Pharmacokinetic evaluation of cefiderocol for the treatment of multidrug resistant Gram-negative infections

ABSTRACT

Introduction

Cefiderocol is a siderophore cephalosporin antibiotic and first of its kind approved by the Food and Drug Administration for the treatment of complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years or older caused by susceptible organisms. Cefiderocol’s unique mechanism of iron chelation improves Gram-negative membrane penetration as the bacteria’s iron uptake mechanism recognizes the chelated iron antibiotic and iron for entry. This also allows for the evasion of cefiderocol from cell entry-related resistance mechanisms.

Areas covered

This review covers the mechanism of action, resistance mechanisms, pharmacokinetics in various patient populations, and pharmacodynamics. Relevant literature evaluating efficacy and safety are discussed.

Expert opinion

Limited treatment options are available for the treatment of carbapenem-resistantorganisms. Clinical trials have demonstrated that cefiderocol is no worse than alternative treatment options for cUTIs and HABP/VABP, but more data are currently available to support the use of beta-lactam beta-lactamase inhibitor agents, where susceptible. Mortality differences demonstrated in patients with pneumonia and bloodstream infections must further be explored and logistical and practical considerations regarding susceptibility testing and use as monotherapy vs. combination therapy must be considered prior to confidently recommending cefiderocol for regular use in systemic infections.

KEYWORDS:

• Carbapenem-resistantAcinetobacter baumannii
• carbapenem-resistant Enterobacteriaceae
• carbapenem-resistantPseudomonas aeruginosa
• cefiderocol
• complicated urinary tract infection
• hospital-acquired bacterial pneumonia
• ventilator-associated bacterial pneumonia

Article highlights

• Cefiderocol is a new siderophore cephalosporin antibiotic with a novel mechanism of action that is approved by the Food and Drug Administration for complicated urinary tract infections and hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible organisms.

• Phase III clinical trials have demonstrated that cefiderocol is no worse than best available therapy for the treatment of complicated urinary tract infections, but an increase in mortality was identified in patients with pneumonia or bacteremia as compared to best available therapy.

• The need for iron-depleted cation-adjusted Mueller–Hinton media for reliable susceptibility testing may be an additional limitation to widespread cefiderocol use.

• Cefiderocol should generally be avoided against Acinetobacter baumannii, and further studies are necessary to further explore the potential benefits of cefiderocol against metallo-beta-lactamase producing Enterobacteriaceae demonstrated in CREDIBLE-CR.

Funding

This paper was not funded.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed speaker’s bureau (Shionogi). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose. Shionogi & Co., Ltd. provided a scientific accuracy review at the request of the journal editor.