Innovations in Antimicrobials Something Old, Something New

Transcription

1 FSHP Disclosure Innovations in Antimicrobials Something Old, Something New Harrison Bachmeier, PharmD, BCPS Pharmacist Specialist-Infectious Diseases LeeHealth Fort Myers & Cape Coral, FL I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation. Objectives Identify the role of older antimicrobial agents in the treatment of complicated infections Compare new agents approved for gram negative infections Discuss the role of bezlotoxumab for the prevention of C.difficile recurrence Describe the utility of long-acting agents for gram positive infections Gram Negative Resistance is Rising Resistance, Resistance, Resistance Among 3 rd Gen Cephalosporins K. pneumoniae Pseudomonas aeruginosa imipenem Rahal JJ. Clin Infect Dis. 2009; 49:S4 10 E. coli ceftazidime Resistance, Acinetobacter baumannii ceftazidime amikacin imipenem Classification of β-lactamases Classification Name Common Genes Substrates Class A Broad Spectrum ESBL Carbapenemases PC1 SHV1 TEM1 SHV derived TEM derived CTX-M KPC Penicillins, 1 st gen cephalosporins Penicillins, 1-3 rd gen cephalosporins, aztreonam Penicillins, extended spectrum cephalosporins, aztreonam and carbapenems IMP 1-3 rd gen cephalosporins, cephamycins, and Class B Metallo-β-lactamases VIM carbapenems NDM rd Class C Cephalosporinases AmpC Penicillins, 1-3 gen cephalosporins, cephamycins Class D Oxacillinases OXA-1, 2,10, Pseudomonas OXA-11, 14, 15 Penicillins, 1 st generation cephalosporins 1-3 rd gen cephalosporins, aztreonam Antibiotic Resistance Threats in the United States, 2013 Pathogen CDC Threat Level Infections per year by species Drug Resistant Infections per year Deaths per year ESBL Enterobacteriaceae SERIOUS 140,000 26,000 1,700 MDR Pseudomonas SERIOUS 51,000 6, MDR Acinetobacter SERIOUS 12,000 7, Carbapenem- Resistant Enterobacteriaceae ESBL= extended spectrum β-lactamase MDR = multiple drug resistant URGENT 140,000 7,900 Klebsiella spp. 1,400 E. coli 600 Misc. $40,000 excess costs/year for each infection At least 3 different antibiotic classes no longer cure Acinetobacter infections Resistant to all or nearly all antibiotics Bush B, Jacoby GA. Antimicrob Agent Chemo 2010;54(3) Acinetobacter OXA-23,24, 58 Above plus cephamycins and carbapenems CDC

2 Are We Entering into a Post-Antibiotic Age? Number of Antibiotics New antibacterial agents approved in the United States Polymyxins: Our Last Line of Defense Polypeptide antibiotics discovered in1947 Formed by both cationic and hydrophobic amino acids Bind to bacterial cell membranes causing permeability changes and ultimately cell death Clinical use began in the 1960s Polymyxin B Susceptible Pathogens Resistant Pathogens Colistin (Polymyxin E) Breakpoint < 2 mcg/ml Pseudomonas spp Proteus spp Acinetobacter spp Serratia spp E. coli Morganella spp. Klebsiella spp Providencia spp. Enterobacter spp. Neisseria spp. Boucher HW et al. Clin Infect Dis. 2009; 48:1 12 Strom DR et al. Annu Rev Biochem. 1977;46: Sorting Through the Polymyxin Alphabet Soup Colistimethate (CMS) Prodrug of Colistin [active] Labeled as Colistin Base Activity (CBA) 1 MU CMS ~ 44.5 mg CMS 1 MU CMS ~ 30 mg CBA Polymyxin B Active chemical Listed in international units 10,000 units = 1 mg Variability of Polymyxin Serum Drug Concentrations Colistin : 40 fold variability in C ss Polymyxin B: 4 fold variability in C ss 1 Vial = 150 mg CBA = 5 MU CMS = 400 mg CMS 500,000 units = 50 mg = 1 Vial Jian L. Antimicrob Agents Chemother. 