RESUMO
The control of malaria is challenged by resistance of Plasmodium falciparum to multiple drugs. New combination regimens are now advocated for the treatment of uncomplicated falciparum malaria, but the extent of resistance to newer agents is incompletely understood. We measured the in vitro sensitivity of P. falciparum parasites cultured from children enrolled in a drug efficacy trial in Kampala, Uganda, from 2006 to 2008. Sensitivities were measured by comparing levels of histidine-rich protein-2 in parasites incubated with different concentrations of drugs with those in untreated controls. The cultured parasites exhibited a wide range of sensitivities to chloroquine (CQ); monodesethylamodiaquine (MDAQ), the major active metabolite of amodiaquine; and quinine (QN). Mean 50% inhibitory concentration (IC(50)) results were above standard cutoffs for resistance for CQ and MDAQ. Parasites were generally sensitive to dihydroartemisinin (DHA), lumefantrine (LM), and piperaquine (PQ). For CQ, MDAQ, and QN but not the other drugs, activities against individual strains were highly correlated. We also assessed known resistance-mediating polymorphisms in two putative transporters, pfcrt and pfmdr1. When parasites that were least and most sensitive to each drug were compared, the pfmdr1 86Y mutation was significantly more common in parasites that were most resistant to CQ and MDAQ, and the pfmdr1 D1246Y mutation was significantly more common in parasites that were most resistant to MDAQ and QN. In summary, we demonstrated in parasites from Kampala a range of sensitivities to older drugs; correlation of sensitivities to CQ, MDAQ, and QN; and good activity against nearly all strains for DHA, LM, and PQ.
Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Resistência a Medicamentos/genética , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Testes de Sensibilidade Parasitária/métodos , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Polimorfismo Genético , Proteínas de Protozoários/genética , Resultado do Tratamento , UgandaRESUMO
Serological markers, combined with spatial analysis, offer a comparatively more sensitive means by which to measure and detect foci of malaria transmission in highland areas than traditional malariometric indicators. Plasmodium falciparum parasite prevalence, seroprevalence, and seroconversion rate to P. falciparum merozoite surface protein-119 (MSP-119) were measured in a cross-sectional survey to determine differences in transmission between altitudinal strata. Clusters of P. falciparum parasite prevalence and high antibody responses to MSP-119 were detected and compared. Results show that P. falciparum prevalence and seroprevalence generally decreased with increasing altitude. However, transmission was heterogeneous with hotspots of prevalence and/or seroprevalence detected in both highland and highland fringe altitudes, including a serological hotspot at 2,200 m. Results demonstrate that seroprevalence can be used as an additional tool to identify hotspots of malaria transmission that might be difficult to detect using traditional cross-sectional parasite surveys or through vector studies. Our study findings identify ways in which malaria prevention and control can be more effectively targeted in highland or low transmission areas via serological measures. These tools will become increasingly important for countries with an elimination agenda and/or where malaria transmission is becoming patchy and focal, but receptivity to malaria transmission remains high.