USHP CE Presentation

No strings attached: Long-acting lipoglycopeptides considerations for gram positive infections in high- risk patients

Stephani Halloran, PharmD No strings attached: Long-acting lipoglycopeptides PGY-2 Internal Medicine Pharmacy Resident considerations for gram positive infections in high-risk patients University of Utah Health Stephani Halloran, PharmD [email protected] November 7, 2020

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PollEverywhere Audience Response Disclosure

• ACPE requires active learning and most prefer real-time participation rather than a graded post-test • Relevant Financial Conflicts of Interest • We are utilizing PollEverywhere software for this process. • CE Presenter, Stephani Halloran, PharmD: University of Utah Health • You may join to participate by 3 different ways: • CE mentor, Ashley Cline, PharmD, BCPS: University of Utah Health • Web Browser: Go to PollEv.com/ushp • PollEverywhere app: Download app and join ushp presentation • CE co-mentor, Karen Fong, PharmD, BCIDP, AAHIVP: University of Utah Health • Text Messaging: Text ushp to 22333 • Off-Label Uses of Medications

• We recommend the PollEverywhere app or web browser as they are easier to respond • Dalbavancin • For each question, you can click on the correct answer in Web Browser or App or text correct • Oritavancin answer to 22333

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1 Learning Objectives - Pharmacists Learning Objectives - Technicians

Explain Explain the mechanism of action and pharmacokinetics of long acting lipoglycopeptides Describe Describe the compounding process for long acting lipoglycopeptides

Evaluate Evaluate literature for utilization of long acting lipoglycopeptides Apply beyond-use-dating requirements to compounded long acting Apply lipoglycopeptides Identify Identify high-risk patient characteristics who may benefit from long acting lipoglycopeptides

Assess the cost associated with long acting lipoglycopeptides Describe Describe the pros and cons of long acting lipoglycopeptide use for treatment Assess

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Patient Case

• CC: right arm pain, redness, erythema, fevers

• HPI: TJ 29-year-old male with PMH of IVDU, homelessness, and psychiatric disorders admitted for IV antibiotic therapy due to a purulent skin and soft tissue infection complicated by right arm osteomyelitis cause by methicillin-resistant S. Aureus Introduction

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2 • More than 13 million people inject drugs worldwide Injection drug use • Approximately 6.5 million have injected drugs increases the risk for in the United States • Viral, bacterial, and fungal infections • People who inject drugs (PWID) are 16 times more likely to develop invasive methicillin- • Recurrent infections due to relapse Background resistant Staphylococcus aureus (MRSA) infections • Multidrug-resistant (MDR) infections • There were nearly 5 times the number of • Incomplete treatment regimens overdose deaths in 2018 compared to 2010 • Frequent contact with healthcare • More than 115,000 Americans died from systems overdoses related to heroin from 1999 to 2018

Journal of Neurological Sciences. 2020;411:1-6 AAFP. 2019;99(2);109-116 CID. 2020:1-8 9 Journal of Neurological Sciences. 2020;411:1-6 10 CDC. 2020 9 10

Bacterial infections in substance use disorder Mechanism for developing infections

• Common pathogens: Staphylococcus aureus, Direct inoculation of bacteria Introduction of Transmission of streptococcus species commensal flora pathogens via present in the Type Rate (%) Cost ($) injection drug into circulation needle sharing Abscesses 59.1 30,064 Skin and soft tissue 53.8 10,254 Poverty, poor Suppression of Unsafe sexual hygiene, Endocarditis 72.4 33,610 immunity practices homelessness Osteomyelitis 60.4 22,607

Journal of Neurological Sciences. 2020;411:1-6 Pharmacotherapy. 2020;40(5):469–478 OFID. 2019; 1-7 11 Journal of Neurological Sciences. 2020;411:1-6 12 CID. 2020:1-8 11 12

3 IVDU

•Increased infection risk •Increased morbidity and mortality Patient Case Strategies for outpatient treatment (oral and OPAT)

Long-acting Lipoglycopeptides What outpatient treatment options Summary Clinical Considerations for Dalbavancin and Oritavancin are available for TJ?

