Multiple ecological and evolutionary mechanisms drive treatment-induced antibiotic resistance

Abstract

The emergence of resistance within patients during antibiotic treatment is an important cause of treatment failure. However, the ecological and evolutionary mechanisms driving within-patient emergence remain poorly understood. Here, we analysed 24,478 Pseudomonas aeruginosa isolates sampled from 180 bronchiectasis patients during a clinical trial to understand how ciprofloxacin-resistant infections emerged over a one-year period of pulse-dosing. Pre-existing resistance predominated, accelerating resistance emergence relative to patients where resistance emerged by spontaneous mutation or strain immigration. Selective sweeps of costly mutations increased resistance over time in some patients, whereas in others oscillating resistance levels were driven by antibiotic treatment and resistance-growth trade-offs between genetically divergent subpopulations. Our findings show that infections under identical treatment follow diverse and sometimes complex ecological and evolutionary paths to antibiotic resistance, with implications for better predicting and managing treatment-induced antibiotic resistance.