2006; 50(12): Lim LM, et al. Pharmacotherapy 2010;30(12): ) Sandri AM et al. Clin Infect Dis 2013;57(4): Garonzik SM et al. Antimicrob. Agents Chemother. 2011;55(7): Polymyxin B Pharmacokinetics Colistimethate (CMS) Pharmacokinetics (Tubular reabsorption) Polymyxin B Parameter Polymyxin B Css avg ~3 mg/ml T ½ 12 hours Protein binding 60 Distribution CSF 5 Urine 4 Respiratory (Tubular secretion) Colistimethate (Tubular reabsorption) Colistin Parameter Colistin Css avg mg/ml C max ~7 hours T ½ 9-13 hours Protein binding 50 Distribution CSF 5 Urine 6-70 Respiratory unknown *Up to 7 hours to achieve maximum serum concentrations Nation RL et al, Clin Infect Dis 2014;59(1):88 94 Nation RL et al, Clin Infect Dis 2014;59(1):

3 Impact of Renal Dysfunction Colistimethate Colistin Polymyxin B Polymyxin B is Associated with Less Nephrotoxicity Nephrotoxicity, Comparison of nephrotoxicity rates P=0.08 P=0.003 Acute Renal Failure, P< CMS = Independent Risk Factor for Acute Renal Failure HR: 3.35; (95 CI, 2.05 to 5.48); P<0.001 Polymyxin B Colistin Polymyxin B CMS Nation RL et al, Clin Infect Dis 2014;59(1):88 94 Phe K et al. Antimicrob Agents Chemother 2014;58:2740e6 Rigatto MH et al. Antimicrob Agents Chemother 2016;60:2443e9. Poor Outcomes Associated with Polymyxins Compared to β-lactams In-Hospital Mortality, Follow up days Retrospective review of 133 patients with P. aeruginosa bacteremia Prospective study with 495 patients with gram-negative infections Median daily dose of polymyxin B: mg Median daily colistin dose: 183mg 83 of comparators received a β-lactam All comparators were β-lactams Factors associated with adjusted in-hospital mortality Multivariate analysis showed increased mortality associated with bacteremia: Polymyxin B - Hazard Ratio 1.9 ( ) p= Adjusted Odds Ratio 1.99 ( ) p= Cumulative Survival, β-lactams 60 Colistin 40 Polymixin-based Combination Therapy Associated with Improved Outcomes Carbapenem- resistant Klebsiella spp. bacteremias are frequently associated with mortality rates around 50 regardless of therapy selected Polymyxin combination therapy seems to be associated with better outcomes but no definitive prospective data is available Polymyxin mono-therapy Polymyxin combo-therapy Mortality Mortality Outcome N, () N, () p- value Tumbarello M, et al CID day mortality 11/22 (50) 13/46 (28) Qureshi ZA, et al AAC day mortality 4/7 (57) 1/7 (14) Zarkotou O, et al Infection related 4/7 (57) 0/14 (0) Clin Micro Infect 2011 mortality Kvitko CH et al. J Antimicrob Chemother. 2011;66(1):175-9 Paul M et al. J Antimicrob Chemother May;65(5): Tumbarello M, et al Clin Infect Dis 2012;55(7): Qureshi ZA, et al Antimicrob Agents Chemo 2012;56(4): Zarkotou O, et al Clin Microbiol Infect 2011; 17: Discrepancies in Approved Colistin Dosing and Target Obtainment Target C ss Attainment, Target C ss Attainment, 1 mg/kg 2.5 mg/kg 3.8 mg/kg 5 mg/kg CBA FDA Dosing/Day Based on ideal body weight OR actual body weight, whichever is lower. > 0.5 mg/l > 1 mg/l > 2 mg/l MIU MIU 9 MIU 9 MIU CMS Europe Medicine Agency Dosing/Day Nation RL et al. Clin Infect Dis 2016;62(5):552 8 Colistin Pharmacokinetic Dosing CMS/colistin pharmacokinetic dosing in critical ill patients (n=102) PK Dosing (MIC < 1 mg/l) Target colistin concentration ~2.5 mg/l Loading Dose CBA (mg) = Colistin target x 2.0 x IBW Maintenance Dose (total daily dose) CBA (mg)/d = colistin target x (1.50 x creatinine clearance + 30) [Q8-12 hour intervals based on renal function] Simplified Dosing Recommendation Based on Updated PK/PD Data (utilized in current NIH study) Loading Dose CrCl >50 ml/min CrCl >30-49 ml/min CrCl >10-29 ml/min 5 mg/kg x 1 (max 300 mg CBA) 5 mg/kg/day divided q8h 3.5 mg/kg/d divided q12h Use ideal body weight or actual body weight, whichever is lower. 2.5 mg/kg/d divided q12h CrCl <10 ml/min or hemodiaylsis 1.5 mg/kg/d divided q24h Garonzik SM et al. Antimicrob. Agents Chemother. 2011;55(7): Pogue JM et al. Clin Microbiol Infect 2017;23: Kaye KS ClinicalTrials.gov. Bethesda (MD): National Library of Medicine(US). 2000e Available at: URL of the record NLM Identifier: NCT

