14 Sept 2020
Hany Elsheikha BVSc, MVSc, PhD, PGCHE, FHEA, DipEVPC discusses the efficacy of macrocyclic lactones across multiple species, as well as considerations before using them.
Hany Elsheikha
Job Title
Interspecies differences – in regard to pharmacokinetics of macrocyclic lactones – exist between donkeys and horses. Image: Edwina Lawson
Macrocyclic lactones (MLs) are a unique group of parasiticides that are commonly used in veterinary practice for the treatment and control of parasitic infections in various animal species.
The importance of MLs lies in their mode of action, which is based on the disruption of chloride channel neurotransmission in endoparasites and ectoparasites. Drugs in this group – such as abamectin, doramectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin and selamectin – are therefore known as endectocides.
For many years, MLs have been used to control nematodes and arthropods (insects, ticks and mites) affecting livestock, companion and exotic pets. In humans, ivermectin has been used in mass treatment programmes to eradicate the vector-borne filarial disease onchocerciasis. Also, some MLs have been found to have a therapeutic potential for the treatment or immunomodulation of some forms of cancer.
Although MLs are considered the most potent parasiticides currently available, their effectiveness is threatened by drug resistance. Indeed, the rise and spread of drug resistance is a major challenge to maintaining a sustainable parasite control that the veterinary profession should address with a multidisciplinary-driven collaboration, not less, in the years to come to preserve the efficacy of MLs and other parasiticides.
Here, the author provides a concise overview of the role of MLs in parasite management in different animal species and discusses issues that should be considered before using ML drugs.
With the high diversity and prevalence of internal and external parasites in livestock, companion animals and exotic animals, a range of antiparasitic drugs have been developed – and are being used – to control parasitic infections and infestations.
In veterinary medicine, when it comes to treatment of parasitic diseases, macrocyclic lactones (MLs) can be easily ranked top of the list of the most powerful therapeutics.
Since the serendipitous discovery of ivermectin in 1981, significant achievements have been made in developing a number of related compounds, which took the practice of parasite control to a new era due to their high efficacy and good safety profiles.
The MLs are produced through fermentation by the soil-dwelling Streptomyces fungi. MLs are known as endectocides because they have intrinsic nematocidal, insecticidal and acaricidal activity.
Many MLs are available on the market, with indications against insects, ticks and nematodes (roundworms). However, MLs are ineffective against other categories of helminths (worms) – such as cestodes (tapeworms) and trematodes (flukes) – because they do not possess the pharmacological target (glutamate‑mediated chloride channels).
MLs include two major subgroups:
avermectins – for example, abamectin, eprinomectin, doramectin, ivermectin and selamectin
milbemycins – for example, milbemycin, moxidectin and nemadectin
ML compounds have a similar general chemical structure, with only minor differences in some substituents.
The ML drugs augment the action of the inhibitory neurotransmitter gamma‑aminobutyric acid (GABA). They exert their action by binding to the membrane of neurons and myocytes, and inducing the production of GABA, which, in turn, activates GABA-gated chloride channels that are specific to invertebrates (roundworms and arthropods [insects, ticks and mites]), causing increased influx of chloride ions into the parasite neurons and myocytes.
This influx hyperpolarises the neuronal membranes and decreases nerve transmission at the neuromuscular junction, leading to flaccid paralysis, and death of the treated arthropods and nematodes (Lanusse et al, 2018).
Ivermectin can also cause permanent opening of other ligand-gated chloride channels − especially glutamate-gated channels in the membrane of the parasite neurons. This inhibits nerves that control the muscles in the pharynx (results in a decrease in food intake and parasite starvation), the uterine muscle (results in a reduction in egg deposition) and the worm body wall muscles (causing flaccid paralysis and expulsion of the worms outside the host).
The large safety margin of ML drugs is attributed to the differential location of the GABA-mediated chloride channels. In the target invertebrate parasites (arthropods and nematodes), these GABA‑mediated chloride channels receptors are located at the neuromuscular junction.
On the other hand, the GABA-mediated chloride channels are present in the CNS in mammals, which are protected from accumulation of MLs inside the brain through the action of a permeability glycoprotein (P-gp) transmembrane efflux pump, which is expressed at high levels in the blood brain barrier (BBB).
Mammalian P-gp transporters are efficient sensor transducers because they can sense the presence of MLs inside brain cells and respond by upregulating the efflux mechanism, which allows the release of MLs outside the cells that results in a reduction of the ML concentrations in the brain. Therefore, a mammalian host can be at risk of the cytotoxic effect of MLs due to entry of these chemotherapeutic agents into the CNS when the P-gp transporter becomes overwhelmed by the drug, in case of overdosage, or if the transporter is inhibited via a prior or concurrent administration of a P-gp inhibiting drug.
