title: In vitro and in vivo activities of the diazabicyclooctane OP0595 against AmpC-derepressed Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa is a common cause for healthcare-associated infections, which have been historically treated by antipseudomonal β-lactam agents in the clinical setting. However, P. aeruginosa has evolved to overcome these β-lactam agents via multiple endogenous resistance mechanisms, including derepression of the chromosomal cephalosporinase (AmpC). In this article, we investigated the effective concentration of OP0595 for combination with piperacillin, cefepime or meropenem in in vitro susceptibility tests, and the antibacterial activity of cefepime in combination with OP0595 in both in vitro time-kill studies and in vivo murine thigh infection model study with AmpC-derepressed P. aeruginosa. The sufficient combinational concentration of OP0595 was a 4 μg ml-1with all these three β-lactam agents. OP0595 increased the antibacterial activity of cefepime in both in vitro and in vivo studies against all strains tested. Taken together, OP0595 is the diazabicyclooctane serine β-lactamase inhibitor with activity against AmpC-derepressed P. aeruginosa and its combinational use with a β-lactam agent will provide a new approach for the treatment of P. aeruginosa infections.
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Morinaka
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsutsumi
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takayama
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Sakakibara
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Takata
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Abe
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Furuuchi
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Inamura
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sakamaki
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Nakako
authors.initials: N
authors.lastname: Tsujii
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ida
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D006801:Humans; D007769:Lactams / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C000608518:nacubactam; C048795:AmpC beta-lactamases; D001618:beta-Lactamases