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