S. aureus: what do we need to know (and to do) in 2007 ? The new antistaphylococcal drugs (tigecycline, daptomycin, telavancin, …): is the future (really) shining ? Françoise Van Bambeke Unité de Pharmacologie cellulaire et moléculaire Université catholique de Louvain Bruxelles, Belgium http://www.facm.ucl.ac.be Sympo – S. aureus – 11/01/07 - 1 do we need new drugs ? Sympo – S. aureus – 11/01/07 - 2 « old » antibiotics: still usable for CA-MRSA ! Rice, Am. J. Med. (2006) 119:S11-9 Sympo – S. aureus – 11/01/07 - 3 « old » antibiotics: still usable for CA-MRSA ! Sabol et al., Ann. Pharmacother. (2006) 40:1125-33 Sympo – S. aureus – 11/01/07 - 4 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... What will be your choice ? Sympo – S. aureus – 11/01/07 - 5 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... Let’s try to find a way … Sympo – S. aureus – 11/01/07 - 6 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... Sympo – S. aureus – 11/01/07 - 7 moxifloxacin and CA-MRSA killing curves - 6 CA-MRSA 0 clindamycin linezolid -1 minocycline rifampicin -2 log CFU/ml Δ -3 sulfametoxazole moxifloxacin 0 6 12 18 24 time (h) rap b idly act eric idal Kaka et al., JAC (2006) 58:680-3 Sympo – S. aureus – 11/01/07 - 8 moxifloxacin: in vitro data Distribution of MICs for 100 MRSA collected in 2002 breakpoint 60 S R cipro 50 levo Lowest MICs moxi among currently 40 available 30 quinolones, 20 but … 10 percentage of strains 0 4 8 1 2 16 32 64 0.5 128 256 0.25 MIC (mg/L) low level high level resistance resistance Noguchi et al., Int. J. Antimicrob. Ag. (2005) 25:374-9 Sympo – S. aureus – 11/01/07 - 9 moxifloxacin: pros and cons • rapidly bactericidal • cross resistance with • easy switch iv-po other quinolones • once-a-day even if MIC lower • no major toxicity issue Æ CA-MRSA only (already quite large • risk of Ê QTc interval clinical experience) (drug interactions !) Sympo – S. aureus – 11/01/07 - 10 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... Sympo – S. aureus – 11/01/07 - 11 linezolid O HN O N N O F O • inhibits the formation of the initiation complex • no cross resistance with other drugs acting on protein synthesis (MLS) • resistance considered for long as improbable … but now well described (due to mutations in 23S rRNA) Bozdogan & Appelbaum, Int. J. Antimicrob. Ag. (2004) 23:113-9 Sympo – S. aureus – 11/01/07 - 12 linezolid: in vitro data Distribution of MICs for 60 MRSA collected from diabetic foot drug range MIC 50 MIC 90 breakpoint vancomycin 0.5-1 0.5 1 8 linezolid 2-8 4 4 4 We slowly reach the limit … Goldstein et al., AAC (2006) 50:2875-79 Sympo – S. aureus – 11/01/07 - 13 linezolid: in vitro data Susceptibility of MRSA by site of isolation 8 4 breakpoint again we approach the limit … Wilson et al., JAC (2006) 58:470-3 Sympo – S. aureus – 11/01/07 - 14 linezolid: clinical experience indication Linezolid Vancomycin 600 mg iv/po 1g iv 2x/day 2x/day cSSTI (1180) 99.2 % 88.5 % Osteomyelitis (66) 84.8 % -- MRSA bacteriaemia (53) 56 % 46 % nosocomial pneumonia (1019) 53 % 52.2 % MRSA (160) 59 % 35.5 % Weigelt et al., AAC (2005) 49:2260-66; Senneville et al., Clin Ther. (2006) 28:1155-63; Shorr et al., JAC (2005) 56:923-929; Wunderink et al., Chest (2003)124:1789-97 Sympo – S. aureus – 11/01/07 - 15 linezolid: pros and cons • excellent biodisponibility • bacteriostatic and tissue penetration • resistance already selected • easy switch iv-po • high price • twice-a-day • serious side effects (myelosuppression) • drug interactions (IMAO) Sympo – S. aureus – 11/01/07 - 16 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... Sympo – S. aureus – 11/01/07 - 17 synercid SA blocks peptide bound formation dalfopristin SYNERGY quinupristin SB blocks the path of the nascent peptide Harms et al., BMB Biol (2004) 2:4 Sympo – S. aureus – 11/01/07 - 18 synercid: in vitro data Susceptibility of 101 MRSA breakpoint 60 S R 50 40 30 20 10 percentage of strains of percentage 0 1 2 0.5 0.25 0.06 0.03 0.125 0.015 0.0625 What about these ? 