BAD BUGS, MORE DRUGS 10/6/2015 UPDATE ON NEWLY FDA APPROVED ANTIBIOTICS FOR THE TREATMENT OF CELLULITIS PHARMACIST OBJECTIVES

BAD BUGS, MORE DRUGS UPDATE ON NEWLY FDA APPROVED ANTIBIOTICS FOR THE TREATMENT OF CELLULITIS HAYLEY MEYER PGY 1 PHARMACY PRACTICE RESIDENT IOWA CITY VETERANS AFFAIRS HEALTHCARE SYSTEM PHARMACIST OBJECTIVES Identify 3 risk factors for MRSA colonization in patients with cellulitis Select first line empiric antibiotics for the treatment of non purulent and purulent cellulitis Review new antibiotics for the treatment of cellulitis and discuss efficacy and monitoring parameters Evaluate a patient s clinical presentation, past medical history and microbiology data to determine whether treatment with a newly approved antibiotic is appropriate Apply knowledge of new and traditional antibiotics used for the treatment of cellulitis to construct effective patient care plans PHARMACY TECHNICIAN OBJECTIVES Identify the incidence of cellulitis in the United States Recognize oral antibiotics typically used for the treatment of cellulitis Explain the key driver for the development of new antibiotics Recall typical starting dosages of newly approved antibiotics for the treatment of cellulitis List the reconstitution solutions for oritavancin, dalbavancin and tedizolid 1

BACKGROUND Definition of cellulitis: skin infection as a result of bacterial entry through a breech in the skin s barrier Baddour, LM. Cellulitis and Erysipelas. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on August 16, 2015) Kevin Berman, MD, PhD, Atlanta Center for Dermatologic Disease, Atlanta, GA. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Bethanne Black, and the A.D.A.M. Editorial team ANNUAL VISITS TO EMERGENCY DEPARTMENTS FOR SKIN AND SOFT TISSUE INFECTIONS Incidence is approximately 200 cases/100,000 patient years Pallin DJ, Egan DJ, Pelletier AJ, et al. Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus. Ann Emerg Med 2008;51: 291 298 MICROBIOLOGY MOST COMMON PATHOGENS Beta hemolytic Streptococcus species Staphylococcus aureus LESS COMMON PATHOGENS Haemophilus infuenzae Non spore forming anaerobes Gram negative aerobic bacilli Other gram positive cocci 3.Eriksson B, Jorup-Rönström C, Karkkonen K, et al. Erysipelas: clinical and bacteriologic spectrum and serological aspects. Clin Infect Dis 1996; 23:1091. 2

CLINICAL PRESENTATION SIGNS Erythema and edema Inflammation Affected skin warm to touch Non elevated lesions +/ drainage, exudates, abscesses Poorly defined margins Lymphadenopathy SYMPTOMS Fevers Chills Malaise Hypotension Dehydration Altered mental status Fish, Douglas N., and Susan L. Pendland. "Chapter 88. Skin and Soft-Tissue Infections." Pharmacotherapy: A Pathophysiologic Approach, 9e. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessPharmacy. Web. 26 Aug. 2015. <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310534>. NON PURULENT CELLULITIS DEFINITION Cellulitis without drainage, exudates or abscesses Microbiology: streptococcus species and staphylococcus aureus SEVERITY OF INFECTION Mild: typical cellulitis with no focus or purulence Moderate: typical cellulitis with systemic signs of infection Severe: patients who have failed oral antibiotics or systemic signs of infection or immunocompromised or clinical signs of deeper infection Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014; 59:147. PURULENT CELLULITIS DEFINITION Cellulitis associated with purulent drainage, exudates or abscesses Microbiology: MRSA SEVERITY OF INFECTION Mild: no systemic signs of infection Moderate: systemic signs of infection present Severe: patients who have failed incision and drainage PLUS oral antibiotics or systemic signs of infection or immunocompromised Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014; 59:147. 3

MILD NON PURULENT CELLULITIS Herchline, TE. Cellulitis. Medscape, New York, NY. (Accessed on August 26, 2015) SEVERE NON PURULENT CELLULITIS Herchline, TE. Cellulitis. Medscape, New York, NY. (Accessed on August 26, 2015) SEVERE PURULENT CELLULITIS http://www.acutemed.co.uk/diseases/cellulitis 4

