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Arthropod parasites (ectoparasites) are a major cause of production losses in livestock throughout the world. In addition, many arthropod species act as vectors of disease for both animals and humans. Treatment with various drugs to reduce or eliminate ectoparasites is often required to maintain health and to prevent economic loss in food animals. The choice and use of ectoparasiticides depends to a large extent on husbandry and management practices, as well as on the type of ectoparasite causing the infestation. Accurate identification of the parasite or correct diagnosis based on clinical signs is necessary for selection of the appropriate drug. The selected agent can be administered or applied directly to the animal, or introduced into the environment to reduce the arthropod population to a level that is no longer of economic or health consequence.
Parasites that live permanently on the skin, such as lice, keds, and mites, are controlled by directly treating the host. Some mange mites burrow into the skin and are therefore more difficult to control with sprays or dips than are lice and keds, which are found on the surface of the skin. However, once these obligate parasites are eradicated, reinfection occurs only from contact with other infected animals.
Nonpermanent parasites (ticks, flies, etc) are less easily controlled. Only a small proportion of the population can be treated at any one time, and other hosts may maintain them. Some tick and mite species stay on the host only long enough to feed, which may be as short as 30 min, or as long as 21 days. Biting flies, such as the horn fly, can be found continuously on the backs and undersides of cattle, where they suck blood up to 20 times a day; other biting flies (such as stable flies and horse flies) and mosquitoes feed to repletion, then leave the animal to lay eggs. Nonbiting flies, such as the face fly or the house fly, may visit infrequently but can be very annoying and may transmit disease agents. Larvae of certain blowflies live on the skin or in tissues of sheep and other animals and cause cutaneous myiasis. Larvae of other flies spend several months inside animals, eg, nasal bots in the nasal passages of sheep and goats, bots in the stomach of horses, and cattle grubs or warbles in the spinal canal, back, or esophageal tissues. (Also see Flies.)
Many ectoparasite infestations are seasonal and predictable and can be countered by prophylactic use of ectoparasiticides. For example, in temperate countries flies are seen predominantly from late spring to early autumn, tick populations increase in the spring and autumn, and lice and mites during the autumn and winter months. Treatments can be targeted at anticipated times of peak activity as a means of limiting disease and parasite populations.
Products are available for both parenteral administration and for topical application by various methods including dips, sprays, pour-ons, spot-ons, dusting powders, and ear tags. The method used depends on the target parasite and host. (see Pharmacology Introduction: Dosage Forms and Delivery Systems.)
Chemotherapeutic Agents
Most ectoparasiticides are neurotoxins, exerting their effect on the nervous system of the target parasite. Those used in large animals can be grouped according to structure and modes of action into the organo-chlorines, organophosphates and carbamates, pyrethrins and pyrethroids, macrocyclic lactones (avermectins and milbemycins), formamidines, insect growth regulators, and a number of miscellaneous compounds, including synergists (eg, piperonyl butoxide). There are also a number of useful compounds that have repellent activity rather than insecticidal activity, including N-octyl bicycloheptene dicarboximide (MGK-264), butoxypolypropylene-glycol, and N, N-diethyl-3-methylbenzamide (DEET, previously called N, N-diethyl-meta-toluamide).
Organochlorines
Organochlorine compounds have been withdrawn in many parts of the world due to concerns regarding environmental persistence. However, some compounds, including lindane (γ benzene hexachloride) and methoxychlor, are still used for topical application and have excellent activity and apparent safety.
Organochlorines fall into 3 main groups: 1) chlorinated ethane derivatives such as DDT (dichlorodiphenyltrichloroethane), DDE (dichlorodiphenyldichloroethane), and DDD (dicofol, methoxychlor); 2) cyclodienes, including chlordane, aldrin, dieldrin, hepatochlor, endrin, and tozaphene; and 3) hexachlorocyclohexanes such as benzene hexachloride (BHC), which includes the γ-isomer, lindane.
Chlorinated ethanes cause inhibition of sodium conductance along sensory and motor nerve fibers by holding sodium channels open, resulting in delayed repolarization of the axonal membrane. This state renders the nerve vulnerable to repetitive discharge from small stimuli that would normally cause an action potential in a fully repolarized neuron.
The cyclodienes appear to have at least 2 component modes of action—inhibition of γ-amino butyric acid (GABA)-stimulated Cl– flux and interference with Ca2+ flux. The resultant inhibitory postsynaptic potential leads to a state of partial depolarization of the postsynaptic membrane and vulnerability to repeated discharge. A similar mode of action has been reported for lindane, which binds to the picrotoxin side of GABA receptors, resulting in an inhibition of GABA-dependent Cl– flux into the neuron.
