Interpretive agreement of susceptibility between broth microdilution and disk diffusion methods for cefiderocol,...

Cefiderocol (FDC) is a siderophore cephalosporin approved for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (MDR-GNB), including carbapenem-resistant (CR) isolates. However, interpretation criteria for both broth microdilution (BMD) and disk diffusion (DD) methods differ among Clinical and Laboratory Standards Institute (CLSI), European Committee on Antimicrobial Susceptibility Testing (EUCAST), and U.S. Food and Drug Administration (FDA) guidelines. This study aimed to assess the categorical agreement (CA) between minimum inhibitory concentrations (MICs) determined by the BMD method and inhibition zone diameters measured by the DD method for FDC, using different interpretive breakpoints across various Gram-negative bacilli (GNB) isolates. A total of 1,170 GNB isolates were collected, including CR and carbapenem-susceptible (CS) isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae complex, Pseudomonas aeruginosa, and Acinetobacter baumannii-calcoaceticus complex. Isolates of Stenotrophomonas maltophilia, Burkholderia cepacia, and Elizabethkingia anophelis-which are not categorized by carbapenem susceptibility-were also included. The CA and error rates (minor error, major error, and very major error) were calculated using MIC interpretation as the reference. Among CR isolates, CA based on CLSI breakpoints ranged from 90.0% to 100% across species. U.S. FDA criteria showed comparable performance, except for A. baumannii-calcoaceticus complex, where CA was lower (63.0%). In contrast, EUCAST breakpoints demonstrated greater variability, with CA ranging from 66.7% to 100%. Among CS isolates, CA was generally high (≥87.5%) across most standards and species, with exceptions including EUCAST in the E. cloacae complex (63.0%) and U.S. FDA in A. baumannii-calcoaceticus complex (73.7%). In conclusion, CLSI breakpoints demonstrated the highest consistency between DD and BMD methods.

Cefiderocol is one of the few remaining treatment options for infections caused by carbapenem-resistant Gram-negative bacilli (GNB). Accurate interpretation of susceptibility testing is essential for guiding effective therapy. However, discrepancies among breakpoints established by the Clinical and Laboratory Standards Institute, the European Committee on Antimicrobial Susceptibility Testing, and the U.S. Food and Drug Administration may result in inconsistent interpretations, particularly when using the disk diffusion (DD) method, which is more practical in many clinical laboratories. This study compares the categorical agreement between broth microdilution and DD method interpretations for Gram-negative bacilli across multiple guidelines and highlights the potential for misclassification. It also provides susceptibility data for Burkholderia cepacia and Elizabethkingia anophelis, for which established interpretive criteria are currently lacking.