Differential risk signals of cutaneous adverse drug reactions among β-lactam antibiotics: ceftriaxone shows increased signals for SJS/TEN in clinical and real-world cohorts.

Background: Cutaneous adverse drug reactions (CADRs) are triggered by numerous antibiotic drugs. Most drug reactions are in the spectrum of a maculopapular eruption (MPE) with a self-limiting disease course. In contrast, severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), are rare but may follow a life-threatening course. In this study, we investigated the key drug-related triggers of CADRs in a retrospective single-center cohort and, based on these findings, evaluated the differential risk of the implicated agents using large-scale real-world data. Methods: Data from 122 patients diagnosed with CADRs, including 5 with confirmed SJS/TEN treated at a tertiary-referral hospital were retrospectively analyzed in a descriptivesingle-center cohort study. To further explore our findings, we performed a large-scale real-world cohort study using TriNetX to assess the occurrence of SJS/TEN following exposure to selected drugs. Separate analyses were conducted comparing ceftriaxone with aminopenicillins, cefazolin, cefuroxime, and allopurinol, which was included as a positive control. Odds ratios were calculated after running propensity-score-matching for demographic characteristics and SJS/TEN-risk factors. Results: In the single-center cohort, MPE was the predominant phenotype among CADRs attributed to aminopenicillins and first- and second-generation cephalosporins. In contrast, among CADRs attributed to third-generation cephalosporins, represented by ceftriaxone in this single-center cohort, SCARs were the predominant reaction type, with ceftriaxone accounting for 40% of SJS/TEN cases. These findings were underlined by the real-world cohort analysis, in which aminopenicillins and early-generation cephalosporins showed significantly lower odds of SJS/TEN than ceftriaxone (0.389 (95% CI 0.291-0.520) for aminopenicillins; 0.392 (0.290-0.529) for cefazolin; 0.300 (0.157-0.572) for cefuroxime). Conclusions: While both datasets need to be interpreted within the context of their respective limitations, our analysis, are in line with previous studies, suggesting that ceftriaxone may have an SJS/TEN risk profile that exceeds the class-wide risk observed among cephalosporins. This underscores the importance of substance-specific, rather than purely class-based approaches in both clinical research and pharmacovigilance.