4 Polymyxin B Dosing Considerations Polymyxin B clearance does not correlate with creatinine clearance Suggested Polymyxin B Dosing (pathogen MIC<1 mcg/ml) GAINing New Antibiotic Approvals New antibacterial agents approved in the United States Polymyxin B clearance scaled to total body weight Loading Dose 2.5 mg/kg (TBW) Maintenance Dose 1.25 mg/kg (TBW) every 12 hours No adjustment for renal dysfunction Pathogen MIC = 2 mcg/ml 1.5 mg/kg (TBW) Q12H [limited clinical/safety data] Number of Antibiotics Dalbavancin; May 2014 Tedizolid; June 2014 Oritavancin; Aug 2014 Ceftolozane-tazobactam; Dec 2014 Ceftazidime-avibactam; Feb 2015 Delafloxacin; June now Filled diamond: CVVHD patient (wt=250 kg) Filled triangle: CVVHD patient Sandri AM et al. Clin Infect Dis 2013;57(4): Boucher HW et al. Clin Infect Dis. 2009; 48:1 12 Introducing New Gram Negative Agents tazobactam Advance cephalosporin/ Ceftolozane β-lactamase inhibitor combinations Enhanced gram negative spectrum of activity Pseudomonas avibactam Enterobacteriaceae Some ESBLs and AmpC Ceftazidime Avibactam is a novel non-β-lactam β-lactamase inhibitor Expanded coverage KPCs Limited to no activity against Class D (Acinetobacter spp) No activity against Class B (metallo-b-lactamases) Zhanel GG et al. Drugs. 2014; 74:31 51 Zhanel GG et al. Drugs. 2013;73: Expanded Spectrum of Activity Pathogen Ceftolozane-tazobactam Ceftazidime-avibactam MIC Range MIC 50 MIC 90 MIC Range MIC 50 E. coli <0.12 to > < 0.03 to ESBL <0.12 to > < to K. pneumoniae <0.12 to > < 0.06 to ESBL < 0.12 to > to KPC 16 to >16 >16 >16 < 0.06 to Enterobacter spp. < 0.03 to > < 0.03 to > AmpC 0.25 to > to > Pseudomonas < 0.12 to > to > MDR Pseudomonas 0.5 to > < 1 to > Acinetobacter < 0.12 to to > 16 Beta-streptococcus < 0.12 to to S. aureus 4 to to >32 16 >32 Bacteroides fragilis < 0.12 to < 0.06 to > MIC 90 Other Bacteroides spp. < 0.12 to to > >128 Zhanel GG et al. Drugs. 2014; 74:31 51 Zhanel GG et al. Drugs. 2013; 73: Flam RK et al. Diagn Microbiol Infect Dis Nov;80(3):233-8 Sader HS et al. Antimicrob Agents Chemother 2014;58(3): FDA Susceptibility Breakpoints Comparative Efficacy for cutis Minimum Inhibitory Concentration, mcg/ml Susceptible Intermediate Resistant Ceftolozanetazobactaavibactatazobactaavibactatazobactaavibactam Ceftazidime- Ceftolozane- Ceftazidime- Ceftolozane- Ceftazidime- Microorganism Enterobacteriaceae <2 < >8 >16 Pseudomonas aeruginosa <4 < >16 >16 Streptococcus anginosus Streptococcus constellatus Streptococcus salivarius < >32 -- Bacteroides fragilis <8 ng/ml >32 -- Ceftolozane-tazobactam Levofloxacin Difference, Outcome 1.5g q8h 750 mg q24h 95 CI Median treatment duration 7 days 8 days Composite cure; Symptom resolution (2.3 to14.6) & microbiological response Microbiological eradication (2.9 to 14.3) ESBL-positive (n=118/800) (9.2 to 42.9) Clinical Cure (-0.8 to 6.2) Ceftazidime-avibactam Doripenem Difference, Outcome 2.5g q8hr 500 mg q8hr 95 CI Median IV treatment duration 7 days 8 days Symptom resolution & (0.3 to 13.12) microbiological response Microbiological response (-2.7to 3.56) ceftazidime-nonsusceptible ( to 16.89) pathogen (n=159/810) Clinical Cure (-4.23 to 4.03) Zerbaxa (ceftolozane-tazobactam) for injection. [package insert] Whitehouse Station, NJ; Rev 10/2016 Avycaz (ceftazidime-avibactam) for injection. [package insert] Irvine, Ca: Allergan USA Inc; Rev 01/2017 Wagenlehner FM et al. Lancet 2015; 385: Wagenlehner FM et al. Clin Infect Dis 2016;63(6):

