Cefiderocol: a novel siderophore cephalosporin for multidrug-resistant Gram-negative bacterial infections

Abstract

Cefiderocol is a novel siderophore cephalosporin that forms a complex with extracellular free ferric iron, which leads to transportation across the outer cell membrane to exert its bactericidal activity through cell wall synthesis inhibition. This pharmacological property has rendered cefiderocol active against several clinically relevant MDR Gram-negative bacteria as evidenced by several in vitro and in vivo studies. Cefiderocol was first approved by the US FDA on 14 November 2019 for the treatment of complicated urinary tract infections. On 28 September 2020, cefiderocol was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. The FDA-approved indications are based on clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In APEKS-cUTI, cefiderocol demonstrated non-inferiority to imipenem/cilastatin for the treatment of complicated urinary tract infection caused by MDR Gram-negative bacteria. In APEKS-NP, cefiderocol demonstrated non-inferiority to meropenem for treatment of nosocomial pneumonia. However, in CREDIBLE-CR, higher all-cause mortality was observed with cefiderocol compared with best available therapy for the treatment of severe infections caused by Gram-negative bacteria, primarily in the subset of patients with Acinetobacter spp. infections. Several case reports/series have demonstrated clinical success with cefiderocol for a variety of severe infections. The purpose of this article is to review available data on the mechanism of action, in vitro and in vivo data, pharmacokinetics, pharmacodynamics, susceptibility testing, efficacy and safety of cefiderocol to address its role in therapy.

In-Depth Analysis of the Role of the Acinetobactin Cluster in the Virulence of Acinetobacter baumannii

“…In the last years, siderophore conjugates using the "Trojan Horse" antibiotic drug delivery strategy has become more popular for combating this microorganism. In fact, cefiderocol (fetcroja) was the first cathecol-substituted siderophore cephalosporin approved by the FDA and EMA (Ji et al, 2012;Wencewicz and Miller, 2013;Parsels et al, 2021).…”

In Vitro Antimicrobial Activity of the Siderophore Cephalosporin Cefiderocol against Acinetobacter baumannii Strains Recovered from Clinical Samples

“…The increasing number of MDR A. baumannii, among other MDR pathogens, has forced the development of antibiotics endowed with novel mechanisms of action against carbapenem-resistant Gram-negative bacteria. Cefiderocol, a siderophore cephalosporin approved in 2019 for the treatment of complicated UTIs, represents a suitable option against MDR infections, under the light of the few therapeutic treatments available [ 20 , 21 , 22 , 23 , 24 ].…”

Clinical Pharmacokinetics and Pharmacodynamics of Cefiderocol

“…Furthermore, the potential effect of hepatic impairment on the treatment with cefiderocol has not been systematically evaluated in clinical trials yet. However, it appears unlikely that hepatic impairment relevantly affects cefiderocol treatments as the liver plays a negligible role in the PK of cefiderocol [5,43].…”