Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

Abstract

Carbapenem-resistant Enterobacterales (CRE) remain a significant public health threat, and, despite recent approvals, new antibiotics are needed. Severe infections caused by CRE, such as nosocomial pneumonia and bloodstream infections, are associated with a relatively high risk of morbidity and mortality. The recent approval of ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, plazomicin, eravacycline and cefiderocol has broadened the armamentarium for the treatment of patients with CRE infections.Cefiderocol is a siderophore cephalosporin with overall potent in vitro activity against CRE. It is taken up via iron transport channels through active transport, with some entry into bacteria through traditional porin channels. Cefiderocol is relatively stable against hydrolysis by most serine-and metallo-beta-lactamases, including KPC, NDM, VIM, IMP and OXA carbapenemases-the most frequent carbapenemases detected in CRE. The efficacy and safety of cefiderocol has been demonstrated in three randomised, prospective, parallel group or controlled clinical studies in patients at risk of being infected by multidrug-resistant or carbapenem-resistant Gram-negative bacteria. This paper reviews the in vitro activity, emergence of resistance, preclinical effectiveness, and clinical experience for cefiderocol, and its role in the management of patients with CRE infections.

Carbapenem-resistant Gram-negative bacteria (CR-GNB) in ICUs: resistance genes, therapeutics, and prevention – a comprehensive review

“…Cefodilol exhibits inherent stability against a wide range of carbapenemases, including class A, B, and D, as well as class C cephalosporinase hydrolases. Patients infected with KPC, NDM, VIM, IMP, and OXA-48 harboring CRE experiencing BSI or urinary tract infections can potentially benefit from cefodilol therapy ( 56 ). However, it is important to acknowledge that resistance may arise when cefiderocol is employed in the treatment of CRE.…”

Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

“…Among the siderophore-β-lactam conjugates, the most promising is the catecholate siderophore–cephalosporin Cefiderocol ( Figure 9 A), which showed a significant antibacterial activity against different Gram-negative bacteria ( P. aeruginosa , Acinetobacter baumannii , Klebsiella pneumoniae , E. coli ) in vitro, [ 109 ] multi- and extensively drug-resistant E. coli strains [ 110 ], carbapenem-resistant Enterobacterales [ 111 ], and Burkholderia pseudomallei clinical isolates [ 112 ]. Most notably, Cefiderocol exhibited a significant in vivo efficacy against MDR P. aeruginosa in a mouse infection model [ 109 ], and displayed good safety and pharmacokinetic profiles [ 113 ].…”

Small-Molecule Antibiotic Drug Development: Need and Challenges

“…Finally, some are exploring “trojan horse” approaches, in which receptors and transporters for required nutrients, such as iron, are subverted to facilitate antibiotic entry . A recently approved example is cefiderocol, which combines siderophore activity with a cephalosporin antibiotic, thus subverting the iron transport machinery of Gram-negative bacteria to gain access across the outer membrane . Future efforts could combine these strategies, leveraging both computational approaches and ongoing characterization of bacterial receptors, transporters, and porins to overcome the formidable cell envelope barrier.…”