Efficacy and safety of atovaquone proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand

The increasing frequency of therapeutic failures in falciparum malaria unde rscores the need for novel, rapidly effective antimalarial drugs or drug co mbinations. Atovaquone and proguanil are blood schizonticides that demonstr ate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducte d in Thailand, adult patients with acute P. falciparum malaria were randoml y assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for thr ee doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percen tage of patients in whom parasitemia was eliminated and did not recur durin g 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory asse ssments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (curl rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and mefloquine treatments did not differ with resp ect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the atovaquone/proguanil group. Transient elevations of l iver enzyme levels occurred more frequently in patients treated with atovaq uone/ proguanil than with mefloquine, but the differences were not signific ant and values returned to normal by day 28 in most patients. The combinati on of atovaquone and proguanil was well tolerated and more effective than m efloquine in the treatment of acute uncomplicated multidrug-resistant falci parum malaria in Thailand.