Cefiderocol

Class and Chemical Structure

 It is a Siderophore cephalosporin, a synthetic conjugate of a cephalosporin moiety and a siderophore moiety. Siderophore moiety binds to the iron and helps the antibiotic to gain entry into bacterial cells using active iron transporters (e.g. CirA and Fiu in E coli, PiuA in P. aeruginosa)– a “Trojan horse” like approach.

 

The chemical structure is similar to both ceftazidime and cefepime.

 It has high stability against beta-lactamase, including ESBL, ampC and carbapenemases. Modifications of C-7 (a carboxypropanoxyimino group, like ceftazidime) and C-3 ( pyrrolidinium group, like cefepime) side chains lead to the stability against β-lactamases, including carbapenemases.

Mechanism of action of cefiderocol

Cefiderocol’s mechanism of action is similar to other beta-lactams – It binds to the Penicillin-binding proteins (PBP)  to prevent cell wall formation. It has a high affinity for PBP3.

PBP, an enzyme, helps to establish a cross-link between L-lys and the 4th D-ala. This cross-link provides structural strength to the cell wall. Bata-lactams, with a similar alanyl-alanine structure, binds to the PBP and prevent the cross-linking and hence, cell wall formation.

Mechanism of resistance of cefiderocol

Some mutations, especially in iron transporters, are associated with an increase in minimum inhibitory concentration (MIC). Some beta-lactamase enzymes may also have a similar effect.

• Mutations in upstream regions of pvdS , which regulates pyoverdine synthesis – overexpression of pyoverdine.
• Mutation in fecI , which regulates the synthesis of iron transporter FecA contributes to the transport of iron citrate.
• Mutation in the iron transporters CirA, Fiu, PiuA.
• D179Y mutation in the Ω-loop of KPC β-lactamases
• Some serine and metallo-betalactamases may increase MIC (PER, NDM) [Yamano]

However, cefiderocol –

• Is not/less affected by porin loss (ompK, oprD) or upregulation of efflux (MexA-MexB-OprM).
• Is stable against many serine and metallo-beta-lactamases. – KPC, OXA, VIM etc. Some resistance has been noted in NDM and PER producers.
•  Is less/not affected by the overproduction of class C beta-lactamase – ampC (e.g dacB gene-mediated).
•  Is not affected by PBP3 mutation like YRIN (ftsI gene-mediated) or YRIK insertion in E coli (It affects beta-lactams except carbapenems). 

PK/PD of cefiderocol

• Three-compartment linear model.
• Mean plasma half-life (t½)  ~ 2.3 h.
• Protein binding – 58%.
• Total drug clearance – 4.6-6.0 L/h.
• Primarily excretion -renally, unchanged – 61-71%
• Dose adjustment required in renal impairment
• Most important pharmacodynamic index  predicting clinical outcome: T > MIC (percentage of time that free drug concentrations exceed the minimum inhibitory concentration).

Spectrum

It is active against:

Enterobacteriaceae – E coli, Klebsiella, Enterobacter etc.
Nonfermenting bacteria: Pseudomonas, Acinetobacter spp, Burkholderia spp, Stenotrophomonas maltophilia.
Other gram negatives – Haemophilus, Moraxella, Bordetella

Higher MIC was seen in Campylobacter, ceftriaxone R gonococcus, and gram-positive bacteria.
Anaerobe sensitivity is variable (as anaerobes rely less on the siderophore system).

Use

It is licensed for –

For the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by susceptible Gram-negative microorganisms, patients 18 years of age or older have limited or no alternative treatment options. (FDA).
Infections  due to aerobic Gram-negative organisms in adults with limited treatment options (EMA)

Studies and papers

Global surveillance studies, SIDERO-WT and SIDERO-CR
APEKS-cUTI
CREDIBLE – CR

Papers:

https://academic.oup.com/cid/article/69/Supplement_7/S519/5624002
https://academic.oup.com/cid/article/69/Supplement_7/S538/5624004
https://academic.oup.com/cid/article/69/Supplement_7/S544/5624008