The search for effective and sustainable treatments for Plasmodium falciparum malaria in Africa:: A model of the selection of resistance by antifolate drugs and their combinations

The extensive data on the relationship between parasite genotype and susceptibility to antifolate drugs can now be coupled with pharmacokinetic information to allow construction of models of the selection and spread of antifolate-resistant Plasmodium? falciparum. In this report, we have modeled the effect on resistance selection processes of combinations of antifolate antimalarial drugs with artesunate and with amodiaquine under a variety of conditions that can be defined by the user. The model is intended to assist policymakers in forecasting the useful therapeutic life (UTL) for a rang, e of potential combination treatments. The model is especially designed for use by African malaria programs so that the interactions of key variables can be explored and appropriate combinations of drugs can be chosen for field testing. The model provides some important general conclusions: 1) for optimal extension of UTL, combination therapy must be deployed before either constituent drug is used as monotherapy; 2) even short periods of monotherapy can severely limit the usefulness of subsequent combination therapy; and 3) that adding a second drug to rescue an antifolate antimalarial that is overtly failing is an inappropriate and ultimately wasteful exercise.