Artemisinin combination therapies (ACTs) have become the global standard for the treatment of Plasmodium falciparum malaria in areas with existing or emerging drug resistance. ACTs have several advantages: combination therapy diminishes the probability of de novo mutation, artemisinin is the most schizonticidal drug and reduces parasite biomass very rapidly resulting in faster clearance rates, and artemisinin kills immature gametocytes reducing subsequent transmission. Unfortunately, mismatch in the half-lives of the partner drugs (artemisinin derivatives have very short half lives of ~1-2 hours) leaves windows of monotherapy during which parasites can gain resistance, or those with pre-existing resistance to the partner drug, rebound and cause treatment failure.
In the latest issue of Emerging Infectious Diseases (CDC – open access), Wrongsrichanalai and Meshnick report the declining efficacy of artesunate-mefloquine along the Thai-Cambodian border. (A full disclaimer: Dr Steven Meshnick is my mentor). This border is the traditional birthplace of most drug resistant strains, and it is no surprise that the first widespread reports of ACT failures arrived from here. The failures are probably due to endemic mefloquine resistance generated by years of prior use rather than resistance to artesunate itself though we cannot exclude that possibility. There’s an important lesson for policy makers here: ACTs with partner drugs which have pre-existing resistance in that area will fail rapidly. Early last year SEARO, the Southeast Asia regional office for the WHO, held a meeting on the “Containment of Malaria Multi-Drug Resistance on the Cambodia-Thailand Border” to discuss this challenge. Unfortunately, for people living along the Thai-Cambodia border few therapeutic options remain.