Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

Abstract

Cefiderocol, formerly S-649266, is a first in its class, an injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many b-lactamases, including extended spectrum b-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol's spectrum of activity encompasses both lactosefermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. Cefiderocol recently received US Food and Drug Administration approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens. The purpose of this article is to review existing data on the mechanism of action, microbiology, pharmacokinetics, pharmacodynamics, efficacy, and safety of cefiderocol to assist clinicians in determining its place in therapy.

Activity of Cefiderocol, Ceftazidime-Avibactam, and Eravacycline against Carbapenem-Resistant Escherichia coli Isolates from the United States and International Sites in Relation to Clonal Background, Resistance Genes, Coresistance, and Region

“…Cefiderocol (CFDC), ceftazidime-avibactam (CZA), and eravacycline (ERV) are recently developed agents with activity against carbapenem-resistant (CR) E. coli strains. CFDC is a novel siderophore cephalosporin active against CR Gram-negative bacteria, including those that produce carbapenemases of all Ambler classes or have porin channel mutations and/or efflux pump overexpression (7)(8)(9). CZA pairs ceftazidime, an extended-spectrum cephalosporin, with avibactam, a non-beta-lactam, beta-lactamase inhibitor that is active against Ambler class A, class C, and some class D beta-lactamases (10)(11)(12).…”

Novel South African Rare Actinomycete Kribbella speibonae Strain SK5: A Prolific Producer of Hydroxamate Siderophores Including New Dehydroxylated Congeners

“…Since siderophores chelate other metal cations (divalent, trivalent, and actinides) in soil and water, they tend to reduce the level of metal contamination in the environment [5]. The siderophore, desferrioxamine B, isolated from several Streptomyces species, is used to remove excess iron in patients suffering from iron overload [6]. Furthermore, siderophores linked to antibiotics show a higher antibacterial potency compared to normal antibiotics due to an enhanced uptake using the siderophore-mediated iron active transport.…”

“…Furthermore, siderophores linked to antibiotics show a higher antibacterial potency compared to normal antibiotics due to an enhanced uptake using the siderophore-mediated iron active transport. Examples of siderophore-enhanced antibiotics are the natural albomycin (thioribosyl pyrimidine antibiotic and tri-hydroxamate siderophore) and the synthetic, FDA-approved cefiderocol (cephalosporin antibiotic and catechol siderophore) [6]. Siderophores are also being explored in the synthesis of sideromycin (siderophore linked to antibiotics) for antibiotic drug discovery and have been explored in a "Trojan horse" approach to a novel anti-tuberculosis agent [7,8].…”

Ceftolozane/Tazobactam and Ceftazidime/Avibactam for Multidrug-Resistant Gram-Negative Infections in Immunocompetent Patients: A Single-Center Retrospective Study

“…Further studies are needed to provide high-quality evidence and guide the selection of effective strategies to treat MDR- Enterobacterales , also considering the novel β-lactamase inhibitors vaborbactam and relebactam and the next-generation antibiotics such as cefiderocol [ 32 , 33 , 34 , 35 ], aminoglycoside plazomicin [ 36 , 37 ], and tetracycline antibiotic eravacycline [ 38 , 39 , 40 , 41 , 42 ], which could be alternative therapeutic options for CRE and CPE infections [ 43 ].…”