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Antimicrobial Agents and Chemotherapy, February 2007, p. 651-656, Vol. 51, No. 2
0066-4804/07/$08.00+0 doi:10.1128/AAC.01023-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
In Vitro Antimalarial Activity of Azithromycin, Artesunate, and Quinine in Combination and Correlation with Clinical Outcome
Harald Noedl,1,2*
Srivicha Krudsood,3
Wattana Leowattana,3
Noppadon Tangpukdee,3
Wipa Thanachartwet,3
Sornchai Looareesuwan,3
Robert Scott Miller,2
Mark Fukuda,2
Krisada Jongsakul,2
Kritsanai Yingyuen,2
Sabaithip Sriwichai,2
Colin Ohrt,4 and
Charles Knirsch5
Department of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria,1 Department of Immunology and Medicine, USAMC-AFRIMS, Bangkok, Thailand,2 Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,3 Division of Experimental Therapeutics, WRAIR, Silver Spring, Maryland,4 Clinical Research and Development, Pfizer, Inc., New York, New York5
Received 16 August 2006/ Returned for modification 24 September 2006/ Accepted 12 November 2006
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.
* Corresponding author. Mailing address: Department of Specific Prophylaxis and Tropical Medicine, Center for Physiology and Pathophysiology, Medical University of Vienna, Kinderspitalgasse 15, A-1090 Vienna, Austria. Phone: 43-1-4277-64882. Fax: 43-1-4277-64899. E-mail: harald.noedl{at}meduniwien.ac.at.
Published ahead of print on 20 November 2006.
Antimicrobial Agents and Chemotherapy, February 2007, p. 651-656, Vol. 51, No. 2
0066-4804/07/$08.00+0 doi:10.1128/AAC.01023-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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