The third – and infamous – possibility is when an animal has a genetic defect in the adenosine triphosphate‑binding cassette subfamily B member 1 (ABCB1) gene (formerly known as multidrug resistance protein 1) that encodes the P-gp transporter (Mealey et al, 2001).
Ironically enough, the mechanism that protects mammalian species from ML toxicity (P-gp transporter-mediated efflux) is the same mechanism that makes parasites “drug resistant”.
MLs have several uses in companion animal parasitology (Nolan and Lok, 2012).
A number of products contain ivermectin, milbemycin oxime, moxidectin or selamectin that are used to treat and control nematodes in dogs and/or cats. These products are formulated for injection, oral route or topical application.
The MLs are mainly used in dogs and cats on a monthly basis as a chemoprophylaxis against heartworm (Dirofilaria immitis) infection to kill the third-stage and fourth‑stage larval stage of the filarial nematode.
Some products contain one ML compound as an active ingredient – for example, milbemycin oxime, moxidectin or selamectin – to expand the label claims to include gastrointestinal nematode species, such as Ancylostoma species (hookworms) and ascarid roundworms of Toxocara species. For example, milbemycin oxime combined with praziquantel is indicated for the prevention of heartworm (D immitis), and for the treatment and control of intestinal hookworms, roundworms and whipworms, and intestinal tapeworms (Dipylidium caninum, Taenia species and Echinococcus species) in dogs.
Topical or ear products containing an ML ingredient – such as selamectin, moxidectin, milbemycin oxime or ivermectin – have been used for the management of fleas, hard ticks and mange (sarcoptic, demodectic and ear) mites.
The MLs have been also used off-label against Capillaria species (nematodes infecting the urinary tract) and the tissue-dwelling nematodes (for example, the filarial nematodes Dipetalonema reconditum and Dirofilaria repens), the eye nematode (Thelazia species) and the oesophageal nematode (Spirocerca lupi) in companion and exotic pets.
Off-label usage of MLs has been also reported against ectoparasites in dogs and cats. These include notoedric mange mite (Notoedres cati), fur mites (such as the walking dandruff mite Cheyletiella and the cat fur mite Lynxacarus radovskyi) and chiggers caused by parasitic larval stage infestation of trombiculid mites.
The MLs are widely used in livestock and horses due to the convenience provided by their broad activity against nematodes and arthropods.
In cattle, MLs have been used to control cattle grubs, an economically important skin infestation by larvae of the warble flies (Hypoderma lineatum and Hypoderma bovis), leading to formation of warts on the skin of the back of infested cattle.
Treatment of cattle grubs is generally recommended in the autumn and spring, because earlier treatment while the fly grubs/larvae are still present near the oesophagus and spinal column can incite severe adverse effects (Lia et al, 2019). In this scenario, substances leaking from the dead larvae can cause paralysis, shock or even death.
MLs are also effective against lice – particularly sucking lice. However, MLs are not effective against lice nits, so further treatments are required to kill newly hatched young lice.
MLs have been also widely used by small ruminant (sheep and goat) producers and – like in benzimidazoles and cholinergic receptor anthelmintics (for example, levamisole) – extensive resistance to the ML group has been recorded in Haemonchus contortus and other trichostrongyle nematodes (Falzon et al, 2013).
Anthelmintic resistance (AR) can arise due to various factors, such as increase of drug efflux pumps, changes in the permeability changes of the cell membrane, enzymatic modification of the drug or modification of the target site.
Regardless of which mechanism is responsible for this problem, the spread of AR represents the most pressing challenge to animal health and welfare, and to a sustainable livestock industry – and even may threaten global food security (Hodgkinson et al, 2019). Therefore, farms using ML drugs should check the efficacy before administering the drug.
Also, regardless of whether an ML product or another anthelmintic is used, the development of drug resistance can/should be controlled by using drugs sensibly and in combination, together with considering other factors (for example, preserving the populations of parasites not exposed to anthelmintics – known as “refugia” in small ruminants and horses).
The Faffa Malan Chart‑based programme has been used in the US for targeted selective treatment in farms where H contortus is the main gastrointestinal nematode in the flock.
In donkeys, ivermectin is indicated for treatment of gastrointestinal (GI) nematodes, the lungworm Dictyocaulus arnfieldi and arthropods. Doramectin has been used to treat GI nematodes and D arnfieldi; eprinomectin was used for D arnfieldi and lice; and moxidectin was used to treat GI nematodes and D arnfieldi, and was used off-label to treat encysted cyathostomin larvae of small redworms.
Evidence for moxidectin resistance was reported in donkeys nearly 15 years ago. In horses, the MLs group of dewormers – such as ivermectin and moxidectin – are commonly used for the control of roundworms, encysted/hypobiotic cyathostomin larvae and bots. Moxidectin is more effective in eliminating encysted small redworms than ivermectin.
Veterinarians should be conscious of the pharmacokinetic differences between donkeys and horses that may influence dosage, treatment intervals, drug potency or even the possibility for side effects (Mendoza et al, 2019).
A number of studies reported the efficacy of MLs against internal and external parasites in some exotic animal species (Nolan and Lok, 2012; Hawkins, 2015).
For example, topical application of selamectin (6mg/kg to 18mg/kg) was used to treat a number of mite species in rabbits. Also, selamectin was shown to be effective against the ear mite in ferrets.
Moxidectin has been used to treat nematodes and mites in various reptiles. Milbemycin was used to treat pinworms in turtles.
Furthermore, ivermectin has been used to treat ear mites in rabbits, Ornithonyssus bacoti in hamsters, and Myocoptes species and pinworms in mice.
Some MLs have been repurposed for medicinal uses in humans. For example, ivermectin has been used in humans since 1987. This drug has been shown to inhibit the P-gp transporter in human multidrug‑resistant leukaemia cells (Didier and Loor, 1996).
Additionally, abamectin significantly decreased tumour growth and augmented the suppressive effect of vincristine on carcinoma (Drinyaev et al, 2004).
A less known ML product in the veterinary world, rapamycin, is derived from the soil bacteria Streptomyces and has antifungal activity – especially against Candida albicans. This drug was approved by the US Food and Drug Administration in the 1990s as an immunosuppressive agent. Rapamycin has been shown to significantly inhibit many cell lines derived from different types of tumours (Huang and Houghton, 2001). Also, rapamycin significantly inhibited the growth of several tumour types in animal models (Hidalgo and Rowinsky, 2000).
Interestingly, ivermectin has been reported to have antiviral effects on many viruses, including avian influenza type A virus, dengue virus, Hendra virus, Newcastle disease virus, Venezuelan equine encephalitis virus, West Nile virus, yellow fever virus and Zika virus. Given its potential effects on many diseases and pathogens, ivermectin has been considered by some scientists as a possible candidate that could be used for the treatment of serious viruses, such as COVID-19 (Heidary and Gharebaghi, 2020).
Ivermectin has been used in the mass treatment programmes of human onchocerciasis to eliminate the larvae (known as microfilariae) of the causative agent Onchocerca volvulus. Onchocerciasis is a neglected tropical disease common in some parts of sub-Saharan Africa, Central America and Latin America.
Ivermectin paralyses the microfilariae, allowing human immune cells (such as macrophages) to remove them before they decay and leak allergenic substances into the circulation that cause shock. Ivermectin treatment also reduces the adverse reaction associated with skin infection by O volvulus.
However, it does not eliminate adult worms living inside skin nodules – known as onchocercomas – and does not influence microfilaria release. Moxidectin is more effective than ivermectin in reducing the skin microfilarial loads (Opoku et al, 2018).
Adverse reactions have been reported two to four days after the administration of ivermectin in some individuals. These side effects include pruritus, rashes, nausea, vomiting, occasional haematomas and ocular irritation associated with death of microfilariae in the eye. Ivermectin should not, therefore, be used in individuals with a coexisting infection with the eyeworm Loa loa, because this triggers more severe reactions.
Having a broad spectrum of activity against external and internal parasites is definitely a big advantage that MLs possess compared to other classes of anthelmintics. However, efficient administration of these endectocides requires some attention.
For example, variations exist among external and internal parasites in terms of their sensitivity to MLs. So, if an ML compound is administered at the recommended dose(s) for a nematode infection, this can expose ticks on the treated animal to an ineffective/suboptimal concentration that can select for resistance in that exposed tick (Rodriguez-Vivas et al, 2018).
Veterinarians should ask clients to be responsible and refrain from any inappropriate application of endectocide products in a manner inconsistent with the indications on the label, and to handle the products safely. Excessive use and/or misuse of an endectocide can lead to drug resistance, which, in the long-term, will have an adverse impact on animals, humans and the environment.
As aforementioned, physiological and pharmacological differences exist between the invertebrate parasites and vertebrate animals. These differences are sufficient to minimise the possibility of occurrence of toxicity due to the use of ML drugs.
Ivermectin exerts toxicity by blocking GABA-mediated neurotransmission.
When used as recommended by the manufacturer, MLs have limited toxicity to most animal species, including dogs with a functional P-gp transporter (Lanusse et al, 2009). However, ML toxicity could happen in any animal species when a large high dose is administered because it can result in saturation of the transport capacity of the P-gp pump.
Therefore, despite the safety and efficacy of the MLs, products containing MLs should be used with care and under a veterinarian’s direction.
In general, MLs are considered safe when used as recommended. However, unintentional exposure to ML-containing products intended for ruminants or horses can cause toxicity in dogs.