5 Non-Inferior ciai Trial Results Ceftazidime-avibactam 2.5g q8hr Meropenem End Points + metronidazole 1g q8hr Mean treatment duration days days Solomkin J et al. Clin Infect Dis 2015;60(10): Mazuski JE et al. Clin Infect Dis 2016;62(11): Ceftolozane-tazobactam 1.5g q8h Meropenem Difference, End Points + metronidazole 1g q8hr 95 CI MITT population Cure, after days (-8.91 to 0.54) ESBL-positive (n=58/806) CrCl ml/min (n=36) Failure Difference, 95 CI Cure, after days (-8.64 to 1.58) Ceftazidime resistant pathogen (n=111/823) ( to 0.17) CrCl >50 ml/min (-6.17 to 3.97) CrCl ml/min a, b (50.15 to -5.36) Cure, late follow up days ( to 2.79) a. Ceftazidime/avibactam dose adjustment = 1.25g q12 hr (33 less than currently recommended dose) b. Within hrs of treatment initiation, 67.9 showed rapid improvement to CrC >50 ml/min Concerning Outcomes Continue in Serious CRE Infections Shields RK et al. Clin Infect Dis. 2016;63: Castón JJ et al. Int J Infect Dis. 2017;59: King M et al. Antimicrob Agents Chemother. 2017; 61(7):e Shields et al. (2016) N=37 All types of CRE infections case series. APACHE II=34, SOFA=5, Monotherapy in day mortality=24; Clinical success=59 (CRRT=17 vs non-crrt=68) Microbiological failure = 27 (30 resistance to ceftazidime-avibactam) Castón et al. (2017) N=31 Ceftazidime-avibactam (n=8) vs other treatment (n=28) for CRE bacteremia 14-day clinical cure: 85.7 vs 34.8; p= day mortality: 25 vs 52.2; p=0.24 King et al (2017) N=60 All types of CRE infections; Charlson index=4.5, Pitt bacteremia=2, ICU=59 In-hospital mortality = 32; Clinical success = 65 Microbiological cure = 53 Dosing Considerations Ceftolozane-tazobactam FDA indications: complicated UTI & complicated IAI (w/ metronidazole) Renal Dose Adjustments Dose: 1.5 g (1g/500 mg) in 100 ml over 1 hour every 8 hours CrCl Renal adjustment CrCl <50 ml/min UTI/IAI HAP/VAP ml/min 750 mg (500/250) q8hr 1.5g (1g/500mg) q8hr Nosocomial Pneumonia trial (ASPECT-NP) ongoing ml/min 375 mg (250/125) q8hr 750 mg (500/250) q8hr Dose: 3 g (2g/1g) every 8 hours (CrCl >50 ml/min) 750 mg (500mg/250) x1 AWP Cost: $115 per 1.5 g vial (~$345/day) HD NA 150 mg(100/50) q8hr Potential stewardship niche: MDR pseudomonas infections Ceftazidime-avibactam FDA indications: complicated UTIs & complicated IAI (w/ metronidazole) Renal Dose Adjustments Dose: 2.5 g (2g/500mg) in ml over 2 hours every 8 hours CrCl UTI/IAI Renal adjustment: CrCl <50 ml/min ml/min 1.25g (1g/250mg) q8 hr Nosocomial Pneumonia trial (REPROVE) completed ml/min 940 mg (750/190) q12 hr AWP Cost: $359 per 2.5 g vial (~$1,077/day) 6-15 ml/min 940 mg (750/190) q24 hr HD 940 mg (750/190) q48 hr Potential stewardship niche:?cre (KPC) infections Spellberg B. Clin Infect Dis 2016;63(12): Zerbaxa (ceftolozane-tazobactam) for injection. [package insert] Whitehouse Station, NJ; Rev 10/2016 Avycaz (ceftazidime-avibactam) for injection. [package insert] Irvine, Ca: Allergan USA Inc; Rev 01/2017 Xiao AJ et al. J Clin Pharmacol. 