DDT and BHC were used extensively for flystrike control but were subsequently replaced in many countries by more effective cyclodiene compounds, such as dieldrin and aldrin. Both the development of resistance and environmental concerns have largely led to their withdrawal. DDT and lindane were widely used in dip formulations for the control of sheep scab, but the organophosphates and subsequently the synthetic pyrethroids have mostly replaced them.
Organophosphates and Carbamates
The organophosphates comprise a large group of chemicals, many of which are available for topical application and in ear tags as well as for premise control of parasites. There have been many products available worldwide for use in domestic animals, although only a few of the available compounds continue to be used for on-animal treatment.
Organophosphates are neutral esters of phosphoric acid or its thio analog that inhibit the action of acetylcholinesterase (AChE) at cholinergic synapses and at muscle endplates. The compound mimics the structure of acetylcholine (ACh); when it binds to AChE it causes transphosphorylation of the enzyme. The transphorylated AChE is unable to break down accumulating ACh at the postsynaptic membrane, leading to neuromuscular paralysis. The degree of transphorylation of the enzyme helps to determine the activity of the organophosphate. This is not an irreversible process; eventually the AChE is metabolized by oxidative and hydrolytic enzyme systems.
Organophosphates can be extremely toxic in animals and humans, causing an inhibition of AChE and other cholinesterases (see Insecticide and Acaricide (Organic) Toxicity: Organophosphates (Toxicity)). Chronic toxicity results from inhibition of the enzyme neurotoxic esterase and is associated with particular compounds. The physiologic function of this enzyme is unknown; however, its inhibition appears to cause structural changes in neuronal membranes and a reduction in conduction velocity, which may be manifest as posterior paralysis in some animals. Cases of organophosphate toxicity are treated with oximes or atropine.
Organophosphates used topically include coumaphos, diazinon, dichlorvos, famphur, fenthion, malathion, trichlorfon, stirofos, phosmet, and propetamphos. Ear tags containing fenthion, chlorpyrifos, and diazinon are available in some countries. These compounds are generally active against fly larvae, flies, lice, ticks, and mites on domestic livestock, although activity varies between compounds and differing formulations. Chlorpyrifos is best used in the microencapsulated form for residual activity and improved safety. Diazinon and propetamphos have been available in dip formulations for the control of psoroptic mange in sheep. Both eliminate mites and protect in a single application when correctly applied. Diazinon provides longer residual protection than propetamphos. In cattle, a number of compounds have been used for the systemic control of warble fly grubs and lice as pour-on applications or in hand sprays, spray races, or dips for tick control.
Products containing haloxon and metrifonate have been used PO for the control of stomach bot fly larvae and helminths in horses.
Carbamate insecticides are closely related to organophosphates and are anticholines-terases. Unlike organophosphates, they appear to cause a spontaneously reversible block on AChE without changing it. The main carbamate compounds used are carbaryl and propoxur. Carbaryl has low mammalian toxicity but may be carcinogenic and is often combined with other active ingredients.
Pyrethrins and Synthetic Pyrethroids
A number of pyrethroids are available in many countries as pour-on, spot-on, spray, and dip formulations with activity against biting and nuisance flies, lice, and ticks on domestic livestock. Flumethrin and high cis-cypermethrin are also active against mites and have been used for the treatment of psoroptic mange of sheep.
Natural pyrethrins are derived from pyrethrum, a mixture of alkaloids from the chrysanthemum plant. Pyrethrum extract, prepared from pyrethrum flower, contains ~25% pyrethrins. The pyrethrins and pyrethroids are lipophilic molecules that generally undergo rapid absorption, distribution, and excretion. They provide excellent knock-down (rapid kill) but have poor residual activity due to instability. Pyrethrin I is the most active ingredient for kill, and pyrethrin II for rapid insect knockdown.
Synthetic pyrethroids are synthesized chemicals modeled on the natural pyrethrin molecule. They are more stable and have a higher potency than natural pyrethrins.
The mode of action of pyrethrins and synthetic pyrethroids appears to be interference with sodium channels of the parasite nerve axons, resulting in delayed repolarization and eventual paralysis. Synthetic pyrethroids can be divided into 2 groups (types I and II, depending on the presence or absence of an α-cyano moiety). Type I compounds have a mode of action (similar to that of DDT) that involves interference with the axonal Na+ gate leading to delayed repolarization and repetitive discharge of the nerve. Type II compounds also act on the Na+ gate but do so without causing repetitive discharge. The lethal activity of pyrethroids seems to involve action on both peripheral and central neurons, while the knockdown effect is probably produced by peripheral neuronal effects only. Some preparations contain piperonyl butoxide, which acts as a synergist by helping to prevent the pyrethrin or pyrethroid breakdown by microsomal mixed-function oxidase systems in insects.
