Incidence and Clinical Significance of Drug‐Induced Antibodies and Hemolytic Anemia Associated With Beta‐Lactam Antibiotics: A Prospective Cohort Study

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA), a rare complication of beta-lactams, lacks population-level data on subclinical antibody prevalence. OBJECTIVE: To quantify drug-induced antibody incidence and hematologic impact in beta-lactam-treated patients. METHODS: Prospective cohort of 4040 patients receiving ceftriaxone, piperacillin/trizobactam, piperacillin/sulbactam 2:1 and piperacillin/tazobactam at a Chinese tertiary hospital (2020.1-2020.9). Antibodies were detected via immunoadsorption assays. The primary outcomes were changes in hemoglobin, bilirubin, and lactate dehydrogenase (LDH) levels. RESULTS: Antibody positivity occurred in 18.07% (730/4040), highest with piperacillin/sulbactam 2:1 (24.02% vs. 0.43% Ceftriaxone, p < 0.001). Seropositive patients had a significant hemoglobin decline (Δ = -5.00 g/L, 95% CI -6.2 to -3.8) and bilirubin elevation (Δ = +0.95 μmol/L, 95% CI +0.4 to +1.5), but only 0.2% (2/730) progressed to severe anemia. Subclinical hemolysis (LDH > 250 U/L) was prevalent (89.3%). CONCLUSION: Beta-lactams exhibit high asymptomatic antibody rates (18.07%) with minimal severe hemolysis risk (0.2%). Protocolized monitoring and HLA screening may optimize safety. This first large-scale prospective cohort quantifies the underrecognized epidemic of subclinical antibody formation, challenging traditional pharmacovigilance frameworks that focus solely on overt hemolysis.