title: In vitro antimalarial activity of azithromycin, artesunate, and quinine in combination and correlation with clinical outcome.
abstract: Azithromycin when used in combination with faster-acting antimalarials has proven efficacious in treating Plasmodium falciparum malaria in phase 2 clinical trials. The aim of this study was to establish optimal combination ratios for azithromycin in combination with either dihydroartemisinin or quinine, to determine the clinical correlates of in vitro drug sensitivity for these compounds, and to assess the cross-sensitivity patterns. Seventy-three fresh P. falciparum isolates originating from patients from the western border regions of Thailand were successfully tested for their drug susceptibility in a histidine-rich protein 2 (HRP2) assay. With overall mean fractional inhibitory concentrations of 0.84 (95% confidence interval [CI]=0.77 to 1.08) and 0.78 (95% CI=0.72 to 0.98), the interactions between azithromycin and dihydroartemisinin, as well as quinine, were classified as additive, with a tendency toward synergism. The strongest tendency toward synergy was seen with a combination ratio of 1:547 for the combination with dihydroartemisinin and 1:44 with quinine. The geometric mean 50% inhibitory concentration (IC50) of azithromycin was 2,570.3 (95% CI=2,175.58 to 3,036.58) ng/ml. The IC50s for mefloquine, quinine, and chloroquine were 11.42, 64.4, and 54.4 ng/ml, respectively, suggesting a relatively high level of background resistance in this patient population. Distinct correlations (R=0.53; P=0.001) between quinine in vitro results and parasite clearance may indicate a compromised sensitivity to this drug. The correlation with dihydroartemisinin data was weaker (R=0.34; P=0.038), and no such correlation was observed for azithromycin. Our in vitro data confirm that azithromycin in combination with artemisinin derivatives or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, and has substantial antimalarial activity on its own.
authors.affiliation: Department of Specific Prophylaxis and Tropical Medicine, Center for Physiology and Pathophysiology, Medical University of Vienna, Austria, and Hospital for Tropical Diseases, 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: Wattana
authors.initials: W
authors.lastname: Leowattana
authors.forename: Noppadon
authors.initials: N
authors.lastname: Tangpukdee
authors.forename: Wipa
authors.initials: W
authors.lastname: Thanachartwet
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: Kritsanai
authors.initials: K
authors.lastname: Yingyuen
authors.forename: Sabaithip
authors.initials: S
authors.lastname: Sriwichai
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Charles
authors.initials: C
authors.lastname: Knirsch
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D017963:Azithromycin / Q000494:pharmacology*; D017322:Clinical Trials, Phase II as Topic; D004341:Drug Evaluation; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011803:Quinine / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate; D017963:Azithromycin; D011803:Quinine