Model-Based Meta-Analysis to Optimize Staphylococcus aureus‒Targeted Therapies for Atopic Dermatitis

Several clinical trials of Staphylococcus aureus (S. aureus)‒targeted therapies for atopic dermatitis (AD) have shown conflicting results about whether they improve AD severity scores. This study performs a model-based meta-analysis to investigate the possible causes of these conflicting results and suggests how to improve the efficacies of S. aureus‒targeted therapies. We developed a mathematical model that describes systems-level AD pathogenesis involving dynamic interactions between S. aureus and coagulase-negative Staphylococcus (CoNS). Our model simulation reproduced the clinically observed detrimental effects of the application of S. hominis A9 and flucloxacillin on AD severity and showed that these effects disappeared if the bactericidal activity against CoNS was removed. A hypothetical (modeled) eradication of S. aureus by 3.0 log(10) colony-forming unit per cm(2) without killing CoNS achieved Eczema Area and Severity Index 75 comparable with that of dupilumab. This efficacy was potentiated if dupilumab was administered in conjunction with S. aureus eradication (Eczema Area and Severity Index 75 at week 16) (S. aureus eradication: 66.7%, dupilumab 61.6% and combination 87.8%). The improved efficacy was also seen for virtual dupilumab poor responders. Our model simulation suggests that killing CoNS worsens AD severity and that S. aureus‒specific eradication without killing CoNS could be effective for patients with AD, including dupilumab poor responders. This study will contribute to designing promising S. aureus‒targeted therapy.