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
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-2
Single-Dose Antimicrobials Route of administration Penicillin G benzathine IM for syphilis Pharmacokinetics Azithromycin for Chlamydia trachomatis Formulation Azithromycin microspheres for CAP CAP = Community-acquired pneumonia Workowski KA. Clin Infect Dis 2015;61(Suppl 8). Abramowicz M et al. Med Lett Drugs Ther 2005;47(1218):78-80. 2016 MFMER slide-3
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-4
Single-Dose Antimicrobials Disadvantages Standardized dosing Antimicrobial stewardship May be lost to follow up Therapeutic drug monitoring Safety data Roberts KD et al. Pharmacotherapy 2015;35:935-48. Crotty MP et al. J Clin Microbiol 2016;54:2225-32. 2016 MFMER slide-5
Dalbavancin and Oritavancin One-Hit Wonders? 2016 MFMER slide-6
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-7
Vancomycin Dalbavancin Oritavancin 2016 MFMER slide-8
13 Oritavancin 1 Dalbavancin 3 1 1 2 2 2 2
Spectrum of Activity Staphylococcus spp. MSSA MRSA hvisa VISA VRSA DNSSA Vancomycin V X X V Dalbavancin V X Oritavancin V = variable 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 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-10
Spectrum of Activity Other organisms Strep spp. VSE VRE G+ anaerobes Gram negatives Vancomycin X X Dalbavancin V X Oritavancin X V = variable VSE = Vancomycin-sensitive Enterococcus VRE = Vancomycin-resistant Enterococcus 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-11
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 InH = Inhibitor InD = Inducer TDM = Therapeutic drug monitoring Crotty MP et al. J Clin Microbiol 2016;54:2225-32. 2016 MFMER slide-12
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-13
Study Design and Treatment DISCOVER 1 & 2 Design International, multicenter, randomized, double-blind, doubledummy 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 Boucher HW et al. N Eng J Med 2014;370(23):2169-79. 2016 MFMER slide-14
Efficacy and Safety Assessments DISCOVER 1 & 2 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 Boucher HW et al. N Eng J Med 2014;370(23):2169-79. 2016 MFMER slide-15
% of patients Treatment Success DISCOVER 1 & 2 100 1.5 (-4.6-7.9) -1.5 (-7.4-4.6) -0.1 (-4.5-4.2) 80 82 83 78 77 80 80 60 40 Vancomycin Dalbavancin 20 0 DISCOVER 1 DISCOVER 2 Both Trials *Absolute difference (95% confidence interval) Boucher HW et al. N Eng J Med 2014;370(23):2169-79. 2016 MFMER slide-16
% of patients Secondary Endpoints DISCOVER 1 & 2 MSSA MRSA Streptococcus spp. 100 80 60 40 20 Investigator-assessed clinical response 97 98 98 97 100 92 0 Staphylococcus aureus MRSA Streptococcus pyogenes Vancomycin Dalbavancin MSSA = Methicillin-Susceptible S. aureus MRSA = Methicillin-Resistant S. aureus Boucher HW et al. N Eng J Med 2014;370(23):2169-79. 2016 MFMER slide-17
Study Critique DISCOVER 1 & 2 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 TDM = Therapeutic drug monitoring Boucher HW et al. N Eng J Med 2014;370(23):2169-79. 2016 MFMER slide-18
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-19
% of patients 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 100 80 81 84 84 85 84 85 85 85 60 40 1-Dose 2-Dose 20 0 48-72 hr 36-75 hr Day 14 Day 18 Treatment response Clinical success ABSSSI = Acute bacterial skin and skin structure infection Dunne MW et al. Clin Infect Dis 2016;62(5):545-51. 2016 MFMER slide-20
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-21
Study Design and Treatment SOLO I & SOLO II 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 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-22
Efficacy and Safety Assessments SOLO I & SOLO II 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 *ECE = Early clinical evaluation (48-72 hours after drug initiation) 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
% of patients % of patients % of patients Primacy Outcome (non-inferiority) SOLO I & SOLO II 100 80 60 40 20 Composite 79 82 83 80 0 SOLO I SOLO II Vancomycin Oritavancin 100 80 60 40 20 0 80 80 81 83 SOLO I Clinical cure Lesion reduction 20% SOLO II 100 80 60 40 20 0 83 87 85 86 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-24
Microbiological Population SOLO I & SOLO II At least one pathogen Difference Staphylococcus aureus MRSA SOLO I SOLO II MSSA Streptococcus species S. anginosus group S. pyogenes -20-15 -10-5 0 5 10 15 20 Vancomycin better Oritavancin better MRSA = Methicillin-Resistant S. aureus MSSA = Methicillin-Sensitive S. aureus 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-25