Pyrethroids are generally safe in mammals and birds but are highly toxic to fish and aquatic invertebrates. Concerns have been expressed over their environmental effects, particularly in relation to the aquatic environment, leading to their withdrawal as sheep dips in some countries.
Some of the more common pyrethroids used include bioallethrin, cypermethrin, deltamethrin, fenvalerate, flumethrin, lambdacyhalothrin, phenothrin, and permethrin. The content of some synthetic pyrethroids is also expressed in terms of the drug isomers, eg, cypermethrin preparations may contain varying proportions of their cis and trans isomers. Thus, cypermethrin (cis:trans 60:40) 2.5% is equivalent to cypermethrin (cis:trans 80:20) 1.25%. In general, cis isomers are more active than the corresponding trans isomers.
Macrocyclic Lactones (Avermectins and Milbemycins)
Avermectins and the structurally related milbemycins, collectively referred to as macrocyclic lactones, are fermentation products of Streptomyces avermitilis and Streptomyces cyanogriseus, respectively. Avermectins differ from each other chemically in side chain substitutions on the lactone ring, while milbemycins differ from the avermectins through the absence of a sugar moiety from the lactone skeleton. A number of macrocyclic lactone compounds are available for use in animals and include the avermectins abamectin, dora-mectin, eprinomectin, ivermectin, and selamectin; and the milbemycins moxidectin and milbemycin oxime. These compounds are active against a wide range of nematodes and arthropods and, as such, are often referred to as endectocides.
Endectocidal activity, particularly against ectoparasites, is variable and depends on the active molecule, the product formulation, and the method of application. Macrocyclic lactones can be given PO, parenterally, or topically (as pour-ons and spot-ons). The method of application depends on the host and, to some degree, on the target parasites. In cattle, eg, available endectocide products can be given PO, by injection, or topically using pour-on formulations. The latter are generally more effective against lice (Lignonathus, Haematopinus, and to some extent Bovicola) and headfly (Haematobia/ Lyperosia) infestations, when compared with equivalent compounds administered parenterally. In sheep, PO administration of some endectocides has little effect against psoroptic mite infestations (Psoroptes ovis), but parenteral administration increases activity, providing both protection and control depending on the product used.
The route of administration and product formulation influence the rates of absorption, metabolism, excretion, and subsequent bioavailability and pharmacokinetics of individual compounds. Avermectins and milbemycins are highly lipophilic, a property that varies with only minor modifications in molecular structure or configuration. Following administration, these compounds are stored in fat, from which they are slowly released, metabolized, and excreted. Ivermectin is absorbed systemically following PO, SC, or dermal administration; it is absorbed to a greater degree and has a longer half-life when given SC or dermally. Excretion of the unaltered molecule is mainly via the feces, with <2% excreted in the urine in ruminants. In cattle, the reduced absorption and bioavailability of ivermectin given PO may be due to its metabolism in the rumen. The affinity of these compounds for fat explains their persistence in the body and the extended periods of protection afforded against some species of internal and external parasites. The prolonged half-life of these compounds also determines residue levels in meat and milk, and subsequent compulsory withdrawal periods following treatment in food-producing animals.
The mode of action of avermectins and milbemycins is not completely understood. Ivermectin is known to act on GABA neurotransmission at 2 or more sites in nematodes, blocking interneuronal stimulation of excitatory motor neurons, leading to flaccid paralysis. It appears to achieve this by stimulating the release of GABA from nerve endings and by enhancing the binding of GABA to its receptor on the postsynaptic membrane of an excitatory motor neuron. The enhanced GABA binding results in an increased flow of Cl– ions into the cell, leading to hyperpolarization. In mammals, GABA neurotransmission is confined to the CNS; the lack of effect of ivermectin on mammalian nervous systems at therapeutic concentrations is probably because it does not readily cross the blood-brain barrier. More recent evidence suggests that ivermectin may exert its effect through action on glutamategated Cl– ion conductance at the postsynaptic membrane or neuromuscular endplate.
Formamidines
Amitraz is the only formamidine used as an ectoparasiticide. It appears to act by inhibition of the enzyme monoamine oxidase and as an agonist at octopamine receptors. Monoamine oxidase metabolizes amine neurotransmitters in ticks and mites, and octopamine is thought to modify tonic contractions in parasite muscles. Amitraz has a relatively wide safety margin in mammals; the most frequently associated adverse effect is sedation, which may be associated with an agonist activity of amitraz on α2-receptors in mammalian species.
