Azithromycin Combination Therapy with Artesunate or Quinine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Adults: A Randomized, Phase 2 Clinical Trial in Thailand

• Published in: Clinical infectious diseases 2006-11, Vol.43 (10), p.1264-1271
• Main Authors: Noedl, Harald, Krudsood, Srivicha, Chalermratana, Kobsiri, Silachamroon, Udomsak, Leowattana, Wattana, Tangpukdee, Noppadon, Looareesuwan, Sornchai, Miller, Robert Scott, Fukuda, Mark, Jongsakul, Krisada, Sriwichai, Sabaithip, Rowan, Jacqueline, Bhattacharyya, Helen, Ohrt, Colin, Knirsch, Charles
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antibacterial agents; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials; Antimalarials - therapeutic use; Antiparasitic agents; Artemisinins - therapeutic use; Articles and Commentaries; Azithromycin - therapeutic use; Biological and medical sciences; Child; Clinical trials; Confidence intervals; Dosage; Drug resistance; Drug Therapy, Combination; Falciparum malaria; Female; Fever; Human protozoal diseases; Humans; Infectious diseases; Malaria; Malaria, Falciparum - drug therapy; Medical cures; Medical sciences; Medical treatment; Medical treatment failures; Parasites; Parasitic diseases; Pharmacology. Drug treatments; Pregnancy; Protozoal diseases; Quinine - therapeutic use; Sesquiterpenes - therapeutic use; Tropical medicine
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1086/508175

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 34 ± 13 h and 20 ± 20 h, the artesunate combinations were found to have led to a significantly (P < .001) faster clinical and parasitological improvement than occurred in the quinine cohorts (74 ± 32 h and 43 ± 37 h, respectively). Treatment-related adverse events were significantly more common in the quinine cohorts (P < .001). 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