Resistance to Antimalarial Monotherapy Is Cyclic

Abstract

Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug resistance and plot the yearly citations of 14 common antimalarials. Remarkably, most antimalarial drugs display cyclic resistance patterns, rising and falling over four decades. The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Exceptionally, the resistance of the two latter drugs can also correlate with a linear rise. Our predicted antimalarial drug resistance is consistent with clinical data reported by the Worldwide Antimalarial Resistance Network (WWARN) and validates our methodology. Notably, the cyclical resistance suggests that most antimalarial drugs are sustainable in the end. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance.

Keywords: Plasmodium; Plasmodium falciparum; Plasmodium vivax; antibiotic resistance; antimalarial resistance; drug of choice; drug resistance; health policy; malaria; parasitology; text-mining.

Figure 1

Antimalarial drug resistance is cyclic. The resistance estimated through PubMed citations (blue dots) and the fitted periodic function (red line) are plotted. The fitted equation is listed above each graph, as is the correlation coefficient, R (in black). Notably, antimalarial drug resistance correlates well with sine functions. Artemisinin and dihydroartemisinin also correlate with a linear rise. The clinical monotherapy resistance reported by WWARN 4 is also plotted (red dots), as is the correlation with the PubMed citations, R (in red). Finally, experimental resistance reported by Singhasivanon23 (green line) and Frosch25 (green dots) is plotted, as is the correlation with PubMed citations, R (in green). Notably, the resistance estimated by the normalized PubMed citations correlates well with clinical and experimental data and validates our methodology.