Cefiderocol API Manufacturers

General Description:

Cefiderocol, identified by CAS number 1225208-94-5, is a notable compound with significant therapeutic applications. 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.

Indications:

This drug is primarily indicated for: Cefiderocol is indicated for the treatment of complicated urinary tract infections with or without pyelonephritis. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Cefiderocol undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Cefiderocol are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Cefiderocol is an important consideration for its dosing schedule: The terminal elimination half-life of cefiderocol is 2-3 h. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Cefiderocol exhibits a strong affinity for binding with plasma proteins: Cefiderocol is 40-60% bound to plasma proteins, predominantly to albumin. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Cefiderocol from the body primarily occurs through: 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Cefiderocol is distributed throughout the body with a volume of distribution of: Cefiderocol has a mean volume of distribution of 18 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Cefiderocol is a critical factor in determining its safe and effective dosage: Cefiderocol has a mean clearance of 5.18 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Cefiderocol exerts its therapeutic effects through: Similarly to other cephalosporins, cefiderocol exerts bactericidal activity against a range of bacterial species. Cefiderocol has primarily shown efficacy against aerobic Gram negative bacteria including *Escherichia coli*, *Klebsiella pneumoniae*, and *Pseudomonas aeruginosa*. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Cefiderocol functions by: 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Cefiderocol is categorized under the following therapeutic classes: Amides, Anti-Bacterial Agents, Antibacterials for Systemic Use, Antiinfectives for Systemic Use, beta-Lactams, Cephalosporins, Drugs that are Mainly Renally Excreted, Heterocyclic Compounds, Fused-Ring, Lactams, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Cefiderocol include:

• logP: -2.265