Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal

• Published in: European journal of clinical microbiology & infectious diseases Vol. 42; no. 11; pp. 1395 - 1400
• Main Authors: Daoud, Land, Allam, Mushal, Collyns, Timothy, Ghazawi, Akela, Saleem, Aqeel, Al-Marzooq, Farah
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2023; Springer Nature B.V
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Aztreonam; Bacteria; beta-Lactamase Inhibitors - pharmacology; beta-Lactamase Inhibitors - therapeutic use; Biomedical and Life Sciences; Biomedicine; Brief Report; Cefiderocol; Cephalosporins; Cephalosporins - pharmacology; Cephalosporins - therapeutic use; Drug resistance; Drug Resistance, Multiple, Bacterial - genetics; E coli; Enzymes; Genomes; Genomic analysis; Genomics; Health sciences; Hospitals; Humans; Infectious diseases; Inhibitors; Internal Medicine; Klebsiella; Klebsiella pneumoniae; Medical Microbiology; Mutation; Nucleotide sequence; Plasmids; Pneumonia; Sepsis; Sepsis - drug therapy; Siderophores - pharmacology; Siderophores - therapeutic use; β Lactamase; ST14; Cefiderocol; Antibiotic resistance; Klebsiella pneumoniae
• ISSN: 0934-9723; 1435-4373
• DOI: 10.1007/s10096-023-04671-0

Cefiderocol (CFDC) is the first-in-class siderophore-cephalosporin.
Klebsiella pneumoniae
strain that is extremely resistant to CFDC (MIC: 256 µg/ml) was isolated for the first time in the United Arab Emirates from a patient with pneumonia and sepsis. It belonged to sequence-type 14 (ST14), with a novel core genome ST. Resistance was driven by the co-expression of β-lactamases (
bla
NDM-1
,
bla
OXA-232
and
bla
CTX-M-15
) and a mutation in catecholate-siderophore receptor, utilized by CFDC to enter the bacterial cell. Synergistic combinations (β-lactamase inhibitors, aztreonam plus CFDC) re-sensitized the bacteria to CFDC. Although CFDC resistance is multifactorial, the combination with β-lactamase inhibitors represents a promising approach in resistance reversal for fighting superbugs.