Cefiderocol: An Overview of Its in-vitro and in-vivo Activity and Underlying Resistant Mechanisms

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Multidrug-resistant Gram-negative bacteria (GNB) pose a significant global health threat due to limited antibiotic options.
• Cefiderocol (CFDC), a novel siderophore cephalosporin, offers a potential therapeutic strategy against aggressive GNB infections.
• Emerging resistance to CFDC necessitates a comprehensive understanding of its activity and resistance mechanisms.

Purpose of the Study:

• To review the in vitro and in vivo activity of cefiderocol against multidrug-resistant Gram-negative bacteria.
• To summarize the known and potential mechanisms of cefiderocol resistance.
• To highlight the importance of judicious clinical application of cefiderocol.

Main Methods:

• Literature review of in vitro and in vivo studies on cefiderocol activity.
• Analysis of reported cefiderocol resistance mechanisms in Gram-negative pathogens.
• Summary of clinical implications regarding cefiderocol use.

Main Results:

• Cefiderocol demonstrates broad-spectrum activity against key MDR GNB, including Enterobacteriaceae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia.
• Resistance to CFDC is associated with the expression of metallo-β-lactamases (e.g., IMP, VIM, NDM) and mutations in β-lactamases and TonB-dependent receptors.
• Carbapenem resistance generally has minimal impact on CFDC susceptibility, though specific carbapenemases may confer resistance.

Conclusions:

• Cefiderocol is a valuable agent for treating infections caused by challenging multidrug-resistant Gram-negative bacteria.
• Understanding resistance mechanisms, particularly those affecting drug entry and target stability, is crucial for preserving CFDC efficacy.
• Prudent clinical use of cefiderocol is essential to mitigate the development of resistance and ensure its long-term therapeutic value.