1. Pharmacodynamics of Glycopeptides Niels Frimodt-Møller, MD DMSc Dept. Of Microbiological R & D Statens Serum Institut, Copenhagen, Denmark

2. Vancomycin (glycopeptide): Molecular structure – mechanism of action Mol. weight 1.449 Binds avidly to metal ions and forms complexes with bacterial cell-wall peptides: Binds tightly to the two terminal D-alanine residues at the free carboxyl end of pentapeptide

3. Vancomycin (glycopeptide): Molecular structure – mechanism of action Mol. weight 1.449 Binds avidly to metal ions and forms complexes with bacterial cell-wall peptides: Binds tightly to the two terminal D-alanine residues at the free carboxyl end of pentapeptide Active site

4. In vitro activity (MIC, mg/ml) of vancomycin, teicoplanin and oritavancin (LY333328) OrganismVancomycinTeicoplaninOritavancin S. aureus, MS0.78 – 20.3 – 1.61 – 4 S. aureus, MR0.5 - 3.10.2 – 3.11 – 4 S. epidermidis1.6 – 6.3 <0.03 – 4 S. pneumoniae0.25 – 0.80.12 – 0.80.015 E. faecalis2.5 – 8.0< 0.03 – 8.0<0.03 – 1 E. faecium2.6 – 4.00.2 – 3.1<0.03 – 1 Listeria sp.1.6 – 4.00.2 – 3.1<0.03–0.125

5. Teicoplanin early failures Early termination of study of teico 200 mg/d iv/im vs. flucloxacillin 8 g/d (Calain et.al JID 1987; 155: 187-91) Failure of teico in 2 neutropenic ptts with CNS bacteraemia (Brunet et.al. EJCMD 1990; 9: 145-7) Failures of teico monotherapy with doses of 2-5 mg/kg (Davey et.al. JAC 1991; 27 suppl.B: 43-50) Failures (6/8) with teico 6 mg/kg (Gilbert et.al. AAC 1991; 35: 79-87)

6. (a) Killing curves for S. aureus ATCC 29213 (b) for S. epidermidis ATCC 29886 both exposed to 2, 4, 8, 16, and 64× the MIC of vancomycin. Time kill studies in vitro for vancomycin vs. S. aureus and S. epidermidis Löwdin E et.al. AAC 1998; 42: 2739-44

7. Time-kill curves for vancomycin (15 µg/ml) for 3 VISA strains and one VSSA MRSA strain ( Aeschlimann JR et.al. AAC 1999, 43: 1914-18) High inoculum Stationary phase Low inoculum HIP5836 14379 Mu50 MRSA 494

8. PAE and PA SME for vancomycin vs. S. aureus and S. epidermidis at 10 x MIC PAE (h) PA SME (h) (0.2 x MIC) S aureus (N = 4) 1.6 – 2.04.6 – 10.0 S epidermidis (N = 4) 1.4 – 4.810 – 13.8 Löwdin et.al. AAC 2001; 42: 2739

9. S. aureus ATCC 2913, T½ 1h S. aureus ATCC 2913, T½ 5 h In vitro kinetic model: Vancomycin vs. S. aureus Löwdin E et.al. AAC 1998; 42: 2739-44 Both experiments at 10 x MIC; arrows indicate T > MIC

10. In vitro kinetic model: Vancomycin vs. S. epidermidis L öwdin E et.al. AAC 1998; 42: 2739-44 S. epidermidis ATCC 29886, T½ 1h S. epidermidis ATCC 29886, T½ 5h Both experiments at 10 x MIC ; arrows indicate T > MIC

11. Activity of oritavancin (x2) and vancomycin(x4) against pneumococcus in in vitro model Coyle EA & Rybak MJ, AAC 2001; 45: 706-9

12. 2 x 20 mg/kg with or without dexa 1 mg/kg 1 x 40 mg/kg with or without dexa 1 mg/kg Pharmacodynamics of Vancomycin for the Treatment of Experimental Penicillin- and Cephalosporin-Resistant Pneumococcal Meningitis ( Ahmed A et.al. AAC 1999; 43: 876-881)

13. Killing of S. aureus ATCC 29213 at 1 x MIC following 8 h incubation in 3 media Killing (%) at 8 h Antibiotic MH BrothMHB + Serum 10 : 90 MHB + Bovine albumin Vancomycin 20 15 Teicoplanin 1000 Oritavancin 99.900 Cloxacillin 99.900 Ciprofloxacin 9990 Zhanel GG et.al. AAC 1998; 42: 2427-2430

14. Glycopeptides: Protein binding and terminal half life Protein bindingHalf life (T½) Hours Vancomycin10 – 50%6 Teicoplanin90%>35 Oritavancin> 80%12

15. Mouse peritonitis model: Vancomycin and teicoplanin against ten PRP with Pen MIC´s from 0.016 to 8 mg/l Vancomycin Teicoplanin MIC (mg/l) 0.125-0.25 0.016-0.05 ED50 (mg/kg) 0.58 0.32 Protein- binding (%) 20-28% 90-94% Knudsen JD et.al. AAC 1997; 41: 1910-15.