0.03125 0.015625 MIC (mg/L) Sambatakou et al., JAC (1998) 51:349-55 Sympo – S. aureus – 11/01/07 - 19 synercid: in vitro data In vitro models - MRSA 3 5 h 24h 2 1 0 -1 -2 log CFU from time 0 time from CFU log Δ -3 -4 -2 -1 0 1 2 MIC Cmax Log concentration (mg/L) time- and concentration-dependent bactericidal effect Baudoux et al., ECCMID (2007) Sympo – S. aureus – 11/01/07 - 20 synercid: in vitro data In vitro pharmacodynamic models • poorly active alone against MRSA; highly active on VRE • combinations synergistic towards MRSA Allen et al., AAC (2002) 46:2606-12 Sympo – S. aureus – 11/01/07 - 21 synercid : pros and cons • highly active on VRE • poorly bactericidal • synergistic in vitro against MRSA with many ABs • bid or tid administration • no oral route • cross-resistance with ML • drug interactions (CYP450 3A4) caution with drugs prolonging QTc • myalgia/arthralgia frequent • high price • not studied in children Sympo – S. aureus – 11/01/07 - 22 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... Sympo – S. aureus – 11/01/07 - 23 daptomycin • very bactericidal towards Gram (+) organisms through membrane destabilization • spare mammalian cells because they lack phosphatidylglycerol (critical for binding to Gram(+) membranes) • fast track registration in the US because of activity against vancomycin-resistant enterococci (VRE) • indications: cSSTI; Phase III trial on bacteriemia completed Sympo – S. aureus – 11/01/07 - 24 daptomycin: in vitro data Distribution of MICs for 60 MRSA collected from diabetic foot drug range MIC 50 MIC 90 breakpoint vancomycin 0.5-1 0.5 1 8 daptomycin 0.25-1 0.5 0.5 1 wait and see … Goldstein et al., AAC (2006) 50:2875-79 Sympo – S. aureus – 11/01/07 - 25 daptomycin: clinical experience indication Daptomycin Vancomycin iv 1x/day or β-lactam cSSTI (902) 4 mg/kg 83.4 % 84.2 % MRSA (28-36) 75 % 69.4 % bloodstream (31) 6 mg/kg 77 % -- MRSA (11) 100 % VRE (11) 45 % Arbeit et al., CID (2004) 38:1673-81; Segreti et al., Pharmacotherapy (2006) 26:347-352 Sympo – S. aureus – 11/01/07 - 26 daptomycin: pros and cons • rapidly bactericidal • inactive in pneumonia • once-a-day • VISA tend to have Ê MICs • high price • no oral route • musculotoxic in animals avoid combination with inhibitors of HMGCoA reductase • safety / efficacy not studied in < 18 years Sympo – S. aureus – 11/01/07 - 27 recent and novel agents for S. aureus recently on the market; (late) stage of brought on the not yet clinical investigational Belgian market in Belgium development moxifloxacin synercid telavancin CS-023/PZ-601 linezolid daptomycin oritavancin MX-2401 tigecycline dalbavancin API-1252 ceftobiprole DK-619 iclaprim new oxazolidinones retapamulin new ketolides WCK-771 ... Sympo – S. aureus – 11/01/07 - 28 tigecycline tigecycline • same binding site as tetracyclines in ribosome 16S RNA; additional interaction site tetracycline • Unaffected by resistance due to minocycline - ribosomal protection - Tet efflux pumps • Approved in USA in 2005 and in Europe in 2006 • wide spectrum, indicated for: cSSTI; intra-abdominal infections Olson et al., AAC (2006) 50:2156-66 Sympo – S. aureus – 11/01/07 - 29 tigecycline: in vitro data Distribution of MICs for 128 MRSA from USA breakpoint 80 S R tigecycline minocycline active 60 on minocycline-R population, but … 40 20 percentage of strains of percentage 0 1 2 4 8 16 32 64 0.5 128 256 0.25 0.125 MIC (mg/L) a few isolates above the breakpoint … Low et al., Int. J. Antimicrob. Ag. (2002) 20:220-2 Sympo – S. aureus – 11/01/07 - 30 tigecycline clinical experience Phase 3 - Skin and skin structure infections Ellis-Grosse et al., Clin. Infect. Dis. (2005) 41:S341-53 Sympo – S.