Ectoparasiticides Used in Large Animals
Arthropod parasites (ectoparasites) are major causes of livestock production losses throughout the world. In addition, many arthropod species can act as vectors of disease agents for both animals and people. Treatment with various parasiticides to reduce or eliminate ectoparasites is often required to maintain health and to prevent economic loss in food animals. Some ectoparasiticides were derived from pesticides used to protect crops. The choice and use of ectoparasiticides depend to a large extent on husbandry and management practices, as well as on the type of ectoparasite causing the infestation. Endectocides are capable of killing both internal and external parasites. Accurate identification of the parasite or correct diagnosis based on clinical signs is necessary for selection of the appropriate parasiticide. 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, can be controlled by directly treating the host. Some mange mites burrow into the skin and are therefore more difficult to control with sprays 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.
Ectoparasites with stages that live off the host (ticks, flies, etc) are less easily controlled. Only a small proportion of the ectoparasite population can be treated on the host at any one time, and other hosts may maintain them. Some tick 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 continually 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 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 back or esophageal tissues). (See also 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 often increase in the spring and autumn, and lice and mite infestations can be more common during the autumn and winter months. Treatments can be targeted at anticipated times of peak activity as a way to limit parasite populations and disease.
Products are available for parenteral administration or 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 Routes of Administration and Dosage Forms.) Importantly, most topical ectoparasiticides used in the USA are pesticides regulated by the U.S. Environmental Protection Agency (EPA). This is an important distinction from products regulated by the U.S. Food and Drug Administration (FDA), because it is illegal to use an EPA-regulated pesticide product inconsistent with its label directions (www.epa.gov). The regulating agency should be identifiable on the product label. The National Pesticide Information Retrieval System (NPIRS) is a searchable database of EPA-registered products (http://ppis.ceris.purdue.edu/).
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 mode of action into the organochlorines, 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 with repellent rather than insecticidal activity, including butoxypolypropylene-glycol and N,N-diethyl-3-methylbenzamide (DEET, previously called N,N-diethyl-metatoluamide).
Organochlorine compounds have been withdrawn in many parts of the world because of concerns regarding environmental persistence.
Organochlorines fall into three 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 toxaphene; 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 two component modes of action: inhibition of γ-aminobutyric 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– ion flux into the neuron.
DDT and BHC were used extensively for flystrike control but subsequently replaced in many countries by more effective cyclodiene compounds, such as dieldrin and aldrin. Both the development of resistance and environmental concerns led to their withdrawal. DDT and lindane were widely used in dip formulations to control sheep scab, but they have mostly been replaced by the organophosphates and subsequently the synthetic pyrethroids.
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 analogue 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. Eventually, the AChE is metabolized by oxidative and hydrolytic enzyme systems.
Organophosphates can be extremely toxic in animals and people, inhibiting AChE and other cholinesterases (see Organophosphates (Toxicity)). Chronic toxicity results from inhibition of an enzyme known as neuropathy target esterase (NTE) or neurotoxic esterase and is associated with particular compounds. NTE hydrolyzes the fatty acids from the membrane lipid, phosphotidylcholine, and inhibition of NTE 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, malathion, tetrachlorvinphos,trichlorfon, phosmet, and pirimiphos. Ear tags containing chlorpyrifos, coumaphos, diazinon, or pirimiphos are available. 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 can be used in microencapsulated form for residual activity and improved safety. Diazinon and propetamphos have been available in dip formulations to control 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 systemic control of warble fly grubs and lice as pour-on applications or in hand sprays, spray races, or dips for tick control.
Carbamate insecticides are closely related to organophosphates and are anticholinesterases. Unlike organophosphates, they appear to cause a spontaneously reversible block on AChE without changing it. The main carbamate compound used in veterinary medicine is propoxur. Carbaryl, another carbamate previously used in veterinary medicine, has been withdrawn from the veterinary market.
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 to treat psoroptic mange of sheep.
