1. Silvano Esposito Dipartimento di Medicina e Chirurgia Università di Salerno Come tratteremo i Gram positivi?

2. Before After cleaning By courtesy of Matthew Dryden

3. Relative frequency of bacterial species/group encountered in clinical specimens from inpatients (Styers D., et al., Ann. Clin. Microb. Microb., 2006)‏ Data is cumulative data: 1998-march 2005 and based on a total of 3,209,413 bacterial isolates

4. Proportion of Methicillin Resistant Staphylococcus aureus (MRSA) Isolates in Participating Countries in 2013

5. Proportion of Methicillin Resistant Staphylococcus aureus (MRSA) Isolates in Participating Countries in 2013

7. Principal characteristics of old agents for MRSA (Rodvold KA; Clin Infect Dis. 2014)

11. Use of antistaphylococcal β lactams to increase daptomycin activity in eradicating MRSA bacteremia DAP-S DAP-R (Dhand A; Clin Infect Dis. 2011)

12. Analysis of antibacterial efficacy of DAP–β-lactams against DAPr MRSA strain ( Mehta S, Antimicrob Agents Chemother. 2012) Oxacillin (OXA), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP)

14. In vitro activity of new agents against staphylococci and therapeutic indications DrugsClassMRSAVISAVRSAIndication Ceftarolineβ-lactam++ ABSSSI/CAP Ceftobiproleβ-lactam++ CAP/HAP Dalbavancinlipoglyco- peptide ++ +ABSSSI Oritavancinlipoglyco-peptide++ ABSSSI Tedizolidoxazolidinone++ ABSSSI Telavancinlipoglyco-peptide++ +SSSI/HAP/VAP (Zhanel GG, Drugs. 2010 ; Kaushik D, Int J Antimicrob Agents, 2011)

15. Activity of Ceftobiprole vs Gram-positive pathogens Europe, Turkey & Israel 2005-2010 (Farrell et al, AAC, 2014) 2 mg/L % strains inhibited 99.5 100 98.3 93.1 100 91.0 99.3 99.8 90.0 92.8 36.4 85.6 15.0 100 94.1 95.9 6.8 CoNS S. pneumoniae S. aureus Other 4 mg/L 2 mg/L 0.5 mg/L MIC 0.25 mg/L 0.5 mg/L

16. Activity of Ceftobiprole vs Gram-negative pathogens Europe, Turkey & Israel 2005-2010 Enterobacteriaceae Other 83.4 89.1 99.2 10.3 72.3 99.2 4.0 93.6 73.8 77.8 83.8 64.6 78.4 22.7 30.7 0.2 100 Non-fermenter 0.25 mg/L 4 mg/L 0.5 mg/L % strains inhibited MIC (Farrell et al, AAC, 2014)

17. Community-acquired pneumonia (CAP-3001) Ceftobiprole study design Double-blind, randomized, multi-center Phase 3 study Primary objective: Demonstrate non-inferiority of ceftobiprole with respect to clinical cure rate at the TOC visit. *Stratified: Pneumonia Severity Index (<90 versus ≥91); need for anti-staphylococcal therapy **In case of persistent bacteremia or necrotising pneumonia on X-ray ***If MRSA suspected by the Investigator (Nicholson et al., Int J Antimicrob Agents, 2012)

18. Nosocomial pneumonia (BAP248/307) Ceftobiprole study design 781 subjects Randomization* Ceftobiprole: 500 mg every 8 hours (N=391) Linezolid 600 mg every 12 hours Ceftazidime 2000 mg every 8 hours (N=390) Efficacy and safety assessments: on-therapy: Days 4, 8, 14 EOT, end-of-treatment : ≤ 24 hours of end of treatment TOC, test-of-cure : 7–14 days after EOT LFU, late-follow-up: 28–35 days after EOT * Stratified: VAP/HAP; APACHE II score 8–19 / 20–25; VAP subjects also stratified (ventilated < 5d or ≥ 5d) Double-blind, randomized, multi-center Phase 3 study (157 sites in 32 countries in N/S America, Europe, SE Asia, Australia, S Africa) Treatment duration 7–14 days Primary efficacy endpoint: Clinical cure rate at TOC visit [NIM 15%] (Farrell et al., AAC, 2014)

19. An ABSSSI is defined as a bacterial infection of the skin with a lesion size area of at least 75 cm 2 (lesion size measured by the area of redness, edema, or induration). The minimum area of involvement of 75 cm 2 is chosen to select patients with acute bacterial skin infections for which a reliable control drug treatment effect can be estimated, given that most drugs for ABSSSI will be studied using noninferiority trial designs. A sufficiently large lesion size also differentiates between minor cutaneous abscess (smaller than approximately 75 cm 2 ) and major cutaneous abscess (greater than approximately 75 cm 2 ). This distinction is important because there appears to be insufficient information to reliably estimate a quantitative treatment effect of an antibacterial drug for patients who have surgical incision and drainage for a minor cutaneous abscess. Definitions of Acute Bacterial Skin and Skin Structure Infection Patients with the following infection types can be enrolled in ABSSSI clinical trials: - Cellulitis/erysipelas: A diffuse skin infection characterized by spreading areas of redness, edema, and/or induration - Wound infection: An infection characterized by purulent drainage from a wound with surrounding redness, edema, and/or induration - Major cutaneous abscess: An infection characterized by a collection of pus within the dermis or deeper that is accompanied by redness, edema, and/or induration U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) October 2013

