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.

FIG 1

Chemical structure of S-649266.

FIG 2

Cumulative percentage of MICs against meropenem-resistant carbapenemase-producing Enterobacteriaceae. The test strains were 110 E. coli, K. pneumoniae, S. marcescens, C. freundii, and E. cloacae isolates that consisted of 40 KPC-type-, 47 NDM-1-, 7 VIM-type-, 7 IMP-type-, 6 SME-type-, 1 NMC-A-, and 2 OXA-48-producing strains. Cation-adjusted Mueller-Hinton broth was used as a medium, but 20 μM human apo-transferrin was supplemented for the MIC determination of S-649266 to obtain a free iron-deficient condition. The broken lines represent 50% and 90% lines.