Natural pyrethrins are derived from pyrethrum, a mixture of alkaloids from the Chrysanthemum plant. Pyrethrum extract, prepared from the pyrethrum flower head, contains several molecules collectively known as pyrethrins (pyrethrin I and II, cinerin I and II, and jasmolin I and II). Pyrethrins are lipophilic molecules that generally undergo rapid absorption, distribution, and excretion. They provide excellent knockdown (rapid kill) but have poor residual activity because of instability. Pyrethrin I is the most active ingredient for kill, and pyrethrin II for rapid insect knockdown.
Pyrethroids are synthesized chemicals modeled on the natural pyrethrin molecule. They are more stable, thus have longer residual activity, 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 two 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, involving 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 peripheral neuronal effects alone probably produce the knockdown effect. Some preparations contain a synergist (eg, piperonyl butoxide), which inhibits breakdown of pesticides by microsomal mixed-function oxidase (cytochrome P450) 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 β-cyfluthrin, bioallethrin, cyfluthrin, cypermethrin, deltamethrin, fenvalerate, flumethrin, lambda cyhalothrin, phenothrin, permethrin, prallethrin, and tetramethrin. 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.
Avermectins and the structurally related milbemycins, collectively referred to as macrocyclic lactones, are fermentation products of Streptomyces avermitilis and S cyanogriseus, respectively. Avermectins differ from each other chemically in side chain substitutions on the lactone ring, whereas 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, doramectin, eprinomectin, ivermectin, and selamectin, and the milbemycins moxidectin and milbemycin oxime. These compounds are active against a wide range of nematodes and arthropods and 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, for example, available endectocide products can be given PO, by injection, or topically using pour-on formulations. The latter are generally more effective against lice (Linognathus, Haematopinus, and to some extent Bovicola) and headfly (Haematobia/Lyperosia) infestations than 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. After administration, these compounds are stored in fat, from which they are slowly released, metabolized, and excreted. Ivermectin is absorbed systemically after 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 urine of 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 the subsequent compulsory withdrawal periods after treatment in food-producing animals.
Macrocyclic lactones bind to glutamate receptors of glutamate-gated chloride channels, triggering Cl– ion influx and hyperpolarization of parasite neurons, leading to flaccid paralysis. These molecules have low affinity for mammalian ligand-gated chloride channels and do not readily cross the blood-brain barrier.
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 controls lice and mange in pigs and psoroptic mange in sheep. In cattle, it has been used in dips, sprays, or pour-ons for control of single-host and multihost 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 before use. Amitraz is contraindicated in horses.
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 (IGRs) 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 directly kill the adult parasite but interfere with growth and development. Because they act mainly on immature parasite stages, IGRs are not usually suitable for rapid control of established adult parasite populations. Where parasites show a clear seasonal pattern, IGRs can be applied before 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, IGRs can be divided into chitin synthesis inhibitors (benzoylphenyl ureas), chitin inhibitors (triazine/pyrimidine derivatives), and juvenile hormone analogues (S-methoprene, pyriproxyfen). Several benzoylphenyl ureas have been introduced to control 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 to prevent 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 to control 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, Rhipicephalus (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 analogues 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 analogues 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. S-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.
Piperonyl butoxide and MGK 264 (N-octyl bicycloheptene dicarboximide) are used as synergistic additives in the control of arthropod pests. They are commonly formulated together with insecticides such as 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 or MGK 264 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 or MGK 264. 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 Pyrethrins and Synthetic Pyrethroids), citronella oil, di-N-propyl isocinchomeronate, butoxypolypropylene glycol, picaridin, 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.
The use of naturally occurring biologic pathogens, such as nematodes, bacteria, fungi, and viruses, offer an interesting approach to ectoparasite management. Bacillus thuringiensis has been used on sheep to prevent blowfly strike and body lice. The use of fungal pathogens such as Metarhizium anisopliae has also been investigated for control of ticks on livestock and mites on cattle and sheep.
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 primary 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 to catch Lucilia cuprina is 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.
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 young, sick, convalescent, or stressed animals.
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, people, 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.