In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

Abstract

Cefiderocol is a new siderophore cephalosporin that is effective against multidrug-resistant Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to evaluate the activity of this new antimicrobial agent against a collection of pathogens using broth microdilution assays and to analyze the possible mechanism of cefiderocol resistance in two resistant Klebsiella pneumoniae isolates. One hundred and ten isolates were tested, comprising 67 Enterobacterales, two Acinetobacter baumannii, one Achromobacter xylosoxidans, 33 Pseudomonas aeruginosa and seven Stenotrophomonas maltophilia. Cefiderocol showed good in vitro activity, with an MIC < 2 μg/mL, and was able to inhibit 94% of the tested isolates. We observed a resistance rate of 6%. The resistant isolates consisted of six Klebsiella pneumoniae and one Escherichia coli, leading to a resistance rate of 10.4% among the Enterobacterales. Whole-genome sequencing analysis was performed on two cefiderocol-resistant Klebsiella pneumoniae isolates to investigate the possible mutations responsible for the observed resistance. Both strains belonged to ST383 and harbored different resistant and virulence genes. The analysis of genes involved in iron uptake and transport showed the presence of different mutations located in fhuA, fepA, iutA, cirA, sitC, apbC, fepG, fepC, fetB, yicI, yicJ, and yicL. Furthermore, for the first time, to the best of our knowledge, we described two Klebsiella pneumoniae isolates that synthesize a truncated fecA protein due to the transition from G to A, leading to a premature stop codon in the amino acid position 569, and a TonB protein carrying a 4-amino acid insertion (PKPK) after Lysine 103. In conclusion, our data show that cefiderocol is an effective drug against multidrug-resistant Gram-negative bacteria. However, the higher resistance rate observed in Enterobacterales underlines the need for active surveillance to limit the spread of these pathogens and to avoid the risks associated with the emergence of resistance to new drugs.

Opportunities and challenges of microbial siderophores in the medical field

“…Here, it was observed that cefiderocol, along with ceftazimideavibactam and meropenem-vaborbactam, are effective against severe, uncommon infections caused by microorganisms producing carbapenemases (Sadek et al 2023). In addition to this, the in vitro evaluation of cefiderocol against Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa, among others, showed that this compound was able to inhibit 94% of the isolates (Padovani et al 2023), and in a surveillance study conducted with Gram-negative bacterial clinical Fig. 1 A schematic representation of the mediated iron uptake by microbial siderophores is shown.…”

“…Here, it was observed that cefiderocol, along with ceftazimide-avibactam and meropenem-vaborbactam, are effective against severe, uncommon infections caused by microorganisms producing carbapenemases (Sadek et al 2023 ). In addition to this, the in vitro evaluation of cefiderocol against Enterobacterales , Acinetobacter baumannii , and Pseudomonas aeruginosa , among others, showed that this compound was able to inhibit 94% of the isolates (Padovani et al 2023 ), and in a surveillance study conducted with Gram-negative bacterial clinical isolates from North America and Europe (2014 to 2019) showed that cefiderocol inhibits in average > 90% of Enterobacterales , > 96% of A. baumannii and > 99% of P. aeruginosa isolates non-susceptible to diverse carbapenems (Karlowsky et al 2022 ). These results are also promising in clinical trials where cefiderocol has been successfully used to treat severe infections with carbapenem-resistant Gram-negative bacteria, achieving clinical and microbiological cure of up to 84.6% of the patients 7 days after the treatment has ended (de la Fuente et al 2023 ).…”

An Overview of Cefiderocol’s Therapeutic Potential and Underlying Resistance Mechanisms

“…Five consecutive annual SIDERO-WT Studies reports a 99.9% of susceptibility to cefiderocol in a total of 7700 isolates. [54,60,74] Whole genome sequencing of P. aeruginosa non-susceptible to cefiderocol identified mutations in major iron transport pathways. The second study reports in vivo development of cefiderocol resistance among four sequential P. aeruginosa clinical isolates ST244 recovered from a single patient, without exposure to cefiderocol.…”

“…[ 54,60,74] S. maltophilia strains evolved cefiderocol resistance through different genetic pathways, but often involved iron transport.…”

“…Thirdly, mutations in the target gene of cefiderocol, the pbp3 gene, might contribute to resistance [63,[86][87][88]. Lastly, and due to its unique way of cell permeability, it is unsurprising that a reduced expression or mutation of genes involving iron transport pathways, especially the siderophore receptor genes (e.g., pirA, cirA, ton, piuA), are associated with cefiderocol resistance in different bacterial species [61,74,77,[89][90][91][92][93][94].…”