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Antimicrobial Agents and Chemotherapy, August 2002, p. 2518-2524, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2518-2524.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Assessment of Azithromycin in Combination with Other Antimalarial Drugs against Plasmodium falciparum In Vitro

Colin Ohrt,1* George D. Willingmyre,1,{dagger} Patricia Lee,1 Charles Knirsch,2,3 and Wilbur Milhous1

Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland,1 Pfizer, Inc.,2 College of Physicians and Surgeons, Columbia University, New York, New York3

Received 20 December 2001/ Returned for modification 5 February 2002/ Accepted 22 April 2002

Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC50s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC50s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

* Corresponding author. Mailing address: Division of Experimental Therapeutics, Room 1A28, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910-7500. Phone: (301) 319-9280. Fax: (301) 319-9449. E-mail: Colin.Ohrt{at}na.amedd.army.mil.

{dagger} Present address: SciQuest, Inc., Morrisville, NC 27560.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2518-2524, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2518-2524.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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