Antimicrobial Resistance Series Part 3: Antiparasitic Resistance

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Antiparasitic Resistance

“The development of antibiotics, antivirals and antimalarials are some of modern medicine’s greatest successes. Now, time with these drugs is running out. Antimicrobial resistance – the ability of bacteria, parasites, viruses and fungi to resist these medicines – threatens to send us back to a time when we were unable to easily treat infections such as pneumonia, tuberculosis, gonorrhoea, and salmonellosis.” – World Health Organization (WHO)

Antimicrobial resistance as one of the top ten global threats in 2019 according to WHO.

In part three of our series, we will be focusing on antiparasitic resistance.

Microbes and Antimicrobial Resistance Review

Microbes are:

Antimicrobial drugs are:

Parasites

Two types of parasites exist:

  • Helminths – Multicellular parasites with complex life cycles within and outside of their hosts.
  • Protozoa – Single-celled organisms that replicate by various mechanisms within the infected host. Protozoan parasites belong to four distinct groups: amebae, flagellates, ciliates, and sporozoa. 

Thus, the antiparasitic medications to combat them are classified as:

  • Anthelmintic
  • Antiprotozoal

Common Parasitic Infections

  • Heartworm
  • Intestinal Worms
  • Malaria

Heartworm Antiparasitic Resistance

Heartworm is a helminthic disease.

An Auburn University study from 2011 proved that antiparasitic drugs are losing their efficacy against heartworm in dogs of the southeast region (Mississippi River Valley) due to development of worm mutations.

The study stated that while all but one of the drugs were less than 100% efficacious, the mean number of heartworms found in the untreated group was 51.6, whereas the treated groups had only about 2-3 worms or worm fragments.

Hemopet and Dr. Dodds advise the use of heartworm preventatives for healthy dogs – once the ambient temperature is above 57 degrees Fahrenheit (14 degrees Centigrade) for approximately two weeks and mosquitoes are prevalent. A basic rule of thumb is Mid-April through November for the majority of the country and basically year-round for the southern states.

It is much easier to treat a dog with 2-3 heartworms compared to a heavy burden. In essence, while the scientific community grapples with this growing inefficacy due to antiparasitic resistance, the currently available drugs are efficacious to a lesser to greater degree and should still be used.

Intestinal Worms

Intestinal worms are also helminths.

In December 2018, the U.S. Food and Drug Administration (FDA) launched an educational campaign to curb antiparasitic resistance in livestock, particularly for grazing species such as cows, goats and sheep, as well as horses. The agency says human health is not directly affected in the United States, but that production losses would be significant. 

The FDA also admits that antiparasitic resistance cannot be stopped. Indeed, we have seen this happening globally.

For instance, ivermectin was introduced in the late 1970’s and the FDA approved it for U.S. use in 1984.

Ring any bells? Most of us know the drug under the brand name, Heartgard, a heartworm preventative for dogs. Bear in mind, the FDA has only approved it for this purpose in canines.

Ivermectin, though, is more broad-spectrum and can actually target intestinal roundworms as well.

In 1988, the first report of parasitic resistance to ivermectin was documented in sheep raised in South Africa. Think about it: it only took ten years for the parasites to develop resistance. Since then, additional cases have been documented to macrocytic lactones, the class of drugs of which ivermectin is a part.

Fast forward to 2019. The FDA still approves ivermectin for roundworm prevention in sheep. The agency is particularly worried about this population, because the barber pole roundworm causes severe disease that could lead to death.  

So, to increase the viability and time of ivermectin and other anthelmintics used in sheep and other grazing animals, the FDA has proposed an innovative sustainable use strategy. There are many management tips such as fecal testing, and avoiding deworming through water or feed. When farmers do this, however, they are not giving a full dose and thereby ultimately increasing antiparasitic resistance. We compare it to a mild case of the flu: one might get a little sick, but then develops immunity to resist that flu strain in the future.  

The most fascinating sustainable use practice is refugia. Basically, a farmer or veterinarian treats 50% of the herd with dewormers.  Yes; intestinal worm eggs and larvae will still be present on the ground from defecation. However, preserving some of the parasites susceptible to antiparasitic drugs will dampen the proportion of resistant parasites within the parasite population and slow their takeover of a farm. 

Farmers should work closely with their veterinarians to implement these changes instead of applying them on their own. [Note: Another fascinating property of ivermectin is as an anticancer agent.]

