Theory 043/Medicine & Health /Antimicrobial resistance
Resistance Is Selected in a Window
Low doses are blamed for resistance. The worst place may be in the middle.
Resistance is selected most strongly at intermediate drug concentrations rather than at high or low ones, so the mutant selection window is the target for dosing rather than the trough.
01The evidence
The mutant selection window concept holds that resistant mutants are enriched when concentrations fall between the minimum inhibitory concentration and the mutant prevention concentration.
02The tension
Dosing guidance focuses on maintaining concentrations above the MIC, which ignores the window above it where selection is strongest.
03The mechanism
At low concentrations, susceptible and resistant strains both grow and the resistant one has a small advantage. At high concentrations both are killed. In between, susceptible cells are inhibited while resistant ones grow, which maximises the advantage.
That makes the window the selection zone, and predicts that regimens which spend time there will enrich resistance even if they exceed the MIC.
04What this is not
MIC targets keep concentrations just above inhibition. This keeps them above the window, which requires higher peaks.
05Predictions
- P1Selection should peak inside the window.
- P2Regimens passing through the window should enrich resistance.
- P3Higher peaks with shorter duration should reduce selection.
06Refutation
Selection increasing monotonically with lower concentration would remove the window.
07What it changes
It would change dose optimisation for resistance.