Cefiderocol (S-649266; GSK-2696266D; S-649266D; trade name Fetroja) is an injectable siderophore cephalosporin antibiotic that has a catechol moiety on the 3-position of the side chain and was under clinical trials by Shionogi. It exhibits potent in vitro activity against the non-fermenting Gram- bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. As of Nov 14, 2019, Cefiderocol has gained FDA approval to treat patients with complicated UTI-urinary tract infections who have no other options available. It is indicated for the treatment of multi-drug-resistant Gram- bacteria such as Pseudomonas aeruginosa.
Physicochemical Properties
| Molecular Formula | C30H34CLN7O10S2 |
| Molecular Weight | 752.21 |
| Exact Mass | 751.149 |
| Elemental Analysis | C, 47.90; H, 4.56; Cl, 4.71; N, 13.03; O, 21.27; S, 8.52 |
| CAS # | 1225208-94-5 |
| Related CAS # | 1883830-01-0 (ditosylate hydrate);1225208-94-5;2009350-94-9 (sulfate tosylate 3:1:4);2135543-94-9 (sulfate tosylate hydrate 3:1:4:1); |
| PubChem CID | 77843966 |
| Appearance | White to off-white solid powder |
| LogP | -1.02 |
| Hydrogen Bond Donor Count | 6 |
| Hydrogen Bond Acceptor Count | 15 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 50 |
| Complexity | 1440 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | ClC1C(=C(C([H])=C([H])C=1C(N([H])C([H])([H])C([H])([H])[N+]1(C([H])([H])C2C([H])([H])S[C@]3([H])[C@@]([H])(C(N3C=2C(=O)[O-])=O)N([H])C(/C(/C2=C([H])SC(N([H])[H])=N2)=N\OC(C(=O)O[H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O)O[H])O[H] |
| InChi Key | DBPPRLRVDVJOCL-FQRUVTKNSA-N |
| InChi Code | 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 |
| Chemical Name | (6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetamido]-3-({1-[2-(2-chloro-3,4-dihydroxybenzamido)ethyl]pyrrolidin-1-ium-1-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate |
| Synonyms | S-649266; S 649266; S649266; GSK2696266D; GSK-2696266D; GSK 2696266D; S-649266D; S 649266D; S649266D; Cefiderocol; Fetroja. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.(2). This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | β-lactam |
| ln Vitro | Cefiderocol (S-649266) is a new parenteral siderophore cephalosporin conjugated with a catechol moiety. It has a strong antibacterial activity against a variety of aerobic Gram-negative bacterial species, including nonfermenting bacteria like Pseudomonas aeruginosa and Acinetobacter baumannii and carbapenem-resistant strains of Enterobacteriaceae. Cefiderocol primarily binds to nonfermenting bacteria, such as GR20263, and PBP3 of the Enterobacteriaceae family. Cefiderocol MICs can rise 16-fold when the iron transporters PiuA in P. aeruginosa or CirA and Fiu in Escherichia coli are deficient, indicating that these iron transporters aid in cefiderocol's penetration through the outer membrane.Cefiderocol activity is not significantly affected by the overproduction of the efflux pump MexA-MexB-OprM in P. aeruginosa or the deficiency of OmpK35/36 in Klebsiella pneumoniae[1]. |
| Cell Assay | Except in situations where MICs under particular circumstances must be determined, iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) is prepared for the purpose of determining the cefiderocol MIC. Cefiderocol's quality control minimum inhibitory concentration (MIC) ranges for E. Coli ATCC 25922 and P. aeruginosa ATCC 27853 are 0.06 to 0.5 μg/mL. Brusecella agar supplemented with hemin, vitamin K1, and laked sheep blood is used for anaerobic bacteria[1]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion 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. 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. 98.6% of cefiderocol is eliminated in the urine with 90.6% as the unchanged parent drug. The remaining 8% is eliminated as metabolites. 2.8% is eliminated in the feces. Less than 10% of cefiderocol is metabolized. Cefiderocol has a mean volume of distribution of 18 L. Cefiderocol has a mean clearance of 5.18 L/h. Metabolism / Metabolites 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). 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. Biological Half-Life The terminal elimination half-life of cefiderocol is 2-3 h. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Although no information is available on the use of cefiderocol during breastfeeding, cephalosporins are generally not expected to cause adverse effects in breastfed infants. Occasionally disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush have been reported with cephalosporins, but these effects have not been adequately evaluated. Cefiderocol is acceptable to use in nursing mothers. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Cefiderocol is 40-60% bound to plasma proteins, predominantly to albumin. |
| References |
[1]. Antimicrob Agents Chemother. 2017 Dec 21;62(1). [2]. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S544-S551. |
| Additional Infomation |
Cefiderocol is a cephalosporin antibacterial drug and exerts a mechanism of action similar to other β-lactam antibiotics. Unlike other agents in this category, cefiderocol is a siderophore able to undergo active transport into the bacterial cell through iron channels. 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. It is indicated for use in complicated urinary tract infections in patients with limited or no alternative treatments available. 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. A concern noted in the trial was a 0.3% higher rate of all cause mortality, the cause of which has not been determined. Cefiderocol is a Cephalosporin Antibacterial. See also: Cefiderocol Sulfate Tosylate (active moiety of). Drug Indication Cefiderocol is indicated for the treatment of complicated urinary tract infections with or without pyelonephritis. FDA Label Fetcroja is indicated for the treatment of infections  due to aerobic Gram-negative organisms in adults with limited treatment options (see sections 4. 2, 4. 4 and 5. 1). Consideration should be given to official guidance on the appropriate use of antibacterial agents. Treatment of infections due to aerobic Gram-negative bacteria 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. Like other β-lactam antibiotics cefiderocol is able to enter bacterial cells via passive diffusion through porins. 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. 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. |
Solubility Data
| Solubility (In Vitro) |
DMSO : ≥ 125 mg/mL (~166.18 mM) H2O : ~1.06 mg/mL (~1.41 mM) Ethanol : < 1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.75 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.75 mg/mL (3.66 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3294 mL | 6.6471 mL | 13.2942 mL | |
| 5 mM | 0.2659 mL | 1.3294 mL | 2.6588 mL | |
| 10 mM | 0.1329 mL | 0.6647 mL | 1.3294 mL |