Malaria

Malaria is a protozoal disease that is spread primarily by mosquitoes. The WHO reports 219 million cases worldwide and 435,000 deaths in 2017.

With malaria, there are few treatment options. Those that are available become quickly exhausted due to mismanagement, wrong dosage, parasitic resistance, or something within in the parasite that becomes resistant to the drugs. In fact, parasite resistance to antimalarial medicines has been documented in 3 out of the 5 malaria species known to affect humans: Plasmodium falciparum, P. vivax and P. malariae.

For a really quick side note, when the phrase “antimalarials” is used, it refers to a special category of drugs such as antiprotozoal medications, antiprotozoal/antibiotic combinations or antibiotics that target malaria. Yes – antibiotics.

How do the antibiotics work here? Antibiotics are not targeting a secondary bacterial infection in the host (human) that may have been caused by the parasite, but are targeting bacteria in the parasite that it needs to survive.

One example is that some antibiotics target the apicoplast of the parasite, a small cellular organ of bacterial origin that the parasite needs to penetrate other cells of the host organism. Of course, it depends upon the antibiotic used.

Sulfadoxine-pyrimethamine is a combination drug of an antibiotic and an antiprotozoal, respectively. This drug works differently because it targets the folate biosynthetic pathway of the malarial parasite, which arrests the nucleic acid biosynthesis and hence causes parasite death.

Unfortunately, certain strains of P. falciparum have developed resistance to sulfadoxine-pyrimethamine and nearly all of the other currently available antimalarial drugs, like mefloquine, halofantrine, quinine and chloroquine.

Chloroquine is possibly the saddest story. This antiprotozoal was used for mass drug administration in the 1950’s and 60’s, which is believed to have contributed to chloroquine-resistance in the parasite.

On top of that, cross resistance compounds the problem. This occurs when resistance to one drug confers resistance to other drugs that belong to the same chemical family or which have similar modes of action.

Currently, the last line of defense against P. falciparum is artemisinin-based drugs. Artemisinin had been used by Chinese herbalists for ages. In the 1970’s, Chinese researchers rediscovered it. It was not widely available outside China until the 1990s.

WHO was very cautious about artemisinin use as a first line treatment option due to concerns of parasitic resistance. However, the organization was pressured to revise this guideline. This revision has hastened parasitic resistance, exactly what WHO was trying to avoid. Now, we are seeing artemisinin resistance cropping up particularly in the Greater Mekong River Delta. The greatest concern is that this resistance will spread quickly across the globe.

Nowadays, medical researchers are still debating if antimalarials should be given as a prophylaxis (preventative). Plus, ongoing research and testing continues for a vaccine against malaria.    

References

“2017 Summary Report on Antimicrobials Sold and Distributed for Use in Food-Producing Animals”. U.S. Food and Drug Administration, Dec. 2018, http://www.fda.gov/media/119332/download.

“Antimalarial Drug Efficacy and Drug Resistance”. World Health Organization, 27 Aug. 2018, http://www.who.int/malaria/areas/treatment/drug_efficacy/en/.

“Antiparasitic Resistance”. U.S. Food and Drug Administration, 6 Dec. 2018, http://www.fda.gov/animal-veterinary/safety-health/antiparasitic-resistance.

Dodds, Jean. “Common Intestinal Worms in Dogs and Cats”. Hemopet, 19 Feb. 2017, https://www.hemopet.org/intestinal-worms-dogs-cats/.

Juarez et al. “The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug”.  Am J Cancer Res.2018;8(2):317-331.

Kornele, Michelle L., et al. “Antiparasitic Resistance and Grazing Livestock in the United States.” Journal of the American Veterinary Medical Association, vol. 244, no. 9, 1 May 2014, pp. 1020–1022., doi:10.2460/javma.244.9.1020, https://avmajournals.avma.org/doi/full/10.2460/javma.244.9.1020.

Packard, Randall M. “The Origins of Antimalarial-Drug Resistance.” New England Journal of Medicine, vol. 371, no. 5, 31 July 2014, pp. 397–399., doi:10.1056/nejmp1403340, https://www.nejm.org/doi/full/10.1056/NEJMp1403340.

“Ten Threats to Global Health in 2019.” World Health Organization, http://www.who.int/emergencies/ten-threats-to-global-health-in-2019.

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