Selection Of Drug-resistant Parasites Research Articles

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

The use of antimalarial drugs is an effective strategy in the fight against malaria. However, selection of drug resistant parasites is a constant threat to the continued use of this approach. Antimalarial drugs are used not only to treat infections but also as part of population-level strategies to reduce malaria transmission toward elimination. While there is strong evidence that the ongoing use of antimalarial drugs increases the risk of the emergence and spread of drug-resistant parasites, it is less clear how population-level use of drug-based interventions like seasonal malaria chemoprevention (SMC) or mass drug administration (MDA) may contribute to drug resistance or loss of drug efficacy. Critical to sustained use of drug-based strategies for reducing the burden of malaria is the surveillance of population-level signals related to transmission reduction and resistance selection. Here we focus on Plasmodium falciparum and discuss the genetic signatures of a parasite population that are correlated with changes in transmission and related to drug pressure and resistance as a result of drug use. We review the evidence for MDA and SMC contributing to malaria burden reduction and drug resistance selection and examine the use and impact of these interventions in Senegal. Throughout we consider best strategies for ongoing surveillance of both population and resistance signals in the context of different parasite population parameters. Finally, we propose a roadmap for ongoing surveillance during population-level drug-based interventions to reduce the global malaria burden.

Schistosoma mansoni sarco/endoplasmic reticulum Ca2+ ATPases (SERCA): role in reduced sensitivity to praziquantel.

Praziquantel leads to increase Ca2+ influx and disrupts Ca2+ homeostasis in adult Schistosoma. However, calcium influx is only one component in a series of molecular events leading to the drug effect and some downstream constituents of the cascade that is initiated by this interaction differ between worms with different degrees of susceptibility to praziquantel. Extensive use of the drug raises the concern regarding the selection of drug resistant parasites. SERCA participates in maintenance of Ca2+ homeostasis. Up-regulation of SERCA has been found in Schistosoma mansoni worms with reduced sensitivity to praziquantel. This could be due to increase cytosolic Ca2+, activation of calmodulin kinase II or may be due to SR/ER stress generated from oxidative stress that leads to impaired protein degradation. The significance of SERCA up-regulation is related to counter action of the drug effect by increasing the worm capacity to restore Ca2+ homeostasis, reducing cytosolic Ca2+ followed by lowering mitochondria Ca2+ and consequently inhibition of apoptosis beside its relation to P-glycoprotein. In schistosomes with reduced sensitivity to praziquantel, the agitations produced by Ca2+ influx and the downstream component of the cascade that is initiated by this interaction may be opposed by up-regulation of SERCA and possibly by certain elements of Ca2+ signaling which modulate the process determining cells entrance in the apoptotic state. Revealing the principal mechanisms of up-regulation of SERCA and its significance in reducing the effect of the drug could lead to possible strategies to reverse drug resistance or develop alternative therapies.

Assessment of mefloquine in-vivo efficacy on juvenile and adult stages of Schistosoma haematobium (Egyptian strain)

Background The large-scale use of praziquantel might result in selection of drug-resistant parasites. Hence, there is an important need to develop new antischistosomal compounds. Objective This study aimed for assessment of antischistosomal properties of an antimalarial drug, mefloquine (MFQ), on juvenile and adult Schistosoma haematobium worms. Materials and methods Infected hamsters were divided into two main groups, I and II, each subdivided into (a) and (b) subgroups. Groups Ia and IIa received 200 mg/kg MFQ as single oral dose, 49 and 82 days postinfection, respectively. Groups Ib and IIb served as untreated controls, respectively. Ten days later, animals were killed. Parasitological assessment (worm burden, tissue egg load, and oogram pattern), histopathological examination, and scanning electron microscopy were performed to evaluate MFQ efficacy. Results MFQ treatment of the juvenile group Ia resulted in considerable worm burden reductions of 75.9, 69.6, and 88.6% for male, female, and coupled worms, respectively. In the treated adult group IIa, the corresponding results were 24.8 and 95% for male and coupled worms, respectively. Separate female worms were detected only in the treated groups. In group IIa treated animals, MFQ also had an observed but statistically insignificant effect on tissue egg load and oogram pattern. Schistosomal granuloma area, diameters, and numbers were insignificantly decreased. Tegumental changes of treated worms in the form of shrunken deformed tegument, loss or flattening of tubercles, furrows, and blebbing were observed. Conclusion Results concluded by this study elucidate promising MFQ antischistosomal efficacy on both juvenile and adult stages of S. haematobium with more evident effect on juvenile forms, which enforces the potential use of MFQ as an effective antischistosomal drug.

Rapid Dissemination of Plasmodium falciparum Drug Resistance Despite Strictly Controlled Antimalarial Use

BackgroundInadequate treatment practices with antimalarials are considered major contributors to Plasmodium falciparum resistance to chloroquine, pyrimethamine and sulfadoxine. The longitudinal survey conducted in Dielmo, a rural Senegalese community, offers a unique frame to explore the impact of strictly controlled and quantified antimalarial use for diagnosed malaria on drug resistance.Methodology/Principal FindingsWe conducted on a yearly basis a retrospective survey over a ten-year period that included two successive treatment policies, namely quinine during 1990–1994, and chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) as first and second line treatments, respectively, during 1995–1999. Molecular beacon-based genotyping, gene sequencing and microsatellite analysis showed a low prevalence of Pfcrt and Pfdhfr-ts resistance alleles of Southeast Asian origin by the end of 1994 and their effective dissemination within one year of CQ and SP implementation. The Pfcrt resistant allele rose from 9% to 46% prevalence during the first year of CQ reintroduction, i.e., after a mean of 1.66 CQ treatment courses/person/year. The Pfdhfr-ts triple mutant rose from 0% to 20% by end 1996, after a mean of 0.35 SP treatment courses/person in a 16-month period. Both resistance alleles were observed at a younger age than all other alleles. Their spreading was associated with enhanced in vitro resistance and rapidly translated in an increased incidence of clinical malaria episodes during the early post-treatment period.Conclusion/SignificanceIn such a highly endemic setting, selection of drug-resistant parasites took a single year after drug implementation, resulting in a rapid progression of the incidence of clinical malaria during the early post-treatment period. Controlled antimalarial use at the community level did not prevent dissemination of resistance haplotypes. This data pleads against reintroduction of CQ in places where resistant allele frequency has dropped to a very low level after CQ use has been discontinued, unless drastic measures are put in place to prevent selection and spreading of mutants during the post-treatment period.