Fetcroja® is a parenteral antibiotic containing cefiderocol – a siderophore cephalosporin – and is indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.1,2

Cefiderocol differs from other antimicrobials due to its novel mode of bacterial cell entry and enhanced stability against all classes of ß-lactamases.2 These properties contribute to its comprehensive activity against a wide variety of Gram-negative aerobic pathogens – including carbapenem-resistant strains.1,2

Discover more about how Fetcroja® works and where it can be utilised by exploring the sections below:

WHO IS FETCROJA® FOR?

Fetcroja® is an antimicrobial treatment for adults with serious aerobic Gram-negative infections who have limited treatment options.1,2

Fetcroja® can be administered regardless of the site of infection.1

Fetcroja® is a suitable option for adult patients with Gram-negative infections where the presence of a multi-drug resistant pathogen with carbapenem-resistance has been confirmed. It may also be suitable in situations where the patient is critically ill with a Gram-negative infection and the presence of a carbapenem-resistant infection is strongly suspected.1

MECHANISM OF ACTION

In common with many other β-lactams, cefiderocol exerts its antimicrobial activity by binding to and inhibiting penicillin-binding proteins (PBPs). This disrupts the bacteria’s ability to synthesize peptidoglycan – the main component of the bacterial cell wall – leading ultimately to cell death.1,2

It does this primarily by binding to PBP3, similar to other oxyimino-cephalosporins.2

Most β-lactams achieve entry into bacteria by diffusing passively through porin channels in the bacterial outer membrane.5 However, this leaves such antimicrobial agents susceptible to resistance via the mutation and/or downregulation of porin channels, reducing the permeability of the bacteria’s outer membrane to otherwise effective antibiotics.5

Fetcroja® overcomes this key resistance mechanism via its novel mode of cell entry.1,2

MODE OF CELL ENTRY

All bacteria need iron to survive, and have therefore developed dedicated methods of scavenging the molecules they need from their iron-depleted host (iron-depletion being a natural defence against bacterial infection).3,4 The bacteria release siderophores into the host, which bind with free extracellular iron.3,4 Once a siderophore-iron complex is created, they are actively transported back into the bacteria via specialised iron–siderophore channels.3,4

Fetcroja® contains the cephalosporin ‘cefiderocol’, the molecules of which have catechol side-chains, meaning they too function as siderophores.1,2 Many multi-drug resistant bacteria have reduced numbers of outer membrane porins, which decreases their permeability to antibiotics.1,2 However, after binding to extracellular iron, cefiderocol is able to exploit the bacteria’s active transport system and pass through the outer membrane into the periplasmic space.1,2

Adapted from Zhanel et al, 2019.

This novel mode of cell entry has been likened to the mythological Trojan Horse:2 the famous legend in which Greek soldiers fooled their enemy into bringing them into the otherwise impenetrable city of Troy by hiding within a huge wooden horse that the Trojans unwittingly brought inside.

HOW DOES THIS SUPPORT THE NICE RECOMMENDATION FOR USE OF FETCROJA® IN ENGLAND?

Cefiderocol is recommended, within its marketing authorisation, as an option for treating severe drug-resistant infections caused by Gram-negative bacteria.6

The decision to offer cefiderocol should be guided by results from tests for microbiological susceptibility and mechanisms of resistance that confirm that the infection is susceptible to cefiderocol, and not susceptible to other suitable antibiotics.6

Prescribers should follow the recommendations on new antimicrobials in the NICE guideline on antimicrobial stewardship.6

ADDITIONAL PROPERTIES

The structure of the cefiderocol molecules that make up Fetcroja® gives it enhanced stability against all known classes of β-lactamases, including the ‘metallo’ class.2,7,8 This includes stability against carbapenemases, which have been shown in vitro to inactivate a broad range of existing antibiotics.2,7,8

MOLECULAR CLASS
TYPE
EXAMPLES
FETCROJA® STABILITY
A
Serine
KPC, TEM, SHV, CTX-M
 checked
B
Metallo
IMP, VIM, NDM
 checked
C
Serine
AmpC, CMY
 checked
D
Serine
OXA-type (inc. -48, -23, -24, -58)
 checked

Data from Ito-Horiyama et al. 20167; Kazmierczak et al. 20198; and Bush 2018.9

Note: carbapenemases are highlighted in bold.

Furthermore, over-expression of efflux pumps appears to have little effect on the antimicrobial activity of cefiderocol, as demonstrated in isolates of both P. aeruginosa and A. baumannii.10,11

References:

  1. Fetcroja® (cefiderocol) Summary of Product Characteristics.
  2. Zhanel GG, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem resistant and multi-drug resistant Gram negative bacilli. Drugs. 2019;79:271–289.
  3. Ito A, et al. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60:7396–7401.
  4. Wilson BR, et al. Siderophores in iron metabolism: from mechanism to therapy potential. Trends Mol Med. 2016;22:1077–1090.
  5. Blair JMA, et al. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015;13:42–51.
  6. NICE. Cefiderocol for treating severe drug-resistant gram-negative bacterial infections, August 2022. Available at: https://www.nice.org.uk/about/what-we-do/life-sciences/scientific-advice/models-for-the-evaluation-and-purchase-of-antimicrobials/cefiderocol. Accessed August 2023.
  7. Ito-Horiyama T, et al. Stability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother. 2016;60:4384–4386.
  8. Kazmierczak KM, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-ϐ-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2019;53:177–184.
  9. Bush K. Past and present perspectives on ϐ-lactamases. Antimicrob Agents Chemother. 2018;62.;e01076-18.
  10. Ito A, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob Agents Chemother. 2018;62:e01454–17.
  11. Iregui A, et al. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26:722–726.
PP-UK-FDC-0865 | August 2023