探讨抗生素与免疫反应在治疗急性自限性感染中的协同作用。

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections.

机构信息

Department of Biology, Emory University, Atlanta, GA 30322.

Department of Biology, Emory University, Atlanta, GA 30322

出版信息

Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8331-8. doi: 10.1073/pnas.1400352111. Epub 2014 May 19.

Abstract

The successful treatment of bacterial infections is the product of a collaboration between antibiotics and the host's immune defenses. Nevertheless, in the design of antibiotic treatment regimens, few studies have explored the combined action of antibiotics and the immune response to clearing infections. Here, we use mathematical models to examine the collective contribution of antibiotics and the immune response to the treatment of acute, self-limiting bacterial infections. Our models incorporate the pharmacokinetics and pharmacodynamics of the antibiotics, the innate and adaptive immune responses, and the population and evolutionary dynamics of the target bacteria. We consider two extremes for the antibiotic-immune relationship: one in which the efficacy of the immune response in clearing infections is directly proportional to the density of the pathogen; the other in which its action is largely independent of this density. We explore the effect of antibiotic dose, dosing frequency, and term of treatment on the time before clearance of the infection and the likelihood of antibiotic-resistant bacteria emerging and ascending. Our results suggest that, under most conditions, high dose, full-term therapy is more effective than more moderate dosing in promoting the clearance of the infection and decreasing the likelihood of emergence of antibiotic resistance. Our results also indicate that the clinical and evolutionary benefits of increasing antibiotic dose are not indefinite. We discuss the current status of data in support of and in opposition to the predictions of this study, consider those elements that require additional testing, and suggest how they can be tested.

摘要

抗生素与宿主的免疫防御协同作用是成功治疗细菌感染的产物。然而,在抗生素治疗方案的设计中,很少有研究探索抗生素与清除感染的免疫反应的联合作用。在这里,我们使用数学模型来研究抗生素和免疫反应对急性、自限性细菌感染的治疗的综合作用。我们的模型结合了抗生素的药代动力学和药效动力学、先天和适应性免疫反应以及目标细菌的种群和进化动态。我们考虑了抗生素-免疫关系的两个极端:一种是免疫反应清除感染的功效与病原体的密度成正比;另一种是其作用在很大程度上与密度无关。我们探讨了抗生素剂量、给药频率和治疗时间对清除感染所需时间以及抗生素耐药菌出现和上升的可能性的影响。我们的研究结果表明,在大多数情况下,高剂量、全疗程治疗比中等剂量治疗更能有效地促进感染的清除,并降低抗生素耐药性出现的可能性。我们的研究结果还表明,增加抗生素剂量的临床和进化效益并非无限的。我们讨论了支持和反对本研究预测的数据的现状,考虑了需要进一步测试的那些因素,并提出了如何对它们进行测试的建议。

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