Choose Your Own Antibiotic/Adventure Gram-Positive Style

Disclosures Consultant for Cubist Pharmaceuticals, Inc Research support from Forest Laboratories Choose Your Own Antibiotic/Adventure Gram-Positive Style I have never seen Star Wars (But I m a big fan of Space Balls, the movie) Monica V. Mahoney, PharmD, BCPS (AQ ID) Objectives At the end of the presentation, the participant should be able to: 1. Evaluate the literature for the newly approved Grampositive medications dalbavancin, oritavancin and tedizolid 2. Compare/contrast the newer agents against older Grampositive antimicrobials 3. Given a patient with a Gram-positive infection, recommend appropriate therapy Dalbavancin Lipoglycopeptide antibiotic 1000 mg IV x 1, then 500 mg IV 7 days later Red man s syndrome, nausea, diarrhea, pruritis $4500 +/- Dalvance Prescribing Information Dalbavancin in Skin/Soft Tissue DISCOVER Dalbavancin in Skin/Soft Tissue cont.. DAL VAN +/- LZD 1000 mg 500 mg Placebo IV q12h +/- PO placebo q12h VAN 1000 mg (15 mg/kg) IV q12h LZD 600 mg PO q12h 1 3 8 10 14 1 endpoint End of therapy n=659 n=653 28 Shortterm f/u 70 Longterm f/u Boucher. NEJM 2014;370:2169-79 Demographics DAL (n=659) VAN / LZD (n=653) Age: mean (range) 48.9 (18-85) years 50.3 (18-84) years Male: no (%) 393 (59.6) 374 (57.3) Diabetes: no (%) 78 (11.8) 92 (14.1) IVDU: no (%) 94 (14.3) 107 (16.4) Infection Type: no (%) Major abscess 162 (24.6) 173 (26.5) Cellulitis 354 (53.7) 349 (53.4) Wound/SSI 142 (21.5) 131 (20.1) Febrile ( 38 C) 549/649 (84.6) 552/649 (85.0) WBC >12,000 cells/m 3 247/627 (39.4) 250/621 (40.3) Infection area: median (range) 324 (26-5100) cm 2 367 (72-3922) cm 2 Boucher. NEJM 2014;370:2169-79 1

Dalbavancin in Skin/Soft Tissue cont.. Results DAL VAN / LZD Success rate at 48-72h 525/659 (79.7%) 521/653 (79.8%) Success rate at EOT 517/570 (90.7%) 502/545 (92.1%) Cellulitis At 48-72h 281/354 (79.4%) 269/349 (77.1%) At EOT 294/324 (90.7%) 276/301 (91.7%) Major Abscess At 48-72h 133/163 (81.6%) 149/173 (86.1%) At EOT 125/133 (94.0%) 133/139 (95.7%) Wound/SSI At 48-72h 111/142 (78.2%) 103/131 (78.6%) At EOT 98/113 (86.7%) 93/105 (88.6%) MRSA (EOT) 72/74 (97.3%) 49/50 (98.0%) Dalbavancin in Skin/Soft Tissue cont.. Adverse Events: Nausea (2.5%), diarrhea (0.8%), pruritis (0.6%) Median duration: 4.0 days (DAL) vs. 3.0 days (VAN/LZD) Conclusion: Once weekly DAL is not inferior to twice daily VAN/LZD for the treatment of acute bacterial skin and skin-structure infections (ABSSSI) Boucher. NEJM 2014;370:2169-79 Boucher. NEJM 2014;370:2169-79 Dalbavancin Future Directions? Single Dose Dalbavnacin: Ph3, DB, RCT: DAL 1500 mg vs. DAL 1000 mg / 500 mg for ABSSSI (NCT02127970) Pediatrics: Ph1, open-label, ages 12-17 ys, bacteremia (NCT00678106) Ph1, open-label, ages 3 mos-11 yrs (NCT01946568) Community Acquired Pneumonia: Ph3, DB, RCT vs. linezolid (NCT02269644) Osteomyelitis: Ph3, DB, RCT vs. cefaz/oxa/naf/van. Ages 2-17 yrs. (NCT02344511) Oritavancin Glycopeptide antibiotic 1200 mg IV x 1 Headache, nausea, vomiting, abscess, diarrhea $2900 http://clinicaltrials.gov Orbactiv Prescribing Information Oritavancin in Skin/Soft Tissue SOLO Oritavancin in Skin/Soft Tissue cont.. ORI VAN 1200 mg Placebo IV q12h 1000 mg (15 mg/kg) IV q12h 1 3 7 10 14 24 1 endpoint End of therapy n=978 n=981 Post-therapy evaluation Corey et al. N Engl J Med. 2014;370:2180-90 Corey et al. Clin Infect Dis 2014; doi: 10.1093/cid/ciu778 Demographics ORI (n=978) VAN (n=981) Age: median 45.6 years ~ 45 years Male: no (%) 639 (65.3) 644 (65.6) Diabetes: no (%) 139 (14.2) 140 (14.3) IVDU: no (%) Not reported Not reported Infection Type: no (%) Major abscess 308 (31.5) 300 (30.6) Cellulitis 387 (39.6) 400 (40.8) Wound/SSI 283 (28.9) 281 (28.6) Febrile ( 38 C) 186/976 (19.1) 185/979 (19.0) WBC >12,000 cells/m 3 216/887 (24.4) 210/879 (23.9) Infection area: median (range) 266.6 (19-4250) cm 2 ~250 (57-3417) cm 2 Corey et al. N Engl J Med. 2014;370:2180-90 Corey et al. Clin Infect Dis 2014; doi: 10.1093/cid/ciu778 2

Oritavancin in Skin/Soft Tissue cont.. Results ORI (n=978) VAN (n=981) Success rate at 48-72h 794 (81.2%) 794 (80.9%) Success rate at PTE 794 (81.2%) 787 (80.2%) Cellulitis At 48-72h 294/387 (76.0%) 302/400 (75.5%) Major Abscess At 48-72h 251/308 (81.5%) 253/300 (84.3%) Wound/SSI At 48-72h 249/283 (88.0%) 239/281 (85.1%) MRSA (EOT) 166/204 (81.4%) 162/201 (80.6%) Oritavancin in Skin/Soft Tissue cont.. Adverse Events: Nausea (9.9%), headache (7.1%), vomiting (4.6%), abscess (3.8%0, diarrhea (3.7%) Average onset: SOLO I: 1.2 days; duration: 2.4 days SOLO II: all within 1-9 days of medication start Conclusion: Single dose IV ORI was non-inferior compared to IV VAN x 7-10 days in the treatment of ABSSSI Corey et al. N Engl J Med. 2014;370:2180-90 Corey et al. Clin Infect Dis 2014; doi: 10.1093/cid/ciu778 Orbactiv Prescribing Information Oritavancin Future Directions? Pediatrics: Ph1, open label, dose-finding study in pediatrics Single ORI infusion for confirmed/suspected bacteremia in patients < 18 years (NCT02134301) Tedizolid Oxazolidinone antibiotic 200 mg IV/PO q24h Nausea, vomiting, diarrhea, headache, dizziness $1400 *6 day course http://clinicaltrials.gov Sivextro Prescribing Information Tedizolid in Skin/Soft Tissue ESTABLISH Tedizolid in Skin/Soft Tissue cont.. TZD LZD 200 mg PO/IV q24h Placebo PO/IV q12h 600 mg PO/IV q12h Placebo PO/IV q24h 1 endpoint Placebo PO q24h 1 3 6 10 11 End of therapy n=664 n=669 18 25 Post-therapy evaluation Prokocimer. JAMA 2013;309:559-69 Moran. Lancet Infect Dis. 2014;14:696-705 Demographics TZD (n=664) LZD (n=669) Age: mean (I and II) 43.6 and 46 years 43.1 and 46 years Male: no (%) 429 (64.6) 412 (61.6) Diabetes: no (%) (II only) 32/332 (10.0) 41/334 (12.0) IVDU: no (%) 183 (27.6) 206 (30.8) Infection Type: no (%) Major abscess 168 (25.3) 166 (24.8) Cellulitis 301 (45.3) 307 (45.9) Wound/SSI 195 (29.4) 196 (29.3) Febrile ( 38 C) 159 (23.9) 160 (23.9) WBC >10,000 cells/m 3 316 (47.6) 284 (42.5) Infection area: median (range) (I only) 188.3 (28.5-5572.8) cm 2 190.0 (27.0-2952.0) cm 2 Prokocimer. JAMA 2013;309:559-69 Moran. Lancet Infect Dis. 2014;14:696-705 3

Tedizolid in Skin/Soft Tissue cont.. Results TZD (n=664) LZD (n=669) Success rate at 48-72h 547 (82.4%) 521/653 (79.8%) Success rate at EOT 518 (78.0%) 534 (79.8%) Cellulitis At 48-72h 235/301 (78.1%) 235/307 (76.5%) At EOT (I only) 85/133 (63.9%) 84/135 (62.2%) Major Abscess At 48-72h 139/168 (82.7%) 145/166 (87.4%) At EOT (I only) 72/100 (72.0%) 78/97 (80.4%) Wound/SSI At 48-72h 173/195 (88.7%) 162/196 (82.7%) At EOT (I only) 73/99 (73.7%) 79/103 (76.7%) MRSA (EOT) (II only) 44/53 (83.0%) 44/56 (78.6%) Tedizolid in Skin/Soft Tissue cont.. Adverse Events: Nausea (8.5%), headache (6.3%), diarrhea (4.5%), abscess (4.2%) Hematologic effects seen less frequently with TZD Conclusion: IV/PO TZD x 6 days was non-inferior compared to IV/PO LZD x 10 days in the treatment