DIAGNOSIS Mild infection: blood culture, needle aspiration, punch biopsy, skin swabs NOT RECOMMENDED Blood cultures positive 5% of cases Culture results from needle aspiration vary from 5 40% Culture results from punch biopsy specimens vary from 20 30% Severe infection: blood cultures recommended; needle aspiration, punch biopsy considered on patient presentation Leppard BJ, Seal DV, Colman G, Hallas G. The value of bacteriology and serology in the diagnosis of cellulitis and erysipelas. Br J Dermatol 1985; 112:559. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014; 59:147. GOALS OF TREATMENT Rapid resolution of the infection Prevention of further complications Effective use of antibiotics Dose optimization Avoid unnecessary antibiotics Minimize toxicity Cost effective Fish, Douglas N., and Susan L. Pendland. "Chapter 88. Skin and Soft-Tissue Infections." Pharmacotherapy: A Pathophysiologic Approach, 9e. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessPharmacy. Web. 26 Aug. 2015. <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310534>. NON ANTIBIOTIC THERAPY Incision and drainage of purulent lesion Elevation & immobilization of infected area Cool, sterile saline dressings Treatment of underlying conditions Fish, Douglas N., and Susan L. Pendland. "Chapter 88. Skin and Soft-Tissue Infections." Pharmacotherapy: A Pathophysiologic Approach, 9e. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessPharmacy. Web. 26 Aug. 2015. <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310534>. 5

EMPIRIC MANAGEMENT Mild infection Moderate infection Severe infection Oral Therapy Penicillin VK Penicillin G Amoxicillin Dicloxacillin Cephalosporins Clindamycin IV/Oral therapy Nafcillin/oxacillin Dicloxacillin Cephalosporins Clindamycin Amoxicillin/ clavulanate Doxycycline MInocycline IV therapy Nafcillin/oxacillin Cefazolin Clindamycin Doxycycline Minocycline Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014; 59:147. EMPIRIC MANAGEMENT Mild infection Moderate infection Severe infection Incision and drainage +/- oral therapy Incision and drainage + oral therapy TMP/SMX Clindamycin Doxycycline Minocycline Incision and drainage + IV therapy Vancomycin Daptomycin Linezolid Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014; 59:147. INTERVENTIONS DE ESCALATION Clinical assessment of patient shows improvement Cultures and susceptibility provide opportunity for deescalation IV TO PO Clinically stable Responding to IV antibiotics Functioning GI tract Tolerating food and/or oral medications Masterson RG. Antibiotic De-Escalation. Critical Care Clinics. 2011 Jan;27(1):149-62. Cyriac JM, James E. Switch over from intravenous to oral therapy: A concise overview. J Pharmacol Pharmacother. 2014 Apr;5(2):83-7. 6

DEFINITIVE THERAPY: STREPTOCOCCAL SPECIES Antibiotic Dose Comment Penicillin V 250-500 mg every 6 First line agent hours PO Penicillin G 2-4 million units every 4- First line agent 6 hours IV Amoxicillin 500 mg every 6 hours PO Good Group A Strep coverage Cefazolin 1-2 g every 8 hours IV Moderate Group A Strep/Good MSSA Cephalexin 500-1000 mg every 6 hours PO Clindamycin 600-900 mg every 8 hours IV Moderate Group A Strep/Good MSSA Beta-lactam allergy Fish, Douglas N., and Susan L. Pendland. "Chapter 88. Skin and Soft-Tissue Infections." Pharmacotherapy: A Pathophysiologic Approach, 9e. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessPharmacy. Web. 26 Aug. 2015. <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310534>. Baddour, LM. Cellulitis and Erysipelas. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on August 16, 2015) Bartlett, JG. Cellulitis. In: John Hopkins POC-IT ABX Guide, Charlottesville, VA. (Accessed on August 16, 2015) DEFINITIVE THERAPY: MSSA Antibiotic Dose Comment Nafcillin or Oxacillin 1-2 g every 4 hours IV First line agent Dicloxacillin 500 mg every 6 hours First line agent PO Cefazolin 1-2 g every 8 hours IV Moderate Group A Strep/Good MSSA Cephalexin 500-1000 mg every 6 hours PO Clindamycin 600-900 mg every 8 hours IV OR 300-450 mg every 6 hours PO Amoxicillin/clavulanate 500/125 mg every 8 hours or 875/125 mg every 12 hours PO Doxycycline, minocycline 100 mg every 12 hours IV/PO Moderate Group A Strep/Good MSSA Beta lactam allergy Good Group A Strep and MSSA activity Group A Strep and MSSA activity Fish, Douglas N., and Susan L. Pendland. "Chapter 88. Skin and Soft-Tissue Infections." Pharmacotherapy: A Pathophysiologic Approach, 9e. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessPharmacy. Web. 26 Aug. 2015. <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310534>. Baddour, LM. Cellulitis and Erysipelas. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on August 16, 2015) Bartlett, JG. Cellulitis. In: John Hopkins POC-IT ABX Guide, Charlottesville, VA. (Accessed on August 16, 2015) DEFINITIVE THERAPY: MRSA Antibiotic Dose Comments Vancomycin 30 mg/kg/day in 2 First line agent divided doses IV Daptomycin 4 mg/kg every 24 hours IV Broad gram positive activity Linezolid Trimethoprim sulfamethoxazole Clindamycin Doxycyline, minocycline 600 mg every 12 hours IV OR PO 1-2 DS tablets every 12 hours PO or 5 mg/kg/day IV 600 mg every 8 hours IV OR 300-450 mg every 6 hours PO 100 mg every 12 hours PO Broad gram positive activity Poor anti-streptococcal activity ; good S. aureus activity Good CA-MRSA coverage Good CA-MRSA coverage Fish, Douglas N., and Susan L. Pendland. "Chapter 88. Skin and Soft-Tissue Infections." Pharmacotherapy: A Pathophysiologic Approach, 9e. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, 2014. n. pag. AccessPharmacy. Web. 26 Aug. 2015. <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310534>. Baddour, LM. Cellulitis and Erysipelas. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on August 16, 2015) Bartlett, JG. Cellulitis. In: John Hopkins POC-IT ABX Guide, Charlottesville, VA. (Accessed on August 16, 2015 7

