Does drug tolerance promote antibiotic resistance despite combination therapy?

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A new study by a team from The Hebrew University of Jerusalem (Israel) has discovered that antimicrobial tolerance can promote the evolution of antimicrobial resistance, even when combination therapy that is expected to prevent this from occurring is used.

Antimicrobial resistance is a growing concern worldwide, especially in potentially life-threatening infections. In the US alone, more than 2.8 million antibiotic-resistant infections were identified in 2019, resulting in more than 35,000 mortalities.

Using combinations of antimicrobial drugs to target stubborn infections has become common practice in attempt to improve patient outcomes and reduce the potential emergence of resistance.

Antimicrobial resistance results in microbes becoming invulnerable to drugs designed to kill them, however, tolerance is often associated with the failure of antibiotic treatment causing the relapse of infections.

When investigating single antibiotic treatments, previous research has demonstrated the rapid emergence of tolerance, which can promote the evolution of resistance. However, the effect of tolerance on emerging resistance is remains unclear when combination therapy is used.

Lead author, Jiafeng Liu (Hebrew University of Jerusalem) and colleagues investigated the evolutionary trajectory of life-threatening methicillin-resistant Staphylococcus aureus isolated from patients undergoing combination treatment for persistent MRSA blood infections.

The team discovered the rapid emergence of tolerance in microbial population that was followed by the development of resistance, despite combination treatment being used.

The authors of the current study reported that once tolerance for just one of the drugs was established, the benefits of combination therapy were lost. These findings were supported by other similar experiments that used different classes of antibiotics.

In a related perspective Assistant Professors Andrew Berti (Wayne State University, MI, USA) and Elizabeth Hirsch (University of Minnesota, MN, USA) commented: “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.”

Following the results from the current study, when designing future antibiotic treatments to prevent antibiotic-resistant pathogens, drug tolerance should also be considered.

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Source: Liu J, Gefen O, Ronin I, Bar-Meir M, Balaban NQ. Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science 367(6474), 200–204 (2020); Berti AD, Hirsch EB. Tolerance to antibiotics affects response. Science 367(6474), 141–142 (2020); https://eurekalert.org/pub_releases/2020-01/aaft-atr010620.php

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