Susceptibility of Plasmodium falciparum to different doses of quinine in vivo and to quinine and quinidine in vitro in relation to chloroquine in Liberia

Abstract

Chloroquine-resistant Plasmodium falciparum has been spreading rapidly after its emergence in 1988 in Yekepa. The in vivo and in vitro susceptibilities to quinine and quinidine, compared to chloroquine, were studied by investigating the number of treatment days required for radical cure and estimating the quinine concentrations concomitantly. The minimal inhibitory concentrations (MIC) for schizont maturation in all successful in vitro tests were 5.12 x 10-6 mol/l for quinine and 1.28 x 10-6 mol/l for quinidine, indicating that all 50 isolates were sensitive to the two drugs. The IC50 and IC90 values were 0.22 and 0.78 x 10-6 mol/l for quinine and 0.07 and 0.26 x 10-6 mol/l for quinidine, respectively. In vitro inhibition of parasites by 1.6 x 10-6 mol/l of chloroquine was obtained in 31 out of 47 isolates, 18 (34%) being resistant. The IC50, IC90 and geometrical mean MIC for quinine were all about two times higher for the chloroquine-resistant than for the chloroquine-sensitive isolates (P = 0.006). P. falciparum infected children (n = 64) were randomly allocated to four groups and treated with quinine (10 mg/kg body weight twice daily) for 1 day (3 doses), 2, 4 and 7 days, respectively. All cleared their parasitaemias by day 4 but 5 out of 15 of those treated with only three doses showed a recurrence of parasitaemia between days 7 and 14; these were considered to be recrudescences. In the other groups, recurrent parasitaemias only occurred between days 17 and 28 and were considered to be reinfections. The mean blood concentrations of quinine in 10 patients on the fourth day of treatment were 17.0, 12.2 and 8.4 x 10-6 mol/l at, respectively, 2, 6 and 12 hours after the last dose. These concentrations are above the in vitro MIC values. Quinine remains a highly effective antimalarial drug in Liberia even after the appearance of chloroquine-resistant P. falciparum strains; the 3-day course appears to be an efficacious regimen in this semi-immune population.