CASE 1 A 21 year old male presents to the ED with suspected skin infection near elbow. Initially, infected area was red, swollen and warm to touch; he thought symptoms were due to spider or insect bite and did not seek treatment. After a couple days, built up of pus present with no resolution of symptoms. No systemic symptoms of infection are present upon evaluation. PMH: none significant Medications: no home medications Allergies: none ANTIBIOTIC DISCOVERY TIMELINE https://www.khanacademy.org/science/health-and-medicine/current-issues-in-health-and-medicine/antibiotics-and-antibioticresistance/a/antibiotics-an-overview NEW FDA APPROVED ANTIBIOTICS Ceftaroline (Teflaro ) 8

CEFTAROLINE Dose: 600 mg every 12 hrs IV Renal impairment: Dose adjustment necessary Hepatic impairment: No dose adjustment necessary Pregnancy category risk: B Administration: slow IV infusion over 60 minutes Stable in D 2.5 W, 1 / 2 NS, D 5 W, LR and NS Availability: 600 mg vial Cost of therapy: $2332.68 400 mg vial Cost of therapy: $2332.68 Lexicomp Online, Ceftaroline, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. CEFTAROLINE 0.3 L/kg 20% Ceftaroline fosamil undergoes rapid conversion to active ceftaroline 2.7 hours Primarily renal Lexicomp Online, Ceftaroline, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. CEFTAROLINE Significant adverse reactions: Positive Coomb s Test (11%) Monitoring parameters: Renal function Drug interactions: Probenecid Lexicomp Online, Ceftaroline, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. 9

CANVAS I AND CANVAS II TRIALS Methods: compared ceftaroline 600 mg IV every 12 hrs and vancomycin PLUS aztreonam each 1 g IV every 12 hrs for 5 14 days Study population: 18 years old Severe infection requiring hospitalization or 5 days of parenteral therapy Deep tissue involvement and/or diabetic patients with lower extremity cellulitis or abscess Primary outcome: non inferiority of the clinical cure rate with ceftaroline monotherapy compared to vancomycin PLUS aztreonam in clinical evaluable and intent to treat populations Corey G, Wilcox M, Talbot G, Friedland H, Baculik T, Witherell G, 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. Clinical Infectious Diseases 2010;51(6):641-50. PRIMARY OUTCOMES Population Ceftaroline Vancomycin plus aztreonam Difference (95% CI) Clinically evaluable 559/610 (91.6%) 549/592 (92.7%) -1.1 (-4.2 2.0) MITT 595/693 (85.9%) 586/685 (85.5%) 0.3 (-3.4 4.0) Corey G, Wilcox M, Talbot G, Friedland H, Baculik T, Witherell G, 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 skinstructure infection. Clinical Infectious Diseases 2010;51(6):641-50. CEFTAROLINE ADVANTAGES Well tolerated Not associated with renal or hepatocellular damage DISADVANTAGES Cost Renal dose adjustments Twice daily dosing No oral formulation Hernandez PO, Lema S, Tyring SK, Mendoza N. Ceftaroline in complicated skin and skin-structure infections. Infect Drug Resist. 2012;5:23 35. Frampton JE. 2013. Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and communityacquired pneumonia. Drugs 73:1067 1094. 10.1007/s40265-013-0075-6. 10

