In vitro
activity assessment of cefiderocol against Enterobacterales,
Pseudomonas aeruginosa,
and
Acinetobacter
spp., including β-lactam nonsusceptible molecularly characterized isolates, collected from 2020 to 2021 in the United States and European hospitals
Authors: Kimbrough John H. , Maher Joshua M. , Sader Helio S. , Castanheira Mariana , Mendes Rodrigo E. 
Published: October 2024

This study reports the activity of cefiderocol against Enterobacterales,
Pseudomonas aeruginosa
, and
Acinetobacter
spp. isolates collected from the United States and Europe, including Israel and Turkey, from 2020 to 2021. Among Enterobacterales, 2.8% were carbapenem nonsusceptible (CNSE); cefiderocol inhibited 96.6%/85.1% [Clinical Laboratory Standards Institute (CLSI)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints] of these isolates. Imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam displayed susceptibilities lower than cefiderocol against CNSE isolates (67.4–84.6% susceptible, CLSI). Cefiderocol was the only agent active against CNSE isolates carrying metallo-β-lactamase (MBL) carbapenemase or multiple carbapenemase genes (84.6%–92.3% susceptible, CLSI). Approximately 18% of carbapenem-susceptible
Escherichia coli
,
Klebsiella pneumoniae
, and
Proteus mirabilis
carried extended-spectrum-β-lactamases and/or plasmid-borne AmpC-encoding genes; cefiderocol inhibited 99.8%–100.0% (CLSI) of these genotypic groups. Multi-drug resistance (MDR) phenotypes were observed in 16.9% and 52.5% of
P. aeruginosa
and
A. baumannii-calcoaceticus
isolates, respectively. Carbapenemase genes were rare (4.9%) among cephalosporin and/or carbapenem nonsusceptible
P. aeruginosa
, compared to 87.6% carriage in
A. baumannii-calcoaceticus
, respectively. Against the MDR and carbapenemase-carrying
P. aeruginosa
and
A. baumannii-calcoaceticus
subsets, cefiderocol was active against 98.6%/98.7% and 97.1%/97.4% (CLSI), respectively. Only 69 isolates (0.3%) across all species groups were identified as cefiderocol nonsusceptible per CLSI criteria (>4 mg/L). Cefiderocol was the most active agent
in vitro
against Enterobacterales,
P. aeruginosa,
and
Acinetobacter
spp., with uniform activity against all phenotypic- and genotypic-resistant subsets. Coupled with the low incidence of nonsusceptibility observed across species groups, these results demonstrate cefiderocol as an important option for treating infections caused by pathogens with diverse mechanisms of resistance in US and European hospitals.

IMPORTANCE

The worldwide spread of multi-drug-resistant
Pseudomonas aeruginosa
and carbapenem-resistant Enterobacterales and
Acinetobacter
spp. poses a serious challenge in healthcare settings as infections caused by these organisms are commonly refractory to many frontline therapeutic agents. Multiple global health organizations highlighted these pathogens as critical priorities for new antibiotic development, thus necessitating continued surveillance of the activities of currently available antimicrobial agents and circulating mechanisms of resistance. To meet this need, this study phenotypically and genotypically characterized priority Gram-negative pathogens collected from patients in US and European hospitals to examine the activity of cefiderocol and other currently available treatment options, including carbapenems and β-lactam-β-lactamase inhibitor combinations. The results presented here provide a detailed perspective to healthcare practitioners of cefiderocol’s broad applicability, manifested in high activity and low nonsusceptibility rates, across phenotypic and genotypic organism groups relative to other agents and further support its use against the most intransigent infections.