Potential of Inaccurate Cefiderocol Susceptibility Results: a CLSI AST Subcommittee Advisory

Cefiderocol (Shionogi, Inc.) is a novel siderophore-conjugate cephalosporin with activity against aerobic, Gram-negative bacteria, including multidrug-resistant strains (1). The mode of action (MOA) for cefiderocol is unique as it exploits active iron transport, binding iron to the siderophore moiety of the antimicrobial and entering the periplasmic space of Gram-negative bacteria via active iron transport mechanisms (2). The cephalosporin moiety then targets penicillin-binding protein 3, inhibiting peptidoglycan synthesis. This unique MOA makes susceptibility testing difficult using Clinical and Laboratory Standards Institute (CLSI) reference methods, as bacterial iron transporters are upregulated under in vivo iron-depleted conditions, but not in the iron concentrations found in cation-adjusted Mueller-Hinton broth used in the CLSI reference broth microdilution (BMD) method (3). A modification of the reference BMD was published by CLSI for testing of cefiderocol, which uses cation-adjusted Mueller-Hinton broth (CA-MHB) depleted of iron to a final iron concentration of ≤0.03 μg/mL; See Appendix I in reference (4). Unlike BMD, disk diffusion (DD) methods were developed to work with standard Mueller-Hinton agar and do not require iron depletion.