Cefiderocol: A Comprehensive Review of Chemistry, Mechanisms of Resistance, and Clinical Applications in the Era of Multidrug Resistance.

The global spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly carbapenem- and colistin-resistant strains, represents a critical public health crisis with limited therapeutic options. Cefiderocol, a first-in-class siderophore cephalosporin, addresses this challenge through an innovative Trojan horse mechanism. Its unique catechol-containing C-3 side chain enables iron chelation and active transport into bacterial periplasmic space, bypassing traditional resistance pathways. This design confers stability against all Ambler class β-lactamases (A-D), including carbapenemases (blaKPC, blaOXA-48, blaNDM, blaVIM, and blaIMP), and maintains potent activity against MDR Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. While clinical trials demonstrate efficacy in complicated urinary tract infections, hospital-acquired pneumonia, and bloodstream infections, emerging resistance and mortality signals in specific populations warrant careful consideration. This comprehensive review examines cefiderocol's molecular structure, mechanisms of action and resistance, pharmacokinetic profile, and clinical applications. We evaluate its position relative to newer β-lactam/β-lactamase inhibitors and explore evidence for combination therapies, ultimately highlighting its crucial role in the antimicrobial arsenal against MDR Gram-negative infections.