Diminished Plasmodium falciparum sensitivity to quinine exposure in vitro and in a sequential multi-drug regimen: A preliminary investigation in Guyana, South America

SummaryObjectivesThis preliminary study sought to investigate the response of uncomplicated falciparum infections to semi-supervised drug administration with quinine and two adjunctive schizontocidal drugs in infected patients in Guyana. Quinine and chloroquine cross-sensitivity was also assessed in vitro.MethodsPatients were treated with quinine 10 mg/kg for 7 days followed by sulfadoxine/pyrimethamine 25 mg/kg single dose (in children) or doxycycline 100 mg daily for 7 days (in adults). Independently, falciparum-infected blood-medium mixtures were cultured in standardized pre-dosed quinine and chloroquine test plates, according to the protocol of the World Health Organization Mark III in vitro test system, for analysis.ResultsThe quinine/doxycycline regimen (N = 12) produced 100% clinical cure (12/12) at day 14 and 100% parasitological cure (11/11) at day 28. However, with the quinine/sulfadoxine/pyrimethamine scheme, 1/12 therapeutic failure (on day 14) and 2/9 parasitological failures (on day 28) were observed. In vitro, parasite development beyond the cut-off concentrations and high IC50 values (geometric mean IC50 quinine 504.65 nM and IC50 chloroquine 506.69 nM), confirmed diminished Plasmodium falciparum sensitivity to both drugs.ConclusionThese findings suggest P. falciparum resistance to both quinine and chloroquine, and support either the use of antibiotics as adjuncts to quinine therapy or drugs with alternate pharmacodynamics as first-line therapy.