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. 2026 Feb 18:108479.
doi: 10.1016/j.ijid.2026.108479. Online ahead of print.

Genotypic-phenotypic discordance for cefiderocol against Enterobacter hormaechei

Vineet Dubey  1 , Alessandro Gerada  2 , Charlotte M Jones  1 , James Cruise  3 , William Hope  4 , Alex Howard  2
Affiliations
Free article

Genotypic-phenotypic discordance for cefiderocol against Enterobacter hormaechei

Vineet Dubey et al. Int J Infect Dis. .
Free article

Abstract

Objectives: The Enterobacter cloacae complex (ECC) is an emerging global cause of healthcare-associated infections, marked by high mortality and limited treatment options due to extensive antimicrobial resistance. Cefiderocol is increasingly used against carbapenem-resistant pathogens, including metallo-β-lactamase producers. However, reports of treatment failure, particularly in isolates with borderline MICs, indicate uncertainty regarding the relationship between phenotypic susceptibility and underlying genomic resistance mechanisms. The objective of this study was to characterise the genomic resistance landscape of a cefiderocol-susceptible Enterobacter hormaechei isolate and to examine potential genomic-phenotypic discordance relevant to cefiderocol activity.

Methods: We conducted genomic and phenotypic characterisation of a clinical Enterobacter hormaechei subsp. hoffmannii isolate recovered at Liverpool Clinical Laboratories (Royal Liverpool Hospital, United Kingdom). The isolate exhibited extensive resistance to β-lactams, carbapenems, aztreonam, most aminoglycosides, and multiple ancillary agents, yet remained phenotypically susceptible to cefiderocol (MIC = 2 mg/L; EUCAST susceptible breakpoint).

Results: Whole-genome sequencing revealed a multifactorial resistance architecture, including blaNDM-1 and widespread mutations across siderophore-mediated iron uptake pathways (tonB, fhu, fep, ent, wzz). Variants in global regulators (fur, ampR) suggested altered iron-acquisition and β-lactamase (blaACT-associated) regulatory networks. Multiple mutations affecting β-lactam targets, including ftsI (PBP3) indicated reduced PBP affinity. Together, these determinants form a complex genomic resistance landscape.

Conclusions: This study highlights a genomic-phenotypic discordance in an E. hormaechei isolate with borderline cefiderocol susceptibility. The findings underscore the risk of overestimating cefiderocol activity based solely on MIC values and emphasise the need for genomic resistance assessment in high-risk Enterobacterales.

Keywords: Cefiderocol; Enterobacter hormaechei; NDM-1; TonB mutation; siderophore uptake.

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Conflict of interest statement

Declaration of competing interest W.H. holds or has recently held research grants with UKRI, EU (FP7, IMI-1, IMI-2), Wellcome, F2G, and the Global Antimicrobial Research and Development Partnership (GARDP). He has served as a consultant for F2G and GSK and participated in multiple advisory committees (GARDP, BSAC Breakpoint Committee). A.H. declares personal consulting work for Pfizer outside the submitted work, and a donation from Pfizer to the University of Liverpool for a public and professional engagement project outside the submitted work.

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