Fig 1. Dynamics of heteroresistance during infection and clinical susceptibility testing.

(A) Schematic showing a patient infected with a heteroresistant bacterial isolate harboring a minor subpopulation of antibiotic-resistant cells (red). (B) Clinical susceptibility testing may not detect the minor resistant subpopulation, and the isolate would therefore be incorrectly designated susceptible to the given antibiotic. (C) Subsequent antibiotic therapy selects for the resistant subpopulation, which is able to grow in the presence of the drug. (D) Continued clinical susceptibility testing involves in vitro subculture of the heteroresistant bacteria in the absence of an antibiotic, which leads to a contraction of the resistant subpopulation. This minor subpopulation is therefore still not detected by clinical testing, and the isolate again appears susceptible. (E) Inappropriate antibiotic therapy ultimately leads to treatment failure and inability to clear the infection.