Comparison of Agar Dilution to Broth Microdilution for Testing In Vitro Activity of Cefiderocol against Gram-Negative Bacilli

Abstract

Cefiderocol (CFDC) is a siderophore cephalosporin with activity against Gram-negative bacterial species that are resistant to carbapenems and other drugs. The MICs of CFDC were determined for 610 Gram-negative bacilli, including 302 multinational Enterobacterales isolates with characterized mechanisms of beta-lactam resistance, 180 clinical isolates from the Mayo Clinic and Mayo Clinic Laboratories not characterized for specific resistance mechanisms, and 128 isolates with CFDC MICs of ≥8 μg/ml obtained from International Health Management Associates, Inc. (IHMA, Schaumburg, IL). Broth microdilution using standard cation-adjusted Mueller-Hinton broth (BMD) and iron-depleted cation-adjusted Mueller-Hinton broth (ID-BMD), and agar dilution (AD) using standard Mueller-Hinton agar were performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. MICs were interpreted according to the investigational CLSI, FDA, and EUCAST breakpoints, and results were compared. MICs inhibiting 50 and 90% of organisms (MIC₅₀ and MIC₉₀, respectively), essential agreement (EA), categorical agreement (CA), and error of different types were determined. Results showed considerable discordance between AD and ID-BMD. CFDC showed low EA and CA rates and high error rates for AD in comparison to ID-BMD. Overall, this study does not support use of standard AD for determining CFDC MICs.

Keywords: Enterobacterales; Gram-negative bacilli; Gram-negative bacteria; agar dilution; broth microdilution; cefiderocol.

FIG 1

The 610 Gram-negative bacillus isolates tested, including 275 nonfermenting bacteria and 335 Enterobacterales.

FIG 2

Scattergrams of cefiderocol MICs obtained by agar dilution (AD) versus broth microdilution using iron-depleted Mueller-Hinton agar (ID-BMD) for Pseudomonas aeruginosa (A), Stenotrophomonas maltophilia (B), Burkholderia cepacia complex (C), Acinetobacter baumannii (D), and Enterobacterales (E). Lines represent the applied resistance breakpoints: red, investigational CLSI breakpoints (26); blue, FDA breakpoints (29); green, EUCAST breakpoints (16); blue-green dashed line, overlapping EUCAST and FDA breakpoints.

FIG 2

Scattergrams of cefiderocol MICs obtained by agar dilution (AD) versus broth microdilution using iron-depleted Mueller-Hinton agar (ID-BMD) for Pseudomonas aeruginosa (A), Stenotrophomonas maltophilia (B), Burkholderia cepacia complex (C), Acinetobacter baumannii (D), and Enterobacterales (E). Lines represent the applied resistance breakpoints: red, investigational CLSI breakpoints (26); blue, FDA breakpoints (29); green, EUCAST breakpoints (16); blue-green dashed line, overlapping EUCAST and FDA breakpoints.