1351. In vitro Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, Against Enterobacteriaceae With Defined Extended-Spectrum Β-Lactamases and Carbapenemases
Authors: Jacobs Michael R , Abdelhamed Ayman M , Good Caryn E , Rhoads Daniel D , Hujer Kristine M , Hujer Andrea M , Domitrovic T Nicholas , Rudin Susan D , Richter Sandra S , Van Duin David , Kreiswirth Barry N , Bonomo Robert A ,   Antibiotic Resistance Leadership Group
Published: November 2018

Abstract

Background
Cefiderocol is a novel siderophore cephalosporin targeted for activity against carbapenem and multidrug-resistant Gram-negative species, including extended-spectrum β-lactamase (ESBL) and carbapenemase-producing strains. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a federally funded, prospective multi-center consortium of 20 hospitals from nine US healthcare systems to track carbapenem-resistant Enterobacteriaceae.

Methods
Minimum inhibitory concentrations (MICs) of cefiderocol and meropenem were determined by broth microdilution according to current CLSI guidelines. Cefiderocol was tested in iron-depleted cation-adjusted Mueller–Hinton (MH) broth, meropenem was tested in cation-adjusted MH broth. Cefiderocol MICs were read as the first drug well in which the growth was significantly reduced (i.e., a button of &lt;1 mm or light/faint turbidity) relative to the growth observed in the growth control well containing the same medium. Trailing endpoints were disregarded. Isolates tested included 35 Escherichia coli, five Enterobacter/Citrobacter group, and 794 Klebsiella pneumoniae. Isolates had characterized β-lactamases including TEM, SHV, and CTX-M ESBLs and KPC, NDM, and OXA carbapenemases.

Results
Cefiderocol MICs ranged from ≤0.03 to &gt;64 mg/L, with overall MIC50 of 0.5 mg/L and MIC90 of 4 mg/L (table). MIC90 value (≤0.03 mg/L) was lowest against isolates with no ESBLs or carbapenemases. MIC90 was 1 mg/L for OXA and TEM/SHV groups, 2–4 mg/L for KPC-3 groups and 8 mg/L for NDM and KPC-2 groups.

Conclusion
Compared with isolates without ESBLs and carbapenemases, cefiderocol shows higher MICs against isolates with ESBLs, including TEM, SHV, and CTX-M and carbapenemases including KPC, NDM, and OXA. The clinical utility of cefiderocol against ESBL and carbapenemase-producing Enterobacteriaceae is dependent on the pharmacokinetic and pharmacodynamic properties of cefiderocol.

Disclosures
M. R. Jacobs, Achaogen: Investigator, Research grant. Shionogi: Investigator, Research grant. S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant. D. Van Duin, Shionogi: Scientific Advisor, Consulting fee. achaogen: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Consultant, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee.