Fig. 1.

Compartment model for combination therapy with two drugs. The box represents a patient’s body and the red and blue shaded areas indicate the presence of drug 1 and drug 2, respectively. Mismatched drug penetration creates regions in the body where only one drug from the combination is present. We refer to these regions as single-drug compartments. Colored circles represent the pathogen genotypes: wild type (light gray), mutant resistant to drug 1 (blue), mutant resistant to drug 2 (red), and double-drug-resistant mutant (purple). In the sanctuary all of the pathogen genotypes can grow because none of the drugs is present. In the single-drug compartments only pathogens carrying a resistance mutation against the active drug can grow; that is, each drug alone suppresses pathogen growth. Finally, in the double-drug compartment only the double-drug-resistant mutant can grow. All of the compartments are connected by migration as indicated by the black arrows. Treatment failure occurs when the double-drug compartment, which always composes the majority of the body, is colonized by the double mutant. Note that we do not always require that both single-drug compartments exist, and the compartment sizes may not follow this particular geometric relationship.