Cost considerations

Addiction Medicine Consult Considerations

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Strategies to facilitate outpatient treatment

Transition to Transition to outpatient parenteral outpatient oral antibiotics therapy antibiotics (OPAT)

Management

15 Pharmacotherapy. 2020;40(5):469–478 16 15 16

4 Limitations to oral antibiotic therapy Limitations to outpatient parenteral antibiotics

Knowledge of Need for IV Maintenance for medication Need for stable access line care administration housing Ability to adhere Lower Risk of techniques to dosing bioavailabity of subtherapeutic intervals select antibiotics concentrations Proper Risk of IV-line Risk of IV-line Insurance medication contamination misuse storage coverage

Pharmacotherapy. 2020;40(5):469–478 17 Pharmacotherapy. 2020;40(5):469–478 18 17 18

Barriers to current strategies Barriers to current strategies

Poor Poor Prolonged Prolonged candidates Increase candidates Increase for hospital for hospital Prevents admission healthcare Prevents admission healthcare outpatient costs, outpatient costs, oral or hospital for oral or hospital for discharge parenteral unnecessary discharge parenteral unnecessary parenteral hospital parenteral hospital antibiotic antibiotic antibiotic exposure antibiotic exposure therapy course therapy course

• Psychiatric disorders • Psychiatric disorders • Poor physical health • Poor physical health • Homelessness • Homelessness • Incarceration • Incarceration • Poor health insurance • Poor health insurance

Journal of Neurological Sciences. 2020;411:1-6 Journal of Neurological Sciences. 2020;411:1-6 Pharmacotherapy. 2020;40(5):469–478 19 Pharmacotherapy. 2020;40(5):469–478 20 19 20

5 IVDU

•Increased infection risk •Increased morbidity and mortality

Strategies for outpatient treatment (oral and OPAT)

•Many limitations to optimal management •PWID are often poor candidates for standard outpatient therapy Long-acting •Leads to prolonged hospitalizations New therapeuticLipoglycopeptides approaches may be are warranteduseful antibioticsto facilitate to transition safe and patients into an outpatient Summary effective hospitalsetting discharge strategies for vulnerable patients

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Knowledge check What high-risk characteristics contribute to Patient Case prolonging length of hospitalization stays? Susceptibility Staphylococcus aureus Daptomycin Sensitive • Psychiatric disorders Linezolid Sensitive Oxacillin Resistant • Poor physical health Rifampin Sensitive • Homelessness Sulfamethoxazole Resistant • Intravenous drug use Vancomycin Sensitive Oritavancin Pending • All the above Dalbavancin Pending

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6 Long-acting Lipoglycopeptides

• Agents: • Oritavancin • Dalbavancin • Semisynthetic derivatives of naturally occurring glycopeptides • Contain lipophilic side chain on heptapeptide core which contributes to prolongs half-life

Long-acting Lipoglycopeptides

25 Pharmacotherapy. 2010;30(1):80–94 26 Clinical Therapeutics. 2015:36(12):2619-2636 25 26

Properties Oritavancin (Orbactiv) Dalbavancin (Dalvance) Concentration-dependent bactericidal Concentration-dependent bactericidal Activity Mechanism of action activity activity FDA Indications ABSSTI ABSSTI Dose 1,200 mg once 1,000 mg IV, then 500 mg IV a week later Increased affinity to the D-ala-D-ala binding site Renal Adjustments None 1125 mg IV, then 750 mg a week later CrCl<30 mL/min Dimerize and stabilize binding to the peptidoglycan cell wall Administration 3-hour IV infusion 30-minute IV infusion Half-life 10 days 14 days Artificially prolong aPTT, increase warfarin Anchor to the membrane via hydrophobic substituents Warnings LFT elevation exposure Headache, Nausea, Vomiting, ALT Adverse effects Nausea, Vomiting, ALT elevations Disrupts bacterial membrane potential (Oritavancin) elevations Drug CYP2C9, CYP2C19 inhibitor None Interactions CYP3A4, CYP2D6 inducer Contraindication UFH for 5 days after use None

Pharmacotherapy. 2010;30(1):80–94 Dalbavancin [package insert]. 2014. Clinical Therapeutics. 2015:36(12):2619-2636 27 Oritavancin [package insert]. 2014. 28 27 28

7 Properties Oritavancin (Orbactiv) Dalbavancin (Dalvance) Properties Oritavancin (Orbactiv) Dalbavancin (Dalvance) Concentration-dependent bactericidal Concentration-dependent bactericidal Concentration-dependent bactericidal Concentration-dependent bactericidal Activity Activity activity activity activity activity FDA Indications ABSSTI ABSSTI FDA Indications ABSSTI ABSSTI Dose 1,200 mg once 1,000 mg IV, then 500 mg IV a week later Dose 1,200 mg once 1,000 mg IV, then 500 mg IV a week later Renal Renal Adjustments None 1125 mg IV, then 750 mg a week later Adjustments None 1125 mg IV, then 750 mg a week later CrCl<30 mL/min CrCl<30 mL/min Administration 3-hour IV infusion 30-minute IV infusion Administration 3-hour IV infusion 30-minute IV infusion Half-life 10 days 14 days Half-life 10 days 14 days Artificially prolong aPTT, increase warfarin Artificially prolong aPTT, increase warfarin Warnings LFT elevation Warnings LFT elevation exposure exposure Headache, Nausea, Vomiting, ALT Headache, Nausea, Vomiting, ALT Adverse effects Nausea, Vomiting, ALT elevations Adverse effects Nausea, Vomiting, ALT elevations elevations elevations Drug CYP2C9, CYP2C19 inhibitor Drug CYP2C9, CYP2C19 inhibitor None None Interactions CYP3A4, CYP2D6 inducer Interactions CYP3A4, CYP2D6 inducer Contraindication UFH for 5 days after use None Contraindication UFH for 5 days after use None