of ABSSSI Prokocimer. JAMA 2013;309:559-69 Moran. Lancet Infect Dis. 2014;14:696-705 Prokocimer. JAMA 2013;309:559-69 Moran. Lancet Infect Dis. 2014;14:696-705 Tedizolid Future Directions? Nosocomial Pneumonia: Ph3, DB, RCT: TZD 200 mg IV q24h x 7 days vs. LZD 600 mg IV q12h x 10 days for Gram-positive HAP/VAP (14 days if concurrent bacteremia) (NCT02019420) Pediatrics: Ph3, DB, RCT: TZD 200 mg IV/PO q24h x 6 days vs. Iv to PO Vanco/LZD/Clinda/Fluclox/Cefaz/Cepha x 10 days (NCT02276482) Young & the Restless Are these new whippersnappers better than the tried and true? Ceftaroline Daptomycin Linezolid Telavancin http://clinicaltrials.gov Ceftaroline Cephalosporin antibiotic 600 mg IV q12h Rash, + Coombs test $2400 Ceftaroline Indications Complicated Skin and Skin Structure: CANVAS Corey. Clin Infect Dis. 2010;51:641-50 CPT 600 mg IV q12h (n=693) vs. VAN + AZT (1g IV q12h each) (n=685) 91.6% CPT vs. 92.7% VAN + AZT (-1.1% diff, 95% CI -4.2 to 2.0) * +/- *Also active against penicillin- and ceftriaxone-resistant S. niae Community Acquired Pneumonia: FOCUS File. Clin Infect Dis. 2010;51:1395-405 CPT 600 mg IV q12h (n=621) vs. CTX 1g IV q24h (n=619) 84.3% CPT vs. 77.7% CTX (6.7% diff, 95% CI 1.6 to 11.8) Teflaro Prescribing Information 4

Ceftaroline Future Directions? NCT01701219: Non-randomized, open-label study of CPT vs. VAN or DAP for MSSA or MRSA bacteremia CPT dosing: 600 mg IV q8h Daptomycin Cyclic Lipopeptide antibiotic 4 or 6 mg/kg IV q24h CPK, myopathy, eosinophilic nia CPK: creatine phosphokinase $3800 http://clinicaltrials.gov/ct2/show/nct01701219?term=nct01701219&rank=1 Cubicin Prescribing Information Daptomycin Indications Skin and Skin Structures: Arbeit. Clin Infect Dis. 2004;38:1673-81 DAP 4 mg/kg IV q24h (n=446) vs. NAF/VAN (n=456) 83.4% DAP vs. 84.2% NAF/VAN (95% CI -4.0 to 5.6) Bacteremia and Endocarditis: Fowler. NEJM. 2006;355:653-65 DAP 6 mg/kg IV q24h (n=124) vs. NAF/VAN + GENT (n=122) 44.2% DAP vs. 41.7% NAF/VAN (2.4% diff, 95% CI 10.2 to 15.1%) Linezolid Oxazolidinone antibiotic 600 mg IV/PO q12h (400 mg IV/PO q12h) Thrombocytopenia, $1400 leukopenia, optic neuritis, (IV) lactic acidosis, serotonin $2700 syndrome (PO) Carries FDA labeled indication for infections Zyvox Prescribing Information Linezolid Indications Complicated Skin and Skin Structures: Weigelt. Antimicrob Agents Chemother. 2005;49:2260-6 LZD 600 mg IV q12h (n=592) vs. VAN 1g IV q12h (n=588) 92.2% LZD vs. 88.9% VAN (p=0.057) MRSA Pneumonia: ZEPHYR Wunderink. Clin Infect Dis. 2012;54:621-9 LZD 600 mg IV q12h (n=224) vs. VAN 15 mg/kg IV q12h (n=224) Clinical cure: 57.6% LZD vs. 46.6% VAN (95% CI 0.5% to 21.6%, p=0.042) 60 day mortality: 15.7% LZD vs. 17.0% VAN (p=ns) Telavancin Lipoglycopeptide antibiotic 10 mg/kg IV q24h Diarrhea, taste disturbance, foamy urine, nephrotoxicity, QTc prolongation $3100 +/- Vibativ Prescribing Information 5

Telavancin Indications Complicated Skin and Skin Structure: ATLAS Stryjewski. Clin Infect Dis. 2008;46:1683-93 TLV 10 mg/kg IV q24h (n=928) vs. VAN 1g IV Q12h (n=939) 88.3% TLV vs. 87.1% VAN (95% CI for diff, -2.1 to 4.6) ATTAIN Hospital-Acquired, Ventilator-Associated Pneumonia: Rubinstein. Clin Infect Dis. 2011;52:31-40 TLV 10 mg/kg IV q12h (n=749) vs. VAN 1g IV q12h (n=754) 58.9% TLV vs. 59.5% VAN (95% CI for diff, -5.6% to 4.3%) Telavancin Future Directions? Uncomplicated Bacteremia: ASSURE Stryjewski. BMC Infect Dis. 2014;14:289 Phase 2 trial of TLV 10 mg/kg IV q24h (n=29) vs. VAN 1g V q12h/naf 2g IV q6h (n=29) 48% MRSA, 52% MSSA CE: 7/8 (88%) TLV vs. 8/9 (89%) VAN/NAF (95% CI for diff, -35.5% to 31.9%) CE: Clinically evaluable Don t Cry for Me Vancomycin The truth is, we never left you Drug of Choice Safe Effective Cheap In Summary: Drug Profiles Drug Dose Route Renal Adj Hepatic Adj Cost* VAN 15 mg/kg IV q12h IV $600 CPT 600 mg q12h IV $2400 DAL 1000 mg x1, then 500 mg 7 days later IV $4500 DAP 4 or 6 mg/kg q24h IV $3800 LZD 600 mg q12h IV PO $1400 $2700 ORI 1200 mg x1 IV $2900 TLV 10 mg/kg q24h IV $3100 TZD 200 mg q24h IV / PO $1400 ; 6 day course In Summary: Spectrum of Activity Drug VAN CPT +/- DAL +/- DAP LZD ORI TLV +/- TZD In Summary: FDA Approved Indications Drug VAN Skin/Soft Tissue CPT DAL CAP HAP / VAP Bacteremia / Endocarditis Infections caused by susceptible organisms DAP LZD ORI TLV TZD 6

Coming Attractions Phase 3 Drug Class MRSA Route Notes Ceftobiprole Cephalosporin IV - ABSSSI, HAP, & CAP - Anti-pseudomonal activity - Approved in Europe for HAP & CAP Delafloxacin Fluoroquinolone IV/PO - ABSSSI & Gonorrhea Iclaprim Omadacycline Dihydrofolate reductase inhibitor Aminomethycycline (tetracycline-like) IV/PO - ABSSSI IV/PO - ABSSSI & CAP Coming Attractions Phase 2 Drug Class MRSA Route Notes BC-3781 Pleuromutilin IV/PO - ABSSSI & CAP Brilacidin Defensin-mimetic IV - ABSSSI Fusidic acid Fusidane PO - ABSSSI - Available outside US for years, different dosing GSK1322322 Hydrazinopyrimidine PO - ABSSSI JNJ-Q2 Fluoroquinolone IV/PO - ABSSSI & CAP Linopristin/ Flopristin togrammin PO - ABSSSI & CAP Radezolid Oxazolidinone IV/PO - ABSSSI & CAP TD-1792 Glycopeptidecephalosporin heterodimer IV - ABSSSI Information compiled from www.clinicaltrials.gov Information compiled from www.clinicaltrials.gov In Summary Dalbavancin Tedizolid Oritavancin ABSSSI Pros Convenience Patient compliance Oral option Administration locations Targets resistant organisms Improvements on Cons Cost Reimbursement issues Medication reconciliation Limited indications Subsequent infections Prolonged? Scenario 1 PH is a 76 year old female who came in through the ED for left lower extremity cellulitis and abscess. The abscess was successfully drained and a line was inserted under IR guidance. The patient completed 3 days of vancomycin, before IV access was lost. The team asks you what the patient can be treated with, if they cannot insert another line. What do you recommend? A. Vancomycin B. Dalbavancin C. Tedizolid D. Oritavancin Scenario 2 GR is a 34 year old male with a history of IV drug abuse. He last used 4 days ago and now presents with a right arm cellulitis. GR has frequent episodes of cellulitis and he admits that he never finishes the course of antibiotics prescribed for him. He is also threatening to leave AMA this afternoon. The team asks for treatment recommendations in this patient. What do you recommend? A. Vancomycin B. Dalbavancin C. Tedizolid D. Oritavancin 7

