The new antistaphylococcal drugs (tigecycline, daptomycin, - PowerPoint PPT Presentation

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

2 Sympo – S. aureus – 11/01/07 - do we need new drugs ?

« 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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... 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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... 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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... WCK-771 Sympo – S. aureus – 11/01/07 - 7

moxifloxacin and CA-MRSA killing curves - 6 CA-MRSA 0 clindamycin linezolid minocycline -1 Δ log CFU/ml rifampicin -2 -3 sulfametoxazole moxifloxacin 0 6 12 18 24 time (h) rapidly bactericidal 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 percentage of strains cipro S R 50 levo Lowest MICs moxi 40 among currently 30 available quinolones, 20 but … 10 0 0.25 0.5 1 2 4 8 16 32 64 128 256 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 � CA-MRSA only • no major toxicity issue • risk of � QTc interval (already quite large 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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... 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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... WCK-771 Sympo – S. aureus – 11/01/07 - 17

synercid S A blocks peptide bound formation dalfopristin SYNERGY quinupristin S B 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 percentage of strains S R 50 40 30 20 10 0 0.015625 0.03125 0.0625 0.125 0.25 0.5 1 2 0.015 0.03 0.06 What about these ? 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 Δ log CFU from time 0 24h 2 1 0 -1 -2 -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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... 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 • VISA tend to have � MICs • once-a-day • 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 MX-2401 oritavancin linezolid daptomycin API-1252 tigecycline dalbavancin ceftobiprole DK-619 new oxazolidinones iclaprim new ketolides retapamulin ... WCK-771 Sympo – S. aureus – 11/01/07 - 28