Cefiderocol

Identification

Name

Cefiderocol

Accession Number

DB14879

Description

Cefiderocol is a cephalosporin antibacterial drug and exerts a mechanism of action similar to other β-lactam antibiotics.^Label Unlike other agents in this category, cefiderocol is a siderophore able to undergo active transport into the bacterial cell through iron channels.² It represents a significant addition to antibacterial treatment option as it has proven to be effective in vitro against multidrug resistant strains including extended spectrum β-lactamase producers and carbapenemase producing bacteria.

Cefiderocol was granted designation as a Qualified Infectious Disease Product and granted priority review status by the FDA on November 14, 2019.⁷ It is indicated for use in complicated urinary tract infections in patients with limited or no alternative treatments available.^Label This indication was supported by a positive clinical trial composed of 448 patients with complicated urinary tract infections which demonstrated a 72.6% rate of symptom resolution and bacterial eradication with cefiderocol compared to 54.6% with the comparator, imipenem/cilastatin.⁴ A concern noted in the trial was a 0.3% higher rate of all cause mortality, the cause of which has not been determined.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Cefiderocol (DB14879)

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Weight

Average: 752.21
Monoisotopic: 751.1497104

Chemical Formula

C₃₀H₃₄ClN₇O₁₀S₂

Synonyms

• Cefiderocol

External IDs

• GSK 2696266
• GSK2696266
• RSC 649266
• S 649266
• S-649266

Pharmacology

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Indication

Cefiderocol is indicated for the treatment of complicated urinary tract infections with or without pyelonephritis.^Label

Associated Conditions

• Complicated Urinary Tract Infection
• Nosocomial Pneumonia
• Pyelonephritis
• Ventilator-associated Bacterial Pneumonia

Contraindications & Blackbox Warnings

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Pharmacodynamics

Similarly to other cephalosporins, cefiderocol exerts bactericidal activity against a range of bacterial species.^Label,2 Cefiderocol has primarily shown efficacy against aerobic Gram negative bacteria including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.²

Mechanism of action

Cefiderocol acts by binding to and inhibiting penicillin-binding proteins (PBPs), preventing cell wall synthesis and ultimately causing death of the bacterial cell.^Label,2 Like other β-lactam antibiotics cefiderocol is able to enter bacterial cells via passive diffusion through porins.^3,Label Unlike other β-lactams, cefiderocol contains a chlorocatechol group which allows it to chelate iron. Once bound to ferric iron cefiderocol is able to undergo active transport into bacterial cells through iron channels in the outer cell membrane such as those encoded by the cirA and fiu genes in E. coli or the PiuA gene in P. aeruginosa. Once inside the cell, cefiderocol binds to and inhibits PBP3 with high affinity thereby preventing the linking of peptodoglycan layers via the pentapeptide bridge.^Label,2,5 PBP1a, 1b, 2,and 4 are also bound and inhibited by cefiderocol but with a lesser potency than PBP3 and are therefore expected to contribute less to its antibacterial effect.

Target	Actions	Organism
APenicillin-binding protein 3	inhibitor	Pseudomonas aeruginosa
APenicillin-binding protein 1A	inhibitor	Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
APenicillin-binding protein 1B	inhibitor	Pseudomonas aeruginosa
APenicillin-binding protein 2	inhibitor	Pseudomonas aeruginosa
AD-alanyl-D-alanine carboxypeptidase DacB	inhibitor	Escherichia coli (strain K12)

Absorption

A single intravenous dose of 2 g of cefiderocol in healthy patients produces a Cmax of 89.7 mg/L and an AUC of 386 mg*h/L.^Label In patients with complicated urinary tract infections and a creatinine clearance of at least 60 mL/min, doses of 2 g cefiderocol every 8 hours produced an AUC of 394.7 mg*h/L and a Cmax of 138 mg/L. However the infusion rate for this chronic dosing was 3 times the recommended rate. Cmax and AUC are known to increase proportionally with dosage.

Volume of distribution

Cefiderocol has a mean volume of distribution of 18 L.^Label

Protein binding

Cefiderocol is 40-60% bound to plasma proteins, predominantly to albumin.^Label

Metabolism

Cefiderocol undergoes a small degree of metabolism to a cefiderocol epimer at the 7 position, cefiderocol catechol-3-methoxy and -4-methoxy, and a pyrrolidine chlorobenzamide product (PCBA).¹ PCBA undergoes further metabolism to sulfated, methylated, and glucuronidated metabolites. The enzymes involved in these reactions have yet to be identified and cefiderocol has not been shown to interfere in the metabolism of other agents.^Label

Route of elimination

98.6% of cefiderocol is eliminated in the urine with 90.6% as the unchanged parent drug.^Label The remaining 8% is eliminated as metabolites. 2.8% is eliminated in the feces. Less than 10% of cefiderocol is metabolized.

Half-life

The terminal elimination half-life of cefiderocol is 2-3 h.^Label

Clearance

Cefiderocol has a mean clearance of 5.18 L/h.^Label

Adverse Effects

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Toxicity

Information on cefiderocol toxicity is not yet available. In case of overdose supportive care is recommended.^Label Hemodialysis has proven effective in removing cefiderocol with a 3-4 hour session removing 60% of circulating drug.

