title: In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains.
abstract: S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clinical isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 β-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90 values of S-649266 against the first set of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae isolates were all ≤1 μg/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of ≥8 μg/ml. In the second set, the MIC values of S-649266 were ≤4 μg/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of ≤2 μg/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 μg/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan naoki.kohira@shionogi.co.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kohira
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: West
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ito
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ito-Horiyama
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Rio
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sato
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rittenhouse
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamano
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D015780:Carbapenems / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000302:isolation & purification; D029968:Escherichia coli Proteins / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D017262:Siderophores / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism; D000097602:Cefiderocol
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D002511:Cephalosporins; D029968:Escherichia coli Proteins; D017262:Siderophores; D001618:beta-Lactamases; D000097602:Cefiderocol; C094219:beta-lactamase Sme-1; C000601047:beta-lactamase OXA-48, E coli; C063912:carbapenemase