French team to win the European Championship © by author ESCMID Online Lecture Library Antistaphylococcal team to fight staphylococci Anti-staphylococcal Pristinamycine Staph 2016 Clindamycine Tigecycline Ceftaroline ceftobiprole © byDaptomycine author Linézolide Fluoroquinolone ESCMIDAminoside Online Lecture VancomycineLibrary Pénicilline M Antistaphylococcal team to fight staphylococci MRSA: b-lactam’exit © by author ESCMID Online Lecture Library Antistaphylococcal team to fight staphylococci MRSA: b-lactam’exit Vancomycine © by author ESCMID Online Lecture Library Antistaphylococcal team to fight staphylococci SARM : exit les péniM Vancomycine : excellent player… but old molecule, toxicity, side effects © by author ESCMID Online Lecture Library Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine © by author Toxicity ComplexESCMID use Online Lecture Library No more available Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine ©« Zahia by call-girl author » scandal involving Franck RIBERY Toxicity ComplexESCMID use Online Lecture Library No more available Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine © by author ESCMID Online Lecture« super-vancomycine Library » so not innovative Renal toxicity ! Not available in France Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine ”Sextape” scandal BENZEMA-VALBUENA© by author ESCMID Online Lecture« super-vancomycine Library » so not innovative Renal toxicity ! Not available in France Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine © by author ESCMID Online LectureFDA and EMALibrary alert in 2011 due to overmortanlity in randomized study use of tigecyclin only in no other alternative Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine ”Sextape” scandal BENZEMA-VALBUENA© by author ESCMID Online LectureFDA and EMALibrary alert in 2011 due to overmortanlity in randomized study use of tigecyclin only in no other alternative Antistaphylococcal team to fight staphylococci So the substitutes of vancomycine ? © by author ESCMID Online Lecture Library Antistaphylococcal team to fight staphylococci … anti-MRSA of the new century • Synergistine injectable: quinupristine/dalfopristine (2000) • Oxazolidinones: linezolid (2001), tedizolid (2015) • Lipopeptide: daptomycine (2006) • Glycylcycline: tigecyclin (2006) • New Cephalosporins : ceftaroline (2012), ceftobiprole (2015) • Lipoglycopeptides: telavancine, dalbavancine, oritavancine © by author ESCMID Online Lecture Library Oxazolidinone familly Linezolid - Tedizolid Real de Madrid Zinédine ZIDANE and his son, Enzo ZIDANE © by author ESCMID Online Lecture Library ESCMID Postgraduate Educaon Course Virulence and resistance in Staphylococcus aureus: 2016 state of the art OXAZOLIDINONES Céline DUPIEUX & Frédéric LAURENT French Naonal Reference Centre for Staphylococci, Lyon, France © by author ESCMID Online Lecture Library Summary • Structure and mechanism of acon • In vivo acvity and clinical use • Mutaonal and plasmidic resistances • Detecon of resistance in roune © by author • Tedizolid, a new oxazolidinone: which advantages? ESCMID Online Lecture Library • Examples of outbreaks of linezolid-resistant staphylococci Introducon • Linezolid ZYVOX®, ZYVOXID® - 1st oxazolidinone introduced into clinical use - FDA approval 2001 © by author • Tedizolid phosphate SIVEXTRO® - « New generaon » oxazolidinone - FDA approval 2014 ESCMID Online Lecture Library Structure of oxazolidinones Synthec anmicrobials Not related to another class of anbiocs Unique mechanism of acon and ≈ no cross-resistance © by author LZD ESCMID Online Lecture Library acetamide Rybak et al. Infect Dis Ther, 2015 Mechanism of acon • Early inhibion of protein synthesis (iniaon): - Binds to the 23S RNA of the 50S subunit of the ribosome (P site, pepdyl transferase