Affected organisms

• Pseudomonas aeruginosa
• Streptococcus pyogenes
• Streptococcus pneumoniae
• Neisseria meningitidis
• Haemophilus influenzae
• Neisseria gonorrhoeae
• Campylobacter jejuni
• Escherichia coli
• Salmonella typhi
• Moraxella catarrhalis
• Serratia marcescens
• Proteus vulgaris
• Proteus mirabilis
• Providencia stuartii
• Providencia rettgeri
• Morganella morganii
• Enterobacter cloacae
• Klebsiella pneumoniae
• Klebsiella oxytoca
• Salmonella paratyphi
• Shigella flexneri
• Pseudomonas putida
• Citrobacter freundii
• Yersinia enterocolitica
• Pseudomonas stutzeri
• Acinetobacter calcoaceticus
• Salmonella typhimurium
• Micrococcus luteus
• Salmonella enteritidis
• Aeromonas hydrophila
• Acinetobacter baumannii
• Elizabethkingia meningoseptica
• Stenotrophomonas maltophilia
• Acinetobacter johnsonii
• Acinetobacter haemolyticus
• Acinetobacter lwoffii
• Salmonella choleraesuis
• Vibrio fluvialis
• Vibrio vulnificus
• Yersinia pseudotuberculosis

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Not Available

Food Interactions

No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Cefiderocol sulfate tosylate	TTP8LBP45D	2135543-94-9	QNMVZYPDWLKAJC-RXVBEKIDSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Fetroja	Injection, powder, for solution	1 g/10mL	Intravenous	SHIONOGI INC.	2020-01-31	Not applicable

Categories

Drug Categories

• Amides
• Anti-Bacterial Agents
• beta-Lactams
• Cephalosporins
• Drugs that are Mainly Renally Excreted
• Heterocyclic Compounds, Fused-Ring
• Lactams
• Sulfur Compounds

Classification

Not classified

Chemical Identifiers

UNII

SZ34OMG6E8

CAS number

1225208-94-5

InChI Key

DBPPRLRVDVJOCL-FQRUVTKNSA-N

InChI

InChI=1S/C30H34ClN7O10S2/c1-30(2,28(46)47)48-36-19(16-13-50-29(32)34-16)24(42)35-20-25(43)37-21(27(44)45)14(12-49-26(20)37)11-38(8-3-4-9-38)10-7-33-23(41)15-5-6-17(39)22(40)18(15)31/h5-6,13,20,26H,3-4,7-12H2,1-2H3,(H7-,32,33,34,35,36,39,40,41,42,44,45,46,47)/t20-,26-/m1/s1

IUPAC Name

1-{[(6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetamido]-2-carboxylato-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{2-[(2-chloro-3,4-dihydroxyphenyl)formamido]ethyl}pyrrolidin-1-ium

SMILES

[H][C@]12SCC(C[N+]3(CCNC(=O)C4=C(Cl)C(O)=C(O)C=C4)CCCC3)=C(N1C(=O)[C@H]2NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC(N)=N1)C([O-])=O

References

General References

1. Miyazaki S, Katsube T, Shen H, Tomek C, Narukawa Y: Metabolism, Excretion, and Pharmacokinetics of [(14) C]-Cefiderocol (S-649266), a Siderophore Cephalosporin, in Healthy Subjects Following Intravenous Administration. J Clin Pharmacol. 2019 Jul;59(7):958-967. doi: 10.1002/jcph.1386. Epub 2019 Feb 7. [PubMed:30730562]
2. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y: In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: AAC.01454-17. doi: 10.1128/AAC.01454-17. Print 2018 Jan. [PubMed:29061741]
3. Kobayashi Y, Takahashi I, Nakae T: Diffusion of beta-lactam antibiotics through liposome membranes containing purified porins. Antimicrob Agents Chemother. 1982 Nov;22(5):775-80. doi: 10.1128/aac.22.5.775. [PubMed:6295267]
4. Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, Tenke P, Nagata TD: Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. doi: 10.1016/S1473-3099(18)30554-1. Epub 2018 Oct 25. [PubMed:30509675]
5. Brunton LL, Hilal-Dandan R, Knollmann BC. eds (2018). Goodman & Gilman's: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education. [ISBN:978-1-25-958473-2]
6. ChemSpider: Cefiderocol [Link]
7. FDA Press Release Cefiderocol [Link]