Dalbavancin [package insert]. 2014. Dalbavancin [package insert]. 2014. Oritavancin [package insert]. 2014. 29 Oritavancin [package insert]. 2014. 30 29 30

Properties Oritavancin (Orbactiv) Dalbavancin (Dalvance) Properties Oritavancin (Orbactiv) Dalbavancin (Dalvance) Concentration-dependent bactericidal Concentration-dependent bactericidal Concentration-dependent bactericidal Concentration-dependent bactericidal Activity Activity activity activity activity activity FDA Indications ABSSTI ABSSTI FDA Indications ABSSTI ABSSTI Dose 1,200 mg once 1,000 mg IV, then 500 mg IV a week later Dose 1,200 mg once 1,000 mg IV, then 500 mg IV a week later Renal Renal Adjustments None 1125 mg IV, then 750 mg a week later Adjustments None 1125 mg IV, then 750 mg a week later CrCl<30 mL/min CrCl<30 mL/min Administration 3-hour IV infusion 30-minute IV infusion Administration 3-hour IV infusion 30-minute IV infusion Half-life 10 days 14 days Half-life 10 days 14 days Artificially prolong aPTT, increase warfarin Artificially prolong aPTT, increase warfarin Warnings LFT elevation Warnings LFT elevation exposure exposure Headache, Nausea, Vomiting, ALT Headache, Nausea, Vomiting, ALT Adverse effects Nausea, Vomiting, ALT elevations Adverse effects Nausea, Vomiting, ALT elevations elevations elevations Drug CYP2C9, CYP2C19 inhibitor Drug CYP2C9, CYP2C19 inhibitor None None Interactions CYP3A4, CYP2D6 inducer Interactions CYP3A4, CYP2D6 inducer Contraindication UFH for 5 days after use None Contraindication UFH for 5 days after use None

Dalbavancin [package insert]. 2014. Dalbavancin [package insert]. 2014. Oritavancin [package insert]. 2014. 31 Oritavancin [package insert]. 2014. 32 31 32

8 Spectrum of Activity CLSI Breakpoints

Microbiology Oritavancin Dalbavancin Staphylococcus ✓ ✓ Streptococcus ✓ ✓ MIC Oritavancin Dalbavancin Enterococcus ✓ ✓ Vancomycin-resistant enterococci (VRE) ✓ (VanA and VanB) ✓ (VanB only) Staphylococcus spp. ≤0.12 ≤0.25 Enterococcus faecalis Vancomycin-intermediate S. aureus (VISA) ✓ ✓ ≤0.12 ≤0.25 (vancomycin-susceptible) Vancomycin-resistant S. aureus (VRSA) ✓ Streptococcus spp. ≤0.25 ≤0.25 Gram-positive aerobes ✓ ✓ Gram-positive anaerobes ✓ ✓

Pharmacotherapy. 2010;30(1):80–94 Dalbavancin [package insert]. 2014. Clinical Therapeutics. 2015:36(12):2619-2636 33 Oritavancin [package insert]. 2014. 34 33 34

Compounding Oritavancin Compounding Dalbavancin

Reconstitution Dilution Storage Reconstitution Dilution Storage

• Add 40 mL of • Withdraw 120 mL • Room • Add 25 mL of • Transfer dose to • Total time from SWFI to 3 vials from a 1000 mL Tem perature: use SWFI or D5W to IV bag of D5W reconstitution to bag of D5W within 6 hours each vial (ONLY) dilution BUD: 48 • Swirl vial until (ONLY) hours completely • Refrigerator: use reconstituted until • Withdraw 40 mL within 12 hours • Swirl vial until • Final clear to light from each vial completely concentration: • Store at room yellow final reconstituted must be 1 – 5 temperature or product until clear to mg/mL in the • Inject all 120 mL light yellow final refrigerator to the D5W bag product

Dalbavancin [package insert]. 2014. 35 Dalbavancin [package insert]. 2014. 36 Oritavancin [package insert]. 2014. Oritavancin [package insert]. 2014. 35 36

