Antimalarial drug resistance and combination chemotherapy

Abstract

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration^e¡ect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly e¡ective combination partners because (i) they are very active antimalarials, producing up to 10 000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

Comparative study of the effects of artemether and artesunate on juvenile and adult Schistosoma mansoni in experimentally infected mice

“…This result is of great significance, since artemisinins are increasingly used in the treatment of severe and uncomplicated malaria, especially in areas where parasites have developed resistance to nearly all currently available antimalarials (PRICE et aZ., 1998(PRICE et aZ., , 1999. Therefore, we suggest that in areas where malaria and schistosomiasis are coendemic and artemisinins will be used in the treatment of malaria-in monotherapy or in combination with other antimalarial drugs (WHITE, 1999) …”

Gametocitemia en malaria por Plasmodium falciparum tratada con amodiaquina o artesunato

“…Los derivados de la artemisinina, como el artesunato, son esquizonticidas y tienen actividad sobre los gametocitos de P. falciparum (40)(41)(42)(43)(44)(45), reducen de forma importante la viabilidad de esos gametocitos jóvenes, tienen poco o nulo efecto sobre los gametocitos maduros y no se sabe cómo afectan la potencialidad infecciosa de los gametocitos para los anofelinos; en resumen, tienen un gran efecto sobre los gametocitos (36,46). La mefloquina tampoco elimina los gametocitos maduros de P. falciparum, sino que evita el desarrollo posterior de esas células por su actividad contra sus precursores (46).…”

“…La mefloquina tampoco elimina los gametocitos maduros de P. falciparum, sino que evita el desarrollo posterior de esas células por su actividad contra sus precursores (46). La sulfadoxina-pirimetamina es un potente esquizonticida sanguíneo y se sospecha que estimula la producción de gametocitos de P. falciparum (47)(48)(49)(50)(51)(52)(53) o eleva la viabilidad de los maduros (36); la sulfadoxina-pirimetamina suprime la capacidad de los gametocitos para infectar los anofelinos (36) y altera las razones de sexo de los gametocitos, lo que influye en la capacidad de causar infección a los mosquitos y la transmisión del paludismo (54); se considera que el efecto neto o global de la sulfadoxinapirimetamina sobre la supresión de la capacidad de infectar es nulo (36).…”

Adherence and effectiveness of drug combination in curative treatment among children suffering uncomplicated malaria in rural Senegal

“…Combination therapy with antimalarial drugs that have different modes of action has been shown to improve the treatment efficacy of individual drugs (WHO, 2001) and decrease the risk of resistance. The introduction of artemisinin-based combination therapy (ACT) has been shown to increase cure rates (White, 1999) and has been officially recommended by WHO (2001).…”