Modified dosing schedule efficacy of fosmidomycin and clindamycin against murine malaria Plasmodium berghei.

Abstract

Fosmidomycin and clindamycin target the Plasmodium apicoplast. Combination clinical trials have produced mixed results with the primary problem being the recrudescent infection frequency by day 28. Given that antibiotic efficacy against bacterial infections often depends on the constant drug presence over several days, we hypothesized that the antimalarial blood or liver stage efficacy of fosmidomycin and clindamycin could be improved by implementing a more frequent dosing schedule. A blood stage murine malaria P. berghei GFP-luciferase low and high parasitemia model was implemented to follow pharmacodynamics and cure for modified dose, schedule and duration of individual and combination fosmidomycin and clindamycin. P. berghei sporozoites were used to investigate fosmidomycin during the 48 h murine liver stage. Here we observed that the same total dose of fosmidomycin and clindamycin, alone and in combination, are more efficacious when scheduled in smaller, more frequent doses. Fosmidomycin added measurably small additional killing in combination with clindamycin. Despite dosing every 6 h during liver stages, fosmidomycin was inhibitory, but noncurative even with addition of atorvastatin to decrease hepatocyte production of mevalonate. We have also demonstrated in vitro efficacy of fosmidomycin and clindamycin against P. falciparum C580Y with IC₅₀s similar to those for drug sensitive P. falciparum. The dosing schedule of quinoline and artemisinin partner drugs fosmidomycin or clindamycin targeting the apicoplast should maximize time above minimum inhibitory concentration.