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Journal of Clinical Microbiology
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Cefiderocol Antimicrobial Susceptibility Testing Considerations: the Achilles' Heel of the Trojan Horse?

Patricia J. Simner, Robin Patel
Carey-Ann D. Burnham, Editor
Patricia J. Simner
aDivision of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Robin Patel
bDivision of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
cDivision of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Carey-Ann D. Burnham
Washington University School of Medicine
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DOI: 10.1128/JCM.00951-20
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ABSTRACT

Cefiderocol (formerly S-649266) is a novel siderophore-conjugated cephalosporin with activity against a broad array of multidrug-resistant (MDR), aerobic Gram-negative bacilli. The siderophore component binds iron and uses active iron transport for drug entry into the bacterial periplasmic space. The cephalosporin moiety is the active antimicrobial component, structurally resembling a hybrid between ceftazidime and cefepime. Like other β-lactam agents, the principal bactericidal activity of cefiderocol occurs via inhibition of bacterial cell wall synthesis by binding of penicillin-binding proteins (PBPs) and inhibiting peptidoglycan synthesis, leading to cell death. Iron concentrations need to be taken into consideration when in vitro antimicrobial susceptibility to cefiderocol is determined. Broth microdilution (BMD) and disk diffusion methods have been developed to determine in vitro activity of cefiderocol. For BMD, cation-adjusted Mueller-Hinton broth (CAMHB) requires iron depletion to provide MICs predictive of in vivo activity. A method to prepare iron-depleted CAMHB (ID-CAMHB) has been described by the Clinical and Laboratory Standards Institute (CLSI). For disk diffusion, standard Mueller-Hinton agar is recommended, presumably because iron is bound in the medium. Currently, clinical FDA and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints and investigational (research-use-only) CLSI breakpoints exist for interpreting cefiderocol susceptibility results for certain Gram-negative bacilli. Cefiderocol does not have clinically relevant activity against Gram-positive or anaerobic organisms. FDA or EUCAST breakpoints should be applied to interpret results for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex for patient care until the investigational status has been removed from CLSI breakpoints. Further clinical outcome data are required to assess the effectiveness of cefiderocol for treatment of other Acinetobacter species (non-baumannii complex) and Stenotrophomonas maltophilia at this time, and, as such, antimicrobial susceptibility testing of these organisms should be limited to research use in the scenario of limited treatment options.

FOOTNOTES

    • Accepted manuscript posted online 29 July 2020.
  • For companion articles on this topic, see https://doi.org/10.1128/JCM.01649-20 and https://doi.org/10.1128/JCM.00966-20.

  • Copyright © 2020 American Society for Microbiology.

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Cefiderocol Antimicrobial Susceptibility Testing Considerations: the Achilles' Heel of the Trojan Horse?
Patricia J. Simner, Robin Patel
Journal of Clinical Microbiology Dec 2020, 59 (1) e00951-20; DOI: 10.1128/JCM.00951-20

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Cefiderocol Antimicrobial Susceptibility Testing Considerations: the Achilles' Heel of the Trojan Horse?
Patricia J. Simner, Robin Patel
Journal of Clinical Microbiology Dec 2020, 59 (1) e00951-20; DOI: 10.1128/JCM.00951-20
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  • Top
  • Article
    • ABSTRACT
    • INTRODUCTION
    • WHAT IS CEFIDEROCOL?
    • WHAT MAKES CEFIDEROCOL DIFFERENT FROM OTHER β-LACTAM AGENTS?
    • IN VITRO ACTIVITY OF CEFIDEROCOL
    • MECHANISMS OF RESISTANCE TO CEFIDEROCOL
    • WHAT ANTIMICROBIAL SUSCEPTIBILITY TESTING METHODS ARE AVAILABLE TO CLINICAL LABORATORIES?
    • HOW SHOULD THE ANTIMICROBIAL SUSCEPTIBILITY TESTING RESULTS FOR CEFIDEROCOL BE INTERPRETED?
    • WHICH ORGANISMS SHOULD BE CONSIDERED FOR CEFIDEROCOL ANTIMICROBIAL SUSCEPTIBILITY TESTING?
    • SUMMARY
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
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KEYWORDS

antimicrobial susceptibility testing
broth microdilution
cefiderocol
disk diffusion

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