1351. In vitro activity of cefiderocol (S-649266), a siderophore cephalosporin, against Enterobacteriaceae with defined extended-spectrum β-lactamases and carbapenemases
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • 1351_AH Cefiderocol poster ID week with QR code Bonomo Jacobs.pdf (765.0 kB)
  • 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 9 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 < 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, 5 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 >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 to 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 cefiderocol

    β-Lactam resistance

    N

    MIC range (mg/L)

    MIC50 (mg/L)

    MIC90 (mg/L)

    ampC

    3

    0.25 - 2

    NA

    NA

    KPC-2

    255

    ≤0.03 - 32

    0.5

    8

    KPC2+OTHER

    101

    ≤0.03 - 16

    2

    8

    KPC-3

    276

    ≤0.03 - 64

    0.25

    2

    KPC3+OTHER

    106

    ≤0.03 - 16

    0.5

    4

    NDM

    28

    0.25 - >64

    2

    8

    OXA

    8

    ≤0.03 - 1

    0.25

    1

    TEM/SHV ESBL

    42

    ≤0.03 - >64

    2

    1

    None

    15

    ≤0.03 - 0.12

    ≤0.03

    ≤0.03

    All

    834

    ≤0.03 - >64

    0.5

    4

     

    Michael R. Jacobs, MD PhD1, Ayman M. Abdelhamed, MD PhD2, Caryn E. Good, MA/MPH3, Daniel D. Rhoads, MD2, Kristine M. Hujer, BS4,5, Andrea M. Hujer, BS4,5, T. Nicholas Domitrovic, MS4,5, Susan D. Rudin, BS4,5, Sandra S. Richter, MD6, David Van Duin, MD, PhD7, Barry N. Kreiswirth, PhD8, Robert A. Bonomo, MD4,5 and Antibiotic Resistance Leadership Group, (1)Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, (2)Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, (3)Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, (4)Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, (5)Case Western Reserve University, Cleveland, OH, (6)Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, (7)Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, (8)Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ

    Disclosures:

    M. R. Jacobs, Achaogen: Investigator , Research grant . Shionogi: Investigator , Research grant .

    A. M. Abdelhamed, None

    C. E. Good, None

    D. D. Rhoads, None

    K. M. Hujer, None

    A. M. Hujer, None

    T. N. Domitrovic, None

    S. D. Rudin, None

    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 .

    B. N. Kreiswirth, None

    R. A. Bonomo, None

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