TELAVANCIN Dose: 10 mg/kg every 24 hours IV Renal impairment: dose adjustment necessary Hepatic impairment: not studied in patient with severe impairment Pregnancy category risk: C Administration: IV infusion over 60 minutes Stable in NS, LR, D 5 W Availability: 250 mg vial Cost of therapy: $5018.16 750 mg vial Cost of therapy: $3002.44 Lexicomp Online, Telavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. TELAVANCIN 0.133 L/kg 90% 6.6-9.6 hours Primarily renal Lexicomp Online, Telavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. TELAVANCIN Significant adverse reactions: Metallic taste (33%) Proteinuria (13%) Psychiatric disturbance (12%) Increased serum creatinine (8 16%) Contraindications: Concomitant IV unfractionated heparin use Drug interactions: Concomitant use with QTc prolonging medications Monitoring parameters: Renal function Lexicomp Online, Telavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. 11

EFFECTS OF A NEW ANTIBACTERIAL, TELAVANCIN, ON CARDIAC REPOLARIZATION IN HEALTHY SUBJECTS QTcF Change from Baseline Mean (msec) Maximum (msec) Telavancin 7.5 mg/kg 4.1 11.6 Telavancin 10 mg/kg 4.6 15.1 Positive control 9.5 21.6 Barriere S, Genter F, Spencer E, Kitt M, Hoelscher D, Morganroth J. Effects of a new antibacterial, telavancin, on cardiac repolarization (QTc interval duration) in healthy subjects. J Clin Pharmacol.2004;44:689 695. ATLAS TRIAL Methods: compared telavancin 10 mg/kg every 24 hrs to vancomycin 1g every 12 hrs for 7 14 days Study population: 18 years old Complicated infection requiring 7 days of parenteral antibiotics Purulent drainage and/or 3 signs/symptoms: erythema, heat and/or localized warmth, fluctuance, swelling and/or induration, pain and/or tenderness to palpation, fever, WBC count >10,000 cells/mm3, or > 15% bands Primary outcome: non inferiority of clinical response of telavancin compared to vancomycin at the test of cure evaluation 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. PRIMARY OUTCOME Population Telavancin Vancomycin Difference (95% CI) Study 0017 Clinically evaluable All treated 304/346 (87.9%) 323/426 (75.8%) 302/349 (86.5%) 321/429 (74.8%) 1.3 (-3.6 6.3) 1.0 (-4.8 6.8) Study 0018 Clinically evaluable All treated 354/399 (88.7%) 387/502 (77.1%) 346/395 (87.6%) 376/510 (73.7%) 1.1 (-3.4 5.6) 3.4 (-1.9 8.7) 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. 12

TELAVANCIN ADVANTAGES Once daily dosing Fewer infusion related reactions Decreased length of stay DISADVANTAGES Cost Renal dosing adjustments Lower clinical cure rates in renal impairment and elderly Nephrotoxicity & hypokalemia No oral formulation Interferes with coagulation tests Possible cross reactivity with vancomycin Saravolatz L, Stein G, Johnson L. Telavancin: a novel lipoglycopeptide. Clin Infect Dis 2009; 49:1908 14. Attwood RJ, LaPlante KL. Telavancin: a novel lipoglycopeptide antimicrobial agent. Am J Health Syst Pharm. 2007;64(22):2335. TEDIZOLID Dose: 200 mg daily IV or PO Renal impairment: no dosage adjustment Hepatic impairment: no dosage adjustment Pregnancy category risk: C Administration: IV infusion over 60 minutes Stable in NS Availability: 200 mg vial Cost of therapy: $1974 200 mg tablet Cost of therapy: $2478 Lexicomp Online, Tedizolid, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. TEDIZOLID Well absorbed (90%) 1.1 L/kg 70 90% Tedizolid phosphate undergoes conversion to active tedizolid 12 hours Feces and urine, both as inactive sulfate conjugates Lexicomp Online, Tedizolid, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. 13

