History of Antibiotic Adaptation Influences Microbial Evolutionary Dynamics During Subsequent Treatment

Abstract

Antibiotic regimens often include the sequential changing of drugs to limit development and evolution of resistance of bacterial pathogens. It remains unclear how history of adaptation to one antibiotic can influence the resistance profiles when bacteria subsequently adapt to a different antibiotic. Here, we experimentally evolved Pseudomonas aeruginosa to six two-drug sequences. We observed drug order-specific effects whereby: adaptation to the first drug can limit subsequent adaptation to the second drug, adaptation to the second drug can restore susceptibility to the first drug, or final resistance levels depend on the order of the two-drug sequence. These findings demonstrate how resistance not only depends on the current drug regimen but also history of past regimens. These order-specific effects have profound clinical implications and provide support for the need to consider history of past drug exposure when designing strategies to mitigate resistance and combat bacterial infections.