F. Van Bambeke, PharmD, PhD - bvikm.org Symposium/31st Van Bambeke... · 6/11/2008 SBIMC-BVIKM 1...
Transcript of F. Van Bambeke, PharmD, PhD - bvikm.org Symposium/31st Van Bambeke... · 6/11/2008 SBIMC-BVIKM 1...
![Page 1: F. Van Bambeke, PharmD, PhD - bvikm.org Symposium/31st Van Bambeke... · 6/11/2008 SBIMC-BVIKM 1 New developments in anti-Gram positive treatment F. Van Bambeke, PharmD, PhD. Unité](https://reader031.fdocument.pub/reader031/viewer/2022022708/5be77b4609d3f2f21b8be311/html5/thumbnails/1.jpg)
1SBIMC-BVIKM 6/11/2008
New developments in antiNew developments in anti--Gram positive treatment Gram positive treatment
F. Van Bambeke, PharmD, PhD
Unité de Pharmacologie cellulaire et moléculaireLouvain Drug Research Institute
Université catholique de LouvainBrussels, Belgium
< www.facm.ucl.ac.be >
La Hulpe, 06/11/2008
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2SBIMC-BVIKM 6/11/2008
The anti-Gram(+) pipeline
recently brought on the
Belgian market
on the market; not yet
in Belgiumwaiting
for approval investigational
moxifloxacinlinezolid
synerciddaptomycin
tigecycline
telavancinoritavancindalbavancinceftobiprole
iclaprim
What will be your choice ?
new oxazolidinonesnew ketolides
...
new quinolonesnew lipopeptides
FabI inhibitors
new β-lactams
antibact. peptides
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3SBIMC-BVIKM 6/11/2008
Let’s travel together …
recently brought on the
Belgian market
on the market; not yet
in Belgiumwaiting
for approval investigational
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4SBIMC-BVIKM 6/11/2008
The anti-Gram(+) pipeline
recently brought on the
Belgian market
on the market; not yet
in Belgiumwaiting
for approval investigational
moxifloxacinlinezolid
synerciddaptomycin
tigecycline
telavancinoritavancindalbavancinceftobiprole
iclaprim
new oxazolidinonesnew ketolides
...
new quinolonesnew lipopeptides
FabI inhibitors
new β-lactams
![Page 5: F. Van Bambeke, PharmD, PhD - bvikm.org Symposium/31st Van Bambeke... · 6/11/2008 SBIMC-BVIKM 1 New developments in anti-Gram positive treatment F. Van Bambeke, PharmD, PhD. Unité](https://reader031.fdocument.pub/reader031/viewer/2022022708/5be77b4609d3f2f21b8be311/html5/thumbnails/5.jpg)
5SBIMC-BVIKM 6/11/2008
The last introduced anti-MRSA: Tigecycline, a glycylcycline
with XL spectrum
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6SBIMC-BVIKM 6/11/2008
Tigecycline: a glycylcycline
NHH3C CH3
OH
C
OOOH OHOH
NH2
NHCH3H3C
NH
CHNH3C
CH3
H3CO
O
minocycline
glycyl-
GAR936
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7SBIMC-BVIKM 6/11/2008
Tigecycline mode of action
Olson et al., AAC (2006) 50:2156-66
tigecycline
tetracyclineminocycline
• same binding site as tetracyclines in ribosome 16S RNA; additional interaction site
• Unaffected by resistance due to - ribosomal protection - Tet efflux pumps; but remains susceptible to broad spectrum efflux pumps of Gram(-) (MexXY in P. aeruginosa)
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8SBIMC-BVIKM 6/11/2008
Tetra- and glycyl-cyclines: activity and resistance
species phenotype tetracycline minocycline tigecycline
E. coli susceptible 1 1 0.25
Efflux (Tet) > 32 16 0.5
Ribosomal protection > 32 > 32 0.25
S. aureus susceptible 0.12 0.06 0.25
Efflux (Tet) > 32 0.25 0.5
Ribosomal protection > 32 4 0.25
Petersen et al., AAC (1999) 43:738-44
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9SBIMC-BVIKM 6/11/2008
Tetra- and glycyl-cyclines: activity and resistance
Dean et al., AAC (2003) 47:972-8
what about Pseudomonas ?
