Ceftriaxone and cefotaxime are widely used third-generation cephalosporins with comparable antibacterial spectra. Owing to its higher biliary excretion, ceftriaxone has been suspected of increasing the selection of resistant Enterobacterales and the risk of Clostridioides difficile Infection (CDI). In accordance with PRISMA-ScR guidelines, the present study is a scoping review of research comparing the two antibiotics and, importantly, trying to determine whether there is sufficient evidence to support restrictive policies.

With this in mind, PubMed® and Embase® were searched from 1976 to 2024 for clinical studies comparing ceftriaxone and cefotaxime with respect to gut microbiota alterations, antimicrobial resistance, CDI, cost, and carbon footprint. Two reviewers first screened abstracts and then proceeded to full-text assessment based on predefined criteria. Included studies were categorized by outcome before being synthesized.

Among 2,634 articles identified, 41 met the inclusion criteria: 11 addressed resistance or microbiota, 9 focused on CDI and 23 evaluated economic outcomes; none, however, assessed carbon footprint. The methodologies applied were diverse and the results somewhat discordant; three interventional and six observational studies reported greater resistance selection or higher CDI rates with ceftriaxone, whereas six interventional and three observational studies found no significant difference. The cost-related studies were outdated and inconsistent due to major variations in drug pricing and approaches.

In conclusion, current evidence does not demonstrate a higher individual-level risk of resistance selection or CDI with ceftriaxone than with cefotaxime. However, ecological studies have suggested that ceftriaxone use may be associated with adverse resistance at the population level. Well-designed clinical and stewardship studies integrating microbiological, economic, and environmental outcomes are needed to guide rational antibiotic selection.