10% OHSU• Concern for hypersensitivity reaction • Renal toxicity?

14 Real World Experience

Clinical indications & safety • Most common indications skin and soft tissue and osteomyelitis • Significant loss-to-follow up OHSU• All adverse events: 8-14%

15 Bork JT et al. Infect Dis Ther 2019 Morrisette T et al. JAC 2019 Bryson-Cahn C et al. OFID 2019 Streifel AC et al. IJAA 2019 Real World Experience

Reasons for use • PWID • Previous antimicrobial failure or adverse effect • Financial complications/ insurance • Prior history of non-compliance OHSU• Inability to physically manage PICC • Patient preference

16 Bork JT et al. Infect Dis Ther 2019 Morrisette T et al. JAC 2019 Bryson-Cahn C et al. OFID 2019 Streifel AC et al. IJAA 2019 Cost Considerations

• Can be infused via peripheral IV • Potential for saved hospital days

Average Wholesale Dose Price ($) OHSUDalbavancin 1500 mg 5,500 Oritavancin 1200 mg 3,500

Daptomycin 500 mg 250-500

Vancomycin 1000 mg 0.18

17 The Debate: Dalbavancin vs Standard of Care

Pros Cons

No need for PICC line Clinical evidence limited in complicated Minimal monitoring infections

Potential for reduced Unable to de-escalate hospital stay OHSUPotential for adverse Well tolerated effects w/ long half life

18 Don’t forget… • Potential future oral options?

OHSUPOET

OVIVA

19 Li HK et al. NEJM 2019 380(5) Iversen K et al. NEJM 2019 380(5) Conclusions

• Clinical evidence for use in complicated infections is limited

• Dalbavancin and oritavancin may provide OHSUvaluable alternative therapeutic option • Use results in significant cost-savings when outpatient antibiotic options are limited

20 OHSUThank You