9 IVDU

•Increased infection risk •Increased morbidity and mortality

Oritavancin Strategies for outpatient treatment (oral and OPAT)

•Many limitations to optimal management •PWID are often poor candidates for outpatient therapy •Leads to prolonged hospitalizations

• 400 mg vial: $1,194.80 Long-acting Lipoglycopeptides •Broad spectrum of activity for gram-positive pathogens •Prolonged half-life due to the addition of a lipophilic side chain • Non-formulary •Oritavancin covers VanA and VanB isolates of VRE •Compatible in D5W only Cost Summary Dalbavancin

• 500 mg vial: $1,896.89 • Non-formulary

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Knowledge Check What pharmacokinetic properties contribute to long- Patient Case acting lipoglycopeptides prolonged duration of action? Susceptibility Staphylococcus aureus •Increased affinity and potency Daptomycin Sensitive Linezolid Sensitive •Dimerize and stabilize binding to the peptidoglycan cell wall Oxacillin Resistant •Dimers anchor to the bacterial membrane by means of their Rifampin Sensitive hydrophobic substituents Sulfamethoxazole Resistant Vancomycin Sensitive •Increased binding affinity to the D-ala-D-ala site Oritavancin No interpretation •All the above Dalbavancin Sensitive MIC <0.25

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10 Patient Case

Would you consider dalbavancin for management of TJ’s infection?

Let's look at the evidence!

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Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Phase II, single-center, 7:1 randomized, open-label, comparator-controlled, parallel-group study from Randomized Clinical Trial of Efficacy and Safety March 2016 and December 2017 Pathogens Population Patients ≥18 years of age with a first episode of osteomyelitis Bacteria Dalbavancin Standard of care Number n=70 n=10 MRSA 4 (5%) 1 (10%) Intervention Dalbavancin 1,500 mg on day 1 and Standard of care twice daily for 4 to 6 day 8 weeks MSSA 38 (54%) 5 (50%) Characteristics CoNS 14 (20%) 2 (20%) Age (mean, yr) 49 (26-79) 54 (29-79) E. Faecalis 7 (10%) 1 (10%) BMI (mean) 26 30 CRP (mean) 43 20 E. Faecium 1 (1%) 0 (0%) ESR (mean) 33 30 Strep spp. 3 (4%) 1 (10%) Bacteremia 4 0 Mixed Infection 11 2 Anaerobes 9 (10%) 0 (0%) Debridement 70 10

OFID. 2019: 1-8. 43 OFID. 2018: 1-8. 44 43 44

11 Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A 2 patients lost to 1 failure due to Randomized Clinicalfollow Trial-up, of clinical Efficacy and Safetyrequiring > 6 weeks of Randomized Clinical Trial of Efficacy and Safety mITTimprovementPrimary Outcomes on day 8 therapy mITT Primary Outcomes Outcomes Dalbavancin (n=67) Standard of Care (n=8) Outcomes Dalbavancin (n=67) Standard of Care (n=8) Clinical cure at day 42 65/67 (97%) 7/8 (87.5%) Clinical cure at day 42 65/67 (97%) 7/8 (87.5%) Secondary Outcomes Secondary Outcomes Clinical Improvement at day 21 63/67 (94%) 5/8 (62.5%) Clinical Improvement at day 21 63/67 (94%) 5/8 (62.5%) Clinical Cure at 6 months 63/67 (94%) 7/8 (87.5%) Clinical Cure at 6 months 63/67 (94%) 7/8 (87.5%) Clinical cure at 1 year 63/67 (94%) 5/8 (87.5%) Clinical cure at 1 year 63/67 (94%) 5/8 (87.5%)

mITT: patients with suspected gram-positive osteomyelitis; excludes patients with only a gram-negative pathogen in blood and/or bone cultures mITT: patients with suspected gram-positive osteomyelitis; excludes patients with only a gram-negative pathogen in blood and/or bone cultures Clinical cure: recovery without need for additional antibiotic therapy Clinical cure: recovery without need for additional antibiotic therapy Clinical Improvement: no worsening of pain or point tenderness compared to baseline and decrease in CRP Clinical Improvement: no worsening of pain or point tenderness compared to baseline and decrease in CRP

OFID. 2018: 1-8. 45 OFID. 2018: 1-8. 46 45 46

Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Baseline Gram-Positive Bacteremia Randomized Clinical Trial of Efficacy and Safety Organism Dalbavancin (n=4) Standard of Care (n=0) Microbiological-mITT Primary Outcomes MSSA 2 (50%) 0 (0%) Outcomes Dalbavancin (n=67) Standard of Care (n=8) CoNS 2 (50%) 0 (0%) Clinical cure at day 42 60/62 (96.8%) 7/8 (87.5%) Secondary Outcomes Baseline Gram-Positive Bacteremia Susceptible to treatment 62/62 (100%) 8/8 (100%) Clinical failure 0 (0%) 7/8 (87.5%) Outcomes Dalbavancin (n=4) Clinical cure at 1 year 63/67 (94%) 5/8 (87.5%) Clearance of bacteremia 4 (100%)

