Plasmodium falciparum in human blood – credit Wikipedia
One of the realities of our never-ending battle against infectious diseases is that these organisms are able to evolve, and adapt, at an amazing rate, and that the antivirals, antibiotics, and other drugs in our arsenal of therapeutic drugs can – over time – lose some or all of their effectiveness.
Antibiotic resistance has been the greatest concern, and in recent years we’ve seen some antiviral drugs falter badly (Amantadine, a stalwart against influenza for decades, became unusable in 2005), often due to poor stewardship.
Anti-malarial drugs are not immune to this sort of evolutionary obsolescence, and any loss in effectiveness would put millions of people at risk of serious illness or even death. Spread by mosquitoes, and caused by a parasite – Plasmodium – Malaria is common in much of the world including Sub-Saharan Africa, Asia and the Americas.
There are four microscopic protozoan parasites in the genus Plasmodium (P. vivax, P. falciparum, P. malariae and P. ovale) that cause malaria in humans around the world. Of these Plasmodium falciparum is generally the most serious.
The parasites multiply in the liver and infect red blood cells, resulting in recurrent fevers and headaches - and in severe cases - coma and death. Despite advances, Malaria remains an extremely serious problem in Africa, where 1 in 5 childhood deaths is due to the disease. According to the WHO’s 10 Facts on Malaria:
About 3.2 billion people – almost half of the world's population – are at risk of malaria. In 2013, there were about 198 million malaria cases (with an uncertainty range of 124 million to 283 million) and an estimated 584 000 malaria deaths (with an uncertainty range of 367 000 to 755 000). Increased prevention and control measures have led to a reduction in malaria mortality rates by 47% globally since 2000 and by 54% in the WHO African Region.
According to the WHO, the best available treatment - particularly for P. falciparum malaria - is artemisinin-based combination therapy (ACT). Earlier treatment options such as choloroquine - the cheapest and for years the most commonly used drug - and the combination of sulfadoxine-pyrimethamine have slowly lost their effectiveness. .
Of concern, since about 2007 evidence of resistance to the newer drug regimen ACT has been showing up on the Cambodian-Thai border, and more recently in Myanmar (see MYANMAR: Anti-malarial drug resistance "hotspots" identified).
For now, ACT seems to be working in Africa, but the following press release from the London School of Hygiene & Tropical Medicine, suggests that success may be in danger. Researchers report finding Plasmodium falciparum malaria parasites with a mutation to the gene Ap2mu were less sensitive to artemisinin.
The abstract and full text to the dauntingly titled study - The Mu Subunit of Plasmodium falciparum Clathrin-Associated Adaptor Protein 2 Modulates In Vitro Parasite Response to Artemisinin and Quinine – is available from Antimicrobial Agents and Chemotherapy.
Fortunately we also have the following press release to go along with it.
London School of Hygiene & Tropical Medicine
Early indicators of the malaria parasite in Africa developing resistance to the most effective drug available have been confirmed, according to new research published in Antimicrobial Agents and Chemotherapy.
Researchers at the London School of Hygiene & Tropical Medicine found Plasmodium falciparum malaria parasites with a mutation to the gene Ap2mu were less sensitive to the antimalarial drug artemisinin.
A study in 2013, also led by the School, suggested an initial link between a mutation in the ap2mu gene and low levels of malaria parasites remaining in the blood of Kenyan children after they had been treated. However, further research was needed to confirm if these genetic characteristics represented an early step towards resistance.
In the new study, researchers genetically altered the malaria parasite in the laboratory to mutate ap2mu in the same way that had been observed in Kenya. They found the altered parasite was significantly less susceptible, requiring 32% more drug to be killed by artemisinin. The genetically altered parasite was also 42.4% less susceptible to the traditional antimalarial drug, quinine.
Earlier this year a different research group discovered mutations in the gene kelch13 which were linked to reduced susceptibility to artemisinin combination treatment in South East Asia. Historically, resistance to antimalarial medicines has emerged in South East Asia and then spread to Africa. But these new findings suggest a different route to drug resistance may be developing independently in Africa.
Lead researcher Dr Colin Sutherland, Reader in Parasitology at the London School of Hygiene & Tropical Medicine, said: "Our findings could be a sign of much worse things to come for malaria in Africa. The malaria parasite is constantly evolving to evade our control efforts. We've already moved away from using quinine to treat cases as the malaria parasite has become more resistant to it, but if further drug resistance were to develop against our most valuable malaria drug, artemisinin, we would be facing a grave situation.
"We now know that the gene ap2mu is an important factor in determining how well our drugs kill malaria parasites. We will be conducting laboratory and field studies to more accurately measure the impact of mutations in the ap2mu gene. We hope our findings will help understand resistance of malaria to drugs, and potentially be an important tool for monitoring malaria treatment in the future."
The World Health Organization estimates more than half a million people die from malaria every year, mostly children under five. Plasmodium falciparum is the most deadly form of the malaria parasite.
If nature weren’t capable enough on its own, helping these parasites along in their arms race has been the fact that a large percentage of the anti-malarial drugs used in Asia and sub-Saharan Africa are either fake, or are of inferior quality (see Lancet: 1/3rd Of Malaria Drugs Fake Or Sub-Standard).
Using drugs that contain too little of their intended active ingredient can contribute to pathogens developing increased and widespread resistance over time.
This is a big enough problem that the CDC maintains a webpage devoted to Counterfeit and Substandard Antimalarial Drugs: Information for Travelers.
With World Malaria Day set for April 25th, we can expect to hear a good deal more about this devastating and often deadly disease over the next week.