Scenario 3 JB is a 47 year old female with diabetes who presents with a wound infection on her left foot. It does not probe to bone. She is slightly hypotensive, so the team admits her to the floor to monitor. They would like to start one of the new antibiotics on her and ask for your recommendation. In speaking to the patient, you uncover that she has an allergy to vancomycin hives. What do you recommend? A. Vancomycin B. Dalbavancin C. Tedizolid D. Oritavancin Scenario 4 OS is a 66 year old male seen in an outpatient clinic for a purulent cellulitis. He receives a dose of oritavancin 1200 mg and is discharged home. Three days later he presents to the ED, complaining of fevers, chills, and feeling lethargic. His cellulitis site looks improved. Laboratory values show a WBC of 14.6 cells/mm 3 and blood cultures are growing GPC in pairs and clusters. The ED pages you asking for drug recommendations. How do you respond? A. The patient already has oritavancin on board, it should cover his current bacteremia. B. Administer another dose of oritavancin to cover the bacteremia. C. Start the patient on vancomycin. D. Start the patient on linezolid, a non-glycopeptide antibiotic. References Choose Your Own Antibiotic/Adventure Gram-Positive Style Monica V. Mahoney, PharmD, BCPS (AQ ID) Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38:1673-81 Babinchak T, Ellis-Grosse E, Dartois N, et al. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis. 2005;41:S354-67 Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014;370:2169-79 Corey GR, Good S, Jiang H, et al. Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study. Clin Infect Dis. 2014; doi: 10.1093/cid/ciu778 Corey GR, Kabler H, Mehra P, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med. 2014;370:2180-90 Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010;51:641-50 Cubicin Prescribing Information. Cubist Pharmaceuticals, Inc. Lexington, MA. 2013. Dalvance Prescribing Information. Durata Therapeutics. Chicago, IL. 2014. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis. 2005;41:S341-53 References cont. File TM, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, double-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired nia. Clin Infect Dis. 2010;51:1395-1405 Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-65 Moran GJ, Fang E, Corey GR, Das AF, DeAnda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014;14:696-705 Orbactiv Prescribing Information. The Medicines Company. Parsippany, NJ. 2014. Prokocimer P, DeAnda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections. JAMA 2013;309:559-69 Rodvold KA, McConeghy KW. Methicillin-resistant Staphylococcus aureus therapy: past, present, and future. Clin Infect Dis. 2014;58:S20-7 Rubinstein E, Lalani T, Corey GR, et al. Telavancin versus vancomycin for hospital-acquired nia due to gram-positive pathogens. Clin Infect Dis. 2011;52:31-40 Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol. 2013;34:1-14 References cont. Sivextro Prescribing Information. Cubist Pharmaceuticals, Inc. Lexington, MA. 2014. Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis. 2008;46:1683-93 Stryjewski ME, Lentnek A, O Riordan W, et al. A randomized phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study. BMC Infect Dis. 2014;14:289 Tanaseanu C, Bergallo C, Teglia O, et al. Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired nia. Diagn Microbiol Infect Dis. 2008;61:329-38 Teflaro Prescribing Information. Forest Laboratories, Inc. St. Louis, MO. 2013. Tygacil Prescribing Information. Pfizer Inc. New York, NY. 2013. Vibativ Prescribing Information. Theravance, Inc. San Francisco, CA. 2014. Weigelt J, Itani K, Stevens D, et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother. 2005;49:2260-6 Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial nia: a randomized, controlled study. Clin Infect Dis. 2012;54:621-9 Zyvox Prescribing Information. Pfizer Inc. New York, NY. 2014. 8