2016;56(1): Clinicaltrials.gov NCT &NCT Adverse Effects Similar to Other Cephalosporins Clostridium difficile Incidence and Mortality is Increasing Adverse Effect Ceftolozane-tazobactam cuti n=533 ciai n=482 Ceftazidime-avibactam cuti n=511 ciai n=509 Rates of C. difficile Infection Among Hospitalized Patients, US Annual C. difficile Related Mortality Rates per Million Patients, US Headache Dizziness 1.1 NR NR NR Pyrexia NR 4.5 Nausea Vomiting NA 4.5 Diarrhea Constipation 3.9 NR Rates per 1,000,000 population Historically, advanced generation cephalosporins are associated with increased Clostridium difficile infection risk Wagenlehner FM et al. Lancet 2015; 385: Solomkin J et al. Clin Infect Dis 2015;60(10): Wagenlehner FM et al. Clin Infect Dis 2016;63(6): Mazuski JE et al. Clin Infect Dis 2016;62(11): National Hospital Discharge Survery, United States Redelings MD et al Emerg Infect Dis 2007;13(9):

6 Current Therapy Against C. difficile is Limited Clostridium difficile Frequently Recurs Despite Treatment Standard of care for CDI treatment includes: Oral/IV metronidazole (increasing failure rates) Oral vancomycin Oral fidaxomicin Antibiotic treatment has limited effects in preventing recurrent disease Metronidazole and vancomycin have broad activity against normal microbiota Although reduced compared to vancomycin, recurrence after fidaxomicin may be related to particular strains Percentage of Recurrent CDI Episodes ~40 ~60 Risk Factors Antibiotic use Advanced age Proton pump inhibitor therapy NAP1/BI/027 strain Prior episode of CDI Cohen SH et al. Infect Control Hosp Epi 2010;31(5): Musher DM et al. Clin Infect Dis 2005;40(11): Aslam S et al Lancet Infect Dis. 2005;5: McFarland LV et al. Am J Gastroenterol. 2002; 97: Novel Non-Antimicrobial Strategies Immune response against C. difficile toxins are correlated with reduced recurrences of CDI Successful cases of IVIG use reported in the literature Non-antibacterial toxin binding agents Tolevamer Inferior clinical cure rates compared to metronidazole or vancomycin Significant reduction in CDI recurrences Tolevamer Metronidazole Vancomycin p-value Clinical Cure <0.001 Recurrence <0.001 There are no approved therapies for the prevention of CDI..until now First Approved non-antimicrobial Strategy Against C. difficile Bezlotoxumab Fully human IgG1 monoclonal antibody (mab) that binds to C. difficile toxin B and prevents it s effects on epithelial cells FDA approval : October Indication: Reduce recurrence of CDI in patients 18 years of age who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence Kyne L et al. N Engl J Med. 2000;342: Kyne L et al. Lancet. 2001;357: Johnson S et al. Clin Infec Dis 2014;59(3): Yang Z et al. Infect Immun. 2015;83(2): Zinplava (Bezlotoxumab) for injection [package insert] Whitehouse Station, NJ: Merck & Co., INC; Rev 10/2016 Bezlotoxumab Reduces CDI Recurrence Patients with CDI Recurrence, One time bezlotoxumab 10 mg/kg added to standard treatment for primary or recurrent C. difficile diarrhea (n=2655) p=0.003 p=0.003 p=0.001 ~40 relative reduction Bezlotoxumab Does Not Impact Clinical Cure Rates Overall Clinical Cure Patient with Clinical Cure, Cumulative Incidence of Clinical Cure, Time to Clinical Cure Bezlotoxumab Placebo Days following Infusion Wilcox MH, et al. N Engl J Med 2017;376: Wilcox MH, et al. N Engl J Med 2017;376:

