August 08, 2014
Rising numbers of drug-resistant pathogens pose a grave concern for the global community. In May, the World Health Organization highlighted the dangers antimicrobial resistance presents on a global scale, with WHO Assistant Director-General Keiji Fukuda declaring that a post-antibiotic era once considered an apocalyptic fantasy is a very real possibility for the 21st century. Just two weeks ago, CDC Director Tom Frieden warned that antimicrobial resistance could be the cause of the next pandemic .
While much of the reporting on the subject focuses specifically on resistant bacteria, resistant malaria parasites also pose a significant threat to the progress made in decades of elimination and control efforts. Malaria is a vector-borne parasitic infection of the red blood cells. Though global malaria mortality rates have decreased by 42% since 2012, these advancements are endangered by reports of artemisinin resistance throughout the Greater Mekong subregion of Southeast Asia in Cambodia, Thailand, Vietnam, Myanmar, and Laos.
The current recommended first-line treatment for uncomplicated Plasmodium falciparum malaria is an artemisinin combination therapy (ACT) consisting of an artemisinin derivative in addition to a partner drug. The artemisinin component attacks the main parasite load for the first few days of treatment, while a partner drug with a longer half-life works to eliminate the remaining parasites over a longer period of time. Historically, as seen with both chloroquine and sulfadoxine-pyrimethamine, resistance has arisen first in the Greater Mekong subregion until spreading to reach Africa, where the malaria burden is already so great that the disease claims one child life per minute.
The best way to combat this increasing resistance is to provide an alternative treatment. However, there is currently no non-artemisinin based therapies set for release in the near future. Therefore, present actions must focus on minimizing the spread of resistance to maintain the therapeutic longevity of ACTs. This issue is important not only for endemic malaria regions but also on a global scale. In the US, malaria has been considered eliminated since the 1950s, yet there are still approximately 1,500 to 2,000 cases reported each year, primarily in individuals who have recently visited endemic malaria regions.
One idea for extending the efficacy of ACTs is the implementation of a policy of multiple first-line therapies (MFTs). By utilizing multiple therapies, parasite exposure can be minimized and the pressure on each individual drug can be reduced. Previous attempts to model a policy of MFTs have, however, arrived at varying conclusions. An early study that modeled this drug deployment strategy utilized an evolutionary-epidemiology model. The study found that MFTs would be a promising method for minimizing the emergence and spread of resistance. However, later research, which utilized a population genetics-based as opposed to an ecology-based model, suggested that an MFT strategy might not constitute a substantial improvement over a sequential drug deployment strategy and that, for high treatment rates, an MFT strategy may actually be less effective than a sequential strategy.
My research at CDDEP builds upon the previous evolutionary-epidemiology modeling framework to more accurately predict the results of an MFT policy. I will refine the model by introducing genetic-based factors, such as multiclonality or multiple resistant subpopulations, to see if this provides a more reliable framework for evaluating a policy of multiple first-line therapies. This research could help to establish a sustainable treatment strategy, which is of paramount importance if we hope to extend the therapeutic life of such a valuable treatment option and minimize the spread of multidrug-resistant malaria.
