β-lactam

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].

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].

Absorption, Distribution and Excretion
Following a single intravenous injection of 2 g Cefiderocol in healthy subjects, the peak plasma concentration (Cmax) was 89.7 mg/L, and the area under the curve (AUC) was 386 mgh/L. In patients with complicated urinary tract infections and a creatinine clearance of at least 60 mL/min, after intravenous injection of 2 g Cefiderocol every 8 hours, the AUC was 394.7 mgh/L, and the Cmax was 138 mg/L. However, this chronic dosing regimen resulted in an infusion rate three times the recommended rate. Cmax and AUC are known to increase proportionally with dose. 98.6% of Cefiderocol is excreted in the urine, of which 90.6% is unchanged. The remaining 8% is excreted as metabolites. 2.8% is excreted in the feces. The metabolic rate of Cefiderocol is less than 10%. The mean volume of distribution of Cefiderocol is 18 liters. The mean clearance of Cefiderocol is 5.18 liters/hour.

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Metabolism/Metabolites
Cefdilol is metabolized to a small amount of its 7-epimer, cefdilol-3-methoxy and -4-methoxy, and pyrrolidinechlorobenzamide (PCBA). PCBA is further metabolized to sulfation, methylation, and glucuronidation metabolites. The enzymes involved in these reactions have not been identified, and cefdilol has not been found to interfere with the metabolism of other drugs.

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Biological Half-Life
The terminal elimination half-life of cefdilol is 2–3 hours.
Cefdilol has a terminal elimination half-life of 2–3 hours.

Effects During Pregnancy and Lactation
◉ Overview of Drug Use During Lactation
While there is currently no information regarding the use of Cefiderocol during lactation, it is generally believed that cephalosporins do not have adverse effects on breastfed infants. There are reports that cephalosporins occasionally disrupt the infant's gut microbiota, leading to diarrhea or thrush, but these effects have not been fully assessed. Cefiderocol can be used by breastfeeding women.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding
Cefiderocol binds to plasma proteins in a rate of 40-60%, primarily albumin.

[1]. Antimicrob Agents Chemother. 2017 Dec 21;62(1).

[2]. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S544-S551.

Cefiderocol is a cephalosporin antibiotic with a mechanism of action similar to other β-lactam antibiotics. Unlike other drugs in its class, Cefiderocol is a siderophore, enabling it to actively transport into bacterial cells via iron channels. It provides an important supplemental option for antimicrobial therapy because in vitro studies have demonstrated its effectiveness against multidrug-resistant strains, including those producing extended-spectrum β-lactamases and carbapenemases. On November 14, 2019, the U.S. Food and Drug Administration (FDA) granted Cefiderocol Qualified Infectious Disease Product (QIDP) designation and priority review status. It is indicated for the treatment of complicated urinary tract infections in patients with limited or no other treatment options. A clinical trial involving 448 patients with complicated urinary tract infections confirmed this indication, showing that Cefiderocol achieved a 72.6% symptom relief and bacterial clearance rate compared to a 54.6% rate in the control group (imipenem/cilastatin). One finding in the trial was a 0.3% higher all-cause mortality rate, the cause of which is not yet determined.
Cefdermoid is a cephalosporin antibiotic.
See also: Cefdermoid Tosylate Sulfate (active ingredient).
Indications
Cefdermoid is indicated for the treatment of complicated urinary tract infections with or without pyelonephritis.
FDA Label
Cefdermoid is indicated for the treatment of aerobic Gram-negative bacterial infections in adults, particularly in cases where treatment options are limited (see Sections 4.2, 4.4, and 5.1). Official guidelines on the rational use of antimicrobial agents should be consulted.
Treatment of Aerobic Gram-Negative Bacterial Infections
Mechanism of Action
Cefdermoid binds to and inhibits the activity of penicillin-binding protein (PBP), preventing cell wall synthesis and ultimately leading to bacterial cell death. Like other β-lactam antibiotics, cefdermoid passively diffuses into bacterial cells via porins. Unlike other β-lactam antibiotics, cefdermoid contains a chlorocatechin group, enabling it to chelate iron. Once bound to ferric iron, cefdil can be actively transported into bacterial cells via iron channels on the outer membrane (such as those encoded by the cirA and fiu genes in E. coli or the PiuA gene in Pseudomonas aeruginosa). After entering the cell, cefdil binds to PBP3 with high affinity and inhibits its activity, thereby preventing the peptidoglycan layer from being connected via pentapeptide bridges. PBP1a, 1b, 2, and 4 can also be bound and inhibited by cefdil, but their inhibitory efficacy is lower than that of PBP3, and therefore their contribution to antibacterial activity is expected to be smaller.

C30H34CLN7O10S2

752.21

751.149

C, 47.90; H, 4.56; Cl, 4.71; N, 13.03; O, 21.27; S, 8.52

1225208-94-5

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);

77843966

White to off-white solid powder

-1.02

6

15

12

50

1440

2

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]

DBPPRLRVDVJOCL-FQRUVTKNSA-N

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

(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

S-649266; S 649266; S649266; GSK2696266D; GSK-2696266D; GSK 2696266D; S-649266D; S 649266D; S649266D; Cefiderocol; Fetroja.

2934.99.9001

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.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 125 mg/mL (~166.18 mM)
H2O : ~1.06 mg/mL (~1.41 mM)
Ethanol : < 1 mg/mL

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.

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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.

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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.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.75 mg/mL (3.66 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)