Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA

Abstract

We report a case of resistance development towards cefiderocol in a patient with intra-abdominal and bloodstream infections caued by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

New Delhi Metallo-Beta-Lactamase Facilitates the Emergence of Cefiderocol Resistance in Enterobacter cloacae

“…There were no alterations in the AmpC nor in pbp3 genes, which have been attributed to reduced susceptibility toward cefiderocol in Enterobacterales ( 14 , 15 ). All five resistant mutants of etcl_1 showed different nonsynonymous mutations in the cirA gene (two point mutations, two deletions, and one transposon insertion), suggesting a divergent evolution and confirming our previously reported in vivo finding ( 11 ). All resistant mutants of KE5351 were identical with an IS5-like transposon insertion on the cirA gene, possibly due to the expansion of a resistant clone ( Fig.…”

“…Although cefiderocol resistance in Enterobacterales can still be considered rare, reports on the emergence of cefiderocol resistance Enterobacterales are cumulating ( 11 , 16 , 24 ). In Klebsiella pneumoniae and E. cloacae , the acquisition of cefiderocol resistance has been linked with mutations in the cirA gene, whereas, in E. coli , the emergence of cefiderocol resistance was associated with an increase in the bla NDM-5 copy number and gene expression.…”

“…To date, this antibiotic substance is not yet widely in clinical use, so that knowledge on the resistance mechanisms and the circumstances under which resistances can emerge is still limited ( 10 ). In a previous clinical case on in vivo emergence of cefiderocol resistance in Enterobacter cloacae during therapy, we demonstrated that, despite heterogeneity (deletion, insertion, and transposon insertion), the frameshift mutations in the cefiderocol-resistant E. cloacae isolates always targeted the cirA gene ( 11 ). The selection for cirA inactivation in E. cloacae suggested the keystone function of this gene in the mode of action of cefiderocol.…”

Proteomic and Transcriptomic Analyses Indicate Reduced Biofilm-Forming Abilities in Cefiderocol-Resistant Klebsiella pneumoniae

“…Also, cefiderocol is very stable and withstands serine- and metal-carbapenemases ( Yamano, 2019 ). Klein et al (2021) found heterogeneous mutations in the cirA gene in carbapenemase-producing Enterobacter cloacae , which encoded a catecholate siderophore receptor, contributing to resistance to cefiderocol. However, the exact mechanism(s) of cefiderocol resistance remain(s) unclear.…”

Will There Ever Be Cure for Chronic, Life-Changing Colistin-Resistant Klebsiella pneumoniae in Urinary Tract Infection?

“…Cefiderocol is another promising novel siderophore cephalosporin against drug-resistant K. pneumoniae due to its enhanced outer membrane penetration ability using iron transport system and intrinsic effective antimicrobial activities (21). Nevertheless, resistance issues were recorded following 21 days of initiating cefiderocol therapy (49).…”