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Pharmacodynamics of Glycopeptides

Pharmacodynamics of Glycopeptides. Niels Frimodt-Møller, MD DMSc Dept. Of Microbiological R & D Statens Serum Institut, Copenhagen, Denmark. Vancomycin (glycopeptide): Molecular structure – mechanism of action. Mol. weight 1.449

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Pharmacodynamics of Glycopeptides

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  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)

  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. Time kill studies in vitro for vancomycin vs. S. aureus and S. epidermidis Löwdin E et.al. AAC 1998; 42: 2739-44 (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.

  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 Mu50 14379 MRSA 494

  8. PAE and PA SME for vancomycin vs. S. aureus and S. epidermidis at 10 x MIC Löwdin et.al. AAC 2001; 42: 2739

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

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

  13. Killing of S. aureus ATCC 29213 at 1 x MIC following 8 h incubation in 3 media Zhanel GG et.al. AAC 1998; 42: 2427-2430

  14. Glycopeptides: Protein binding and terminal half life

  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 Med1982; 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 ED50, mg/kg No. of doses Knudsen JD et.al. AAC 2000; 44: 1247-54

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

  19. Pharmacodynamics of Glycopeptides in the Mouse Peritonitis Model of Streptococcus pneumoniae or Staphylococcus aureus Infection Knudsen JD et.al. AAC, 2000; 44: 1247-1254 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-freeR2 was 0.65 and Cmax-free/MIC R2 was 0.76; for effect and teicoplanin, T>MIC-freeR2 was 0.82 and Cmax-free/MIC R2 was 0.96.

  20. Pharmacodynamics of glycopeptides in the mouse peritonitis model: Correlation of pk/pd parameters with effect in multidosing trial 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 Survival, % 2,7 mg/kg 0,7 mg/kg 4,7 mg/kg 0,6 mg/kg S. aureus S. pneumoniae Knudsen JD et.al. AAC 2000; 44: 1247-54

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

  23. Once-daily vs. Twice-daily iv vancomycin for infections in hospitalized patientsCohen et.al. JAC 2002; 49: 155-60.

  24. Teicoplanin therapy for S. aureus septicaemiaHarding 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

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