Aggressive chemotherapy and the selection of drug resistant pathogens.
Aggressive chemotherapy and the selection of drug resistant pathogens.
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DOI：
10.1371/journal.ppat.1003578
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发表时间：
2013-09
期刊：
影响因子：
6.7
通讯作者：
Read AF
中科院分区：
文献类型：
--
作者：
Huijben S;Bell AS;Sim DG;Tomasello D;Mideo N;Day T;Read AF
耐药病原体是21世纪世纪的主要公共卫生挑战之一。人们普遍认为，耐药性的最佳管理方法是使用药物迅速消除患者体内的目标病原体，以尽量减少病原体重新获得耐药性的可能性。然而，强大的药物压力迫使通过减轻与野生型种群的竞争来进行有利于耐药性的激烈选择。因此，积极的化疗产生了相反的进化力量，共同决定了耐药性出现的速度。确定治疗方案，最好地延缓耐药性演变，同时最大限度地提高健康收益和减少疾病传播，需要结合临床结果和传染性的措施，在体内的耐药性演变的经验分析。在实验室小鼠中使用啮齿类疟疾，我们发现，侵略性较低的化疗方案大大降低了耐药性向前传播的可能性（>150倍），而不会影响健康结果。我们的实验表明，在某些情况下，除了尽可能快地减少病原体负担的治疗方案外，还可以更有效地管理耐药性演变。抗药性是一个主要的公共卫生问题。耐药管理的传统观点是使用积极的化疗来尽快杀死病原体，以防止它们获得耐药性。这就是为什么医生经常要求病人完成药物疗程，即使他们不再感到恶心。然而，这种方法是基于这样的概念，即我们只需要防止新的抗性突变体的出现。我们假设，在治疗时这些突变体已经存在的情况下，更积极的化疗将通过快速杀死所有敏感的竞争对手来最快地选择这些突变体。在这里，我们证明了在啮齿动物疟疾模型，这种选择确实发生更强烈的侵略性治疗后比侵略性较低的治疗，没有任何好处，主机的健康或传染性。这表明，在某些情况下（也许是许多情况下），积极的化疗并不是延缓耐药性演变的最佳方法。我们认为，需要在广泛的传染病中采用循证方法来管理耐药性演变。
Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible. Drug-resistance is a major public health problem. Conventional wisdom on resistance management is to use aggressive chemotherapy to kill pathogens as rapidly as possible so as to prevent them from acquiring resistance. This is the reason why physicians frequently exhort patients to finish drug courses even after they no longer feel sick. However, this approach is based on the notion that we need only prevent new resistant mutants from arising. We hypothesize that in the situation where such mutants are already present at the time of treatment, more aggressive chemotherapy will select for these the fastest by rapidly killing all sensitive competitors. Here we demonstrate in a rodent malaria model that such selection indeed occurs more intensely following aggressive treatment than following less aggressive treatment, without any benefit to host health or infectivity. This suggests that aggressive chemotherapy will not be the best way to retard resistance evolution in some - perhaps many - circumstances. We suggest that an evidence-based approach across a wide range of infectious diseases is needed to manage resistance evolution.
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