Micro-mITT: subset of the mITT patients that had a gram-positive pathogen in blood and/or bone cultures Clinical cure: recovery without need for additional antibiotic therapy Clinical Improvement: no worsening of pain or point tenderness compared to baseline and decrease in CRP

OFID. 2018: 1-8. 47 OFID. 2018: 1-8. 48 47 48

12 Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety All patients had elevated CRP Pharmacoeconomic Outcomes in both treatment groups Outcomes Dalbavancin (n=67) Standard of Care P value (n=8) CRP decreased in all patients Length of stay (mean, days) 15.8 ± 7.1 33.3 ± 14.2 < 0.001 IV infusion (mean, hours) 1 ± 0.02 101.3 ± 20.8 - by day 28 Treatment duration (mean, days) 2.0 ± 0 31.6 ± 7.0 -

OFID. 2018: 1-8. 49 OFID. 2018: 1-8. 50 49 50

Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial A Two-Year, Multicenter, Retrospective Study of Efficacy and Safety Two-year, multicenter, retrospective, descriptive study from January 1, 2016 to December 31, 2018 Safety Population Patients diagnosed with acute osteomyelitis receiving oritavancin monotherapy Outcomes Dalbavancin (n=67) Standard of Care (n=8) Number n=134 Drug-related adverse effects 1 (1.4%) 0 (0%) Intervention Oritavancin 1200 mg followed by 800 mg once weekly for 4 to 5 weeks Deaths 1 (1.4%) 0 (0%) Characteristics Male 66 (49%) Age, years, mean (range) 60 (19-97) Conclusion • Demonstrated positive clinical efficacy rates on both the mITT and micro-mITT analyses Weight, kg, mean (range) 78 (38-164) • Achieved clearance of blood cultures in patients with gram-positive bacteremia BMI, kg/m2, mean (range) 27 (15.8-48.4) • Displayed mild adverse effect profile and medication tolerance Bacteremia 9 (6.7%) • Identified statistically significant shorter length of stay in the dalbavancin group Debridement 121 (90.3%) • Estimates shorter total IV-infusion time and active days on therapy IVDU 6 (4.5%) Limitations Single center study design, small sample size, descriptive, open-label and non-blinded, Prosthetic device 24 (17.9%) limited to primary osteomyelitis Previous antibiotics 18 (13.4%) > 3 co-morbidities 55 (43.5%)

OFID. 2018: 1-8. 51 Drugs - Real World Outcomes. 2020: 7(1): S41–S45 52 51 52

13 Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: A Two-Year, Multicenter, Retrospective Study A Two-Year, Multicenter, Retrospective Study Primary Outcomes Pathogens isolated (n=128) Outcomes ETE (n=134) PTE (n=130) MRSA 92 (77%) Clinical success 118 (88.1%) 104 (80.0%) MSSA 25 (21%) Persistent relapsing infection VRE 7 (5%) Secondary Outcomes VISA 2 (1%) Outcomes ETE (n=134) PTE (n=130) VRE (daptomycin MIC > 4) 2 (1%) Clinical failure 9 (6.7%) 4 (3.0%)

ETE: assessment 7–10 days after the end of the last dose PTE: assessment 3 and 6 months after the end of last dose Clinical success: resolution of symptoms or improvement in symptoms, no further need for treatment Clinical failure: lack of improvement, need of additional antibiotics for osteomyelitis, admission to hospital for osteomyelitis, or loss to follow up

Drugs - Real World Outcomes. 2020: 7(1): S41–S45 53 Drugs - Real World Outcomes. 2020: 7(1): S41–S45 54 53 54

Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: A Two-Year, Multicenter, Retrospective Study Subgroups evaluated at ETE Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: Outcomes 4-dose regimen (n=118) 5-dose regimen (n=16) A Two-Year, Multicenter, Retrospective Study Clinical success 107 (90.7%) 11 (68.8%) Conclusion • Demonstrated low failure rates in both the ETE and PTE analysis • Showed clinical success while including patients with co-morbidities Baseline Gram-Positive Bacteremia • Achieved clearance of blood cultures in patients with gram-positive bacteremia • Displayed mild adverse effect profile and medication tolerance Outcomes Oritavancin (n=9) • Included patients with all ranges of renal function without high rates of adverse effects Clearance of bacteremia 9 (100%) • A five-dose regimen may not provide additional benefit in clinical success rates Limitations Retrospective, observational, non-comparative methodology

