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Abstract：
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 log10 colony-forming unit per cm2 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.
摘要：
金黄色葡萄球菌的几项临床试验(S.金黄色葡萄球菌）-特应性皮炎（AD）的靶向治疗在是否改善AD严重程度评分方面显示出相互矛盾的结果。这项研究进行了基于模型的荟萃分析，以调查这些相互矛盾的结果的可能原因，并提出如何提高金黄色葡萄球菌靶向疗法的疗效。我们开发了一个数学模型，描述了系统水平的AD发病机理，涉及金黄色葡萄球菌和凝固酶阴性葡萄球菌（CoNS）之间的动态相互作用。我们的模型模拟再现了在临床上观察到的应用人源A9和氟氯西林对AD严重程度的有害影响，并表明如果消除了对CoNS的杀菌活性，这些影响就消失了。假设的(模拟的)根除金黄色葡萄球菌3.0log10集落形成单位/cm2而不杀死CoNS实现了与dupilumab相当的湿疹面积和严重程度指数75。如果将dupilumab与金黄色葡萄球菌根除联合使用，则会增强这种疗效（16周时湿疹面积和严重程度指数75）（S.金黄色葡萄球菌根除率：66.7%，dupilumab61.6%和联合87.8%)。对于虚拟dupilumab不良反应者也观察到了改善的功效。我们的模型模拟表明，杀死CoNS会使AD严重程度恶化，而不杀死CoNS的金黄色葡萄球菌特异性根除可能对AD患者有效，包括dupilumab不良反应者。这项研究将有助于设计有前途的金黄色葡萄球菌靶向治疗。
