Research Article| Volume 21, ISSUE 5, P841-852, May 1999

Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in zambia

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      Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate in vitro synergy against drug-resistant strains of Plasmodium falciparum. When coadministered, they may therefore be effective for the treatment of malaria in regions where there is known or suspected drug resistance. In an open-label, randomized, parallelgroup, clinical trial conducted in Zambia, 163 patients (age range, 14 to 54 years) with acute P falciparum malaria were randomly assigned to receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg, respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or pyrimethamine/sulfadoxine (75/1500 mg administered orally as a single dose; n = 81). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was determined by sequential clinical and laboratory assess ments over 28 days. Cure rates did not differ significantly between patients treated with atovaquone and proguanil (100%) and those treated with pyrimethamine/ sulfadoxine (98.8%). Patients in the atovaquone and proguanil group had a significantly shorter FCT than patients in the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P < 0.05) but a longer PCT (mean, 64.0 vs 51.4 hours; P < 0.05). Both treatments were well tolerated; adverse events and laboratory abnormalities were typical of those normally observed in patients with malaria. In this study, the combination of atovaquone and proguanil was equally effective and as well tolerated as pyrimethamine/sulfadoxine for the treatment of acute, uncomplicated, drugresistant falciparum malaria in Zambia.

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        • Boudreau EF
        • Ekue JM
        • Sheth UK
        Curative treatment of P falciparum infections in school children: A controlled comparative study between Fansimef and chloroquine.
        in: WHO/CHEMAL Study Report. World Health Organization, GenevaAugust 1989
        • Boudreau EF
        • Ekue JM
        • Kawasha J
        A Phase III comparative clinical trial of four regimens of halofantrine and chloroquine in treatment of P falciparum malaria.
        in: O/CHEMAL Study Report. World Health Organization, GenevaSeptember 1993
        • Ekue JM
        • Phiri DE
        • Sheth UK
        • Mukunyandela M
        A double-blind trial of a fixed combination of mefloquine plus sulfadoxine-pyrimethamine compared with sulfadoxine-pyrimethamine alone in symptomatic falciparum malaria.
        Bull WHO. 1987; 65: 369-373
        • Hernborg A
        Stevens-Johnson syndrome after mass prophylaxis with sulfadoxine for cholera in Mozambique.
        Lancet. 1985; ii: 1072-1073
        • Miller KD
        • Lobel HO
        • Satriale RF
        • et al.
        Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar®) for malaria prophylaxis.
        Am J Trop Med Hyg. 1986; 35: 451-458
        • Zitelli BJ
        • Alexander J
        • Taylor S
        • et al.
        Fatal hepatic necrosis due to pyrimethaminesulfadoxine (Fansidar®).
        Ann Intern Med. 1987; 106: 393-395
        • Weinke T
        • Trautmann M
        • Held T
        • et al.
        Neuropsychiatric side effects after the use of mefloquine.
        Am J Trop Med Hyg. 1991; 45: 86-91
        • Bem JL
        • Kerr L
        • Stuerchler D
        Mefloquine prophylaxis: An overview of spontaneous reports of severe psychiatric reactions and convulsions.
        Am J Trop Med Hyg. 1992; 95: 167-179
        • Kosten F
        • Ter Kuile OF
        • Luxemburger C
        • et al.
        Cardiac effects of antimalarial treatment with halofantrine.
        Lancet. 1993; 341: 1054-1056
        • Monlun E
        • le Metayer P
        • Szwandt S
        • et al.
        Cardiac complications of halofantrine: A prospective study of 20 patients.
        Trans R Soc Trop Med Hyg. 1995; 89: 430-433
        • Fry M
        • Pudney M
        Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4- (4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80).
        Biochem Pharmacol. 1992; 43: 1545-1553
        • Dollery C
        Proguanil (hydrochloride).
        in: Dollery C Therapeutic Drugs. Vol 2. Churchill Livingstone, New York1991: 247-251
        • Canfield CJ
        • Pudney M
        • Gutteridge WE
        Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro.
        Exp Parasitol. 1995; 80: 373-381
        • Looareesuwan S
        • Viravan C
        • Webster HK
        • et al.
        Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand.
        Am J Trop Med Hyg. 1996; 54: 62-66
        • Radloff PD
        • Philipps J
        • Nkeyi M
        • et al.
        Atovaquone and proguanil for Plasmodium falciparum malaria.
        Lancet. 1996; 347: 1511-1514
        • de Alencar FE
        • Cerutti Jr., C
        • Durlacher RR
        • et al.
        Atovaquone and proguanil for the treatment of malaria in Brazil.
        J Infect Dis. 1997; 175: 1544-1547
        • Rolan PE
        • Mercer AJ
        • Weatherly BC
        • et al.
        Examination of some factors responsible for a food-induced increase in absorption of atovaquone.
        Br J Clin Pharmacol. 1994; 37: 13-20
        • World Health Organization
        Advances in malaria chemotherapy.
        WHO Tech Rep Ser. 1973; 529: 30-32
      1. Smith PG Morrow RH Methods for Field Trials of Interventions Against Tropical Diseases. Oxford University Press, Oxford, England1991: 283
        • Looareesuwan S
        • Chulay JD
        • Canfield CJ
        • Hutchinson DB
        Malarone (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria.
        Am J Trop Med Hyg. 1999; 60: 533-541
      2. Bustos DG, Canete-Miguel E, Canfield CJ, Hutchinson DBA. Atovaquone/proguanil compared with chloroquine and chloroquine/sulfadoxine/ pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. J Infect Dis. In press.

        • Wolday D
        • Kibreab T
        • Bukenya D
        • Hodes R
        Sensitivity of Plasmodium falciparum in vivo to chloroquine and pyrimethaminesulfadoxine in Rwandan patients in a refugee camp in Zaire.
        Trans R Soc Trop Med Hyg. 1995; 89: 654-656
        • Landgraf B
        • Kollaritsch H
        • Wiedermann G
        • Wernsdorfer WH
        Plasmodium falciparum: Susceptibility in vitro and in vivo to chloroquine and sulfadoxine-pyrimethamine in Ghanaian schoolchildren.
        Trans R Soc Trop Med Hyg. 1994; 88: 440-442
        • Benito A
        • Roche J
        • Molina R
        • et al.
        In vitro susceptibility of Plasmodium falciparum to chloroquine, amodiaquine, quinine, mefloquine, and sulfadoxine/pyrimethamine in Equatorial Guinea.
        Am J Trop Med Hyg. 1995; 53: 526-531
        • Kamugisha J
        • Kipp W
        • Burnham G
        In vivo sensitivity of Plasmodium falciparum to chloroquine, amodiaquine and sulfadoxine-pyrimethamine in western Uganda.
        Trop Geogr Med. 1994; 46: 364-365
        • Barat LM
        • Bloland PB
        Drug resistance among malaria and other parasites.
        Infect Dis Clin North Am. 1997; 11: 969-987
        • Shanks GD
        • Gordon DM
        • Klotz FW
        • et al.
        Efficacy and safety of atovaquone/proguanil for suppressive prophylaxis against Plasmodium falciparum malaria.
        Clin Infect Dis. 1998; 27: 494-499
        • Lell B
        • Luckner D
        • Ndjave M
        • et al.
        Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children.
        Lancet. 1998; 351: 709-713