Challenges of drug combinations Combinations of antibiotics are used to treat intractable infections such as methicillin-resistant Staphylococcus aureus. Clinically, however, drugs tend to be used empirically, and results can be contradictory. Liu et al. translated observations made in vitro to patient samples to understand the role of antibiotic tolerance in promoting or suppressing resistance when drug combinations are used (see the Perspective by Berti and Hirsch). Although bacterial populations exposed to multiple antibiotics can develop tolerance to multiple drugs, one drug in a combination may be able counter resistance to a partner drug and provide effective therapy. However, if tolerance has already emerged to one drug, the combination may end up promoting the transmission of resistance to a partner drug. Science, this issue p. 200; see also p. 141 When used in the clinic, antibiotic combination therapy needs to be applied cautiously if tolerance to one of the drugs has emerged. Drug combinations are widely used in clinical practice to prevent the evolution of resistance. However, little is known about the effect of tolerance, a different mode of survival, on the efficacy of drug combinations for preventing the evolution of resistance. In this work, we monitored Staphylococcus aureus strains evolving in patients under treatment. We detected the rapid emergence of tolerance mutations, followed by the emergence of resistance, despite the combination treatment. Evolution experiments on the clinical strains in vitro revealed a new way by which tolerance promotes the evolution of resistance under combination treatments. Further experiments under different antibiotic classes reveal the generality of the effect. We conclude that tolerance is an important factor to consider in designing combination treatments that prevent the evolution of resistance.

中文翻译：

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耐药性对药物组合下抗生素耐药性演变的影响

药物组合的挑战 抗生素组合用于治疗难治性感染，例如耐甲氧西林金黄色葡萄球菌。然而，在临床上，药物往往是凭经验使用的，结果可能相互矛盾。刘等人。将体外对患者样本的观察结果转化为了解抗生素耐受性在使用药物组合时促进或抑制耐药性的作用（参见 Berti 和 Hirsch 的观点）。尽管暴露于多种抗生素的细菌群体可以对多种药物产生耐受性，但一种药物组合可能能够对抗对伙伴药物的耐药性并提供有效的治疗。但是，如果对一种药物已经出现耐受性，则这种组合最终可能会促进对伙伴药物的耐药性传播。科学，这个问题 p。200；另见第 141 在临床上使用时，如果出现对其中一种药物的耐受性，则需要谨慎应用抗生素联合治疗。药物组合广泛用于临床实践以防止耐药性的发展。然而，关于耐受性（一种不同的生存模式）对药物组合预防耐药性演变的功效的影响知之甚少。在这项工作中，我们监测了正在接受治疗的患者体内进化的金黄色葡萄球菌菌株。尽管进行了联合治疗，但我们检测到耐受性突变的迅速出现，随后出现了耐药性。体外临床菌株的进化实验揭示了耐受性促进联合治疗下耐药性进化的新途径。在不同抗生素类别下的进一步实验揭示了效果的普遍性。我们得出结论，耐受性是设计防止耐药性演变的联合治疗时要考虑的重要因素。