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1 Hospital Universitario Virgen Macarena, Seville New drugs against MRSA and VRE L. Eduardo López Cortés Seville, 8th July

2 Tedizolid Oxazolidinone Ceftaroline // Ceftobiprole 5 th gen cephalosporin Overview Dalbavancin // Oritavancin // Telavancin Lipoglycopeptide

3 TEDIZOLID

4 Oxazolidinone Dosage: 200 mg/once-daily Hepatic and renal insufficiency: don t need adjustment Mechanism of action: inhibition protein synthesis Bacteriostatic Active against Enterococci spp., Staphylococci spp., and Streptococci spp. (including MRSA and VRE) Adverse events linezolid: Vomiting, nausea, diarrhea Myelosuppression : Thrombocytopenia Anemia Tedizolid Lactic acidosis: no cases in patients treated 21 days (phase I trials) Peripheral and optic neuropathy: no cases in patients treated 21 days (phase I trials) Flanagan S. AAC 2014; 58(11): Lodise TP. AAC. 2014;58(12):

5 PK/PD: Good correlation with AUC/MIC 200 mg/day MIC 0.5 mg/l: 98% achieved PK/PD goal MIC 1 mg/l: 70% achieved PK/PD outcome OV biodisponibility: 91% Protein binding: 70-90% Volumen of distribution: high (67-80 L) Elimination: 80% dregs 20% urine Half life: 12 hours MICs 4 times lower than linezolid: Burdette SD. Clin Infect Dis 2015;61(8): Ong V. Drug Metab Dispos. 2014;42(8): Flanagan S. AAC 2014; 58(11): Lodise TP. Clin Infect Dis 2014;58 Suppl 1:S28-34 Tedizolid

6 Randomised double-blind, phase 3, non-inferiority trials. Tedizolid (200 mg for 6 days) vs twice-daily linezolid (600 mg for 10 days) SSTI: Cellulitis or erysipelas, major cutaneous abscess, or wound infection 75 cm2. Primary endpoint: efficacy* at 48 to 72 h, EOT (days 11 13), and post-therapy evaluation (7-14 days after the EOT). Secondary endpoint: decreased lesion area, absence, or near resolution of signs and symptoms, no treatment discontinuation due to AE, and no major protocol violations (e.g: no unplanned surgical interventions, no osteomyelitis) at the end of treatment (day 11). *20% reduction in area lesion, did not receive systemic concomitant antibiotics, and did not die as a result of any cause within 72 h.

7 Early clinical response according to : Shorr AF. AAC 2015; 59(2):

8 Platelet counts <150,000 cells/mm3 at the EOT: tedizolid 4.9% vs linezolid 10.8%, P<0.001 Nausea (most frequently reported AE): tedizolid 8.2% vs linezolid 12.2%,P= days tediz. vs 10 linez. Shorr AF. AAC 2015; 59(2):

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10 Ceftaroline 5th generation cephalosporin group Approved by EMEA in 2012

11 Spectrum activity of ceftaroline Enterobacteria (not ESBL / AmpC) Staphylococcus aureus Including MRSA Includes VISA strains S. pneumoniae (including penicillin-resistant) Other Gram positive S. pyogenes Not active against enterococci Not active against "atypical respiratory bacteria Morata L et al. New antibiotics against gram-positives: present and future indications. Current Opinion in Pharmacology 2015, 24:45 51.

12 PK/PD: Good correlation with ƒ%t > MIC Clinical trials: 600 mg/12 h ƒ%t > MIC > 55 higher eradication rate Protein binding: 20% Elimination: 60% urine Dose adjustment (30-50 ml/min): 400 mg every 12 hours Half life: h Ceftaroline Don t affect P450 enzymes activity

13 Corey GR et al. Integrated analysis of CANVAS 1 and 2: Phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline vs vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010;51:641 File TM et al. Integrated Analysis of FOCUS 1 and FOCUS 2: Randomized, Doubled-Blinded, Multicenter Phase 3 Trials of the Efficacy and Safety of Ceftaroline Fosamil versus Ceftriaxone in Patients with Community-Acquired Pneumonia. Clin Infect Dis 2010;51(12):

14 EC FOCUS Figure. Confidence intervals for the difference in clinical cure rates at TOC, individual and integrated community-acquired pneumonia studies. ME: microbiologically evaluable mmitte: microbiological modified intent-to-treat efficacy [mmitte] populations.

15 EC CANVAS Cure rate and the microbiological eradication rate were similar in both groups, except in the subgroup of patients with a gram- negative infection: Could be explained due to the lower activity of ceftaroline against gramnegatives particularly P. aeruginosa in comparison to aztreonam.

16 Potential future indications MRSA Good results from CANVAS in MRSA Growing number of publications promising results in bacteremia, endocarditis, and bone and joint infections (maybe with higher doses: 600 mg every 8h) Stryjewski ME et al. Ceftaroline: clinical and microbiology experience with focus on methicillin-resistant Staphylococcus aureus after regulatory approval in the USA. Diagnostic Microbiology and infectious diseases 2015.

