Association of Early Antibiotic Exposure with Kawasaki Disease

Background Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that primarily affects children under five years old. Emerging evidence suggests that gut microbiota alterations may contribute to KD pathogenesis. Because antibiotics modify intestinal microbial composition, their inappropriate or repeated use in early childhood may increase KD susceptibility. However, population-based evidence linking antibiotic exposure with KD onset remains limited, and the influence of antibiotic class, number of classes, and administration route has not been systematically evaluated. Objectives To examine the association between antibiotic type, number of antibiotic classes, route of administration, and KD onset in a nationwide dataset. Methods We conducted a matched case–control study using the JMDC database (2005–2024). Children aged 0–18 years were eligible. Newly diagnosed KD cases (n = 17,410) and controls (n = 68,621) were matched 1:4 by age, sex, and birth year. Antibiotic exposure within 12 months before the KD index date was assessed by class (penicillins, cephalosporins, macrolides, quinolones, others), number of distinct classes, and administration route (oral vs. intravenous). Multivariable conditional logistic regression estimated odds of KD onset adjusted for low birth weight, pneumonia, otitis media, allergic rhinitis, and asthma. Results Among 86,031 children, exposure to penicillins (OR, 1.18; 95% CI, 1.11–1.24), cephalosporins (OR, 1.11; 95% CI, 1.05–1.18), quinolones (OR, 1.32; 95% CI, 1.13–1.55), and macrolides (OR, 1.16; 95% CI, 1.05–1.27) was associated with increased KD risk. Risk rose with more antibiotic classes (≥3 classes: OR, 1.20; 95% CI, 1.15–1.26). Oral antibiotic use showed a significant association (OR, 1.22; 95% CI, 1.16–1.27), while intravenous use did not. Conclusions Exposure to multiple antibiotic classes, especially via oral administration, was significantly associated with KD development. These findings support a possible link between antibiotic-related microbiome disruption and KD susceptibility and highlight the need for cautious pediatric antibiotic stewardship.