Cefiderocol: a novel siderophore cephalosporin

ABSTRACT

Introduction: The emergence of multidrug-resistant bacterial pathogens has led to a global public health emergency and novel therapeutic options and drug-delivery systems are urgently needed. Cefiderocol is a siderophore cephalosporin antibiotic that has recently been developed to combat a variety of bacterial pathogens, including β-lactam- and carbapenem-resistant organisms.

Areas covered: This paper provides an overview of the mutational and plasmid-mediated mechanisms of β-lactam and carbapenem resistance, the biochemical pathways of siderophores in bacterial iron metabolism, and how cefiderocol may be able to provide better targeted antimicrobial therapy that escape these drug-resistant mechanisms. We also explore the pharmacokinetics of this new compound as well as results from preclinical and clinical studies.

Expert opinion: There is an urgent need for novel antimicrobial agents to address the emergence of multidrug-resistant pathogens, which are an increasing cause of morbidity and mortality worldwide. Our understanding of multidrug-resistance and bacterial biochemical pathways continues to expand, and the development of cefiderocol specifically targeting siderophore-mediated iron transport shows potential in escaping mechanisms of drug resistance. Cefiderocol, which demonstrates a favorable side effect profile, has the potential to become first-line therapy for our most aggressive and lethal multidrug-resistant Gram-negative pathogens.

KEYWORDS:

• Siderophore
• carbapenemase
• resistance
• Gram negative
• urinary tract infection

Article highlights

• The rapid spread of community-acquired bacterial isolates that produce extended-spectrum β-lactamase (ESBL) enzymes capable of hydrolyzing almost all cephalosporin and carbapenem antibiotics has recently emerged as a global public health emergency

• Cefiderocol (formerly known as S-649266) is a novel siderophore cephalosporin that has significant antimicrobial activity against a variety of MDR-bacteria, including strains that produce carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM)-1.

• Rigorous in vitro work, includingthe first global surveillance study for cefiderocol, demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa, and S. maltophilia.

• In the coming years, cefiderocol may emerge as a powerful new option for the treatment of MDR-pathogents and it may spawn a host of other “Trojan Horse” antimicrobial agents designed to evade the hydrolytic properties of β-lactamases and carbapenemases.

This box summarizes key points contained in the article.

Declaration of Interest

M. McCarthy has served as a paid consultant to Allergan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. A reviewer on this manuscript has disclosed that their laboratory is conducting in vitro testing of this compound at present in a grant sponsored by Shionogi.

Additional information

Funding

This paper was not funded.