Background.Because antimalarial drug resistance is spreading, there is an urgent need for new combination treatments for malaria, which kills >1 million people every year. Azithromycin is a macrolide antibiotic that is particularly attractive as an antimalarial because of its safety in children and the extensive experience with its use during pregnancy.

Methods.We undertook a randomized, controlled, 28‐day inpatient trial involving patients with acute, uncomplicated Plasmodium falciparum malaria. We compared the safety and efficacy of 2 azithromycin‐artesunate combinations and 2 azithromycin‐quinine regimens in adults with malaria. Treatments were as follows: cohort 1 received 3 days of azithromycin (750 mg twice daily) plus artesunate (100 mg twice daily), cohort 2 received 3 days of azithromycin (1000 mg once daily) plus artesunate (200 mg once daily), cohort 3 received 3 days of azithromycin (750 mg twice daily) plus quinine (10 mg/kg twice daily), and cohort 4 received 3 days of azithromycin (500 mg 3 times daily) plus quinine (10 mg/kg 3 times daily). The enrollment target was 25 evaluable subjects per group.

Results.The 28‐day cure rates were similarly high in the artesunate and the standard‐dose quinine cohorts: 92.0% (95% confidence interval [CI], 74.0%–99.0%), 88.9% (95% CI, 70.8%–97.6%), and 92.0% (95% CI, 74.0%–99.0%), for cohorts 1, 2, and 4, respectively. Late R1 treatment failures were seen in each of the artesunate and the standard‐dose quinine cohorts. The cure rate for cohort 3 was 73.3% (95% CI, 44.9%–92.2%). In this cohort, 3 early treatment failures led to the termination of enrollment after 16 subjects had been enrolled. With mean parasite and fever clearance times (±SD) of h and h, the artesunate combinations were found to have led to a significantly ( ) faster clinical and parasitological improvement than occurred in the quinine cohorts ( h and h, respectively). Treatment‐related adverse events were significantly more common in the quinine cohorts ( ). No deaths or drug‐related serious adverse events were observed. In vitro results suggest that the treatment failures—particularly in the low‐dose quinine cohort—were associated with decreased susceptibility to quinine, as well as with mefloquine cross‐resistance.

Conclusions.These data suggest that azithromycin‐artesunate, even when given only once daily for 3 days, and azithromycin‐quinine, given 3 times daily, are safe and efficacious combination treatments for uncomplicated falciparum malaria, and they deserve additional study in special patient populations.