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Facing up to anthelmintic resistance

by
01 November 2016, at 12:00am

Nick Thompson believes that with resistance to all major classes of anthelmintics becoming increasingly widespread, it’s time to take a serious look at how we treat these parasites.

ACCORDING TO THE WORLD HEALTH ORGANIZATION, over two billion people, including tens of millions of young children and pregnant women, are infected with helminths or parasitic worms.

In humans, these parasites cause malnutrition, diarrhoea, dysentery and anaemia and can even lead to death, while the economic impact on worldwide livestock production is substantial and often devastating. 

You would be wrong for thinking this is solely a developing country problem. The UK Government’s Medicines and Healthcare Products Regulatory Agency website states that “it is estimated that up to 40% of children under 10 in the UK may be affected [by worms] at any one time”.

Yet the drugs used to treat worm infestations in both humans and animals are becoming less and less effective. The emergence of multi-drug resistance in this eld is no surprise. Anthelmintic drug treatments have for too long been limited to three major chemical classes – benzimidazoles, imidazothiazoles and macrocyclic lactones – all of which rely on compounds that act in similar ways. So resistance to one compound inevitably leads to resistance to another, with more and more worms developing resistance to all three.

In recent decades, very few significant alternatives have been introduced. Since the introduction of moxidectin (the most recent and most effective of the macrocyclic lactones) in 1997, only one new class of anthelmintics has been discovered.

Amino- acetonitrile derivatives (AADs) came to market in 2009 but resistance to them emerged only five years later. All these drugs, once effective, now have significant worm resistance problems. Multi- drug resistance (worms resistant to all available drugs) is now a global phenomenon.

Drug resistance is not new. The antibiotics introduced in response to Alexander Fleming’s renowned discoveries hit resistance, on average, within a decade. Remarkably, penicillin- resistant bacteria first appeared in 1941, before the drug was even in full production.

The recent Review on Antimicrobial Resistance, commissioned by the UK Government in collaboration with the Wellcome Trust and led by economist Jim O’Neill, predicts that by 2050 antibiotic resistance could lead to the loss of 10 million human lives a year, incurring an annual global cost of $100 trillion.

Significantly, the Review, which published its findings in two reports in 2015 and 2016, highlighted the similarity between the development of antibiotic and anthelmintic resistance: “Many of the solutions we have put forward could be applied to this important area [parasites] too. In particular, we recognise that resistance to antiparasitics for certain zoonotic parasites [has] become a major problem.”

Finding a sustainable solution

Understanding how the current interventions work – or don’t work – is the key to finding a sustainable solution. The problem with resistance is not the worm’s ability to survive a dose of anthelmintic that would normally be effective but the fact that this ability is hereditary. The worm can pass this ability to survive on to its offspring.

The flaw in anthelmintics is that they have never been 100% effective. There are always survivors. With the competition removed, the survivors do what survivors do best: thrive and reproduce, establishing a new generation of worms with the ability to resist the only drugs available to kill them.

So it could be argued that the more often the drugs are used, the greater the opportunity afforded to those with the rare ability to resist them to thrive. In fact, it is widely believed that overuse of wormer drugs in animals, food-producing species in particular, is a major causative factor in the emergence of anthelmintic resistance. 

Professor Ray Kaplan, a leader in the eld of veterinary parasite resistance in the US, advocates a global roll-out of Norwegian and Dutch anthelmintic control models. These approaches include the restriction of wormers to prescription-only status, under the exclusive control of vets.

In Norway alone, this measure has seen a 40% drop in the rate of development of resistance in the country’s livestock. Furthermore, the vets in these countries follow strict guidelines governing how and when to prescribe anthelmintic drugs.

Understanding the scope and scale of the challenge is also critical. Kaplan argues that funding is needed to develop and implement a more efficient and frequent anthelmintic resistance testing system. Other interventions include strict quarantine measures for livestock, the limited and selective dosing of herds, combination drug strategies, worm-trapping fungi, anti- parasitic vaccines and botanical (often called herbal) wormers.

The experience of antibiotic resistance suggests the direction in which worm control is heading. It is not unreasonable to expect that the devastating antibiotic resistance story of today will be the story of anthelmintic resistance tomorrow.

Whatever the parallels, anthelmintic resistance is now so frequent, so widespread and poses such a threat both to global public health and to worldwide livestock production that it requires urgent attention.

As far back as 1997, studies (starting with Chan, M.S., Parasitol Today) have suggested the disease burden of helminths might be as great as those of malaria or tuberculosis and yet still we do nothing to tackle the problem of anthelmintic resistance. It really is now time to act.