cefiderocol and Escherichia-coli-Infections

As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent.. We describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ß-lactamase (NDM)-5-producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance, using 5 sequential clinical E. coli isolates obtained from the patient.. In all 5 isolates, blaNDM-5 genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 μg/mL for isolates 1-2, 3, and 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 and 10 copies of the blaNDM-5 gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of blaNDM-5 messenger RNA expression analysis, in which isolates 4 and 5 expressed blaNDM-5 1.7- and 2.8-fold, respectively, compared to, isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was successfully treated with this combination and remained infection free 1 year later.. The findings in our patient suggest that increased copy numbers of blaNDM genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased blaNDM-5 expression in contributing to cefiderocol resistance needs investigation.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefiderocol; Cephalosporins; DNA Copy Number Variations; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Gene Expression; Humans; Microbial Sensitivity Tests; Plasmids; RNA, Messenger

The ability of broad-spectrum β-lactamases to reduce the susceptibility to ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam, meropenem-vaborbactam, aztreonam-avibactam (AZA), and cefiderocol (FDC) was evaluated both in Pseudomonas aeruginosa and in Escherichia coli using isogenic backgrounds. Although metallo-β-lactamases conferred resistance in most cases, except for AZA, several clavulanic-acid-inhibited extended-spectrum β-lactamases (PER, BEL, SHV) had a significant impact on the susceptibility to CZA, C/T, and FDC.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; beta-Lactamase Inhibitors; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Drug Combinations; Escherichia coli; Escherichia coli Infections; Humans; Lactams; Microbial Sensitivity Tests; Pseudomonas aeruginosa

A multidrug-resistant (carbapenems, aztreonam + avibactam, and cefiderocol) ST167 Escherichia coli clinical isolate recovered from a patient hospitalized in Switzerland produced NDM-35 showing ca. 10-fold increased hydrolytic activity toward cefiderocol compared to NDM-1. The isolate co-produced a CMY-type β-lactamase, exhibited a four amino-acid insertion in PBP3, and possessed a truncated iron transporter CirA protein. Our study identified an association of unrelated resistance mechanisms leading to resistance to virtually all β-lactams in a high-risk E. coli clone.

Topics: Anti-Bacterial Agents; beta-Lactamases; beta-Lactams; Cefiderocol; Cephalosporins; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Escherichia coli; Escherichia coli Infections; Humans; Microbial Sensitivity Tests; Pharmaceutical Preparations