The evolutionary biology of chemotherapy against infectious agents: towards rati

描述(由申请人提供)：在抗菌药因病原体进化而变得无用之前，一个非常重要的决定因素--药物在治疗上的有用寿命--是选择耐药性的强度。这是两件事的结果：有多少感染(患者)正在接受治疗，以及他们正在如何接受治疗。目前大多数患者治疗方案背后的耐药性管理理念是，通过尽快消除可变病原体，使耐药性从一开始就很难出现。但是，如果已经出现了耐药性，迅速消除易感寄生虫是在人群中传播耐药性的最有效方式。如何通过选择患者治疗方案来最好地处理这些突变和选择压力并不明显：最好的耐药性管理策略很可能因感染源和流行病学情况而异。当敏感和耐药寄生虫在同一宿主内竞争时，从抗性管理的角度来看，旨在彻底清除病原体的制度尤其有问题。在那里，药物治疗最大限度地增加了耐药性的选择性优势：不仅敏感寄生虫的适应度降至零，而且由于它们的竞争对手被清除，耐药寄生虫的适应度提高了。我们在动物模型中对疟疾寄生虫进行的实验研究表明，根治寄生虫非常有效地增加了耐药性的传播，因此将非常显著地加速耐药性的演变。由于目前的药物方案经常持续超过恢复患者健康所需的时间(因此患者依从性问题)，我们假设还有其他方案在临床上同样有效，但更好地延缓耐药性的演变。我们建议对这些想法进行实验测试，并利用流行病学进化模型，在人群水平上评估这种疗法的后果。我们认为，对于许多传染病来说，围绕患者治疗的进化后果存在着一个重要的知识鸿沟。要最大限度地延长现有药物和新药的有效寿命--药物管理--需要有一个经验基础，以评估对比药物治疗方案的进化后果。 公共卫生相关性：抗药性病原体的演变对人类福祉和卫生预算产生重大影响。进化论假说表明，药物治疗机制与传统智慧相矛盾，但在某些情况下可以更好地阻止耐药病原体的传播。我们想测试这些疗法的耐药性管理潜力：它们可以延长我们已经拥有的药物和那些目前正在研发中的药物的有效治疗寿命。

DESCRIPTION (provided by applicant): A very major determinant of the time until an antimicrobial drug is rendered useless by pathogen evolution - the therapeutically useful lifespan of a drug - is the strength of selection for resistance. This is a consequence of two things: how many infections (patients) are being treated, and how they are being treated. The resistance management philosophy behind most current patient treatment regimes is to make it hard for resistance to arise in the first place by eliminating mutable pathogens as fast as possible. But if resistance has already arisen, rapidly eliminating susceptible parasites is the most efficient way of driving resistance through a population. How these mutational and selection pressures should be best manipulated by choice of patient treatment regimen is not obvious: quite possibly the best resistance management strategy varies among infectious agents and epidemiological circumstances. Regimes aimed at radical pathogen clearance are particularly problematic from a resistance management point of view when susceptible and resistant parasites compete within the same host. There, drug treatment maximally increases the selective advantage of resistance: not only is the fitness of susceptible parasites reduced to zero, the fitness of resistant parasites is increased because their competitors have been removed. We have shown in experimental studies with malaria parasites in an animal model that radical parasite cure very effectively increases the transmission of resistance, and so will very significantly speed the evolution of resistance. Since current drug regimens often continue beyond that required to restore patient health (hence issues of patient compliance), we hypothesize that there are other regimens which are equally effective clinically but which better retard resistance evolution. We propose to test these ideas experimentally and, using epidemiological evolutionary models, to evaluate the consequences of such regimens at a population level. We contend that, for many infectious diseases, there is an important knowledge gap surrounding the evolutionary consequences of patient treatment. Maximizing the useful lifespan of existing and new drugs - drug stewardship - requires an empirical base for evaluating the evolutionary consequences of contrasting drug treatment regimens. PUBLIC HEALTH RELEVANCE: The evolution of drug resistant pathogens significantly impacts on human wellbeing and health budgets. Evolutionary hypotheses suggest drug treatment regimes that contradict conventional wisdom but which could in some cases better retard the spread of drug resistant pathogens. We want to test the resistance management potential of these regimes: they could prolong the useful therapeutic lifespan of drugs we already have, and those currently in the discovery pipeline.