Amitraz is available as a spray or dip for use against mites, lice, and ticks in domestic livestock. It has been shown to be effective for controlling lice and mange in pigs and psoroptic mange in sheep. In cattle, it has been used in dips, sprays, or pour-ons for the control of single-host and multi-host tick species. In dipping baths, amitraz can be stabilized by the addition of calcium hydroxide and maintained by standard replenishment methods for routine tick control. An alternative method involves the use of total replenishment formulations in which the dip bath is replenished with full concentration of amitraz at weekly intervals prior to use. Amitraz is contraindicated in horses.
Chloronicotinyls and Spinosyns
Imidacloprid is a chloronicotinyl insecticide, a synthesized chlorinated derivative of nicotine. Spinosad is a fermentation product of the soil actinomycete Saccharopolyspora spinosa. Both compounds bind to nicotinic acetylcholine receptors (but at different sites) in the insect's CNS, leading to inhibition of cholinergic transmission, paralysis, and death. Spinosad has been developed in some countries for use on sheep to control blowfly strike and lice.
Insect Growth Regulators
Insect growth regulators are used throughout the world and represent a relatively new category of insect control agents. They constitute a group of chemical compounds that do not kill the target parasite directly, but interfere with growth and development. They act mainly on immature parasite stages and are not usually suitable for the rapid control of established adult parasite populations. Where parasites show a clear seasonal pattern, insect growth regulators can be applied prior to any anticipated challenge as a preventive measure. They are widely used for blowfly control in sheep but have limited use in other livestock.
Based on their mode of action, insect growth regulators can be divided into chitin synthesis inhibitors (benzoylphenyl ureas), chitin inhibitors (triazine/pyrimidine derivatives), and juvenile hormone analogs. Several benzoylphenyl ureas have been introduced for the control of ectoparasites. Chitin is a complex aminopolysaccharide and a major component of the insect's cuticle. During each molt, it has to be newly formed by polymerization of individual sugar molecules. The exact mode of action of the benzoylphenyl ureas is not fully understood. They inhibit chitin synthesis but have no effect on the enzyme chitin synthetase. It has been suggested that they interfere with the assembly of the chitin chains into microfibrils. When immature insect stages are exposed to these compounds, they are not able to complete ecdysis and die during molting. Benzoylphenyl ureas also appear to have a transovarial effect. Exposed adult female insects produce eggs in which the compound is incorporated into the egg nutrient. Egg development proceeds normally, but the newly developed larvae are incapable of hatching. Benzoylphenyl ureas show a broad spectrum of activity against insects but have relatively low efficacy against ticks and mites. The exception is fluazuron, which has greater activity against ticks and some mite species.
Benzoylphenyl ureas are highly lipophilic molecules. When administered to the host they build up in body fat, from which they are slowly released into the bloodstream and excreted largely unchanged. Diflubenzuron and flufenoxuron are used for the prevention of blowfly strike in sheep. Diflubenzuron is available in some countries as an emulsifiable concentrate for use as a dip or shower. It is more efficient against first-stage larvae than second and third instars and is therefore recommended as a preventive, providing protection for 12–14 wk. It may also have potential for the control of a number of major insect pests such as tsetse flies. Fluazuron is available in some countries for use in cattle as a tick development inhibitor. When applied as a pour-on, it provides longterm protection against the 1-host tick Boophilus microplus.
Triazine and pyrimidine derivatives are closely related compounds that are also chitin inhibitors. They differ from the benzoylphenyl ureas both in chemical structure and mode of action, ie, they appear to alter the deposition of chitin into the cuticle rather than its synthesis.
Cyromazine, a triazine derivative, is effective against blowfly larvae on sheep and lambs and also against other Diptera such as houseflies and mosquitoes. At recommended dose rates, cyromazine shows only limited activity against established strikes and must therefore be used preventively. Blowflies usually lay eggs on damp fleece of treated sheep. Although larvae are able to hatch, the young larvae immediately come into contact with cyromazine, which prevents the molt to second instars. The efficacy of a pour-on preparation of cyromazine does not depend on factors such as weather, fleece length, and whether the fleece is wet or dry. Control can be maintained for up to 13 wk after a single pour-on application, or longer if cyromazine is applied by dip or shower.
Dicyclanil, a pyrimidine derivative, is highly active against dipteran larvae. A pour-on formulation, available in some countries for blowfly control in sheep, provides up to 20 wk of protection.