TEDIZOLID Significant adverse reactions: Decreased hemoglobin Monitoring parameters: CBC Decreased platelets Drug interactions: Caution with concomitant use with SSRIs, TCAs, triptans, meperidine, buspirone Lexicomp Online, Tedizolid, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. ESTABLISH I AND ESTABLISH II TRIALS Methods: compared tedizolid 200 mg IV daily and linezolid 600 mg twice daily with optional oral step down Study population: 12 years old Minimum lesion area of 75 cm2 Suspected or documented gram positive pathogen Primary outcome: non inferiority of early clinical response with tedizolid compared to linezolid in the intent to treat population Shorr AF, Lodise TP, Corey GR, De Anda C, Fang E, Das AF, Prokocimer P.2015. Analysis of the phase 3 ESTABLISH trials of tedizolid versus linezolid in acute bacterial skin and skin structure infections. Antimicrob Agents Chemother59:864 871. 10.1128/AAC.03688-14. PRIMARY OUTCOME Tedizolid Linezolid Difference (95% CI) No increase in lesion surface area from baseline and oral temperature of 37.6 C, confirmed by a second temperature measurement within 24 hours at 48-72 hours Trial 1 264/332 (79.5%) 266/335 (79.4%) 0.1 (-6.1 6.2) At least a 20% decrease from baseline in lesion area at 48-72 hours Trial 2 283/332 (85.2%) 276/334 (82.6%) 2.6 (-3.0 8.2) Shorr AF, Lodise TP, Corey GR, De Anda C, Fang E, Das AF, Prokocimer P.2015. Analysis of the phase 3 ESTABLISH trials of tedizolid versus linezolid in acute bacterial skin and skin structure infections. Antimicrob Agents Chemother59:864 871. 10.1128/AAC.03688-14. 14

TEDIZOLID ADVANTAGES No renal dose adjustments Once daily dosing IV and PO formulation DISADVANTAGES Cost Bacteriostatic Hematologic adverse effects Weak monoamine oxidase inhibitor Shorter duration of therapy Zhanel GG. Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens. Drugs. 2015 Feb;75(3):253-70 DALBAVANCIN Dose: 1000 mg IV once, followed by 500 mg IV once after 7 days Renal impairment: dose adjustment necessary Hepatic impairment: not studied in patients with moderate to severe impairment Administration: IV infusion over 30 minutes Stable in D 5 W Availability: 500 mg vial Cost of therapy: $5364 Pregnancy category risk: C Lexicomp Online, Dalbavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. DALBAVANCIN 0.22 L/kg 93% Minor metabolite (hydroxy-dalbavancin) 346 hours (2 weeks) Primarily real; 20% in feces Lexicomp Online, Dalbavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. 15

DALBAVANCIN Significant adverse reactions: Hepatotoxicity Monitoring parameters: Renal function Liver function Drug interactions: no significant drug interactions Lexicomp Online, Dalbavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. DISCOVER I AND DISCOVER II TRIALS Methods: dalbavancin 1 g IV on day 1, followed by 500 mg IV on day 8 vs. vancomycin 1 g or 15 mg/kg IV every 12 hrs for 3 days, with an option to switch to oral linezolid to complete 10 14 days of therapy Study population: 18 years old Diagnosis of acute bacterial skin and skin structure infection requiring 3 days of parenteral therapy 1 systemic signs of infection Erythema PLUS 2 local signs of infection Primary outcome: non inferiority of early clinical response with dalbavancin compared to vancomycin in the intent to treat population Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014; 370:2169. PRIMARY OUTCOME Primary end point Dalbavancin Vancomycin Linezolid Difference (95% CI) DISCOVER 1 240/288 (83.3%) 233/285 (81.8%) 1.5 (-4.6 7.9) DISCOVER 2 285/371 (76.8%) 288/368 (78.3%) -1.5 (-7.4 4.6) Both Trials 525/659 (79.7%) 521/653 (79.8%) -0.1 (-4.5 4.2) Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014; 370:2169. 16

DALBAVANCIN ADVANTAGES Once weekly dosing Outpatient administration Potential cost savings Quality of life DISADVANTAGES Cost Renal dose adjustments Hepatotoxicity Long half life Lack of follow up Possible cross reactivity with vancomycin Das B, Sarkar C, Biswas R, Pandey S. Review: dalbavancin--a novel lipoglycopeptide antimicrobial for gram positive pathogens. Pak J Pharm Sci. 2008 Jan;21(1):78-87. ORITAVANCIN Dose: 1200 mg once IV Renal impairment: not studied in CrCl < 30 ml/min Hepatic impairment: not studied in patients with severe hepatic impairment Pregnancy category risk: C Administration: IV infusion over 3 hours Stable in D 5 W Availability: 400 mg vial Cost of therapy: $3480 Lexicomp Online, Oritavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. ORITAVANCIN 1.25 L/kg 85% 245 hours Unchanged in the feces and urine Lexicomp Online, Oritavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. 17

