TROJAN-MDR: in vitro activity of cefiderocol and comparators against multidrug-resistant Enterobacterales and Pseudomonas aeruginosa strains in Southern France, evaluation of available testing methods performances

Abstract

Background: Cefiderocol, a newly introduced siderophore cephalosporin, exhibits activity against various multidrug-resistant (MDR) Gram-negative bacilli (GNB), including producers of Ambler class A, B and D carbapenemases. The TROJAN-MDR study aimed to (i) compare the in vitro activity of cefiderocol with other last-resort antibiotics against a well-characterized collection of Enterobacterales and Pseudomonas aeruginosa strains from Southern France, and (ii) assess the performance of available cefiderocol antimicrobial susceptibility testing (AST) methods.

Methods: The collection comprised 127 Enterobacterales from various clones, including 119 carbapenemase producers (93.7%), and 53 MDR P. aeruginosa. The minimum inhibitory concentrations (MICs) of cefiderocol were determined using the UMIC^® broth microdilution method (BMD) as the reference. Comparators MICs were measured using Sensititre™ EUMDRXXF plates and Liofilchem strips for aztreonam-avibactam. Results were interpreted according to EUCAST breakpoints, with CLSI breakpoints also used for cefiderocol. The performance of the ComASP^® BMD and disk diffusion on two different Mueller-Hinton media (Bio-Rad and BD) were evaluated according to ISO 20776-2:2007 and 2021.

Results: Cefiderocol demonstrated potent activity on Enterobacterales (81.9% susceptible) and P. aeruginosa (84.9%) using EUCAST breakpoints. Among Enterobacterales, the most effective comparators were colistin, aztreonam-avibactam, meropenem-vaborbactam, and amikacin, with susceptibility rates of 99.2%, 98.4%, 85%, and 76.4%, respectively. For P. aeruginosa, only colistin exhibited better activity (100%). The disk diffusion method showed superior performance on BD medium compared to Bio-Rad. The ComASP^® method did not provide sufficient performance to be considered reliable.

Conclusions: Cefiderocol was highly active against a large collection of MDR GNB, including high-risk clones. It is crucial to assess susceptibility to this last-resort antibiotic using a validated method when considering clinical use.

Keywords: Pseudomonas aeruginosa; Antimicrobial susceptibility testing; Aztreonam-avibactam; Carbapenemase; Cefiderocol; ComASP®; Difficult-to-treat; Enterobacterales; Multi-drug resistance; UMIC®.

Fig. 1

Distribution of cefiderocol MICs among Enterobacterales (A) and Pseudomonas aeruginosa (B) isolates and clinical categorization according to EUCAST and CLSI breakpoints. S, Susceptible; I, Intermediate (susceptible increased exposure); R Resistant, CPE Carbapenemase-Producing Enterobacterales

Fig. 2

MICs of cefiderocol using ComASP^® BMD method compared to UMIC^®. ME Major Error, VME Very Major Error. MICs corresponding to Categorical Agreement (CA) are in white, to Essential Agreement (EA) in grey (light + dark), to ME in blue and to VME in salmon-pink. Red lines correspond to EUCAST breakpoints

Fig. 3

Cefiderocol inhibition zone diameter on BD BBL™ MH II agar (left) and Bio-Rad MH agar (right) compared to MICs using UMIC^® for Enterobacterales. ME Major Error, VME Very Major Error, ATU Area of Technical Uncertainty (21–23 mm). MICs corresponding to Categorical Agreement (CA) are in white, to ME in blue and to VME in salmon-pink. Red lines correspond to EUCAST breakpoints, blue lines correspond to EUCAST ATU

Fig. 4

Cefiderocol inhibition zone diameter on BD BBL™ MH II agar (left) and Bio-Rad MH agar (right) compared to MICs using UMIC^® for P. aeruginosa. ME Major Error, VME Very Major Error, ATU Area of Technical Uncertainty (20–21 mm). MICs corresponding to Categorical Agreement (CA) are in white, to ME in blue and to VME in salmon-pink. Red lines correspond to EUCAST breakpoints, blue lines correspond to EUCAST ATU