The spread of antibiotic resistance is attracting increased attention to combination-based treatments. Although drug combinations have been studied extensively for their effects on bacterial growth^{1,2,3,4,5,6,7,8,9,10,11}, much less is known about their effects on bacterial long-term clearance, especially at cidal, clinically relevant concentrations^12,13,14. Here, using en masse microplating and automated image analysis, we systematically quantify Staphylococcus aureus survival during prolonged exposure to pairwise and higher-order cidal drug combinations. By quantifying growth inhibition, early killing and longer-term population clearance by all pairs of 14 antibiotics, we find that clearance interactions are qualitatively different, often showing reciprocal suppression whereby the efficacy of the drug mixture is weaker than any of the individual drugs alone. Furthermore, in contrast to growth inhibition^6,7,8,9,10 and early killing, clearance efficacy decreases rather than increases as more drugs are added. However, specific drugs targeting non-growing persisters^15,16,17 circumvent these suppressive effects. Competition experiments show that reciprocal suppressive drug combinations select against resistance to any of the individual drugs, even counteracting methicillin-resistant Staphylococcus aureus both in vitro and in a Galleria mellonella larva model. As a consequence, adding a β-lactamase inhibitor that is commonly used to potentiate treatment against β-lactam-resistant strains can reduce rather than increase treatment efficacy. Together, these results underscore the importance of systematic mapping the long-term clearance efficacy of drug combinations for designing more-effective, resistance-proof multidrug regimes.

抗生素耐药性的蔓延正在引起对基于联合治疗的更多关注。尽管药物组合对细菌生长的影响已被广泛研究^{1,2,3,4,5,6,7,8,9,10,11}，但对其对细菌长期清除的影响知之甚少，尤其是在 cidal，临床相关浓度^12,13,14。在这里，我们使用整体微量电镀和自动图像分析，系统地量化金黄色葡萄球菌长期暴露于成对和高阶杀灭药物组合期间的存活率。通过量化所有 14 种抗生素对的生长抑制、早期杀伤和长期群体清除，我们发现清除相互作用在性质上是不同的，通常显示出相互抑制，即药物混合物的功效比任何单独的药物都弱。此外，与生长抑制^6,7,8,9,10和早期杀灭相比，随着添加更多药物，清除功效会降低而不是增加。然而，针对非生长持久性的特定药物^15,16,17规避这些抑制作用。竞争实验表明，相互抑制的药物组合选择对抗对任何单个药物的抗性，甚至在体外和在大肠球菌幼虫模型中对抗耐甲氧西林金黄色葡萄球菌。因此，添加一种通常用于增强对β-内酰胺耐药菌株的治疗的β-内酰胺酶抑制剂可以降低而不是提高治疗效果。总之，这些结果强调了系统绘制药物组合的长期清除功效对于设计更有效、抗耐药性的多药方案的重要性。