Tolerance is the key to understanding antimalarial drug resistance

The evolution of antimalarial drug resistance is often considered to be a single-stage process in which parasites are either fully resistant or completely sensitive to a drug. However, this does not take into account the important intermediate stage of drug tolerance. Drug-tolerant parasites are killed by the high serum concentrations of drugs that occur during direct treatment of the human host. However, these parasites can spread in the human population because many drugs persist long after treatment, and the tolerant parasites can infect people in which there are residual levels of the drugs. This intermediate stage between fully sensitive and fully resistant parasites has far-reaching implications for the evolution of drug-resistant malaria.