Most dogs with normal ABCB1 gene and functional P-gp transporter tolerate oral ivermectin treatment up to 2.5mg/kg before signs of toxicity develop; however, a possibility exists that some dogs may exhibit some mild signs (Merola and Eubig, 2012).
Some dog breeds – especially collies and others including the Australian shepherd dog, English shepherd dog, German shepherd dog, whippet (long‑haired), McNab, Old English sheepdog, Shetland sheepdog, silken windhound, Wäller and white Swiss shepherd – possess genetic mutations in the ABCB1 gene, which results in a defective P-gp transporter in the BBB. These ML-sensitive dog breeds are, therefore, more prone to ivermectin toxicity at a low dose (80µg/kg to 100µg/kg).
ABCB1-defective dogs can be also sensitive to milbemycin and exhibit side effects at 5mg/kg.
Neurological signs were reported in a one‑year‑old male cat that were attributed to interaction between milbemycin oxime and spinosad, even though both drugs were administered as per the label recommendations (Jenkins et al, 2019).
The insecticide spinosad, an ML of the spinosyn class, is generally used for the management of fleas. The clinical signs of neurotoxicity can occur at lower doses in not only individuals with a defective P-gp, but also in young animals with immature BBB that is more permeable to the drug. Therefore, ivermectin should not be given to kittens because of a high possibility it crosses the BBB.
Likewise, older animals may be at risk of toxicity because P-gp expression was found to be reduced significantly in dogs older than eight years old compared to dogs younger than three years old (Pekcec et al, 2011).
The downregulation of the P-gp may lead to a reduction in the elimination of MLs from the brain.
Some exotic species – such as Chelonians, lizards and snakes – seem to be sensitive to ivermectin.
Some Chelonians are highly vulnerable to ML toxicity – the leopard tortoise can develop adverse signs even at a dose of 25µg/kg. The reason for the high sensitivity of Chelonians – whether caused by dysfunctional BBB or another reason(s) – is yet to be determined.
Abamectin has been found to cause testicular pathology in rats.
Livestock seem more tolerant to MLs than companion pets. The main concern about the use of MLs in farm animals is the adverse impact on untargeted dung‑feeding invertebrate species, which play various roles in maintaining the ecosystem function and the agricultural landscape.
The influence of body condition and physiology on ML toxicosis remains inconclusive, but it has been reported that pharmacokinetics of ivermectin, eprinomectin and moxidectin were significantly affected in obese dogs (Bargues et al, 2009).
Ivermectin has a high affinity to albumin and lipoproteins in the blood (González Canga et al, 2009), which means that in malnourished or hypoalbuminaemic animals, more severe clinical signs may develop due to increase in the free drug concentration.
Cats with low body condition scores are more likely to develop severe toxicity than their counterparts with higher body condition scores (Jourdan et al, 2015).
In recent years, concerns have been increasing over the growing prevalence of obesity in companion pets. The influence of obesity on ML toxicosis remains incompletely defined and more investigations are required to identify appropriate dosing for current therapeutics in obese animals, which are excluded from clinical trials.
However, it is possible that in obese animals, a longer treatment duration may be required due to the longer time needed for drug distribution into the large fat compartment and the higher drug elimination half time.
Chemotherapeutics – such as MLs and other parasiticides – are essential component of the treatment and control plan against parasitic infections.
However, a chemotherapy-alone approach is not going to achieve the expected outcome that meets the expectation of the animal owners and pharmaceutical companies. Also, the growing resistance to anthelmintic agents is one of the major obstacles to the successful treatment of parasite infection – especially in small ruminants.
Therefore, parasite control programmes should implement additional, non‑pharmacological measures to support the chemotherapeutic treatment.
Endectocides (MLs) achieved an unparalleled legacy when it comes to the control of metazoan parasites (worms and arthropods). By providing protection against both endoparasitic nematodes and ectoparasitic arthropods, endectocides offer a high degree of convenience and flexibility that veterinarians and animal owners enjoyed for many years.
Simultaneous treatment of endoparasites and ectoparasites can simplify the parasite control programme, and, in some occasions, reduces the cost of treatment. Unfortunately, the growing and rapid emergence of drug‑resistant parasites is increasingly endangering the efficacy of antiparasitic drugs.
While the search for new parasiticides will continue, getting new anthelmintics to market takes a long time. Also, the cost of developing new drugs is escalating, meaning the motivation for new drug discovery waxes and wanes.
Therefore, given the excellent track record of endectocides for safety and efficacy in treating parasite infections/infestations, it is essential to implement parasite control practices that preserve the efficacy of these drugs as much and as long as possible.
Also, while parasiticides are the mainstay of parasite control plans, other complementary measures should not be ignored – such as hygiene and proper husbandry – that are as important as chemotherapeutic treatment.
Some drugs mentioned in this article are used under the cascade.
The author declares no competing financial interest.
