Resistance, Ineffectiveness, and Off-Label Use Related to Cephalosporins from the Reserve Group—A Pharmacovigilance Signal Detection Study on EudraVigilance Database

<b>Background/Objectives</b>: Antimicrobial resistance (AMR) is considered a major threat by the healthcare community. In this context, the AWaRe (Access, Watch, Reserve) classification of antibiotics is a valuable tool that can assist physicians during the clinical decision process and pharmacists in promoting the rational use of antibiotics. Pharmacovigilance studies based on real-world evidence offer valuable insight into the AMR phenomenon. The aim of this study was the assessment of the resistance, ineffectiveness, and off-label use signals of all five cephalosporins belonging to the Reserve group (ceftazidime/avibactam, ceftaroline, cetolozane/tazobactam, ceftobiprole, and cefiderocol). <b>Methods</b>: The study was conducted using descriptive approaches on EudraVigilance data and disproportionality analyses comparing each of the fourteen cephalosporins in the Watch group. <b>Results</b>: Ceftazidime/avibactam (<i>n</i> = 904, 38.6%) topped the reports, followed by ceftaroline (<i>n</i> = 559, 23.9%) and ceftolazane/tazobactam (<i>n</i> = 560, 23.9%). The lowest number of reports was submitted for cefiderocol (<i>n</i> = 176, 7.5%) and ceftobiprole (<i>n</i> = 146, 6.2%). The resistance to ceftazidime/avibactam, cefiderocol, and ceftolozane/tazobactam was reported with a higher probability than all others, the strongest signal being observed for cefiderocol against cefixime (ROR: 171.25, 95% CI 79.64-368.27). All cephalosporins from the Reserve group (except ceftobiprole) have higher probability for reporting ineffectiveness than cephalosporins from the Watch group; the strongest signal was observed for cefiderocol-cefditoren (ROR: 14.70, 95% CI 6.73-32.11). All cephalosporines from the Reserve group had a higher probability of reporting off-label use by comparison with the ones from the Watch group, except for two cases of no disproportionate signal between cefiderocol-cefoperazone and cefiderocol-ceftizoxime; the strongest signal was observed for ceftolozane/tazobactam-cefotaxim (ROR: 43.61, 95% CI 30.14-63.09). <b>Conclusions</b>: This analysis supplements information from clinical trials and current clinical practice, underscoring the critical need for rigorous antibiotic stewardship programs. Notably, even restricted use of cephalosporins demonstrated therapeutic failure and inappropriate utilization.