Study Critique SOLO I & SOLO II 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 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-26
Safety Possibly more serious anaphylactic reactions Dalbavancin Hypotension in phase 2 studies Oritavancin Infusion-related reactions Osteomyelitis Coagulation test abnormalities 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. 2016 MFMER slide-27
Question 2 34 y/o M POD 8 s/p Whipple s procedure is readmitted 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-28
Dalbavancin and Oritavancin Outside of Acute Bacterial Skin and Skin Structure Infections 2016 MFMER slide-29
% of patients Dalbavancin Catheter-Related Bloodstream Infection Open-label, randomized, controlled, phase 2 trial Adults with signs of bacteremia possibly/definitely associated with a catheter Dalbavancin 1000mg IV day 1 then 500mg IV day 8 CoNS MSSA MRSA Vancomycin 1000mg IV q12h E. faecalis Success at Test-of-Cure Visit 100 80 60 p<0.05 87 87 79 96 Vancomycin Dalbavancin 40 50 50 20 0 Overall Clinical Microbiological 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-30
Bone Dalbavancin (mcg/g) Dalbavancin Bone and Articular Tissue Infection Pharmacokinetic modeling of two Phase I studies 12 10 8 6 4 2 Single 1000mg IV dose Observed Predicted Plasma* 15.3 Synovium 15.9 Synovial fluid* 6.2 Bone 4.1 Skin 13.8 *mcg/ml mcg/g Day 14 Concentrations 0 0 200 400 600 800 1000 Time (hr) Dunne MW et al. Antimicrob Agents Chemother 2014;59(4):1849-55. 2016 MFMER slide-31
Dalbavancin Activity against Staphylococcal biofilms Minimum biofilm inhibitory concentration (MBIC) Minimum biofilm bactericidal concentration (MBBC) Dalbavancin Vancomycin MIC 50 MIC 90 MBIC 50 MBIC 90 MBBC 50 MBBC 90 MBBC 50 MBBC 90 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 MRSE = Methicillin-resistant S. epidermidis MSSE = Methicillin-sensitive S. epidermidis MIC = Minimum inhibitory concentration 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. 2016 MFMER slide-32
Oritavancin Blood Stream Infection Two exploratory phase 2 multicenter, openlabel, uncontrolled studies Dose escalation in gram-positive bacteremia q24h for 7-10 days Dose finding in subjects with S. aureus bacteremia q24h for 10-14 days 3 mg/kg then 2 mg/kg/day 4 mg/kg then 3 mg/kg/day 5 mg/kg then 4 mg/kg/day 5 mg/kg/day 6.5 mg/kg/day 8 mg/kg/day 10 mg/kg/day 9/10 complete eradication of grampositive pathogens from blood cultures No serious adverse effects 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%) Information provided by The Medicines Company for Healthcare Professionals only. V01-11-0116 2016 MFMER slide-33
Oritavancin 78 y/o M w/ bioprosthetic aortic valve endocarditis Enterococcus faecium (Vancomycinresistant) Daptomycin 8 mg/kg 8 weeks in, re-admitted CVC infection Oral linezolid x 2 weeks Bacteremia recurred @ 72 hours (Daptomycinresistant) Linezolid + tigecycline Bacteremia recurred @ 48 hours Tigecycline added 5 months later VRE bacteremia Daptomycin + 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)* *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-34
Oritavancin 78 y/o M w/ bioprosthetic aortic valve Completed 7 weeks of Oritavancin Bacteremia recurred @ 2 weeks AVR/MVR + Linezolid + Tigecycline 10 weeks later LFT abnormalities Oritavancin stopped 8 days later VRE bacteremia Oritavancin 1200mg twice weekly Antibiotic 8 mo. Antibiotic 8 mo. Post-operatively anorexia, nausea, lactate Oritavancin 1200mg twice weekly 7 months: LFTs returned normal 17 months: blood cultures clear 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) * -- Test Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase Value 84 U/L 77 U/L 333 U/L *Kirby Bauer disk diffusion (mm) Minimum inhibitory concentration (mcg/ml) VRE = Vancomycin-resistant Enterococcus AVR = aortic valve replacement MVR = mitral valve replacement LFT = Liver function test Johnson JA et al. Open Forum Infect Dis 2015;2(4):ofv156. 2016 MFMER slide-35
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-36
Vancomycin 1500mg q12h x 14 days $121.80 Dalbavancin 1500mg $4,176 Oritavancin 1200mg $2,704 2016 MFMER slide-37
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 *Withdrawn prior to enrollment 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 2016 MFMER slide-38
Question 3 In the event a patient experiences anaphylaxis to oritavancin, he/she should be emergently taken to dialysis True False 2016 MFMER slide-39
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-40
Questions & Discussion 2016 MFMER slide-41