Drugs - Real World Outcomes. 2020: 7(1): S41–S45 55 Drugs - Real World Outcomes. 2020: 7(1): S41–S45 56 55 56

14 DALBACEN cohort: dalbavancin as consolidation therapy in patients DALBACEN cohort: dalbavancin as consolidation therapy in patients with endocarditis and/or bloodstream infection produced by gram-positive with endocarditis and/or bloodstream infection produced by gram-positive cocci cocci IE Baseline Microbiology Multicenter, observational, retrospective study from 2016 to December 2017. CoNS 15 (43%) Population Patients > 18 years of age with gram-positive cocci infective endocarditis or blood MSSA 7 (20%) stream infection MRSA 3 (8%) Number n=83 Strep spp. 7 (20%) Intervention Patients received at least 1 dose of dalbavancin E. faecalis 3 (8%) Characteristics Male 61 (73.5%) BSI Baseline Microbiology Age, median (range) 73 (53-77) CoNS 17 (34.7%) Bacteremia 49 (59%) Infective Endocarditis 34 (41%) MSSA 15 (30.6%) Mean Charleston Index Score 2 MRSA 9 (18.4%) DBV-covered days 14 Strep spp. 2 (4.1%) E. faecalis 1 (2%) E. Facium 2 (4.1%)

Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 57 Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 58 57 58

DALBACEN cohort: dalbavancin as consolidation therapy in patients DALBACEN cohort: dalbavancin as consolidation therapy in patients with endocarditis and/or bloodstream infection produced by gram-positive with endocarditis and/or bloodstream infection produced by gram-positive cocci cocci Primary Outcome - Infective Endocarditis (n=34) Primary Outcome – Bloodstream infections Outcomes Dalbavancin Outcomes Dalbavancin (n=49) Clinical cure 33 (97%) Clinical Cure 49 (100%) Clinical failure• 3 deaths unrelated to 1 (3%) DBV treatment Secondary Outcome – Bloodstream infections Secondary• 2 patients’ Outcome with new - Infective Endocarditis (n=34) episodes of endocarditis Outcomes Dalbavancin (n=49) Outcomesdue to different organism Dalbavancin 90-day relapse 0 (0%) 90-day relapse 0 (0%) Reduction in length of stay (mean, days) 14 days Clinical cure at 12-months 33 (85%) Negative follow-up blood cultures (n=36) 35 (97.2%) Negative follow-up blood cultures (n=17) 17 (100%)

• Clinical cure: recovery without relapse of IE due to the same microorganism within 3 months • Clinical cure: recovery without repeat positive blood cultures due to the same microorganism • Failure: persistent or breakthrough BSI during the IE treatment or when the same microorganism was isolated in the blood • Failure: persistent or breakthrough BSI during the IE treatment or when the same microorganism was isolated in the blood culture of a patient with IE requiring surgery after completing antibiotic therapy culture of a patient with IE requiring surgery after completing antibiotic therapy

Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 59 Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 60 59 60

15 DALBACEN cohort: dalbavancin as consolidation therapy in patients with endocarditis and/or bloodstream infection produced by gram-positive DALBACEN cohort: dalbavancin as consolidation therapy in patients cocci with endocarditis and/or bloodstream infection produced by gram-positive Outcomes Dalbavancin (n=83) cocci Adverse effects 3 (4%) Estimated Pharmacoeconomic Outcomes Development of CDI 0 (0%) Outcomes Dalbavancin Reduction in hospital stay for BSI (sum, days) 636 Conclusions • Demonstrated low failure rates in patients with IE or BSI • Achieved clearance of blood cultures in patients with gram-positive bacteremia Reduction in hospital stay for IE (sum, days) 557 • Displayed mild adverse effect profile and medication tolerance Early Discharges (sum, patients) 71 • Showed low relapse rates of infections due to the same pathogen Cost savings for BSI (sum, Euro) 315,424.20€ Limitations Small sample size, no comparator group, retrospective descriptive study design, multiple dosing regimens Cost savings for IE (sum, Euro) 283,187.45€

Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 61 Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 62 61 62

IVDU

• Increased infection risk • Increased morbidity and mortality Knowledge Check

Strategies for outpatient treatment (oral and OPAT) Based on the Dalbavancin for the Treatment of Osteomyelitis • Many limitations to optimal management in Adult Patients: A Randomized Clinical Trial of Efficacy and • PWID are often poor candidates for outpatient therapy • Leads to prolonged hospitalizations Safety trial, what were the clinical observations found with

Long-acting Lipoglycopeptides Dalbavancin?

