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
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
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
In vitro activity (MIC, mg/ml) of vancomycin, teicoplanin and oritavancin (LY333328)
Organism Vancomycin Teicoplanin Oritavancin
S. aureus, MS 0.78 – 2 0.3 – 1.6 1 – 4
S. aureus, MR 0.5 - 3.1 0.2 – 3.1 1 – 4
S. epidermidis 1.6 – 6.3 1.6 – 6.3 <0.03 – 4
S. pneumoniae 0.25 – 0.8 0.12 – 0.8 0.015
E. faecalis 2.5 – 8.0 < 0.03 – 8.0 <0.03 – 1
E. faecium 2.6 – 4.0 0.2 – 3.1 <0.03 – 1
Listeria sp. 1.6 – 4.0 0.2 – 3.1 <0.03–0.125
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)
(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
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 inoculumHIP5836
14379
Mu50
MRSA 494
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 – 2.0 4.6 – 10.0
S epidermidis
(N = 4)
1.4 – 4.8 10 – 13.8
Löwdin et.al. AAC 2001; 42: 2739
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
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
Activity of oritavancin (x2) and vancomycin(x4) against pneumococcus in in vitro model Coyle EA & Rybak MJ, AAC 2001; 45: 706-9
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)
Killing of S. aureus ATCC 29213 at 1 x MIC following 8 h incubation in 3 media
Killing (%) at 8 h
Antibiotic MH Broth MHB + Serum
10 : 90
MHB + Bovine albumin
Vancomycin 20 20 15
Teicoplanin 10 0 0
Oritavancin 99.9 0 0
Cloxacillin 99.9 0 0
Ciprofloxacin 99 90 90
Zhanel GG et.al. AAC 1998; 42: 2427-2430
Glycopeptides: Protein binding and terminal half life
Protein binding Half life (T½)
Hours
Vancomycin 10 – 50% 6
Teicoplanin 90% >35
Oritavancin > 80% 12
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.
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)
Pharmacdynamics of glycopeptides in the mouse peritonitis model: ED50´s of different 48 h dosing regimens for vancomycin and teicoplanin against pneumococcus
0
1
2
3
4
5
6
7
1 2 4 8 12 24
VancoTeico
No. of doses
ED50, mg/kg
Knudsen JD et.al. AAC 2000; 44: 1247-54
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
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 R2
was 0.65 and Cmax-free/MIC R2 was 0.76;
for effect and teicoplanin, T>MIC-free R2
was 0.82 and Cmax-free/MIC R2 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
Pharmacodynamics of glycopeptides in the mouse peritonitis model: Correlation of pk/pd parameters with effect in
multidosing trial
Drug No. of regimens
Parameter selected
Spearman rho
(all P<0,001)
Vancomycin 39 T>MIC-free
C-max-free/MIC
AUC/MIC
0,78
0,79
0,83
Teicoplanin 40 T>MIC-free
C-max-free/MIC
AUC/MIC
0,83
0,85
0,77
Vanco + teico 79 T>MIC-free
C-max-free/MIC
AUC/MIC
0,82
0,80
0,75
Knudsen JD et.al. AAC 2000; 44: 1247-54
Pharmacodynamics of glycopeptides in the mouse peritonitis model: Effect on survival of doses close to ED50
0
10
20
30
40
50
60
70
80
90
1 dose 2 doses 1 dose 2 doses
VancoTeicoControl
S. aureus S. pneumoniae
Survival, %4,
7 m
g/kg
2,7
mg/
kg
0,7
mg/
kg
0,6
mg/
kg
Knudsen JD et.al. AAC 2000; 44: 1247-54
The glykopeptide pk/pd problem
Conc.
Cfu
Time
For drugs with long T½:Peak><AUC><T>MIC ?
Time-kill takes place before end of drug elimination – it is therefore difficult to model for differences in PD-parameters
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
47 49
Culture still pos. 3 4
Trough conc., mg/l mean + SD
13.2 + 8.2 11.6 + 6.4
Peak conc., mg/l mean + SD
42.8 + 16.1 27.0 + 9.2
Red man syndrome 7/51 5/52
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)
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