Optimizing the Timing and Composition of Therapeutic Phage Cocktails: A Control-Theoretic Approach.
Optimizing the Timing and Composition of Therapeutic Phage Cocktails: A Control-Theoretic Approach.
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DOI：
10.1007/s11538-020-00751-w
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发表时间：
2020-06-12
影响因子：
3.5
通讯作者：
Weitz JS
中科院分区：
文献类型：
--
作者：
Li G;Leung CY;Wardi Y;Debarbieux L;Weitz JS
感染细菌的病毒，噬菌体或“噬菌体”越来越多地被认为是控制和清除细菌感染的治疗选择，特别是作为多药耐药感染的同情使用疗法。在实践中，噬菌体的临床使用通常涉及同时或顺序地应用多种治疗性噬菌体。然而，治疗性噬菌体递送的选择和时机在很大程度上仍然是特设的。在这项研究中，我们评估了为什么谨慎应用多噬菌体（即，"鸡尾酒“）可能导致治疗成功，这与单菌株噬菌体治疗控制感染的失败形成对比。首先，我们使用一个非线性动力学模型内的主机相互作用，以显示快速的主机内噬菌体衰变，细菌之间的噬菌体抗性的演变，和/或妥协的免疫反应的组合可能会限制单菌株噬菌体治疗的有效性。为了解决这些问题，我们结合联合收割机的噬菌体，细菌和宿主免疫细胞群体的动态建模与控制理论的原则（通过最优控制理论），设计进化稳健的噬菌体鸡尾酒和交付时间表，以控制细菌种群。我们的数值结果表明，单菌株噬菌体治疗的最佳管理可能是足够的免疫功能正常的患者的治疗结果，但可能会失败，由于噬菌体耐药性的免疫缺陷的主机。我们表明，优化的治疗与两个噬菌体鸡尾酒，其中包括一个反抗性噬菌体可以恢复在免疫缺陷宿主的治疗效果。
Viruses that infect bacteria, i.e., bacteriophage or ‘phage,’ are increasingly considered as treatment options for the control and clearance of bacterial infections, particularly as compassionate use therapy for multi-drug-resistant infections. In practice, clinical use of phage often involves the application of multiple therapeutic phage, either together or sequentially. However, the selection and timing of therapeutic phage delivery remains largely ad hoc. In this study, we evaluate principles underlying why careful application of multiple phage (i.e., a ‘cocktail’) might lead to therapeutic success in contrast to the failure of single-strain phage therapy to control an infection. First, we use a nonlinear dynamics model of within-host interactions to show that a combination of fast intra-host phage decay, evolution of phage resistance amongst bacteria, and/or compromised immune response might limit the effectiveness of single-strain phage therapy. To resolve these problems, we combine dynamical modeling of phage, bacteria, and host immune cell populations with control-theoretic principles (via optimal control theory) to devise evolutionarily robust phage cocktails and delivery schedules to control the bacterial populations. Our numerical results suggest that optimal administration of single-strain phage therapy may be sufficient for curative outcomes in immunocompetent patients, but may fail in immunodeficient hosts due to phage resistance. We show that optimized treatment with a two-phage cocktail that includes a counter-resistant phage can restore therapeutic efficacy in immunodeficient hosts.
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