Antimicrobial tolerance can promote the evolution of antimicrobial resistance even under combination drug treatments widely used and expected to prevent it from occurring, a new study finds. The results suggest the need to consider drug tolerance when designing antibiotic treatments to prevent antibiotic-resistant pathogens. The rise of antimicrobial resistance in potentially life-threatening infections is a growing concern worldwide. In the United States alone, more than 2.8 million antibiotic-resistant infections were identified in 2019, resulting in more than 35,000 deaths. To improve patient outcomes as well as to reduce the potential for the emergence of resistance, it's become common clinical practice to use combinations of antimicrobial drugs to treat the most serious and stubborn infections. Whereas antimicrobial resistance renders microbes invulnerable to the drugs designed to kill them, they can also become more tolerant of them, which is often associated with the failure of antibiotic treatments and the relapse of infections. Previous studies have demonstrated the rapid emergence of tolerance during single antibiotic treatments, which can subsequently promote the evolution of resistance. However, the effect of tolerance on the emergence of resistance when drug combinations are used remains unclear. Jiafeng Liu and colleagues closely monitored the evolutionary trajectory of life-threatening methicillin-resistant Staphylococcus aureus isolated from patients undergoing combination treatment for persistent MRSA blood infections. Liu et al. observed the rapid emergence of tolerance in microbial populations that was followed by the development of resistance, despite combination treatment. According to the authors, once tolerance was established for just one of the drugs, the benefits of using drug combinations were lost. Experiments using different classes of antibiotics produced similar results. "Although these results suggest that many benefits are lost when microbes become tolerant, additional studies assessing clinical outcomes in patients with antimicrobial-tolerant infections will be necessary to guide clinical decision making," write Andrew Berti and Elizabeth Hirsch in a related Perspective.