1. F. Van Bambeke & P.M. Tulkens
GLYCOPEPTIDE ANTIBIOTICS from Old Mississipi mud … … to new derivatives: a critical appraisal
F. Van Bambeke & P.M. Tulkens
Pharmacologie cellulaire et moléculaire
Université catholique de Louvain – Brussels - Belgium
Presented at the 5th European Congress of Chemotherapy, Rhodes, Greece, October 2003

2. Glycopeptide story: from natural to semi-synthetic derivatives
~ 1950 :
discovery of vancomycin in Mississipi mud
~ 1985 :
large clinical use in USA
Gram(+) infections and digestive tract decontamination
Problem:
toxicity of vancomycin due to impurities  better purification procedures
~ 1980 :
discovery of teicoplanin, as a natural GP with improved PK
largely used in Europe

3. Glycopeptide story: from natural to semi-synthetic derivatives
~ 1990 :
Launching of large scale research program for finding
GP with optimized properties  hemi-synthetic compounds
Malabarba and Nicas
Med Res Rev. (1997) 17:69-137; Curr Med Chem. (2001) 8:1759-7
vancomycin
teicoplanin
oritavancin
dalbavancin
phase II / III
(1999)
(1996)
(2003)

4. Peptidoglycan synthesis
reticulation
cell wall
D-ala
cytosol
precursor
synthesis

5. Glycopeptide mechanism of action
binding to D-Ala-D-ala
prevents the reticulation
of peptidoglycan
precursors

6. But resistance came in ...

7. Resistance in enterococci
large clinical use in USA
started in ~ 1985
Bonten et al,
Lancet ID (2001) 1:

8. Resistance in enterococci

glycopeptide binding
to depsipeptide
D-Lac, D-Ser
P. Courvalin et al’s work

9. Resistance in enterococci
from susceptible …
… to resistant
1 hydrogen bound is missing !
Arthur et al, Trends Microbiol (1996) 4:

10. Resistance in enterococci

glycopeptide binding
to depsipeptide
D-Lac, D-Ser

11. Resistance in staphylococci (GISA)
MIC
AMP
VAN
GEN
RIF
LVX
TET
SMX
Q-D
LZD 64 8
128
2048
0.125
0.5 2 AB

12. Resistance in staphylococci (GISA)
tickened
Cell wall
multiplication
of the target !
Hiramatsu Lancet ID (2001) 1:
Cui et al J Clin Microbiol (2003) 41:5-14

13. Resistance in staphylococci (GRSA)
MIC
VAN TEC 32 4 AB

14. Glycopeptides: what can we improve ?
parameter
vanco - teico
ideal glycopeptide
spectrum
Gram (+) & MRSA
but VRE - GISA
Gram (+)
& MRSA, GISA, VRE
quickly, conc. dependent
bactericidal
t ½ 
diffusibility (CNS)
side effects 
AUC/MIC & Cmax/MIC  PD
static or slowly
bactericidal PK
t ½ short for vanco
PK/PD
high doses to reach
appropriate
AUC/MIC & Cmax/MIC
safety
(red-man syndrome)
oto-& nephrotoxicity

15. Glycopeptide updated mechanism of action
dimerization
and / or
membrane anchoring
 activity

16. Glycopeptide updated mechanism of action in VRE
efficient binding
still possible !

17. Glycopeptides: how can we improve ?3 2

18. Glycopeptides: how can we improve ?3 2
binding to
D-Ala-D-Ala

19. Glycopeptides: how can we improve ?3 2
dimerization
binding to
D-Ala-D-Ala

20. Glycopeptides: how can we improve ?
membrane anchoring,
transglycosylase inhibition O N H C l 3 2
dimerization
binding to
D-Ala-D-Ala

21. Molecules in clinical development: DESIGN

22. From vancomycin to oritavancinH C l 3 2

23. From vancomycin to oritavancinH C l 3 2
epi-vancosamine O H

24. From vancomycin to oritavancinH O H O
4‑epi-vancosamine
self-association
capacity O O H O O C H H N 3 2 O C l O H H C 3 O O O H 2 N C 3 H O C l O O O H H N N N N N H H H H N O O N H C H O 3 C O N H 2 H O O C O H
LY264626 H O O H

25. From vancomycin to oritavancinl
lipophilic side chain
activity
including against resistant enterococci H O H O O O O H O C H H N 3 O C l O H H C 3 O O O H 2 N C 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 C O N H O 2 H O O C O H H O O H

26. From teicoplanin to dalbavancinH N H O H O O C l O H O O O O H O H O H O O C l O N H A c O O H H N H O N N 2 N N N H H H H N O O H O O C H O O O H O H H O O O H O O H O H O H

27. From teicoplanin to dalbavancinH N H O H O O O H O O O O H O H O H O O C l O N H A c O O H H N
HCH O N N 3 N N N H H H H N O C l O H O O C H O O O H O H H O O O H O O H O H O H