• Broad spectrum of activity for gram-positive pathogens • Prolonged half-life due to the addition of a lipophilic side chain • Positive clinical efficacy Summary • Oritavancin covers VanA and VanB isolates of VRE Clinical and Cost Considerations for Dalbavancin and Oritavancin • Clearance of blood cultures

• Demonstrated low failure rates in patients with osteomyelitis, endocarditis, and bacteremia • Mild adverse effect • Achieved clearance of blood cultures in patients with gram-positive bacteremia • Displayed mild adverse effect profile and medication tolerance • Shorter length of stay • Identified potential benefit to shorten length of stay decrease total IV-infusion time, and reduced healthcare expenses • Shorter total IV-infusion time • All the above

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16 Knowledge Check Patient Case What are the potential benefits of initiating a long- acting lipoglycopeptide in a high-risk PWID?

• Dalbavancin was considered as an alternative • No PICC required antibiotic agent for TJ • Potential health care cost savings • Uncontrolled psychiatric illness and substance • No level monitoring use disorder • Convenient dosing regimen • All the above • Addiction and psychiatry consultation • Continued vancomycin for 6 weeks of IV therapy

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Addiction Medicine Consultations Reduce Readmission Rates for Patients With Serious Infections From Opioid Use Disorder Retrospective chart review from January 2016 and January 2018 Population Patients defied via ICD-10 code for IDU, OUD, and ICD-10 code for serious infections that generally require prolonged parenteral antibiotics Number n=125 Intervention Consultation with an addiction medicine physician Characteristics Addiction Consult (n=38) Non-Addiction Consult (n=87) Female 21 (55%) 46 (52%) Age, yr, median (range) 36 (19-63) 35 (19-67) IV heroin use 37 (97%) 81 (93) Bipolar Disorder 2 (5%) 6 (7%) Osteomyelitis 7 (18%) 19 (22%) Bacteremia 9 (24%) 21 (24%) Endocarditis 25 (66%) 43 (49%) Diabetes 2 (5%) 3 (3%) Addiction Medicine Considerations HCV 25 (66%) 34 (39%)

67 OFID. 2020. 1-4 68 67 68

17 Addiction Medicine Consultations Reduce Readmission Rates for Patients With Serious Infections From Opioid Use Disorder Primary Outcomes Outcomes Addiction Consult No Addiction Consult P Value (n=38) (n=87) Addiction Medicine Consultations Reduce Readmission Rates for Patients Medication-assisted 33 (87%) 15 (17%) <.0001 With Serious Infections From Opioid Use Disorder treatment Conclusions • Demonstrated statistically significant improvements in receiving MAT therapy Antibiotic completion 30 (78.9%) 35 (40.2%) <.0001 • Achieved statistically significant rates of antibiotic completion • Displayed statistically significant few patients who elopement or leave AMA Elopements/AMA 6 (15.8%) 43 (49.4%) 0.0003 • Showed significantly fewer readmissions within 90 days after discharge Limitations Small sample size, single center, retrospective study design, section bias, 90-day Readmission treatment/consult refusal Addiction medicine consultation reduced readmissions within 90 days of discharge (HR 0.378; 95% CI 0.21-0.69)

CID 2019:68: 1-3. 69 OFID. 2020. 1-4 70 69 70

IVDU

• Increased infection risk Addiction Medicine Consults in PWID • Increased morbidity and mortality Strategies for outpatient treatment (oral and OPAT)

• Many limitations to optimal management • PWID are often poor candidates for outpatient therapy • Growing evidence suggest improved care in patients who • Leads to prolonged hospitalizations are admitted for serious infections requiring prolonged Long-acting Lipoglycopeptides • Broad spectrum of activity for gram-positive pathogens antibiotic therapy and hospitalization • Prolonged half-life due to the addition of a lipophilic side chain Summary • Oritavancin covers VanA and VanB isolates of VRE Clinical Considerations for Dalbavancin and Oritavancin Increase Decrease Increase Reduce Reduce • Demonstrated low failure rates in patients with osteomyelitis, endocarditis, and patient healthcare antibiotic bacteremia hospital stay elopements • Achieved clearance of blood cultures in patients with gram-positive bacteremia engagement costs completion • Displayed mild adverse effect profile and medication tolerance • Identified potential benefit to shorten length of stay decrease total IV-infusion time, and reduced healthcare expenses

Addiction Medicine Consult Considerations

• Increased MAT treatment • Increased likelihood of antimicrobial completion • Reduced readmission rates 71 71 72

18 Knowledge check Knowledge Check If dalbavancin was ordered for TJ in the outpatient setting, How long would TJ’s dalbavancin product be stable for what IV solution must dalbavancin be compounded in? if kept in the fridge?