7 Effects on CDI Recurrence Based on Specific Risk Factors CDI Recurrence Rate, Overall Age >65 years < 65 years CDI History (6 months) Yes NO Previous Episodes (ever) >2 <1 Immunocompromised Severe CDI Hypervirulent Strain 027 Strain Yes NO Yes NO Yes NO Yes NO Wilcox MH, et al. N Engl J Med 2017;376: Bezlotoxumab vs Placebo Group Bezlotoxumab Placebo Favors Bezlotoxumab Difference () & 95 CI Overall Age > 65 years Age < 65 years Recent CDI history No Recent CDI history > 2 previous episodes < 1 previous episodes Immunocompromised Not immunocompromised Severe CDI Non-severe CDI Hypervirulent strain positive Non-hypervirulent strain Positive for 027 strain Negative for 027 strain Administration of Bezlotoxumab Dosage 10 mg/kg in 0.9 NaCL (or D5W) single infusion over 60 min No dose adjustments for renal/hepatic dysfunction Administration Given any time during antibiotic therapy for CDI CDI Recurrence Relative to Timing of Administration Bezlotoxumab given relative to SoC treatment Cost (AWP) $ per 1000 mg/40 ml vial Placebo n=773 Bezlotoxumab n= days after days after > 5 days after SoC= standard of care treatment Wilcox MH, et al. N Engl J Med 2017;376: Zinplava (Bezlotoxumab) for injection [package insert] Whitehouse Station, NJ: Merck & Co., INC; Rev 10/2016 Bezlotoxumab: Adverse Effects Adverse effects Infusion related reaction (10) Nausea (7) Pyrexia (5) Headache (4) Warning/precautions Increased risk of serious cardiac adverse effects including mortality in patients with existing heart failure Wilcox MH, et al. N Engl J Med 2017;376: Baseline CHF No Baseline CHF n=325 n=2019 Serious Adverse Effect Bezlotoxumab Bezlotoxumab + Acto Placebo Death Bezlotoxumab Bezlotoxumab + Acto Placebo Adverse effects among subjects with baseline CHF Bezlotoxumab Bezlotoxumab + Acto Placebo n=118 n=103 n=104 Treatment emergent adverse effect Serious Adverse Effect Death Comprehensive Strategies to Reduce Clostridium difficile Recurrences Strengthen infection prevention practices Limit unnecessary antibiotic use Reduce inappropriate acid suppressive therapy Targeted use of fidaxomicin in high risk groups Adjunct bezlotoxumab High risk groups Age > 65 years Immunosuppressed Recent previous CDI episode Prolonged systemic antibiotic use + acid suppressive therapy Reducing C. difficile Exposure Avoid hospital admission Reduce length of stay Limit unnecessary broad spectrum antibiotics Challenge for patients who require IV antibiotic therapy Failed oral antibiotic treatment Questionable compliance Medication/outpatient follow up Risks with prolonged intravenous access Thrombosis Phlebitis Impropriate access (IVDU) IVDU=intravenous drug user Introducing New Gram Positive Antimicrobial Agents Dalbavancin Semisynthetic derivative of teicoplanin Schwalbe RS Antimicrob Agents Chemother. 1996;40(10): Steiert M et al. Curr Opin Investig Drugs. 2002;3(2): Smith JR et al. Infect Dis Ther 2015;4: Karaoui LR et al. Am J Health Syst Pharm 2013;70:23-33 Lipoglycopeptide Enhanced gram-positive activity Multi-modal mechanisms of action Extended half-lives Oritavancin Semisynthetic derivative of vancomycin 7

8 In vitro Activity Against Gram Positive Pathogens MIC 90 mcg/ml Organism Dalbavancin Oritavancin Vancomycin Staphylococcus aureus MRSA VRSA >4 Streptococcus pyogenes Streptococcus agalactiae Viridans group streptococcus Streptococcus pneumoniae Enterococcus faecalis Enterococcus faecium VanA VRE > >512 VanB/C VRE >512 Mechanism of Enhanced Antimicrobial Activity albavancin Template peptidoglycan Cytoplasm Cell Death ritavancin Mature peptidoglycan D-alanyl-d-alanine Lipid II Cell membrane Jones RN et al. J Chemother. 2005;17: Arhin FF et al. Antimicrob Agents Chemother. 2009; 53: Bailey J et al. Am J Health-Syst Pharm. 