Cephalosporins: from cefazolin to cefiderocol

Objective. This study aimed to systematize and analyze contemporary data on the evolution of cephalosporin antibiotics from the first to the fifth generation, with a focus on changes in their antimicrobial spectrum, pharmacokinetic properties, and safety profile in the context of rising antibiotic resistance.
Materials and methods. A review of the scientific literature was conducted, sourcing data from PubMed, Google Scholar, CyberLeninka, elibrary.ru, and library resources using keywords such as "cephalosporins", "antibiotic resistance", "MRSA", "Gram-negative bacteria", and "cefiderocol". The analysis included systematic reviews, randomized clinical trials, cohort studies, and meta-analyses published over the last two decades, as well as foundational historical works.
Results. The review demonstrates a clear evolutionary trajectory in the development of cephalosporin. First- and second- generation agents remain relevant for treating infections caused by Gram-positive cocci and some communities of Gram-negative microorganisms. Third- and fourth-generation cephalosporins have become the cornerstone of empirical therapy for nosocomial infections because of their expanded spectrum of activity against Gram-negative flora, including Pseudomonas aeruginosa. Fifth-generation drugs (ceftobiprole and ceftaroline) were developed to overcome MRSA resistance. A separate analysis was dedicated to the innovative agent, cefiderocol — the first siderophore cephalosporin, which possesses a unique transport mechanism into the bacterial cell and demonstrates activity against carbapenem-resistant strains of Enterobacterales, P. aeruginosa, and A. baumannii. Despite its unique properties, cefiderocol resistance is already emerging. The specific pharmacokinetic profiles (administration routes, half-life, and blood-brain barrier penetration) and spectrum of adverse reactions (allergic, hematological, and neurological) of different generations were analyzed.
Conclusion. Cephalosporins remain a cornerstone of modern antimicrobial therapy because of their favorable efficacy and safety profile. The introduction of new generations, particularly cefiderocol, represents a direct response to the global challenge of antibiotic resistance. However, the rapid emergence of resistance mechanisms even to the most advanced agents underscores the critical importance of antimicrobial stewardship programs and strict adherence to the principles of rational antibiotic therapy to preserve the future clinical value of this drug class.

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