Antimalarial activity of azithromycin, artemisinin and dihydroartemisinin in fresh isolates of Plasmodium falciparum in Thailand

Abstract

Antibiotics with antimalarial activity may offer an interesting alternative for the treatment of multidrug-resistant falciparum malaria. Azithromycin, a relatively recent semisynthetic derivative of erythromycin, was tested for its in vitro activity against fresh isolates of Plasmodium falciparum. As the reportedly slow onset of action of azithromycin suggests its combination with fast-acting substances, such as artemisinin-derivatives, dihydroartemisinin (DHA) was tested parallel as a possible combination partner. The effective concentrations found for azithromycin in this study (EC 50=29.3 μmol/l, EC 90=77.1 μmol/l blood medium mixture (BMM)) are comparable to those of other antimalarials in the antibiotics class and are considerably higher than those found for mefloquine or quinine. The absence of an activity correlation between azithromycin and chloroquine, quinine and artemisinin emphasises the independence of azithromycin drug response from the sensitivity to these drugs. A weak activity correlation ( ρ EC90=0.352; p=0.028), which could point to a potential cross-sensitivity but is probably of little clinical importance, was found with mefloquine above the EC 50 level. Provided that further clinical trials support the combination of these drugs, DHA may offer an interesting combination partner for azithromycin owing to its rapid onset of action and the comparatively low effective concentrations (EC 50=1.65 nmol/l, EC 90=7.10 nmol/l BMM). This combination may serve as an interesting alternative for tetracycline and doxycycline, which cannot be used in pregnant women and children, and exhibit phototoxicity. Nevertheless, the relatively high cost of this combination, as well as the controversial reports of the clinical efficacy, may limit the usefulness of azithromycin in malaria therapy and require an adjustment of previously used treatment regimens.