2008; 65: Zhanel GG et al. Clin Infect Dis 2012;54(S3):S214 9 Highly Bactericidal Agents Against Staphylococcus aureus Log cfu/ml Dalbavancin against MRSA 9 Control 7 Dalbavancin 0.25 mg/l 5 Oritavancin against MRSA Dalbavancin 1 mg/l Oritavancin against VRSA Time, hours Log cfu/ml Log cfu/ml 10 Control Vancomycin Daptomycin Oritavancin Time, hours 10 Control Vancomycin 8 6 Daptomycin 4 FDA Susceptibility Breakpoints Minimum Inhibitory Concentration, mcg/ml Susceptible Intermediate* Resistant* Dalbavancin Oritavancin Dalbavancin Oritavancin Dalbavancin Oritavancin Microorganism Staphylococcus aureus <0.25 < (including MRSA isolates) Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, <0.25 < Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius Enterococcus faecalis (vancomycin-susceptible isolates only) <0.25 < *The current absence of data on resistant isolates precludes defining any category other than "Susceptible" 2 Oritavancin McKay GA et al. J Antimic Chemo 2009;63: Time, hours Durata Therapeutics International B.V. Dalbavancin for injection. NDA FDA Briefing Document. March 31, 2014 Orbactiv (oritavancin) for injection [package insert]. Parsippany, NJ: Medicines Company; Rev 08/14 Dalvance (dalbavancin) for injection [package insert]. Parsippany, NJ: Durata Therapeutics; Rev 01/2016 Attractive Pharmacokinetics Oritavancin plasma Dalbavancin plasma concentration, mcg/ml concentration, mg/l Plasma Concentration Time-Profile of 2-Dose Dalbavancin st Dose: Dalbavancin 1000 mg 2 nd Dose: Dalbavancin 5000 mg on day Total Drug Dalbavancin Oritavancin 10 Parameter 1000 mg 1200 mg C max 287 mg/l 138 mcg/ml 1 AUC 0-day mg*h/l 0- : 2800mcg*h/mL Calculated Free Drug Volume of 15.7 L 87.6 L 0.1 distribution Half life 204 hr (8.5 days) 245 hr (10.2 days) 300 Time, Days Clearance L/hr L/hr 100 Plasma Concentration Time-Profile of Single Dose Oritavancin 1200mg Protein binding 10 Renal 33 < 5 elimination Day 14 Orbactiv (oritavancin) for injection [package insert]. Parsippany, NJ: 1 Medicines Company; Rev 08/14 Dalvance (dalbavancin) for injection [package insert]. Parsippany, NJ: Durata Therapeutics; Rev 01/ Time, Days Dalbavancin non-inferior to Standard Care for absssi Dalbavancin* 1000 mg (d1) Vancomycin/ Absolute Difference End Point 500 mg (d8) linezolid (95 CI) No lesion spread at hr DISCOVER ( ) DISCOVER ( ) Both Trials combined ( ) Early >20 reduction of infection area at hr DISCOVER ( ) DISCOVER ( ) Both Trials combined ( ) Investigator s Clinical Cure (-3.0 to 1.5) *Dose adjustment for CrCl <30 ml/min: 750 mg (day 1) & 375 mg on day 8 Boucher HW, et al. N Engl J Med 2014;370:

9 Similar Outcomes with Consolidated Single Dose Dalbavancin Dunne MW, et al. Clin Infect Dis 2016;62(5): Dalbavancin 1500 mg x 1 Dalbavancin 1000 mg (D1) 500 mg (D8) Absolute Difference (95 CI) Assessment at hours Treatment response; >20 decrease in lesion (-8.5 to 2.8) Day 14 Clinical success (-6.1 to 4.1) Day 28 Clinical success ( -4.9 to 4.4) Dose adjustment for CrCl <30 ml/min: 1000 mg x mg (D1) 375 mg (D8) FDA approved single dose CrCl < 30 ml/min = 1125 mg Non-inferiority of Oritavancin for the Treatment of absssi Oritavancin Vancomycin Absolute Difference Outcome 1200 mg x 1 15mg/kg Q12H (95 CI) Primary Endpoint* SOLO I (-1.6 to 8.4) SOLO II (-7.5 to 2.0) Early Lesion size reduction >20 SOLO I ( 0.5 to 8.6) SOLO II (-3.7 to 5.0) Clinical Cure SOLO I ( 2.3 to 6.2) SOLO II (-4.9 to 1.6) *Cessation of spreading or a reduction in the size of the baseline lesion, the absence of fever, and the absence of a need for rescue antibiotic medication Corey RG, et al. N Engl J Med 2014;370: Corey RG, et al Clin Infect Dis 2015;60(2): Potential Interactions with Oritavancin Potential drug-drug interactions Weak CYP 2C9 and CYP2C19 inhibitor Warfarin AUC increased increased omeprazole : 5-hydroxy-omeprazole ratio Weak CYP3A4 and CYP2D6 inducer 18 decrease in midazolam AUC 31 decrease