title: In Vitro and In Vivo Activities of OP0595, a New Diazabicyclooctane, against CTX-M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae.
abstract: Gram-negative bacteria are evolving to produce β-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine β-lactamase inhibitor which acts also as an antibiotic and as a β-lactamase-independent β-lactam "enhancer" against Enterobacteriaceae Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, in in vitro time-kill studies and an in vivo infection model against five strains of CTX-M-15-positive Escherichia coli and five strains of KPC-positive Klebsiella pneumoniae An OP0595 concentration of 4 μg/ml was found to be sufficient for an effective combination with all three β-lactam agents. In both in vitro time-kill studies and an in vivo model of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all β-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a β-lactam agent is important to exert the antimicrobial functions of OP0595.
authors.affiliation: Meiji Seika Pharma Co., Ltd., Yokohama, Japan akihiro.morinaka@meiji.com.
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: D053961:Azabicyclo Compounds / Q000494:pharmacology*; D000077723:Cefepime; D002511:Cephalosporins / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000378:metabolism; D007769:Lactams / Q000494:pharmacology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D010878:Piperacillin / Q000494:pharmacology; D013845:Thienamycins / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D053961:Azabicyclo Compounds; D002511:Cephalosporins; D007769:Lactams; D013845:Thienamycins; D000077723:Cefepime; C000608518:nacubactam; D001618:beta-Lactamases; D000077731:Meropenem; D010878:Piperacillin