28. From teicoplanin to dalbavancinH N
removal of
N-acetylglucosamine
activity
(against resistant enterococci) H O H O O O H O O O HO C l O O O H H N
HCH O N N 3 N N N H H H H N O C l O H O O C H O O O H O H H O O O H O O H
A40926 O H O H

29. From teicoplanin to dalbavancinH N H O H O O O H O O O HO
activity C l O O O H H N
HCH O N N 3 N N N H H H N H- H N O C l O O C H O O O H O H H O O O H O O H O H O O H H

30. Molecules in clinical development: IN VITRO DATA microbiology pharmacodynamics

31. Most of data from Candiani, et al. (1999) JAC 44: 179-92
Spectrum of activity
strain
resist.
vanco
orita
teico
dalba
enterococci
susc.
VanA
VanB
0.25-4
>128
8-128 
64->128
0.13-8
0.5->128
0.02-2
S. aureus
Methi-S
Methi-R
VISA
VRSA
0.13-1
0.5-4 8 32
0.13-4
1-8
0.25
8-32 4
<
0.06-1 2
S. epiderm.
1-4
0.25-1
1-16  
S. pyogenes 
S. pneumo
Peni-S
Peni-R
0.25-2
Most of data from Candiani, et al. (1999) JAC 44:

32. Pharmacodynamic properties of oritavancin
conc. dependent,
bactericidal effect
static effect
Allen & Nicas, FEMS Microbiology Rev (2003) 26:

33. PK/PD properties of oritavancin in a model of S
PK/PD properties of oritavancin in a model of S.aureus infected macrophages
control
ORI
VAN
100
200
300
Cellular accumulation
VAN
ORI
107
2.5 µg/ml
25 µg/ml
0.25 µg/ml
10 µg/ml
50 µg/ml
105
CFU / mg prot
103
101 5 10 15 20 25
Time (h)
Seral et al AAC (2003) 47 :

34. Molecules in clinical development: IN VIVO DATA pharmacokinetics pharmacodynamics

35. Pharmacokinetic properties
parameter
Vanco
(15 mg/kg)
Orita
(3 mg/kg)
Teico
(6 mg/kg)
Dalba
peak (mg/L)
20-50 31 43
300
through (mg/L)
5-12
(24 h)
1.7
< 5 40
(168 h)
protein binding
10-55 %
90 %
90 %
98 %
terminal t½ (h)
4-8
360
83-168
257 h
once-a-day
administration
once-a-week
administration
Intermune, Inc, data on file
Steiert & Schmitz,
Curr.Opin.Investig.Drugs (2002) 3:

36. PK/PD profile PK/PD breakpoints : parameter Vanco Orita Teico Dalba
(15 mg/kg)
bid
Orita
(3 mg/kg) qd
Teico
(6 mg/kg)
Dalba
AUC / MIC = 125
total
free 4 2 1
0.1
0.4
185
Cmax / MIC = 10 10 5 3
0.3 30
0.6
MRSA
VISA
VRE
0.06-1 2
0.5->128
0.13-8
8-32
64->128
0.13-4
1-8
0.5-4 8
>128
MIC of target bugs :

37. preliminary data from Phase I and Phase II
Safety profile
preclinical studies
preliminary data from Phase I and Phase II
oritavancin and dalbavancin
well tolerated
but more patients
are needed …

38. Molecules in clinical development: IN VIVO DATA clinical studies

39. followed by oral cephalexin
Clinical experience
complicated skin and skin structure infection
caused by Gram (+) including MRSA
(phase II/III; double blind, randomized)
517 pts
Vancomycin 15 mg/kg bid
3-7days
followed by oral cephalexin
10-14 days
Oritavancin mg/kg qd
3-7 days
SUCCESS :
bacteriological
clinical
with MRSA
76 %
80 %
74 %
76 % =
Wasilewski et al 41st ICAAC (2001)

40. Vancomycin, ceftriaxone, cefazolin or clindamycin
Clinical experience
complicated skin and skin structure infection
caused by Gram (+) including MRSA
(phase II; controlled, randomized)
42 pts
Vancomycin, ceftriaxone,
cefazolin or clindamycin
for 7-21 days
Dalbavancin
15 mg/kg day 1
+ 7.5 mg/kg day 8
SUCCESS :
bacteriological
clinical
64 %
76 %
73 %
94 %
Selzer et al 13th ECCMID (2003)

41. In which indications could they be useful ?
which organisms ?
MRSA certainly YES
VRE oritavancin only
VISA limited activity,
… but synergy for dalba + -lactam
S. pneumo other alternatives
which organs ?
severe skin and soft tissues
septicemia / deep organs
endocarditis (combination ?)
CNS infections (penetration ?)
clinical experience
still lacking

42. Research is still active …
TD-6424

43. Research is still active …
TD-6424
in vitro data: MIC MRSA 1 µg/ml
MIC VISA 4 µg/ml
antibacterial activity: bactericidal
inhibitor of lipid synthesis
activity in animal models endocarditis
subcutaneous infections
Phase I studies t ½ ~ 8 h  once-a-day

44. We are looking forward these new antibiotics …
… but how strong will they be ?