in dextromethorphan metabolism Potential drug-lab interactions Binds to phospholipid reagents in coagulation tests (falsely elevates) activated partial thromboplastin time (aptt) prolonged prothrombin time/international normalized ratio (PT/INR) IV heparin is contraindicated within first 48 hours of oritavancin infusion Adverse Effects Comparison Oritavancin Vancomycin Adverse Effect N=976 N=983 Diarrhea 36 (3.7) 32 (3.4) Nausea 97 (9.9) 103 (10.5) Vomiting 45 (4.6) 46 (4.7) Dizziness 26 (2.7) 26 (2.6) Headache 69 (7.1) 66 (6.7) Infusion site phlebitis 24 (2.5) 15 (1.5) Infusion site reaction 19 (1.9) 34 (3.5) Tachycardia 24 (2.5) 11 (1.1) Abscess 37 (3.8) 23 (2.3) (limb & subcutaneous) AST elevation 27 (2.8) 15 (1.5) ALT elevation 18 (1.8) 15 (1.5) Drug discontinuation 36 (3.7) 41 (4.2) Dalbavancin Comparators Adverse Effect N=1178 N=1224 Serous adverse effect 109 (6.1) 80 (6.5) Drug discontinuation 53 (3) 35 (2.8) Nausea 98 (5.5) 78 (6.4) Vomiting 50 (2.8) 37 (3) Diarrhea 79 (4.4) 72 (5.9) Headache 83 ( (4.8) Rash 48 (2.7) 30 (2.4) Pruritus 38 (2.1) ) ALT 3x ULN 12 (0.8) 2 (0.2) Drug Discontinuation 53 (3.0) 35 (2.9) Orbactiv (oritavancin) for injection [package insert]. Parsippany, NJ: Medicines Company; Rev 08/14 Corey RG, et al. N Engl J Med 2014;370: Corey RG, et al Clin Infect Dis 2015;60(2): Durata Therapeutics International B.V. Dalbavancin for injection. NDA FDA Briefing Document. March 31, 2014 Despite a Long Half Life; Duration of Adverse Effects is Limited Duration of Treatment-Emergent Adverse Events: Pooled Phase II/III Safety Database Durata Therapeutics International B.V. Dalbavancin for injection. NDA FDA Briefing Document. March 31, 2014 Early Interventions to Reduce Healthcare Costs Average hospital length of stay for primary SSSI ~ 3-5 days DRG: $4500-$10,000 Dalbavancin Costs: $4470 Oritavancin Costs: $2700 Shift care from inpatient hospitalization to outpatient infusion centers Identify potential candidates Require IV antibiotic therapy Limited-to-no systemic signs of severe/complicated infection $14,000 $12,000 $10,000 $8,000 $6,000 $4,000 $2,000 $0 Dalbavancin or Oritavancin Jauregui, et al. Clin Infect Dis 2005;41: Kaye K et al. PLoS One 2015; 10(11):1-13 Healthcare Cost and Utilization Project (HCUP). National and regional estimates on hospital use for all patients from the HCUP National (Nationwide) Inpatient Sample (NIS). Agency for Healthcare Research and Quality. Rockville, MD. Accessed May 20, 2017 Cost Comparison by Key Components Vancomycin Daptomycin + Linezolid Drug Cost (Inpatient) Drug Cost (outpatient) Inpatient Medical Outpatient Medical 9

10 Patient (& Provider) Counseling Single dose antibiotic = novel approach to antimicrobial therapy Sustained therapeutic drug concentrations x 2 weeks Continued antimicrobial activity post infusion Resolution of lesion takes time Day 1 Day 5 Day 14 Summary Multidrug resistant infections remain a serious healthcare problem Improved pharmacokinetic understanding of polymyxin agents Polymyxin B more attractive than colistin Ceftolozane-tazobactam and ceftazidime-avibactam are welcomed additions to our armamentarium for MDR gram negative infections appropriate use is essential Bezlotoxumab is the first non-antibacterial agent to address and reduce C.difficile recurrent infections Long acting gram positive agents are novel strategies to limit/reduce inpatient hospitalizations FSHP Innovations in Antimicrobial Something Old, Something New Harrison Bachmeier, PharmD, BCPS Pharmacist Specialist-Infectious Diseases LeeHealth Fort Myers & Cape Coral, FL 10