SLIDE 1
- P. aeruginosa : resistance and therapeutic options
Are there new molecules Are there new molecules for for Pseudomonas Pseudomonas in the pipeline ? in the pipeline ?
Université catholique de Louvain
Unité de Pharmacologie cellulaire et moléculaire
SLIDE 2
Is there a need for new drugs against Pseudomonas ?
SLIDE 3
Is there a need for new drugs against Pseudomonas ?
SLIDE 4
What is new over the last years ?
FDA approvals Gram(+) Gram(-) moxifloxacin linezolid ertapenem 2001 2002 gemifloxacin 2003 daptomycin 2004 telithromycin 2005 tigecycline
But no anti-Pseudomonas agent …
SLIDE 5
What is in the pipeline for Pseudomonas ?
preclinical Phase I Phase II Phase III registration
SLIDE 6 O HO N S O H N O N O N OH N N NH S NH2 H
PBP2a β-lactamases
BAL9141
Anti - Pseudomonas cephalosporins ?
preclinical Phase I Phase II Phase III registration ceftobiprole
BAL5788
prodrug
N O O O O O
SLIDE 7
BAL9141
As active as cefepime cephalosporine
MIC range (mg/L) MIC 50 MIC 90
ceftriaxone 1 - 128 16 128 BAL9141 0.5 - 16 2 8 cefepime 0.5 – 32 2 8
Issa et al., Diagn Microbiol Infect Dis. (2004) 48:73-5
SLIDE 8
BAL5788
Which dose for which bug ?
MIC 8
Mouton et al. AAC (2004) 48:1713-8
SLIDE 9 Anti - Pseudomonas carbapenems ?
preclinical doripenem
Peninsula pharmaceuticals
penetration into Gram-negative; zwitterion Pseudomonas
O OH N S O OH NH N H S NH2 O O H H
fast track for nosocomial pneumonia
Phase I Phase II Phase III registration
SLIDE 10
Doripenem
In vitro activity slightly higher than that of meropenem
MIC CAR
≤ 16 32-128 256 ≥ 512
Mushtaq et al., AAC (2004) 48:3086-92
SLIDE 11
Doripenem
Influence of resistance mechanisms carbapenem
MexAB MexEF OprD metallo β-lactamase
r R R R R r nd r/R R doripenem R imipenem S meropenem R
R : MIC > 8 mg/L r : MIC < 8 mg/L Dalhoff et al., Biochem. Pharmacol. (2006) 71:1085-95
SLIDE 12
Doripenem
PK/PD in support to dosing : t > MIC ~ 20 %
MIC = 1 MIC = 4
500 mg q 8 h
Bhavnani et al., AAC (2005) 49:3944-47
SLIDE 13
Doripenem
Pk/PD in support to dosing : t > MIC ~ 20 %
MIC = 4
continuous infusion
Bhavnani et al., AAC (2005) 49:3944-47
SLIDE 14
Doripenem
But what is the sensitivity of clinical isolates ?
Traczewski et al., AAC (2006) 50:819-21
SLIDE 15 Anti - Pseudomonas carbapenems ?
preclinical
O OH N S O N OH H H NH H N NH NH2 O
Phase I Phase II RO 4908463 Phase III registration
SLIDE 16
RO 4908463
In vitro activity comparable to other carbapenems carbapenem
MIC range (mg/L) β-lactamase hydrolysis (class C & A)
RO 4908463 0.06 - 32 < 10 % < 10 % 12 % imipenem 0.25 - 32 meropenem 0.06 - 32
Koga et al., AAC (2005) 49:3239-50
SLIDE 17 Anti-Pseudomonas fluoroquinolones ?
H2N N Cl F N O F O OH
increased activity broad spectrum
preclinical Phase I Phase II Phase III sitafloxacin (Japan) registration
SLIDE 18 Sitafloxacin
MIC distributions in WT and resistant strains
0.25 0.5 1 2 4 8 16 32 64 128 10 20 30 40 50 60 70 MIC SITA CIPRO
WT
0.25 0.5 1 2 4 8 16 32 64 128 10 20 30 40 50 MIC SITA CIPRO
GyrA
0.25 0.5 1 2 4 8 16 32 64 128 10 20 30 40 50 60 70 MIC SITA CIPRO
ParC
more active than ciprofloxacin!
Kitamura et al., AAC (1995) 39:1467-71
SLIDE 19
Sitafloxacin
Higher affinity than ciprofloxacin for mutated targets
IC 50 (mg/L) DNA Gyrase Topo IV WT T831I WT S871I
1.85 2.12 8.62 8.29 33.0 4.06 sitafloxacin 0.42 ciprofloxacin 0.55 fluoroquinolone
Kitamura et al., AAC (1995) 39:1467-71
SLIDE 20 Anti-Pseudomonas fluoroquinolones ?
H2N N Cl F N O F O OH
preclinical Phase I Phase II Phase III registration DK 507k sitafloxacin (Japan)
reduced risk of phototoxicity
H2N N OCH3 F N O F O OH
SLIDE 21
DK 507k
Less active than sitafloxacin against Pseudomonas fluoroquinolone
MIC range (mg/L) MIC 50 MIC 90
sitafloxacin 0.015 – 0.5 0.03 0.25 DK 507k 0.03 - 4 0.06 0.5 ciprofloxacin 0.015 - 16 0.03 0.5
Otani et al., AAC (2003) 47:3750-9
SLIDE 22
Inhibitors of Pseudomonas efflux pumps ?
preclinical Phase I MP 601,205 Phase II Phase III registration
SLIDE 23 Inhibitors of Pseudomonas efflux pumps
Shift of MIC distributions with pumps inhibitors !
MIC 50 (µg/ml) MIC 90 (µg/ml)
LVX
0.5 8
LVX + MC-207,110
0.03 0.5 Lomovskaya et al. JMMB (2001) 3: 225-36
SLIDE 24
Inhibitors of Pseudomonas efflux pumps
www.mpexpharma.com
SLIDE 25 Do wide spectrum glycylcyclines act upon Pseudomonas ?
preclinical tigecycline
OH OH O N OH O NH2 O OH N H H
minocycline
evades resistance by
- efflux by Tet pumps
- ribosomal protection
N H O H N
tigecycline
Phase I Phase II Phase III registration
SLIDE 26
Tigecycline
XXL spectrum ….what about Pseudomonas ?
Dean et al., AAC (2003) 47:972-8
∆ mexXY 0.5 phenotype
MIC (mg/L)
WT 8 deceiving … interesting ! combine with efflux pump inhibitors ?
SLIDE 27 Which of these weapons will win the battle ?
ceftobiprole doripenem s i t a f l
a c i n p u m p i n h i b i t
s Joyeuses fêtes de Pâques !
