Are there new molecules Are there new molecules for Pseudomonas for - PowerPoint PPT Presentation

P. aeruginosa : resistance and therapeutic options Are there new molecules Are there new molecules for Pseudomonas for Pseudomonas in the pipeline ? in the pipeline ? Unité de Pharmacologie F. Van Bambeke Université catholique de cellulaire et moléculaire Louvain

Is there a need for new drugs against Pseudomonas ?

Is there a need for new drugs against Pseudomonas ?

What is new over the last years ? FDA Gram(+) Gram(-) approvals moxifloxacin 2001 linezolid ertapenem 2002 gemifloxacin 2003 daptomycin 2004 telithromycin 2005 tigecycline But no anti-Pseudomonas agent …

What is in the pipeline for Pseudomonas ? registration preclinical Phase III Phase II Phase I

Anti - Pseudomonas cephalosporins ? β -lactamases NH 2 S preclinical N N prodrug PBP2a H H N S N O Phase I O OH O N N O N NH O O O O HO O BAL9141 BAL5788 Phase II Phase III ceftobiprole registration

BAL9141 As active as cefepime MIC range cephalosporine MIC 50 MIC 90 (mg/L) BAL9141 0.5 - 16 2 8 ceftriaxone 1 - 128 16 128 cefepime 0.5 – 32 2 8 Issa et al., Diagn Microbiol Infect Dis. (2004) 48:73-5

Mouton et al . AAC (2004) 48:1713-8 MIC 8 Which dose for which bug ? BAL5788

Anti - Pseudomonas carbapenems ? preclinical OH Phase I O O H H S S N NH 2 H N O NH Phase II O OH Phase III doripenem penetration Peninsula into pharmaceuticals registration Gram-negative; zwitterion fast track for nosocomial Pseudomonas pneumonia

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

Doripenem Influence of resistance mechanisms metallo carbapenem MexAB MexEF OprD β -lactamase doripenem R nd r R imipenem S r/R R R meropenem R R r R R : MIC > 8 mg/L r : MIC < 8 mg/L Dalhoff et al., Biochem. Pharmacol. (2006) 71:1085-95

Doripenem PK/PD in support to dosing : t > MIC ~ 20 % 500 mg q 8 h MIC = 4 MIC = 1 Bhavnani et al., AAC (2005) 49:3944-47

Doripenem Pk/PD in support to dosing : t > MIC ~ 20 % continuous infusion MIC = 4 Bhavnani et al., AAC (2005) 49:3944-47

Doripenem But what is the sensitivity of clinical isolates ? Traczewski et al., AAC (2006) 50:819-21

Anti - Pseudomonas carbapenems ? OH preclinical H H S N O H N O N NH 2 Phase I O NH OH NH Phase II RO 4908463 Phase III registration

RO 4908463 In vitro activity comparable to other carbapenems β -lactamase carbapenem MIC range (mg/L) hydrolysis (class C & A) RO 4908463 0.06 - 32 < 10 % imipenem 0.25 - 32 < 10 % meropenem 0.06 - 32 12 % Koga et al., AAC (2005) 49:3239-50

Anti-Pseudomonas fluoroquinolones ? O O F OH preclinical N N Cl Phase I H 2 N F Phase II broad spectrum increased activity Phase III sitafloxacin (Japan) registration

Sitafloxacin MIC distributions in WT and resistant strains 70 more active 60 SITA 50 than ciprofloxacin! CIPRO 40 30 20 10 50 0 SITA 0.25 0.5 1 40 2 4 8 CIPRO 16 32 64 128 30 WT MIC 20 70 60 SITA 10 CIPRO 50 0 0.25 40 0.5 1 2 4 8 16 30 32 64 128 GyrA 20 MIC 10 0 0.25 0.5 1 2 4 8 16 32 64 128 ParC MIC Kitamura et al., AAC (1995) 39:1467-71

Sitafloxacin Higher affinity than ciprofloxacin for mutated targets IC 50 (mg/L) DNA Gyrase Topo IV fluoroquinolone WT T831I WT S871I sitafloxacin 0.42 1.85 2.12 8.62 ciprofloxacin 0.55 8.29 4.06 33.0 Kitamura et al., AAC (1995) 39:1467-71

Anti-Pseudomonas fluoroquinolones ? O O preclinical DK 507k F OH N N Phase I OCH 3 H 2 N F Phase II reduced risk of phototoxicity Phase III sitafloxacin (Japan) O O registration F OH N N Cl H 2 N F

DK 507k Less active than sitafloxacin against Pseudomonas MIC range fluoroquinolone MIC 50 MIC 90 (mg/L) DK 507k 0.03 - 4 0.06 0.5 sitafloxacin 0.015 – 0.5 0.03 0.25 ciprofloxacin 0.015 - 16 0.03 0.5 Otani et al., AAC (2003) 47:3750-9

Inhibitors of Pseudomonas efflux pumps ? preclinical Phase I MP 601,205 Phase II Phase III registration

Inhibitors of Pseudomonas efflux pumps Shift of MIC distributions with pumps inhibitors ! MIC 50 MIC 90 (µg/ml) (µg/ml) 0.5 8 LVX LVX + 0.03 0.5 MC-207,110 Lomovskaya et al . JMMB (2001) 3: 225-36

www.mpexpharma.com Inhibitors of Pseudomonas efflux pumps

Do wide spectrum glycylcyclines act upon Pseudomonas ? preclinical minocycline N N Phase I tigecycline H H OH O H N NH 2 Phase II N H OH O OH O OH O Phase III evades resistance by • efflux by Tet pumps tigecycline registration • ribosomal protection

Tigecycline XXL spectrum ….what about Pseudomonas ? phenotype MIC (mg/L) deceiving … WT 8 ∆ mexXY 0.5 interesting ! combine with efflux pump inhibitors ? Dean et al., AAC (2003) 47:972-8

will win the battle ? s r o t i b Joyeuses fêtes de Pâques ! i h n i p n m i c a u x p o l Which of these weapons f a t i s doripenem ceftobiprole