ORITAVANCIN Significant adverse reactions: Subcutaneous abscess Limb abscess Contraindications: Concomitant IV unfractionated heparin use Drug interactions: Warfarin Monitoring parameters: Renal function Osteomyelitis Lexicomp Online, Oritavancin, Hudson, Ohio: Lexi Comp, Inc.; August 16, 2015. SOLO I AND SOLO II TRIALS Methods: compared single IV dose of oritavancin 1200 mg followed by IV administered placebo or an IV dose of vancomycin every 12 hours for 7 10 days Study population: 18 years old Probable or documented gram positive acute bacterial skin and skin structure infection Requires 7 days of therapy Signs/symptoms of systemic infection Primary outcome: non inferiority of early clinical response with oritavancin compared to vancomycin in intent to treat population 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. PRIMARY OUTCOME ORBACTIV Vancomycin Difference (95% CI) SOLO I 391/475 (82.3%) 378/479 (78.9%) 3.4 (-1.6, 8.4) SOLO II 403/503 (80.1%) 416/502 (82.9%) -2.7(-7.5, 2.0) *Important safety data: more cases of osteomyelitis were reported in patients treated with oritavancin compared to vancomycin in SOLO II trial 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. 18

ORITAVANCIN ADVANTAGES Single infusion Outpatient Potential cost savings Quality of life DISADVANTAGES Cost Not studied in patients with a CrCl <30 ml/min Long half life Lack of follow up Possible cross reactivity with vancomycin Interacts with anticoagulation tests Tice A. Oritavancin: A New Opportunity for Outpatient Therapy of Serious Infections. Clin Infect Dis. (2012) 54 (suppl 3): S239-S243. USE OF NEW ANTIBIOTICS All are FDA approved for acute bacterial skin and skin structure infections Criteria for use should be developed to avoid overuse Duration of therapy for severe infections is 7 14 days Choice of alternative agent should be individualized to each patient Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014; 59:147. CASE 2 A 67 year old female is admitted to the general medicine floor with RLE severe purulent cellulitis. After incision and drainage, she is initiated on vancomycin 1000 mg every 12 hours. Variable Day 1 Day 2 Day 3 Fever 39.1ºC 39.1ºC 39.6ºC BP 112/79 108/77 104/77 WBC 17.1 x 10 9 /L 18.4 x 10 9 /L 18.9 x 10 9 /L Vancomycin trough N/A N/A 15.6 µg/ml Given lack of improvement on vancomycin, provider would like to switch therapy to linezolid 600 mg every 12 hours IV/PO 19

CASE 2 Culture results: Staphylococcus aureus Susceptibility: Ampicillin Cefazolin Oxacillin Vancomycin R 4 R 32 R 8 S 2 CASE 2 PMH: hypertension, depression, migraines, history of poor compliance Medications: Medication Dose Indication Enalapril 40 mg daily Hypertension Amlodipine 5 mg daily Hypertension Escitalopram 10 mg daily Depression Acetaminophen 650 mg every 4-6 hours PRN Osteoarthritis CASE 3 A 30 year old male presents to the ER with LLE severe purulent cellulitis. Infection has progressively worsened over 30 days of which he failed oral TMP/SMX; his girlfriend finally persuaded him to visit the ED. Patient is very agitated being in the ED and refuses to be admitted. After incision and drainage, the ED physician would like a recommendation for antibiotic therapy. PMH: ADHD, substance abuse, poor compliance Medications: Methylphenidate ER 36 mg every morning 20

SUMMARY Most common pathogens for cellulitis infections include streptococcus species, MSSA and MRSA Clinical presentation, risk factors for MRSA and blood cultures when appropriate should be used to determine appropriate empiric therapy New FDA approved antibiotics should be reserved for complicated infections with treatment failure or intolerable adverse effects with vancomycin Choice of new antibiotic should be individualized to the patient Resistance is a growing concern and novel antibiotic classes are needed FUTURE RESEARCH Dosing in renal impairment and dialysis Dosing on obese patients Randomized controlled trials between new FDA approved antibiotics Cost savings analysis QUESTIONS? 21