In vitro and in vivo synergy of fosmidomycin, a novel antimalarial drug, with clindamycin

Abstract

Fosmidomycin acts through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, a key enzyme of the nonmevalonate pathway of isoprenoid biosynthesis. It possesses potent antimalarial activity in vitro and in murine malaria. In a recent clinical study, fosmidomycin was effective and well tolerated in the treatment of patients with acute uncomplicated Plasmodium falciparum malaria but resulted in an unacceptably high rate of recrudescence. In order to identify a potential combination partner, the interaction of fosmidomycin with a number of antimalarial drugs in current use was investigated in a series of in vitro experiments. Synergy was observed between fosmidomycin and the lincosamides, lincomycin and clindamycin. The efficacy of a combination of fosmidomycin and clindamycin was subsequently demonstrated in the Plasmodium vinckei mouse model.

FIG. 1.

Representative isobolograms of the interaction of fosmidomycin with quinine, artemisinin, proguanil, clindamycin, or lincomycin. The interaction of proguanil with atovaquone was assessed as a control experiment (upper left panel). The P. falciparum strain used for each experiment is indicated.

FIG. 2.

Dose response of P. falciparum growth to fosmidomycin in the presence of different constant clindamycin concentrations. P. falciparum-infected erythrocytes were incubated with a serial dilution of fosmidomycin in the absence (filled circles) or in the presence of clindamycin at 43 ng/ml (diamonds), 210 ng/ml (inverted triangles), or 850 ng/ml (triangles). Parasite growth was monitored by radioactive hypoxanthine incorporation. The clindamycin concentrations selected did not have intrinsic antimalarial activity under the assay conditions. Results obtained by independent experiments with P. falciparum strains HB3 (upper panel) and A2 (lower panel) are presented.

FIG. 3.

In vivo efficacy of fosmidomycin plus clindamycin in P. vinckei-infected mice. (A) For suppressive treatment, drugs were administered on days 1 and 2 postinfection and parasitemia was monitored on days 3 to 5. (B) For curative treatment starting with high parasitemia, drugs were administered on days 3 and 4 and parasitemia was monitored from days 3 to 8. Geometric mean values and ranges of observed values are indicated. Fos, fosmidomycin; Cli, clindamycin.