• Normal Saline • 24 hours • Dextrose 5% Water • 12 hours • Sterile water for injection • 6 hours • 48 hours

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Knowledge Check Dalbavancin was ordered in clinical for treatment of osteomyelitis. Pros Cons Based on the Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety trial, the Safety profile Evidence growing for dose studied was 1500 mg on day 1 and day 8. Approximately how Long-acting use in non-ABSSSI much will total treatment cost in dollar amount? lipoglycopeptides PICC not required for Oritavancin contraindicated with use heparin for 5 days • $11,300.00 No drug-level monitoring Only compatible in D5W • $7,700.00 Dalbavancin 500 mg vial: Convenient dosing • $15,900.00 Expensive!! $1,897 regimen • $21,100.00

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19 • Limited evidence demonstrates that long-acting lipoglycopeptides may be a • Long-acting lipoglycopeptides use may facilitate earlier discharges into beneficial alternative to oral and IV-treatment for osteomyelitis, bacteremia, outpatient settings and endocarditis for specific patients • Earlier transitions to outpatient settings may lead to decreased heath care costs • Use may avoid the need for PICC-line placement, risk of line-associated infections, or line misuse • Outpatient management may limit time spent in hospital and exposure to nosocomial pathogens • Potential beneficial option to consider to maintain parenteral antibiotic therapy and avoid oral regimens with lower bioavailability’s • Addiction consult services significantly improved patient care outcomes in receiving MAT therapy, completing antibiotic treatment and lower 90- • Once weekly dosing regimens may a patient-centered regimen to avoid the readmission rates for patients with opioid use disorder complexity of home infusions • Large, randomized comparator clinical trials are warranted to compare of • Evidence shows mild adverse event profiles long-acting lipoglycopeptides long-acting lipoglycopeptides to standards of care

Summary Summary

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References

• Kolla B. et al. Infectious disease occurring in the context of substance use disorder: a concise review. Journal of Neurological Sciences. 2020;411:1-6 • Visconti A. et al. Primary Care for Persons Who Inject Drugs. AAFP. 2019;99(2);109-116 • McCarthy N. et al. Bacterial Infections Associated With Substance Use Disorders, Large Cohort of United States Hospitals, 2012–2017. 2020. 1-8 • Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose Deaths — United States, 2013–2017. MMWR Morb Mortal Wkly Rep 2019;67:1419–1427. DOI: http://dx.doi.org/10.15585/mmwr.mm675152e1 • Understanding the Epidemic. CDC. 2020. DOI: https://www.cdc.gov/drugoverdose/epidemic/index.html • Opioid Data Analysis and Resources. CDC. 2020. DOI: https://www.cdc.gov/drugoverdose/data/analysis.html • Krsak M. Advantages of Outpatient Treatment with Long-Acting Lipoglycopeptides for Serious Gram-Positive Infections: A Review. Pharmacotherapy. 2020;40(5):469–478 • Buehrle D. Risk Factors Associated with Outpatient parenteral Antibiotic Therapy Program Failure Among Intravenous Drug Users. OFID. 2019; 1-7 • Guskey M. A Comparative Review of the Lipoglycopeptides: Oritavancin, Dalbavancin, and Telavancin. Pharmacotherapy. 2010;30(1):80–94) • Roberts K. et al. Dalbavancin and Oritavancin: An Innovative Approach to the Treatment of Gram-Positive Infections. Pharmacotherapy. 2015;35(10):935–948 • Klinker K. Borgert S. Beyond Vancomycin: The Tail of the Lipoglycopeptides. Clinical Therapeutics. 2015:36(12):2619-2636 • Fanucchi L. Outpatient Parenteral Antimicrobial Therapy Plus Buprenorphine for Opioid Use Disorder and Severe Injection-related Infections. CID. 2020:70: 1226-1229 • Dalbavancin [package insert]. 2014. • Oritavancin [package insert]. 2014. • Rappo U. et al. Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety. Open Forum Infect Dis. 2019 Jan; 6(1): 1-8 • Van Hise N. et al. Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: A Two-Year, Multicenter, Retrospective Study. Drugs - Real World Outcomes. 2020: 7(1): S41–S45 • Marks L. et al. Addiction Medicine Consultations Reduce Readmissions Rates for Patients with Serious Infections from Opioid Use Disorder. CID. 2018;67: 795-798 • Hidalgo-Tenorio C. DALBACEN cohort: dalbavancin as consolidation therapy in patients with endocarditis and/or bloodstream infection produced by gram-positive cocci Ann Clin Microbiol Antimicrob. 2019; 18(30):1-10 Questions?

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