title: 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.
abstract: 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 combination treatments for uncomplicated falciparum malaria, and they deserve additional study in special patient populations.
authors.affiliation: 1Department of Immunology and Medicine, USAMC-AFRIMS, Bangkok, Thailand. harald.noedl@meduniwien.ac.at
authors.forename: Harald
authors.initials: H
authors.lastname: Noedl
authors.forename: Srivicha
authors.initials: S
authors.lastname: Krudsood
authors.forename: Kobsiri
authors.initials: K
authors.lastname: Chalermratana
authors.forename: Udomsak
authors.initials: U
authors.lastname: Silachamroon
authors.forename: Wattana
authors.initials: W
authors.lastname: Leowattana
authors.forename: Noppadon
authors.initials: N
authors.lastname: Tangpukdee
authors.forename: Sornchai
authors.initials: S
authors.lastname: Looareesuwan
authors.forename: Robert Scott
authors.initials: RS
authors.lastname: Miller
authors.forename: Mark
authors.initials: M
authors.lastname: Fukuda
authors.forename: Krisada
authors.initials: K
authors.lastname: Jongsakul
authors.forename: Sabaithip
authors.initials: S
authors.lastname: Sriwichai
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rowan
authors.forename: Helen
authors.initials: H
authors.lastname: Bhattacharyya
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Charles
authors.initials: C
authors.lastname: Knirsch
mesh_terms: D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D017963:Azithromycin / Q000627:therapeutic use*; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D011247:Pregnancy; D011803:Quinine / Q000627:therapeutic use*; D012717:Sesquiterpenes / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate; D017963:Azithromycin; D011803:Quinine