Δ
mexXY 0.5
phenotype MIC (mg/L)
WT 8
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10SBIMC-BVIKM 6/11/2008
Tigecycline: pharmacokinetics
parameter healthy volunteers (n=5)
cSSSTI(n=43)
Cmax (mg/L) 0.621 0.40
Cmin (mg/L) 0.145 0.14
AUC 24h (mg.h/L) 6.14 4.48
Van Wart et al., JAC (2006) 50:3701-7 McGowan, JAC (2008) 62: suppl.1 i11-i16
Initial bolus: 100 mg; followed by 50 mg q12h
low !
but needs to be considered in the light of MICs
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11SBIMC-BVIKM 6/11/2008
Tigecycline: pharmacokinetics
Rodvold, JAC (2006) 58:1221-9 Conte et al., Int J Antimicrob Agents (2005) 25:523-9
Sing
le d
ose:
100
mg
tissue AUC24h (mg.h/L)
serum/tissue AUC ratio
bile 2815 537
bladder 120 23
colon 17.3 2.6
lung 9.19 2
bone 2.05 0.4
synovial fluid 1.68 0.31
CSF 0.46 0.11
ELF 4.54 1.31
alveolar MΦ 268 77.5
100
mg
+ 6x
50 m
g q1
2h
routes of
elimination
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12SBIMC-BVIKM 6/11/2008
Tigecycline: setting up the breakpoint
Meagher et al., AAC (2007) 51:1939-45McGowan, JAC (2008) 62: suppl.1 i11-i16
Pharmacodynamic breakpointfor Gram(+) infections
AUC/MIC ≥
18
MIC ≤
18/5 = 0.25 mg/L
breakpoint
to avoid splitting the WT distribution …
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13SBIMC-BVIKM 6/11/2008
Tigecycline breakpoint: how does it fit with Belgian MICs ?
Denis et al., AAC (2006) 50:2680-85
0.062
50.1
25 0.25 0.5 1 2 4 8 16 32 64 128
256
0
25
50
75
100
TGCMINTET
MIC
cum
ulat
ive
perc
enta
ge511 MRSA isolates from 112 Belgian hospitals
MIC90
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14SBIMC-BVIKM 6/11/2008
dose et voie d'administr.
compartiment AUC AUC/MIC(0.25 mg/L)
AUC/MIC(0.5 mg/L)
100 mg iv serum 5.2 20.8 10.4lung 9.2 36.8 18.4bone 2.1 8.4 4.2synovial fluid 1.7 6.8 3.4
PK/PD of Tigecycline in different compartments
Rodvold et al., JAC (2006) 58:1221-29
MIC 90 in Belgium
Breakpoint EUCAST
PK/PD predicts success for AUC/MIC > 18
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15SBIMC-BVIKM 6/11/2008
Tigecycline clinical experience
Ellis-Grosse et al., Clin. Infect. Dis. (2005) 41:S341-53
1. Phase 3 - Skin and skin structure infections TGC 100 mg/ 50 mg q12h vs VAN/AZM 1g/2g q12h; up to 14 days
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16SBIMC-BVIKM 6/11/2008
Tigecycline clinical experience
Florescu et al., JAC (2008) 62 Suppl 1:i17-28.
