Antibiotic resistance has significantly impacted humankind, primarily due to the prolonged misuse of antibacterial drugs (Menz et al., 2021). Of particular concern is the global expansion of carbapenem-resistant gram-negative bacteria (CR-GNB), which poses a serious threat to public health. Despite the emergence of several new β-lactamase inhibitor combination products, such as ceftazidime/avibactam, meropenem/vabrobactam, and imipenem/relebactam, the clinical needs for antibacterial drugs are still in demand. The long-term use of multiple antibiotics increases the possibility of extensively drug-resistant (XDR) or even pan-drug resistant (PDR) bacteria. Therefore, it is crucial to explore new antimicrobial agents to combat the threat of CR-GNB (Pulingam et al., 2022).

Cefiderocol (S-649266), a new injectable iron carrier cephalosporin antibacterial drug (trade name: Fetcroja) developed by Shionogi, Japan, appears to address the current medical need. Cefiderocol has a broad antimicrobial activity and is highly stable against GNB due to its two main features: (1) the ability to be actively taken up by GNB (“Trojan horse” strategy); and (2) high stability against various types of β-lactamases (Poirel et al., 2018). In November 2019, cefiderocol was approved by the U.S. Food and Drug Administration (FDA) for adults aged 18 years and above with complicated urinary tract infections (cUTIs) and pyelonephritis (“FDA Briefing Document,” 2019). Subsequently, in April 2020, the European Medicines Agency approved its use for adults with infections caused by aerobic GNB, with limitations on the treatment scheme (EMA, 2020). In September 2020, the FDA further expanded its approval to include adults with cUTIs, hospital-acquired pneumonia, and ventilator associated bacterial pneumonia (VABP) (Matteo Bassetti et al., 2020). Nevertheless, the clinical application of cefiderocol is still limited, and the understanding of its clinical drug resistance mechanism is incomplete. In this review, we aim to provide a comprehensive summary of its chemical structure, mechanism of action, antimicrobial activity, clinical trials, clinical applications, drug resistance mechanisms, and combination therapy. In conducting this review, a comprehensive search strategy was employed to gather relevant literature from the databases of PubMed, Web of Science, and Ovid. The search, conducted without language restrictions, utilized the keywords 'cefiderocol' or 'S-649266' and included articles published before September 2023. Our goal is to offer insights for the clinical use of cefiderocol and strategies to reduce cefiderocol resistance.