Effect of tolerance on the evolution of antibiotic resistance under drug combinations

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Science  10 Jan 2020:
Vol. 367, Issue 6474, pp. 200-204
DOI: 10.1126/science.aay3041

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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


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.

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