Class and Chemical structure:

Siderophore cephalosporin.

 It is a synthetic conjugate, of a cephalosporin moiety and a siderophore moiety. Siderophore moiety bind 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 a high degree of 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

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.

Main component of the bacterial cell wall is peptidoglycan (helps bacteria to retain stability against osmotic pressure, maintain shape and morphology). Peptidoglycan is consists of two amino-sugars:
N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM).
A pentapeptide structure is attached to NAM, with two terminal D-ala.

PBP, an enzyme, helps to establish a cross link between L-lys and the 4th D-ala. This cross link provides the 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 action of antibiotics:

        Mechanisms can be grouped into five major types

  • Cell wall – e.g. prevent cell wall formation (Penicillin, glycopeptide)
  • Cell membrane – e.g. depolarisation of cell membrane (Colistin)
  • Inhibiting protein synthesis – (Macrolide, tetracycline)
  • Prevent nucleic acid formation – (Trimethoprim)
  • Prevent DNA repair/supercoiling or cause damage – Metronidazole, Quinolone

Mechanism of resistance

Some mutations are found to be associated with an increase in MIC:

  • Mutations in upstream regions of pvdS , which regulates pyoverdine synthesis – overexpression of pyoverdine.
  • Mutation in fecI , which regulates the synthesis of iron transporter FecA contributing 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]

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:

  • 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 (less reliant on siderophore system).

Use:

It is licensed for –

For the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by susceptible Gram-negative microorganisms, in patients 18 years of age or older who have limited or no alternative treatment options. (FDA).

Infections  due to aerobic Gram-negative organisms in adults with limited treatment options (EMA)

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