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 toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused 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.

Keywords: Enterobacter cloacae; cirA siderophore receptor; Cefiderocol; antibiotic resistance; carbapenemase.

Figure 1.

(a) Timeline of events and antimicrobial therapy from the first detection of carbapenem-resistant Enterobacter cloacae until exitus letalis. High-level cefiderocol resistance was first detected on day 21 after therapy initiation (day 96 after liver retransplantation). Dark gray bars indicate antimicrobial therapy duration. Dosages: daptomycin IV 700 mg every 24 hours; meropenem IV 2 g initial bolus followed by 2 g every 8 hours with prolonged infusion time; colistin IV 9 Mio loading dose followed by 2.5 Mio every 12 hours for 3 days and 4.5 Mio every 12 hours for another 3 days; cefiderocol IV 2 g initial bolus followed by 1 g every 8 hours (dose adjusted to renal clearance) for 26 days and 2 g every 8 hours for 6 days; linezolid IV 600 mg every 12 hours; caspofungin IV 70 mg on the first day and then 50 mg every 24 hours. (b) Phenotypic resistance profile of all Enterobacter cloacae blood culture isolates. (c) Phylogeny by SNPs of E. clocae isolates indicated close clonal relationship (ST96, 0 to 9 SNPs). Isolates etcl_6 to _9 exhibited high-level resistance to cefiderocol (>256 mg/L). Abbreviations: FDC-R, cefiderocol-resistant; FDC-S, cefiderocol-susceptible; I, intermediate; IV, intravenous; MIC, minimum inhibitory concentration in mg/L; MLST, multi-locus sequence typing; R, resistant; S, susceptible; SNPs, single nucleotide polymorphisms.