The juvenile hormone analogs mimic the activity of naturally occurring juvenile hormones and prevent metamorphosis to the adult stage. Once the larva is fully developed, enzymes within the insect's circulatory system destroy endogenous juvenile hormones, prompting development to the adult stage. The juvenile hormone analogs bind to juvenile hormone receptor sites, but because they are structurally different, are not destroyed by insect esterases. Metamorphosis and further development to the adult stage does not proceed. Methoprene is a terpenoid compound with very low mammalian toxicity that mimics a juvenile insect hormone and is used as a feed-through larvicide for hornfly (Haematobia) control on cattle.
Miscellaneous Compounds
Piperonyl butoxide is a methylenedioxyphenyl compound that has been widely used as a synergistic additive in the control of arthropod pests. It is commonly used as a synergist with natural pyrethrins. The degree of potentiation of insecticidal activity is related to the ratio of components in the mixture; as the proportion of piperonyl butoxide increases, the amount of natural pyrethrins required to evoke the same level of kill decreases. The insecticidal activity of other pyrethroids, particularly of knockdown agents, can also be enhanced by the addition of piperonyl butoxide. The enhancement of activity of synthetic pyrethroids is normally less dramatic. Piperonyl butoxide inhibits the microsomal enzyme system of some arthropods and is effective against some mites. In addition to having low mammalian toxicity and a long record of safety, it rapidly degrades in the environment.
Various products from natural sources, as well as synthetic compounds, have been used as insect repellents. Such compounds include cinerins, pyrethrins and jasmolins (see Ectoparasiticides: Pyrethrins and Synthetic Pyrethroids), citronella, indalone, garlic oil, MGK-264, butoxypolypropylene-glycol, DEET, and DMP (dimethylphthalate). The use of repellents is advantageous as legislative and regulatory authorities become more restrictive toward the use of conventional pesticides. They are used mainly to protect horses against blood-sucking arthropods, particularly midges (Culicoides).
Insecticides may be used to provide environmental control of some insects by application to premises. The insect pheromone (Z)-9-tricosene is incorporated into some products to attract insects to the site of application.
Other Control Methods
Biological Control
The use of naturally occurring biological pathogens, such as nematodes, bacteria, fungi, and viruses, offer a particularly interesting approach to ectoparasite management. Bacillus thuringiensis has been used on sheep for the prevention of blowfly strike and body lice. The use of fungal pathogens such as Metarhizium anisopliae has also been investigated for the control of ticks on livestock and mites on cattle and sheep.
Off-host Control
The control of populations of arthropod pest species using nonreturn traps and targets (screens), usually accompanied by semiochemical baits, has been considered widely for parasites such as ticks or flies. The aim is to attract and kill targeted pests in appropriate numbers during the stages in which they are off the host. This approach has been used as a component of the eradication of the screwworm fly, Cochliomyia hominivorax, from North America and for control of the horn fly, Haematobia irritans. Given the large numbers of adult females that must be attracted and killed to achieve effective population management, this is often not possible with the visual and olfactory baits available. One notable exception is in the control of the tsetse fly (Glossina spp), for which high levels of control can be achieved due to their very low rate of reproduction and the availability of highly effective baits and traps. In Australia, a nonreturn insecticide-free trap for catching Lucilia cuprina has been developed and is now commercially available. The ability of this trap and bait system to suppress fly populations and to reduce strike incidence has been investigated in the southern hemisphere with variable results, although reductions in strike incidence of up to 46% have been reported.
Safety Restrictions
It is important to be aware of and follow safety restrictions to prevent poisoning or injury to treated animals. All organophosphates available for use on animals are cholinesterase inhibitors. They should not be used simultaneously or within a few days before or after treatment or exposure to other cholinesterase-inhibiting drugs, pesticides, or chemicals. They should not be applied to animals that are young, sick, convalescent, or stressed.
Pyrethroid insecticides available for use on large animals are considered safe but have general precautionary statements on their labels, particularly in relation to disposal and their potential ecotoxicologic effects.
Some parasiticides may be used only by or under the supervision of a veterinarian; others are available via agricultural suppliers and pharmacists directly to the public. Approvals vary from country to country. Labels for pesticides contain explicit information on hazards to animals, humans, and the environment; storage of unused insecticide; and disposal of the container. For each insecticide, the label is the primary source of information on uses and safety instructions, which should be carefully followed.
Restrictions are applied to many of the ectoparasiticides indicated for use in food-producing animals to ensure that unacceptable residues are not present in products intended for human consumption. These restrictions may require that animals are not slaughtered for prescribed periods after administration of the product or that the product is not used in animals producing milk for human consumption. Labels and data sheets on all products contain specific instructions on restrictions, including withdrawal periods, and must be followed.
Last full review/revision March 2012 by Mike A. Taylor
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