Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 20 3 2025, Pages S1198-743X(25)00618-4 CefiderocolFinder: a tool for detecting genetic adaptations implicated in cefiderocol resistance. van den Brand B, Notermans DW, Verkaik NJ, Lansu S, Rossen JWA, Hendrickx APA, Dutch CPE surveillance study group, van Arkel ALE, Leversteijn-van Hall MA, van den Bijllaardt W, van Mansfeld R, van Dijk K, Zwart B, Diederen BMW, Berkhout H, Ott A, Waar K, Ang W, da Silva J, Vlek ALM, Stohr JJJM, Bode LGM, Jansz A, Paltansing S, van Griethuysen AJ, Lo Ten Foe JR, van Trijp MJCA, Wong M, Muller AE, van der Linden MPM, van Rijn M, Debast SB, Kolwijck E, Al Naiemi N, Schulin T, Dinant S, van Mens SP, Melles DC, Stuart JWTC, Gruteke P, van Dam AP, Rahamat-Langendoen J, Maraha B, Sinnige JC, van der Vorm E, van Meer MPA, de Graaf M, de Jong E, Vainio SJ, Heikens E, Reijer MD, Dorigo-Zetsma JW, Troelstra A, Bathoorn E, de Vries J, van Dam DW, de Brauwer EIGB, Steingrover R, Oliveira Dos Santos C
Objectives
Cefiderocol is a novel last-resort cephalosporin antimicrobial increasingly used for difficult-to-treat infections by multidrug-resistant microorganisms (MDRO), and is effective against carbapenem-resistant Enterobacterales and Pseudomonas species. Multiple chromosomally encoded genetic determinants have been implicated in cefiderocol resistance, including mutations, deletions and/or frameshifts. However, identification of these determinants remains labour-intensive and time-consuming. Therefore, we share CefiderocolFinder, a bioinformatics pipeline to detect 25 genetic adaptations implicated in cefiderocol resistance from short-read whole genome sequencing (WGS) data.
Methods
CefiderocolFinder was built using Python, supports WGS data of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, and contains alignment, variant calling, annotation and filtering steps. A short-read WGS dataset (n=98) and validation WGS dataset (n=21) with cefiderocol antimicrobial susceptibility testing (AST) results was used to interpret and validate CefiderocolFinder.
Results
Using CefiderocolFinder, with WGS data from 98 MDRO collected from Ukrainian patients in 2022, six unique genetic adaptations were detected. These adaptations were associated with higher MICs in AST with cefiderocol. Loss of function mutations were found in the siderophore receptor cirA, the general porins oprD, ompC, ompF, negative regulator of the acrAB-tolC efflux operon acrR and a conservative in-frame insertion YRIN in ftsI encoding for Penicillin-binding protein 3. The adaptations were identified in 12 of 16 E. coli (75%), 1 of 60 K. pneumoniae (1%), 6 of 17 P. aeruginosa (35%) and 0 of 5 A. baumannii (0%) isolates. CefiderocolFinder was validated using publicly available datasets.
Conclusions
CefiderocolFinder provides context to corroborate phenotypical AST from WGS data, especially when the result is in an area of technical uncertainty. For E. coli, CefiderocolFinder can be a valuable tool for informing the clinician of specific genetic adaptations associated with resistance to cefiderocol, where for K. pneumoniae and P. aeruginosa the prediction of phenotypical resistance can be improved. CefiderocolFinder is available open access at http://github.com/Bryan-vd-Brand/CefiderocolFinder.
