Figure 1.

Schematic representation of the evolutionary path of bacteria in chronic lung infections during continuous antibiotic treatment. Initially, the bacteria causing the infection are sensitive (MIC below the clinical breakpoint) to the treating antibiotic as determined by the MIC at the clinical microbiology laboratory, leading to treatment. Next, the antibiotic does not distribute equally throughout the lungs, such that certain niches only obtain a minimal amount of antibiotic. In these niches, an efflux pump active population conferring low-level clinical resistance can survive and persist. However, when tested at the clinical microbiology laboratory, this efflux pump active population is categorized as sensitive to the treating antibiotic, leading to continuous treatment. Lastly, the low-level-resistant population now has an evolutionary opportunity, while surviving in sublethal antibiotic concentrations, to evolve to high-level resistance through mutations in antibiotic target genes (e.g., mutations A and B). These evolved bacteria are now resistant (MIC above the clinical breakpoint) to the administrated antibiotic, leading to treatment failure for the patient. The figure is created with BioRender.com.