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18 Ceftobiprole

19 Fifth-generation cephalosporin Ceftobiprole Broad spectrum ceftroline (including MRSA), plus: Active against E. faecalis (but not E. faecium) Activity against P. aeruginosa (> cefepime) PK/PD goal is ƒ%t > MIC: 500 mg/8h (in 120 min) probability of ƒ%t > MIC of 60 is >90% when MIC is 2 mg/l Approved for: Skin and soft tissue infections CAP HAP (not VAP)

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21 Further investigation is needed before recommending the use of ceftobiprole in VAP

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23 Dalbavancin

24 Lipoglycopeptide Dalbavancin Bactericidal cell wall inhibition Prolonged half-life up to 8.5 days loading dose (1000 mg) 500 mg/once a week Active against: MRSA (including hvisa, VISA), E. faecium Not active against VRSA Approved for skin and soft tissue infections

25 DISCOVER I & DISCOVER II Phase III trial, double-blind, multicenter, non-inferiority design. Safety and efficacy vs. vancomycin (± sequential treatment with linezolid) Inclusion criteria: cellulite, abscess or wound infection > 75 cm2. Exclusion criteria: 14 days prior antibiotic treatment Primary endpoint: clinical cure at the end of treatment (day 14-15) Secondary variables: Early response (48-72h) and clinical cure short-term (28 ± 2). Boucher HW, et al. N Engl J Med. 2014; 370:

26 Boucher HW, et al. N Engl J Med. 2014; 370:

27 Boucher HW, et al. N Engl J Med. 2014; 370:

28 Dunne MW, et al. AAC. 2015;59:

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30 TELAVANCIN

31 Once-daily, intravenous, lipoglycopeptide Mechanisms of action: inhibition of bacterial wall synthesis + disruption of bacterial membrane function Respect other glycopeptides: Concentration-dependent Against Gram-positive, including MRSA (including VISA & hvisa) and S. pneumoniae Active against VRSA and daptomycin non-susceptible S aureus Approved for: Skin and soft tissue infections Hospital acquired pneumonia Telavancin

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33 A pooled analysis of data showed a higher risk of nephrotoxicity and serious adverse events among telavancin-treated patients compared to vancomycin (16% vs 10%) An increased mortality was reported in patients with HAP and moderate-to-severe renal impairment treated with telavancin [In the subset of patients without severe renal impairment clinical and safety outcomes were similar in the telavancin and vancomycin treatment groups] Future Microbiol 2014; 9:

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35 Oritavancin

36 Lipoglycopeptide Oritavancin Prolonged terminal half-life (393 h) Extensive tissue distribution Very high concentrations within macrophages ( frequent intracellular residence of S. aureus) MICs are two to eight-fold lower than vancomycin Active against VRSA and daptomycin non-susceptible S aureus Approved for SSTI

37 SOLO I & II TRIALS Double-blinded, active controlled multicenter, randomized trials ABSSIs: wound infections, cellulitis, or major skin abscesses (minimum 75 cm2 erythema) that the clinician thought needed at least 7 days of parenteral therapy 1 dose (1200 mg) of oritavancin vs. vancomycin for 7 10 days Outocomes: early (2 3 days), EOT, post-therapy evaluation (7 14 d)

38 Primary outcome: SOLO 1: oritavancin 82.3% vs 78.9% SOLO 2: oritavancin 80.1% vs 82.9% Also similar according to type of pathogen

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41 Summary

42 Tedizolid SSSI Summary Ceftaroline // Ceftobiprole (No VAP) SSSI & CAP-HAP Dalbavancina// Oritavancin // Telavancin SSSI [Telavancin: HAP]

43 PK/PD summary

44 Advantages & disadvantages Antibiotic Advantages Disadvantages Tedizolid Ceftaroline Ceftobiprole Dalbavancin Oritavancin Telavancin Active against MRSA and VRE Good orally biodisponibility Low myelotoxicity Bactericidal Well tolerated Moderately expensive Broad-spectrum activity, including MRSA and P. aeruginosa Good tolerability profile Activity against VISA, VRSA Rapidly bactericidal Once weekly OPAT programmes Activity against VISA, some VRSA, and daptomycin nonsusceptible S aureus In vitro bactericidal biofilm activity Once weekly OPAT programmes Rapidly bactericidal MRSA, VISA, and VRSA Active against MRSA strains resistant to vancomycin, linezolid, and daptomycin Bacteriostatic Limited reports on treatment of MRSA infections other than ABSSSIs Positive Coombs test (without hemolysis 11%) Red man syndrome ALT elevations Coagulation test interference Nephrotoxicity Lower clinical outcomes in patients with reduced renal function in VAP Coagulation test interference

45 Acknowledgements Hospital Macarena Bacteremia Team Hospital Macarena IDs team Investigators from Hospital Universitario Virgen Macarena and REIPI

46 Thank you for your attention!!