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One hundred nine adult patients with acute uncomplicated falciparum malaria were randomly selected to receive combinations of either doxycycline plus mefloquine or doxycycline plus artesunate. Fifty-four patients received mefloquine (1,250 mg divided between two doses of 750 and 500 mg six hours apart) with doxycycline and 55 patients received artesunate (300 mg total for 2.5 days; 100 mg followed by 50 mg every 12 hr for 2.5 days) with doxycycline. Doxycycline was administered in doses of 200 mg once a day for seven days. All patients were admitted to the hospital for 28 days to exclude reinfection. Ninety-seven patients completed the study; 12 patients left prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 96% (46 of 48) for mefloquine plus doxycycline and 80% (39 of 49) for artesunate plus doxycycline. Mean fever and parasite clearance times were significantly shorter in the group that received artesunate plus doxycycline (38.7 and 41.3 hr) than mefloquine plus doxycycline (64.3 and 69.0 hr), respectively. In vitro drug sensitivity testing of selected isolates obtained prior to treatment indicated that eight of nine admission isolates were resistant to mefloquine; all isolates were susceptible to artesunate. Recrudescent isolates failed to show a pattern of decreased sensitivity to the drugs to which the parasites had been exposed during treatment; the studies showed decreased sensitivity to doxycycline in only two of eight isolates tested. The overall results of the study indicate that the combination of mefloquine plus doxycycline is effective and well-tolerated in patients suffering from acute uncomplicated malaria and is an alternative treatment for multidrug-resistant falciparum malaria in areas of severe drug resistance.