Impact of drug dose and treatment time on the synergism between pyrimethamine and sulfadoxine in the mouse malaria model
Open Access
- Author:
- Lai, Michelle Song
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Andrew Fraser Read, Thesis Supervisor
Sarah Mary Assmann, Thesis Honors Advisor - Keywords:
- drug resistance
malaria
pyrimethamine
sulfadoxine
treatment timing
drug dose
combination therapy - Abstract:
- One of the most threatening and quickly growing health issues is drug resistance, and malaria is a disease with a rampant history of it. A common strategy to battle resistant parasites is to apply another drug aggressively; however, doing so selects for resistance to the whole combination. This is especially true in synergistic drugs, where the primary and partner drugs potentiate each other to be more effective as a combination than either drug is on its own. There is evidence suggesting that different partner drug ratios and treatment timings at different points in immune response development could alter resistant parasite growth. This project examines changes in these factors in a classic failed antimalarial combination sulfadoxine-pyrimethamine (S/P), which synergistically impairs the parasite folate synthesis pathway that is necessary for growth. Different levels of sulfadoxine were tested in combination with a constant high dose of pyrimethamine on pyrimethamine-resistant parasites, first 1 day post-infection and in another experiment 6 days post-infection. In early treatment, higher doses of sulfadoxine increased the synergism and delayed growth rather than killing the parasites, which suggests that these doses may be optimal for inhibition without killing and as a result selecting for resistance to S/P. This could mean that S/P failed due to the ratio of partner to primary drug being too high. In later treatment, the effect of synergism changed to clearing infection, with even small doses of sulfadoxine clearing parasites immediately. However, sulfadoxine in later treatment also increased the probability of recrudescence, suggesting that no sulfadoxine treatment is actually better when pyrimethamine-resistant parasites are at their peak. Host health measured by anemia did not differ much by timing of treatment. Ultimately, these results lead to better understanding of how best to use antimicrobial drugs in combination and when to prescribe treatment, and they will contribute to the goal of developing treatment strategies that avoid inadvertently promoting the growth of drug-resistant pathogens. Future experiments are planned to test high, medium, and low S/P ratios in mixed infections to explore the chance of preventing S/P resistance development by competitive suppression and to determine the optimal dose.