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.