External Links

ChemSpider

52084902

RxNav

2265702

ChEMBL

CHEMBL3989974

Wikipedia

Cefiderocol

FDA label

Download (387 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Bloodstream Infections (BSI) / Complicated Urinary Tract Infection / Healthcare-associated Pneumonia (HCAP) / Nosocomial Pneumonia / Sepsis / Ventilator-associated Bacterial Pneumonia	1
3	Completed	Treatment	Healthcare-associated Pneumonia (HCAP) / Nosocomial Pneumonia / Ventilator-associated Bacterial Pneumonia	1
2	Completed	Treatment	Urinary Tract Infection	1
2	Recruiting	Treatment	Bloodstream Infections	1
2	Recruiting	Treatment	Bloodstream Infections (BSI) / Complicated Intra-abdominal Infection (cIAI) / Complicated Urinary Tract Infection / Gram-Negative Bacterial Infections / Nosocomial Pneumonia / Sepsis / Ventilator-acquired Pneumonia	1
2	Recruiting	Treatment	Complicated Urinary Tract Infection / Gram-Negative Bacterial Infections	1
1	Terminated	Treatment	Pneumonia, Bacterial	1
Not Available	Approved for Marketing	Not Available	Bacterial Infections	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	1 G
Injection, powder, for solution	Intravenous	1 g/10mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9238657	No	2016-01-19	2031-11-19
US10004750	No	2018-06-26	2035-09-03
US9949982	No	2018-04-24	2035-09-03

Properties

State

Solid

Experimental Properties

Property	Value	Source
logP	-2.265	ChemSpider: Cefiderocol

Predicted Properties

Property	Value	Source
Water Solubility	0.00201 mg/mL	ALOGPS
logP	1.84	ALOGPS
logP	-2.9	ChemAxon
logS	-5.6	ALOGPS
pKa (Strongest Acidic)	2.64	ChemAxon
pKa (Strongest Basic)	4.05	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	13	ChemAxon
Hydrogen Donor Count	6	ChemAxon
Polar Surface Area	256.9 Å2	ChemAxon
Rotatable Bond Count	13	ChemAxon
Refractivity	204.1 m3·mol-1	ChemAxon
Polarizability	72.74 Å3	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Penicillin-binding protein 3

Kind

Protein

Organism

Pseudomonas aeruginosa

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Known to bind to PBP3 of E. coli NIHJ JC-2, K. pneumoniae SR22291, P. aeruginosa ATCC 27853, and A. baumannii ATCC 17978.

General Function

Peptidoglycan glycosyltransferase activity

Specific Function

Not Available

Gene Name

pbpB

Uniprot ID

Q51504

Uniprot Name

Cell division protein

Molecular Weight

62855.78 Da

References

1. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y: In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: AAC.01454-17. doi: 10.1128/AAC.01454-17. Print 2018 Jan. [PubMed:29061741]

Details2. Penicillin-binding protein 1A

Kind

Protein

Organism

Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Known to bind to PBP1a of E. coli NIHJ JC-2, K. pneumoniae SR22291, and P. aeruginosa ATCC 27853. May bind to either PBP1a, PBP1b or both of A. baumannii ATCC 17978.

General Function

Transferase activity, transferring glycosyl groups

Specific Function

Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...

Gene Name

mrcA

Uniprot ID

Q07806

Uniprot Name

Penicillin-binding protein 1A

Molecular Weight

91198.715 Da

References

1. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y: In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: AAC.01454-17. doi: 10.1128/AAC.01454-17. Print 2018 Jan. [PubMed:29061741]

Details3. Penicillin-binding protein 1B

Kind

Protein

Organism

Pseudomonas aeruginosa

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Known to bind to PBP1b of E. coli NIHJ JC-2, K. pneumoniae SR22291, and P. aeruginosa ATCC 27853. May bind to either PBP1a, PBP1b or both of A. baumannii ATCC 17978.

General Function

Peptidoglycan glycosyltransferase activity

Specific Function

Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...

Gene Name

ponB

Uniprot ID

Q9X6W0

Uniprot Name

Penicillin-binding protein 1B

Molecular Weight

85486.615 Da

References

1. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y: In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: AAC.01454-17. doi: 10.1128/AAC.01454-17. Print 2018 Jan. [PubMed:29061741]

Details4. Penicillin-binding protein 2

Kind

Protein

Organism

Pseudomonas aeruginosa

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Known to bind to PBP3 of E. coli NIHJ JC-2, K. pneumoniae SR22291, and P. aeruginosa ATCC 27853, and A. baumannii ATCC 17978.

General Function

Penicillin binding

Specific Function

Not Available

Gene Name

pbpA

Uniprot ID

Q9X6V3

Uniprot Name

Penicillin-binding protein 2

Molecular Weight

72212.855 Da

References

1. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y: In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: AAC.01454-17. doi: 10.1128/AAC.01454-17. Print 2018 Jan. [PubMed:29061741]

Details5. D-alanyl-D-alanine carboxypeptidase DacB

Kind

Protein

Organism

Escherichia coli (strain K12)

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Known to bind to PBP4 of E. coli NIHJ JC-2, K. pneumoniae SR22291, and P. aeruginosa ATCC 27853.

General Function

Serine-type d-ala-d-ala carboxypeptidase activity

Specific Function

Not involved in transpeptidation but exclusively catalyzes a DD-carboxypeptidase and DD-endopeptidase reaction.

Gene Name

dacB

Uniprot ID

P24228

Uniprot Name

D-alanyl-D-alanine carboxypeptidase DacB

Molecular Weight

51797.85 Da

References

1. Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y: In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: AAC.01454-17. doi: 10.1128/AAC.01454-17. Print 2018 Jan. [PubMed:29061741]

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Drug created on May 20, 2019 14:32 / Updated on February 21, 2021 18:54