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In Vitro Activity of Pyrimethamine, Cycloguanil, and Other Antimalarial Drugs Against African Isolates and Clones of Plasmodium falciparum

The in vitro activity of two dihydrofolate reductase (DHFR) inhibitors, pyrimethamine and cycloguanil, was evaluated against African clones and isolates of Plasmodium falciparum using an isotopic, semimicro drug susceptibility test. Three susceptibility levels (susceptible, intermediate, and resistant) were observed in the response of culture-adapted clones and strains to pyrimethamine (50% inhibitory concentration [IC₅₀]) < 100, 100–2,000, and > 2,000 nM) and cycloguanil (IC₅₀ < 50, 50–500, and > 500 nM). Based on these susceptibility levels, 73 and 68 of 96 fresh clinical isolates were susceptible to pyrimethamine (mean IC₅₀ 15.4 nM) and cycloguanil (mean IC₅₀ 11.1 nM), respectively. Thirteen and 18 isolates were resistant to pyrimethamine (mean IC₅₀ 9,440 nM) and cycloguanil (mean IC₅₀ 2,030 nM), respectively. A highly significant positive correlation was found between pyrimethamine and cycloguanil (r = 0.786), indicating in vitro cross-resistance between these antifolates. The spread of resistance to one of the DHFR inhibitors in Africa may compromise the utility of the other DHFR inhibitor.

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