Cethromycin combines a quinoline nucleus and a macrolide for broad-spectrum antibacterial and antiprotozoan activity. Here, we characterized the murine pharmacokinetics and Plasmodium berghei lifecycle stage pharmacodynamics for the cethromycin base. Liver pharmacokinetic studies in mice show peak mM drug concentrations in the liver with 20 hour sustained levels above 10 μM. Peak concentrations in the liver were double the lung and about 440 times that of plasma. Immunofluorescence imaging of in vitro cethromycin-treated infected hepatocytes shows complete ablation of the apicoplast. We observed complete cure of P. berghei liver-stage infection by a single oral dose of 60 mg/kg in mice, which is equivalent to the 5 mg/kg human dose of 300 mg a day used in bacterial pneumonia studies. Cethromycin at 60 mg/kg daily for 7 days was curative in the high parasitemic P. berghei mouse model. Both mosquito membrane feeding of Plasmodium falciparum gametocytes incubated with 20 μM cethromycin and oral dosing in mice demonstrated no decrease in oocyst numbers. Cethromycin has been evaluated for efficacy against bacterial pneumonia in more than 5,000 patients with good safety profiles. Cethromycin has potential for rapid clinical development for casual malaria prophylaxis and possibly radical cure of dormant liver Plasmodium vivax.
Keywords: antimalarial agents; blood stage; cethromycin; chemotherapy; liver stage.