The evolutionary biology of chemotherapy against infectious agents: towards rati

描述（由申请人提供）：决定抗菌药物因病原体进化而变得无用的时间的一个非常重要的决定因素-药物的治疗有用寿命-是耐药性选择的强度。这是两件事的结果：有多少感染者（病人）正在接受治疗，以及他们是如何接受治疗的。目前大多数患者治疗方案背后的耐药性管理理念是，首先通过尽可能快地消除可变病原体，使耐药性难以产生。但是，如果耐药性已经出现，迅速消灭易感寄生虫是在种群中推动耐药性的最有效方法。如何通过选择患者治疗方案来最好地控制这些突变和选择压力尚不清楚：很可能最佳的耐药性管理策略因感染因子和流行病学情况而异。当易感和耐药寄生虫在同一宿主内竞争时，从耐药性管理的角度来看，旨在彻底清除病原体的制度尤其成问题。在那里，药物治疗最大限度地增加了耐药性的选择优势：不仅易感寄生虫的适合度降低到零，而且耐药寄生虫的适合度也增加了，因为它们的竞争对手已经被移除。我们在动物模型中对疟疾寄生虫进行的实验研究表明，寄生虫根治非常有效地增加了耐药性的传播，因此将大大加快耐药性的进化。由于目前的药物治疗方案经常持续超过恢复患者健康所需的时间（因此患者的依从性问题），我们假设存在其他治疗方案，这些方案在临床上同样有效，但可以更好地延缓耐药性的演变。我们建议通过实验测试这些想法，并使用流行病学进化模型，在人口水平上评估这些方案的后果。我们认为，对于许多传染病，围绕患者治疗的进化后果存在重要的知识差距。最大化现有药物和新药的有效寿命——药物管理——需要一个经验基础来评估对比药物治疗方案的进化后果。

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.