centre) - Prevents the formaon of the 70S complex: stops the protein synthesis before © by author it begins ESCMID Online Lecture Library Swaney et al. AAC, 1998; Bozdogan et al. Int J Anmicrob Agent, 2004 Mechanism of acon © by author ESCMID Online Lecture Library Swaney et al. AAC, 1998; Bozdogan et al. Int J Anmicrob Agent, 2004 Mechanism of acon Oxazolidinone © by author ESCMID Online Lecture Library Swaney et al. AAC, 1998; Bozdogan et al. Int J Anmicrob Agent, 2004 Distorts the N-formyl-Met-tRNA Mechanism of acon (iniator tRNA) binding site overlapping both 50S and 30S subunits Oxazolidinone © by author ESCMID Online Lecture Library Swaney et al. AAC, 1998; Bozdogan et al. Int J Anmicrob Agent, 2004 Distorts the N-formyl-Met-tRNA Mechanism of acon (iniator tRNA) binding site overlapping both 50S and 30S subunits Oxazolidinone © by author ESCMID Online Lecture Library Swaney et al. AAC, 1998; Bozdogan et al. Int J Anmicrob Agent, 2004 Inhibits the formaon of a Mechanism of acon funconal 70S iniaon complex which is crucial for translaon Oxazolidinone © by author ESCMID Online Lecture Library Inhibion of protein synthesis Swaney et al. AAC, 1998; Bozdogan et al. Int J Anmicrob Agent, 2004 Mechanism of acon © by author ESCMID Online Lecture Library If 70S already formed, LNZ inhibits translocaon of the pepde chain to P site from A site during formaon of the pepde bond Bozdogan et al. Int J Anmicrob Agent, 2004 Spectrum and suscepbility • Gram-posive bacteria +++: • Staphylococci, including methicillin-resistant staphylococci • Streptococci and enterococci, including vancomycin-resistant enterococci • Corynebacterium sp, Listeria • Anaerobes (Clostridium, Peptostreptococcus, Fusobacterium) • Legionella, some Mycobacteria © by author ESCMID Online Lecture Library • Binding site conserved both in Gram-posive and Gram-negave bacteria but efflux pumps in most of Gram-negave aerobic or anaerobic bacteria Inac9ve on Pseudomonas, Enterobacteriaceae, Neisseria… In vivo acvity and clinical use • Bacteriostac acvity against staphylococci and enterococci • Time-dependent effect • Linezolid: - treatment of community acquired pneumonia and nosocomial pneumonia - treatment of complicated skin and so ssue infecons only when microbiological tesng has © established by author that the infecon is known to be caused by suscepble Gram posive bacteria ESCMID Online Lecture Library • Tedizolid: - treatment of acute bacterial skin and so ssue infecons - bacteriostac in vitro but bactericidal in vivo? Linezolid-resistant staphylococci Most common mechanisms = ribosomal modificaons • Mutaons ! domain V of 23S rRNA - G2576U+++ - Rare mutaons (G2447U, T2500A, T2504A…) © by author ! ribosomal proteins L3, L4, L22 • ESCMIDAcquision of transmissible Online Lecturecfr ribosomal methyltransferase Library (plasmids, transposons) Tsiodras et al. Lancet, 2001; Kehrenberg et al. AAC, 2006; Long et al. AAC, 2012 23S rRNA mutaons Mulple copies (5-6) of the 23S rRNA gene present in S. aureus Resistance usually requires mutaons in two or more copies (successive mutaons or one mutaon followed by homologous recombinaon) © by author Low rate of resistant mutants selecon in vitro (10-9-10-11) • Selecon oen occurred during prolonged treatment ESCMID Online Lecture Library • No cross-resistance with other families of anbiocs Tsiodras et al. Lancet, 2001; Kehrenberg et al. AAC, 2006; Long et al. AAC, 2012 Résistances23S rRNA mutaons par mutation sur l’ARN 23S © by author ESCMID Online Lecture Library Long et al. AAC, 2012 23S rRNA mutaons © by author ESCMID Online Lecture Library Iguchi et al. PloS One, 2016 RésistancesRibosomal proteins mutaons par mutation sur l’ARN 23S © by author ESCMID Online Lecture Library Long et al. AAC, 2012 Cfr methylaon of 23S rRNA Cfr gene = chloramphenicol-florfenicol