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Azithromycin, the most potent antimalarial macrolide antibiotic, is synergistic with quinine against Plasmodium falciparum in vitro. We assessed combinations of azithromycin and quinine against uncomplicated P. falciparum malaria at the Armed Forces Research Institute of Medical Sciences–Kwai River Clinical Center along the Thailand-Myanmar border, an area with a high prevalence of multidrug-resistant P. falciparum. Four regimens were assessed in an open-label dose-ranging design involving 61 volunteers. All received oral quinine (Q; 30 mg/kg/day divided every 8 hours for 3 days) with oral azithromycin (Az; 500 mg twice a day for 3 days, 500 mg twice a day for 5 days, or 500 mg three times a day for 3 days). A comparator group received quinine and doxycycline (Dx; 100 mg twice a day for 7 days). Study observation was 28 days per protocol. Sixty volunteers completed the study. Seven days of QDx cured 100% of the volunteers. One failure occurred in the lowest QAz regimen (on day 28) and none occurred in either of the two higher Az regimens. Cinchonism occurred in nearly all subjects. Overall, the azithromycin regimens were well tolerated, and no volunteers discontinued therapy. Three- and five-day azithromycin-quinine combination therapy appears safe, well tolerated, and effective in curing drug-resistant P. falciparum malaria. Further evaluation, especially in pediatric and obstetric populations, is warranted.
Received May 15, 2005. Accepted for publication September 29, 2005.
Acknowledgments: We thank Douglas Tang for assistance with statistical design and Harald Noedl for his review of the manuscript. We also thank the staff at Kwai River Christian Hospital, particularly Sabaithip Sriwichai and Panjan Watchara, for providing most of the clinical nursing care, and the dedicated staff of the Malaria Clinic in Sangkhlaburi, Thailand, and the Field Studies and Epidemiology team of the Department of Immunology and Medicine of the Armed Forces Research Institute of Medical Sciences for their support of this trial. This study was presented in part at the 51st Annual Meeting of the American Society of Tropical Medicine and Hygiene, Denver, Colorado, October 10–14, 2002.
Financial support: This study was supported by Pfizer, Inc. and U.S. Army Medical Research and Materiel Command.
Disclosure: Charles Knirsch is an employee of Pfizer, Inc and has equity interest in the company.
Disclaimer: The opinions reflected herein reflect those of the authors and do not necessarily reflect the official views of the U.S. Army or the U.S. Department of Defense.
* Address correspondence to R. Scott Miller, Department of Immunology and Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Rd., Phayathai, Bangkok 10400, Thailand, APO AP, USA 96546. E-mail: robert.s.miller{at}us.army.mil
Authors’ addresses: R. Scott Miller and Nillawan Buathong, Department of Immunology and Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Rd., Phayathai, Bangkok 10400, Thailand, APO AP, USA 96546, Telephone: 66-2-644-5775, Fax: 66-2-644-4784, E-mails: robert.s.miller{at}us.army.mil and nillawanb{at}afrims.org. Chansuda Wongsrichanalai, National Institute of Public Health/Naval Medical Research Unit No. 2 Laboratory, P.O. Box 131, Phnom Penh, Cambodia, E-mail: chansuda{at}namru2.med.navy.mil. Philip McDaniel, 10803 SE Cherry Blossom Drive, Portland, OR 97216-3107, E-mail: philmcd{at}concentric.net. Douglas Walsh, Department of Clinical Trials, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, E-mail: douglas.walsh{at}us.army.mil. Charles Knirsch, Worldwide Medical Division, Pfizer Inc., New York, NY 10017-5755, E-mail: charles.knirsch{at}pfizer.com. Colin Ohrt, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, Telephone: 301-319-9280, Fax: 301-319-9449, E-mail: colin.ohrt{at}us.army.mil.
Reprint requests: R. Scott Miller, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, APO AP, USA 96546, E-mail: robert.s.miller{at}us.army.mil.
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