Rapid evolution drives the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection

It is well established that antibiotic treatment selects for resistance. However, the responses of pathogen populations to antibiotic treatment during acute infections remain poorly resolved. Here we map the responses of Pseudomonas aeruginosa to treatment in high definition during a single lung infection. Antibiotic therapy (meropenem, colistin) caused a rapid crash of the P. aeruginosa population, but this decline was followed by the spread of meropenem resistance mutations that restrict antibiotic uptake (oprD) or modify LPS biosynthesis (wbpM). Low fitness strains with high-level meropenem resistance (oprD) were then replaced by high fitness strains with 'anti-resistance' mutations in the MexAB-OprM efflux pump, causing a rapid decline in resistance to both meropenem and a collateral loss of resistance to a broad spectrum of antibiotics. Our work highlights the ability of natural selection to drive both the rapid rise, and fall, of resistance.