2. Phase 3 – MRSA serious infections TGC 100 mg/ 50 mg q12h vs VAN 1g q12h; 7-28 days
population tigecycline vancomycin
ME 80.2 % (69/86) 83.9 % (26/31)
MRSA m-mITT 74 % (74/100) 81.8 % (27/33)
microbiological response
clinical response
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17SBIMC-BVIKM 6/11/2008
Tigecycline clinical experience
Tanaseanu et al., Diagn Microbiol Infect Dis. (2008) 61:329-38
3. Phase 2/3 – CAP: TGC 100 mg/ 50 mg q12h vs LVX 500 mg q24h or q12h; 7-14 days
Most are non-severe patients … but: Only a few PenI/R isolates
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18SBIMC-BVIKM 6/11/2008
Tigecycline clinical experience
Tanaseanu et al., Diagn Microbiol Infect Dis. (2008) 61:329-38
3. Phase 2/3 – CAP: TGC 100 mg/ 50 mg q12h vs LVX 500 mg q24h or q12h; 7-14 days
Most are non-severe patients … but:tigecycline levofloxacin
90.9 % (20/22) 72.2 % (13/18)
Bacteriemic patients
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19SBIMC-BVIKM 6/11/2008
Tigecycline clinical experience
EMEA/382036/2008
4. Phase 3 – HAP/VAP (withdrawn): TGC 100 mg/ 50 mg q12h vs IMI 500-1000 mg q8h (adj. AB if MRSA or P.a.);
7-14 days
patients population tigecycline imipenem/cilastatin
VAP/HAPCE 67.9 % 78.2 %
mITT 62.7 % 67.6 %
Non-VAPCE 75.4 % 81.3 %
mITT 69.3 % 71.2 %
clinical response
patients species tigecycline imipenem/cilastatin
Non VAP MRSA 47.1 % (8/17) 78.9 % (15/19)
microbiological response
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20SBIMC-BVIKM 6/11/2008
Tigecycline : pros and cons
• XL spectrum ?• not affected by some tet resistance mechanisms (Tet efflux, ribosomal protection)
• large tissue distribution• efficient in cSSTI and CAP (MRSA; bacteraemia)
• XL spectrum ?• bacteriostatic• CI – pregnancy, children• no oral route• low efficacy in HAP/VAP (MRSA)
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21SBIMC-BVIKM 6/11/2008
Ceftobiprole & Ceftaroline, two anti-MRSA S. aureus
with improved binding capacity to PBP2a
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22SBIMC-BVIKM 6/11/2008
Ceftobiprole
OHO
N
S
O
HN
O
NO
N
OH
N N
NH
S
NH2
H
BAL5788
Prodrug (medocaril)
N O
O
O
O
O
OHO
N
S
O
HN
O
NO
N
OH
N N
NH
S
NH2
H
2+
BAL9141
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23SBIMC-BVIKM 6/11/2008
Ceftobiprole
Lovering et al., ECCMID (2006) P1586 Hebeisen et al., AAC (2001) 45:825-31
BAL9141
β-lactamases
2+
OHO
N
S
O
HN
O
NO
N
OH
N N
NH
S
NH2
HPBP2a
open conformation
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24SBIMC-BVIKM 6/11/2008
Ceftaroline
Ishikawa et al., Bioorg Med Chem. (2003) 11:2427-37
OHO
NS
S
O
HN
S
N
O
N
OEt
N N
S
NH
H
NCH3
PO3H2
TAK-599
+
Prodrug (fosamyl)
TAK-91825
β-lactamases
PBP2a
+OHO
NS
S
O
HN
S
N
O
N
OEt
N N
S
NH2
H
NCH3
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25SBIMC-BVIKM 6/11/2008
Ceftobiprole & Ceftaroline: in vitro activity
Pillar et al., JAC (2008)61:595-602Ge et al., AAC (2008) 52:3398-404
strainceftobiprole ceftaroline
MIC50 MIC90 range MIC50 MIC90 range
MSSA 0.25 0.5 0.12-1 0.25 0.25 ≤
0.03-1
MRSA 1 2 0.25-4 0.5 1 0.12-2
S. pneumo PenS 0.008 0.015 ≤
0.002-0.06 ≤
0.008 0.015 ≤
0.008-0.25
S. pneumo PenI 0.06 0.25 0.008-0.5 0.015 0.06 ≤
0.008-0.5
S. pneumo PenR 0.5 0.5 0.25-1 0.12 0.12 ≤
0.008-0.5
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26SBIMC-BVIKM 6/11/2008
Ceftobiprole : pharmacodynamics in animals
Craig and Andes, AAC (2008) 52:3492-6
open: S; closed: R
Maximal effect for conc > MIC for 40 % of time
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27SBIMC-BVIKM 6/11/2008
Ceftobiprole : setting up PK/PD breakpoints
Lodise et al., AAC (2007) 51:2378–2387
provisional breakpoint Mouton et al, AAC (2004) 48:1713-8.
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28SBIMC-BVIKM 6/11/2008
Ceftobiprole « breakpoint »: how does it fit with Belgian MICs ?