16. Bactericidal activity of vancomycin in bacteraemia in humans Mean duration of bacteraemia Vancomycin, MRSA endocarditis 7 days (Levine et.al. Ann Intern Med 1991; 115: 674-80) Nafcillin, MSSA endocarditis 3 days (Korzeniowski et.al. Ann Intern Med 1982; 97: 496-503)

17. Pharmacdynamics of glycopeptides in the mouse peritonitis model: ED50´s of different 48 h dosing regimens for vancomycin and teicoplanin against pneumococcus No. of doses ED50, mg/kg Knudsen JD et.al. AAC 2000; 44: 1247-54

18. Vancomycin, 1mg/kg Teichoplanin, 1 mg/kg Pharmacodynamics of Glycopeptides in the Mouse Peritonitis Model of Streptococcus pneumoniae or Staphylococcus aureus Infection Knudsen JD et.al. AAC, 2000; 44: 1247-1254

19. Vancomycin:solid lines and circles. Teicoplanin: broken lines and crosses. The goodness of fit of values for the curves were as follows: for effect and vancomycin, T >MIC-free R 2 was 0.65 and C max-free /MIC R 2 was 0.76; for effect and teicoplanin, T >MIC-free R 2 was 0.82 and C max-free /MIC R 2 was 0.96. Pharmacodynamics of Glycopeptides in the Mouse Peritonitis Model of Streptococcus pneumoniae or Staphylococcus aureus Infection Knudsen JD et.al. AAC, 2000; 44: 1247-1254

20. Pharmacodynamics of glycopeptides in the mouse peritonitis model: Correlation of pk/pd parameters with effect in multidosing trial DrugNo. of regimens Parameter selected Spearman rho (all P<0,001) Vancomycin39 T>MIC-free C-max-free/MIC AUC/MIC 0,78 0,79 0,83 Teicoplanin40 T>MIC-free C-max-free/MIC AUC/MIC 0,83 0,85 0,77 Vanco + teico79 T>MIC-free C-max-free/MIC AUC/MIC 0,82 0,80 0,75 Knudsen JD et.al. AAC 2000; 44: 1247-54

21. Pharmacodynamics of glycopeptides in the mouse peritonitis model: Effect on survival of doses close to ED50 S. aureusS. pneumoniae Survival, % 4,7 mg/kg 2,7 mg/kg 0,7 mg/kg0,6 mg/kg Knudsen JD et.al. AAC 2000; 44: 1247-54

22. The glykopeptide pk/pd problem Conc. Cfu Time For drugs with long T½: Peak> MIC ? Time-kill takes place before end of drug elimination – it is therefore difficult to model for differences in PD-parameters

23. Once-daily vs. Twice-daily iv vancomycin for infections in hospitalized patients Cohen et.al. JAC 2002; 49: 155-60. OD (n = 51) 30 mg/kg BD (n = 52) 15 mg/kg x 2 Clinical outcome favourable 4749 Culture still pos.34 Trough conc., mg/l mean + SD 13.2 + 8.211.6 + 6.4 Peak conc., mg/l mean + SD 42.8 + 16.127.0 + 9.2 Red man syndrome7/515/52

24. Teicoplanin therapy for S. aureus septicaemia Harding et.al. JAC 2000; 45: 835-41. Retrospective analysis of 80 ptts treated with teico: 69 cured, 11 failures. Multiple logistic analysis: Two factors significantly P<0.05) related to failure: age (cure 49 y, failure 61y) pre-dose serum conc. (cure 7.8, failure 4.4)

25. Conclusion: PK/PD for glycopeptides Concentration independent, time-dependent time-kill activity denotes Time>MIC as most important PD- parameter PK-properties, however, i.e. long elimination half-lives, high protein-binding tend to obscure differences in PD- parameters (i.e. high corr. between AUC/Peak/T>MIC) Cmax(free)/MIC ratio has major importance (>10-20XMIC) Vancomycin 2g x 1 or 1g x 2 seem equally effective Teicoplanin optimal dose > 6 mg/kg