1351. In vitro Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, Against Enterobacteriaceae With Defined Extended-Spectrum Β-Lactamases and Carbapenemases

Abstract

BackgroundCefiderocol 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.MethodsMinimum 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 <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.ResultsCefiderocol MICs ranged from ≤0.03 to >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.ConclusionCompared 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.Table:Activity of Cefiderocolβ-Lactam ResistanceNMIC range (mg/L)MIC50 (mg/L)MIC90 (mg/L)ampC30.25 to 2NANAKPC-2255≤0.03 to 320.58KPC2 + Other101≤0.03 to 1628KPC-3276≤0.03 to 640.252KPC3 + Other106≤0.03 to 160.54NDM280.25 to >6428OXA8≤0.03 to 10.251TEM/SHV ESBL42≤0.03 to >6421None15≤0.03 to 0.12≤0.03≤0.03All834≤0.03 to >640.54Disclosures 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.