Denis et al., AAC (2006) 50:2680-85
511 MRSA isolates from 112 Belgian hospitals
MIC90
0.062
50.1
25 0.25 0.5 1 2 4 8 16 32 64 128
256
0
25
50
75
100
BPR
MIC
cum
ulat
ive
perc
enta
ge
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29SBIMC-BVIKM 6/11/2008
Ceftobiprole intracellular activity
Lemaire et al., ICAAC (2007) A1438
Similar activity against intracellular MSSA and MRSA
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30SBIMC-BVIKM 6/11/2008
Ceftobiprole & Ceftaroline: pharmacokinetics
Schmitt-Hoffmann, AAC (2004) 48:2576-80Ge et al. ICAAC (2007): A34
parameterCeftobiprole
(500 mg)Ceftaroline
(600 mg q12h)Cmax (mg/L) 40.6 23.5
Cmin (mg/L) 0.46
T ½ (h) 3.6 2.6
Prot. binding (20%) < 20 % < 20 %
T > MIC 4 mg/L ~ 6 h
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31SBIMC-BVIKM 6/11/2008
Ceftobiprole: clinical experience
Noel et al., AAC (2008) 52:37-44
1. Phase 3 - Skin and skin structure infections BPR 500 mg q12h vs VAN 1g q12h ; 7-14 days
(+ metronidazole or aztreonam before identification)
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32SBIMC-BVIKM 6/11/2008
Ceftobiprole: clinical experience
Noel et al., AAC (2008) 52:37-44
1. Phase 3 - Skin and skin structure infections [Gram(+)] BPR 500 mg q12h vs VAN 1g q12h ; 7-14 days
(+ metronidazole or aztreonam before identification)
« caramel-like »
But is this an adverse
effect ?
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33SBIMC-BVIKM 6/11/2008
Ceftobiprole: clinical experience
Noel et al., CID (2008) 46:647–655
2. Phase 3 - Skin and skin structure infections [mixed] BPR 500 mg q8h vs VAN 1g q12h/CAZ 1g q8h ; 7-14 days
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34SBIMC-BVIKM 6/11/2008
Ceftobiprole: clinical experience
Basilea press release, Sept. 2007
3. Phase 3 – community acquired pneumonia BPR vs CRO +/- LZD
ceftobiprole comparator
Clinical cure 86 % 87 %
If S. pneumoniae 93 % 89 %
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35SBIMC-BVIKM 6/11/2008
Ceftobiprole: clinical experience
Noel et al., ICAAC (2008) K486
4. Phase 3 – Nosocomial pneumonia BPR 500 mg q8h vs CAZ 2g q8h/LZD 600 mg q12h
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36SBIMC-BVIKM 6/11/2008
Ceftaroline: clinical experience
Corey et al., ICAAC (2008) L1515a
1. Phase 3 - Skin and skin structure infections CPT 600 mg q12h vs VAN/AZM 1 g/1g q12h ; 5-14 days
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37SBIMC-BVIKM 6/11/2008
Ceftaroline: clinical experience
Corey et al., ICAAC (2008) L1515a
1. Phase 3 - Skin and skin structure infections CPT 600 mg q12h vs VAN/AZM 1 g/1g q12h ; 5-14 days
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38SBIMC-BVIKM 6/11/2008
Ceftobiprole: pros and cons
• broad spectrum ? (polymicrobial infections)
• bactericidal• synergistic with AG• tissue penetration• efficient in cSSTI, CAP
• broad spectrum ?• trend to MIC increase• IV only• 2-3 x/day• dysgeusia, nausea• inefficient in VAP
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39SBIMC-BVIKM 6/11/2008
Ceftobiprole: current status
Seeked indication : cSSTI including diabetic foot infections
• Regulatory approvement from Health Canada authorizing the marketing of ZEFTERA (TM) for the treatment of complicated skin and skin structure infections including diabetic foot infections
• New Drug Application submitted to the FDA; response to queries considered completed
• Marketing Authorization Application submitted; currently under review by EMEA.
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40SBIMC-BVIKM 6/11/2008
Lipoglycopeptides, bactericidal glycopeptides
with multiple modes of action (membrane destabilization)
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41SBIMC-BVIKM 6/11/2008
New glycopeptides
Van Bambeke, Cur. Opin. Pharmacol. (2004) 4:471-8
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42SBIMC-BVIKM 6/11/2008
New glycopeptides: structure-activity relationship
Van Bambeke, Cur. Opin. Pharmacol. (2004) 4:471-8
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43SBIMC-BVIKM 6/11/2008
In vitro activity
Draghi et al.,AAC (2008) 52:2383-2388 ICAAC (2008) C1-146,150,151
species phenotype ORI TLV DAL VAN
S. aureus
MSSA 0.25/0.5 0.25/0.5 0.06/0.06 1/1
MRSA 0.25/0.5 0.25/0.25 0.06/0.06 1/1
VISA 1/1 0.5-1 0.25/2 4/4
VRSA 0.5* 2-4 16* 16*
S. pneumoPenS ≤
0.002/0.004 ≤
0.06/≤
0.06 ≤
0.03/≤
0.03 ≤
0.25/≤
0.25
Pen nonS ≤0.002/0.004 ≤
0.06/≤
0.06 ≤
0.03/≤
0.03 ≤
0.25/≤
0.5
EnterococciVanS 0.12/0.5 0.12/0.5 0.06/0.25 1/2
VanR 0.03* 4-16 16*
* Median value
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44SBIMC-BVIKM 6/11/2008
X
oritavancinO O
NH
HN
NH
HN
NH
O
ClO
O
O
O
HOOH
ONHCH3
HN
HOOC
OH
CONH2
Cl
O OH
HOHO
OO
H3C
CH3HNOH
Cl
O
H2N
CH3O
HOH3C
O
OH
transpeptidase
transglycosylase
Van Bambeke et al., TIPS (2008) 29:124-34
Proposed mode of action
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45SBIMC-BVIKM 6/11/2008
XX
telavancin
transpeptidase
transglycosylase
O O
NH
HN
NH
HN
NH
O
HOClO
O
O
O
HOOH
ONHCH3
HN
O
HOOC
OH
CONH2
Cl
O OH
HOHO
OO
H3C
CH3NHHO
OH
HN
NH
PO3H2
Proposed mode of action
Van Bambeke et al., TIPS (2008) 29:124-34
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46SBIMC-BVIKM 6/11/2008
Bactericidal effect and membrane permeabilization
0 6 12 18 24-6
-5
-4
-3
-2
-1
0
1
2MSSAHA-MRSACA-MRSAVISAVISA
Time (h)
Δlo
g C
FU fr
om ti
me
0
Baudoux et al., ICAAC (2008) A971
Bactericidal effect on bacteria
PE:PG
PE:PC
calcein entrapped at a self-quenching
concentration
increase in fluorescence signal upon release and dilution
in the external medium
0 10 20 30 40 50 600
25
50
75
100
Incubation Time (min)
% c
alce
in r
elea
sed
Permeabilization of liposomes
abundant in bacterial membranes
Domenech et al., ICAAC (2008) C1-199
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47SBIMC-BVIKM 6/11/2008
Intracellular activity
Barcia-Macay et al., AAC (2006) 50:841-51
THP-1; 24 h, MSSA ATCC25923, antibiotics at Cmax
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48SBIMC-BVIKM 6/11/2008
Extra- and Intracellular activity against SCVs
THP-1; 24 h, antibiotics at Cmax
Nguyen et al., RICAI 2007, poster 325
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49SBIMC-BVIKM 6/11/2008
Oritavancin tentative PK/PD breakpoint
Bhavnani et al., ICAAC (2008) A994
Probability of PK/PD target attainment for different MIC targets at 48 h for 200 mg once-daily oritavancin against S. aureus
according to oxacillin susceptibility status
proposed PK/Pd Bkpt
MIC90 MRSA
S. aureusoxaSoxaR
Static - 1 log - 2 log
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50SBIMC-BVIKM 6/11/2008
Pharmacokinetics
parameter VAN ORI TLV TEC DAL
Dosage(mg/kg)
15 3 7.5 6 16
Cmax(mg/L)
20-50 46 90 43 312
Cmin(mg/L)
5-12 (12 h)
10 (24 h)
~ 8 (24 h)
5 (24 h)
40 (168 h)
AUC(mg.h/L)
260 457 668 600 27100
(%) prot. binding 55 90 95 88-94 95
T ½ (h)1 (β)
3-9 (γ)18 (β)360 (γ)
810 (β)168 (γ)
149-321 (β)
Van Bambeke ICAAC (2006)
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51SBIMC-BVIKM 6/11/2008
New glycopeptides: clinical experience
Van Bambeke, Curr. Opin. Investig. Drugs (2006) 7:740-9
oritavancin (5-10 mg/kg 1x day ~ 10 days)• skin and soft tissue infection • bloodstream infections (Phase II)
telavancin (10 mg/kg 1x day ~ 10 days)• skin and soft tissue infection
fast track designation by the FDA for the treatment of hospitally-acquired pneumonia (MRSA or multiresistant S. pneumoniae)MRSA-associated complicated skin and skin structure infection
dalbavancin (1 g followed by 500 mg 1 week later) • skin and skin structure infections • catheter-related bloodstream infections (Phase II)
priority review status by the FDA for the treatment of MRSA complicated skin and soft tissue infections.
withdrawnOct. 2008
withdrawnSept. 2008
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52SBIMC-BVIKM 6/11/2008
Telavancin withdrawal: why ?
