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Title: In vitro antimalarial activity of azithromycin, artesunate, and quinine in combination and correlation with clinical outcome
Authors: Harald Noedl
Srivicha Krudsood
Wattana Leowattana
Noppadon Tangpukdee
Wipa Thanachartwet
Sornchai Looareesuwan
Robert Scott Miller
Mark Fukuda
Krisada Jongsakul
Kritsanai Yingyuen
Sabaithip Sriwichai
Colin Ohrt
Charles Knirsch
Medizinische Universitat Wien
Armed Forces Research Institute of Medical Sciences, Thailand
Mahidol University
Walter Reed Army Institute of Research
Pfizer Inc.
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Feb-2007
Citation: Antimicrobial Agents and Chemotherapy. Vol.51, No.2 (2007), 651-656
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. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
ISSN: 00664804
Appears in Collections:Scopus 2006-2010

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