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

Abstract

Objectives: This 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.

Methods: Patients were treated with quinine 10mg/kg for 7 days followed by sulfadoxine/pyrimethamine 25mg/kg single dose (in children) or doxycycline 100mg 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.

Results: The 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 IC(50) values (geometric mean IC(50) quinine 504.65nM and IC(50) chloroquine 506.69nM), confirmed diminished Plasmodium falciparum sensitivity to both drugs.

Conclusion: These 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.