Stryjewski et al., CID (2008) 46:1683-93
Phase 3 - Skin and skin structure infections TLV 10 mg/kg q24h vs VAN 1 g q12h ; 7-14 days
Clinical outcome
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53SBIMC-BVIKM 6/11/2008
Telavancin withdrawal: why ?
« metallic/soapy »
Safety profile
Stryjewski et al., CID (2008) 46:1683-93
this is less nice …
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54SBIMC-BVIKM 6/11/2008
Oritavancin: clinical experience
Hartman et al., ICAAC (2008) L1514
Clinical outcome
Phase 3 - Skin and skin structure infections ORI 1.5-3 mg/kg q24h (3-7 days)
vs VAN 15 mg/kg q12h followed by oral cephalexin (10-14 days)
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55SBIMC-BVIKM 6/11/2008
Oritavancin: clinical experience
ICAAC (2008) L1514, L1515
Safety profile
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56SBIMC-BVIKM 6/11/2008
Oritavancin : pros and cons
• rapidly bactericidal• once-a-day / a-week• active on VRSA and VISA to some extent
• safety
• no oral route• once-a-week ?• prolonged retention in the organism ?
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57SBIMC-BVIKM 6/11/2008
Oritavancin: current status
bacteremia, osteomyelitisSSTI, infrequent dosage
Clostridium difficile colitis
• FDA; to be discussed at the end of November
• EMEA
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58SBIMC-BVIKM 6/11/2008
Iclaprim, a bactericidal diaminopyridine
that works without sulfamide combination
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59SBIMC-BVIKM 6/11/2008
From trimethoprim to iclaprim
stronger H bond, remains possible to mutated enzyme
additional interactions
Dale et al., J. Mol. Biol. (2007) 266:23–30
N
N
O
OO
NH2H2N
NH2N
N
OO
O
H2N
trimethoprim
iclaprim
AR-100
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60SBIMC-BVIKM 6/11/2008
Iclaprim: pharmacokinetics
Ullman et al., ECCMID (2008): P546Andrews et al., JAC (2007) 60:677-70
parametericlaprim
(0.8 mg/kg)Cmax (mg/L) 0.8
T ½ (h) 2.5
AUC (mg.h/L) 2.08
low !
but needs to be considered in the light of MICs
parametericlaprim
(1.6 mg/kg)serum (mg/L) 0.6
ELF (mg/L) 12.6
Mφ
(mg/L) 24.5
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61SBIMC-BVIKM 6/11/2008
Iclaprim: in vitro activity
Weiss et al., ECCMID (2008): P588ICAAC (2007) E904,907,911
strain MIC90
MSSA 0.06
MRSA 0.125
GAS 0.03
GBS 0.25
AUC/MIC
35
17
708
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62SBIMC-BVIKM 6/11/2008
Iclaprim: clinical experience
Hadvari et al., ICAAC (2008) L1512
Phase 3 - Skin and skin structure infections ICL 0.8 mg/kg q12 vs. LZD 600 mg q12h (10-14 days)
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63SBIMC-BVIKM 6/11/2008
Iclaprim : pros and cons
• rapidly bactericidal• IV / oral• large tissue distribution / cellular accumulation
• low Cmax and AUC
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64SBIMC-BVIKM 6/11/2008
Iclaprim: current status
IV form, cSSTI: Phase III completed
• NDA submitted to the FDA; to be discussed end of November• MAA submitted to the EMEA
Currently running phase II studies
• oral form (bioavailability 40 %)• HAP/VAP
Other molecule in the pipeline : AR-709
highly potent on MDR pneumococciICAAC 2006 F1 1959
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65SBIMC-BVIKM 6/11/2008
Conclusion: what is the best choice ?
Tigecycline ?Yes, but spectrum
vs indication ?
Ceftobiprole ?Yes, but MIC already close
to probable breakpoint ?
Oritavancin ?Yes, but will it remain
enough active on VISA ?
Iclaprim?Yes, but what will be
the breakpoint ?
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66SBIMC-BVIKM 6/11/2008
The way is probably still long to the ideal molecule…