20. The terms "skin and skin structure infection" and "skin and soft tissue infection" (SSTI) were coined to describe infectious processes such as cellulitis, erysipelas, cutaneous abscesses, and infected wounds, ulcers, or burns. The designation of more severe SSTI included a lowercase "c" (cSSTI) for "complicated" skin and soft tissue infection and typically implied a need for inpatient management, surgical procedures, or a significant underlying comorbidity such as diabetes or systemic immunosuppression that complicates response to therapy. In 2013, to identify more clearly a severe subset of SSTI that would typically be treated with parenteral antibiotic therapy, the United States (US) Food and Drug Administration (FDA) issued guidance that standardized the nomenclature to be used in the evaluation of new antimicrobial treatments for cSSTI, which are now referred to as acute bacterial skin and skin structure infections, or ABSSSIs. The rationale for developing this terminology was to provide a consistent means of identifying infections for which a reliable drug treatment effect can be estimated. The agents to be studied under the new definition are most often administered parenterally, and patient level of illness is reflected in parameters such as lesion size, leukocytosis, fever, and systemic inflammatory response syndrome. The specific verbiage from the FDA is as follows: ABSSSIs include cellulitis/erysipelas, wound infection, and major cutaneous abscess with a minimum lesion surface area of 75 cm 2. Diabetic foot ulcers and burn wound infections are excluded. Bacterial pathogens that commonly cause ABSSSI include Streptococcus pyogenes and Staphylococcus aureus, including MRSA strains. Less commonly identified bacteria include other Streptococcus species, Enterococcus faecalis, and Gram-negative bacteria. Why ABSSSI and not cSSTI? Charles V. Pollack Jr. et al J Emerg Med. 2015;48(4):508-519.

21. Description A semi-synthetic, bactericidal, lipoglycopeptide antibacterial drug with a PK/PD profile that supports a once-weekly dosage regimen Indication Adult patients with acute bacterial skin and skin structure infections (ABSSSI), as caused by susceptible strains of Gram-positive microorganisms, including methicillin-resistant strains Dosing and Administration 1000 mg on Day 1 and 500 mg on Day 8, each administered over 30 minutes by intravenous infusion In chronic renal insufficiency (known creatinine clearance <30 mL/min, not receiving regularly scheduled renal dialysis), the recommended regimen is a reduction to 750 mg on Day 1 and 375 mg on Day 8 Clinical Evidence Dalbavancin was non-inferior to the comparator regimen (intravenous vancomycin 1000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days) in two clinical studies treating ABSSSI patients with a lesion size of >75cm 2 (median size >300cm 2 ) and at least one systemic sign of disease Safety/ Tolerability Dalbavancin was studied in 1778 patients in a total of seven Phase 2 and Phase 3 trials The most common adverse reactions occurring in >2% of patients were nausea (2.8%) and diarrhea (2.5%) The median duration of adverse reactions was similar (4.0 days) in both treatment groups Serious adverse reactions occurred in 0.2% of patients treated with Dalbavancin and 0.7% of patients treated with the comparator. Dalbavancin was discontinued in 1% of patients due to an adverse reaction versus 1.6% for the comparator Dalbavancin Profile

22. Primary Endpoint: early response at 48-72 hours post initiation of therapy cessation of spread of the erythema of the lesion, and resolution of fever. Secondary Endpoint: Clinical Status at End of Therapy (Day 14-15, EMA primary endpoint). Primary Endpoint: early response at 48-72 hours post initiation of therapy cessation of spread of the erythema of the lesion, and resolution of fever. Secondary Endpoint: Clinical Status at End of Therapy (Day 14-15, EMA primary endpoint). Dalbavancin - Phase 3 study design

23. Tedizolid profile Class Novel oxazolidinone administered as a microbiologically inactive prodrug (tedizolid phosphate) Mechanism of action Binds to the 50S subunit of the bacterial ribosome, resulting in inhibition of protein synthesis Overview Efficacy in ABSSSI in a 6-day course in all patients Once daily treatment - 200 mg - IV and PO No required dose adjustments or drug monitoring

24. Design of Phase 3 Studies bid = twice-daily dosing; EOT = end of therapy; LFU = late follow up; PTE = posttherapy evaluation; qd = once-daily dosing. (Prokocimer P, JAMA, 2013; Moran GJ, Lancet Infect Dis. 2014) ● Linezolid 600 mg bid ● Tedizolid 200 mg qd ●● ● ● ● ● ● ●●● Posttherapy evaluation ● Early 48-72 h Day 7EOT (Day 11) PTE (Day 18-25) LFU (Day 29-38) ● Study Visits ●● ● ● ● ● ● ●●● Safety Analysis ESTABLISH-1: Oral tedizolid phosphate 200 mg QD x 6 days (with placebo dose to match BID administration of comparator arm), then 4 days of placebo BID ESTABLISH-2: Intravenous (IV) then oral tedizolid phosphate 200 mg QD x 6 days (with placebo dose to match BID administration of comparator arm), then 4 days of placebo BID Comparator: Linezolid 600 mg every 12 hours for 10 days (route to match tedizolid phosphate delivery)

26. Early switch and early discharge criteria

27. Comparison of actual and hypothetical intravenous days and bed- days in ealrly switch -eligible and early discharge -eligible patients

29. Clinical and microbiological response rates of study subjects receiving either dalbavancin or vancomycin for treatment of CVC bloodstream infections