Antibiotic use and immune-related adverse events in patients treated with immune checkpoint inhibitors: analysis of the FAERS database

Background: The use of antibiotics may influence the efficacy and toxicity of immune checkpoint inhibitors (ICIs) by altering the gut microbiota. However, current evidence on the link between antibiotic use and immune-related adverse events (irAEs) is limited. This study aims to evaluate whether antibiotics increase the risk of irAEs in ICI-treated patients and to examine their relationship to the timing of irAEs onset. Methods: We analyzed data from the FAERS database from 2014 to the fourth quarter of 2024. Using multivariable logistic regression and descriptive statistical analyses, we evaluated the association between antibiotic co-reporting and irAE reporting frequency and the timing across different antibiotic categories and ICIs regimens. Results: Our study included 155,157 patients treated with ICIs, of whom 9,518 (6.1%) received antibiotic therapy. Patients who used antibiotics had a significantly higher reported frequency risk of irAEs (OR = 1.17; 95%CI: 1.12-1.23; FDR<0.001) compared to those who did not. The strongest associations were observed in patients receiving fluoroquinolones, sulfonamides, penicillin, macrolides, cephalosporins, and monobactams. Co-reporting was associated with a higher reported frequency of irAEs in patients receiving PD-L1 inhibitors (OR = 1.51; 95% CI: 1.39-1.65; FDR<0.001). In exploratory descriptive analysis restricted to patients who reported irAEs, the median time to first reported irAE was shorter in the antibiotic co-reporting group than in the non-co-reporting group (31 days (IQR: 9-105) vs. 42 days (IQR: 14-122), Wilcoxon rank-sum test P < 0.001). Stratified analysis by ICI type showed that this pattern was most evident in patients receiving PD-1 inhibitors. Conclusions: Analysis of the FAERS database suggests that antibiotic co-reporting during ICIs therapy is associated with a higher reported frequency of irAEs and a shorter median time to first reported irAE among patients who experienced irAEs. These findings are subject to the inherent limitations of the FAERS database, including the inability to determine the temporal sequence of antibiotic and ICI exposure, unmeasured confounding, reporting artifacts, and the unsuitability of spontaneous reporting data for formal time-to-event analysis. Prospective cohort studies with detailed medication timing, clinical phenotyping, and microbiome profiling are needed to validate these signals.