Small animal - January 2020

Introduction
Routine ectoparasite control forms an important part of any health protocol for dogs and cats and is essential as part of the investigation and management of pruritic skin disease. In order to be able to select a suitable ectoparasiticide, it is important that the veterinary surgeon has an appreciation of the mode of action of the plethora of different products that are available and their spectrum of activity. This review will briefly discuss the most important ectoparasitic conditions in primary care veterinary practice (in the UK) and consider the different products available for treatment. This will include their current licensed indications plus any evidence around their suitability for therapy of fleas, ticks, harvest mites, lice, Cheyletiella spp. Sarcoptes scabiei, and Demodex spp. in the dog and cat. 

Over the last 12 months there have been changes in ectoparasiticide availability. Several products have switched distributors, a few such as spinosad have been discontinued, and drugs such as the neonicotinoids, although still available for use in small animals, has been banned in farming. There is, at this present time, no hard evidence to suggest that chemicals like fipronil and imidocloprid in water sources (that are thought to have contributed to the worrying decline in populations of small invertebrates in river systems), are due to their topical use on pets. However, there have been calls for research to be undertaken to investigate the potential direct and indirect environmental exposure pathways for dog parasiticide products in relation to the effect of veterinary use on levels of neonicotinoids in the environment.   

Ectoparasite control

Fleas (Ctenocephalides felis)
The most common species of flea encountered on dogs and cats in the UK is Ctenocephalides felis. All animals will react to flea bites but where individuals are not sensitised to flea bites, the irritation is generally transient and does not lead to clinical signs. Where dogs are hypersensitive to flea salivary antigens injected intradermally during flea feeding, they will develop much more severe and widespread clinical signs. Dogs with flea allergic dermatitis (FAD) develop signs of pruritic skin disease principally affecting the caudo-dorsal lumbosacral area and often with extension of signs onto the dorsal tail head, caudomedial thighs, abdomen and flanks. Lesions include pruritic, papular, crusting eruptions with secondary erythema and self-inflicted trauma. In cats, flea bite hypersensitivity is the most common cause of pruritic skin disease and presents in a myriad of different ways including miliary dermatitis, self-inflicted alopecia or as part of the eosinophilic granuloma complex. In addition to causing skin disease C. felis has been shown to act as a vector for numerous pathogens including Rickettsia spp., Bartonella spp.,  Mycoplasma spp. and the intermediate host of the cestode Dipylidium caninum.¹

In the last 20 years, a wide range of insecticides have been registered as flea products either as mono or combined therapies. Most of the actives such as fipronil, imidacloprid, lufenuron, methoprene, permethrin and pyriproxyfen registered prior to 1997 are still available and, despite anecdotal reports suggesting otherwise, resistance to these products is uncommon. According to the Arthropod Pesticide Resistance database there have, to date, only been reports of C. felis resistance to organochlorines, carbamates, organophosphates, pyrethroids and pyrethrin. Drugs such as fipronil and imidacloprid have been rejuvenated by being released as generics; other have benefited from changes in formulation, application technology and by being combined with other actives.² Most insecticides licensed for veterinary use are available as prescription-only medication – veterinarian (POM-V) products. Drugs such as mono formulations of imidacloprid and fipronil are available without veterinary prescription (as non-food producing animal – veterinarian, pharmacist, SQP [NFA-VPS]). 

While a high degree of efficacy and persistence is essential for any flea product, the speed of kill (SOK) is also important to reduce feeding time which is important in animals with flea-bite hypersensitivity.

Ticks (Ixodidae spp.)
Both hard (Ixodidae) and soft (Argasidae) ticks occur in the UK but it is the hard ticks Ixodes spp. (ricinus, hexagonus, canisuga) that principally affect dogs, cats are rarely infested. Dermacentor reticulatus and Haemaphysalis punctata are also occasionally found. Ticks tend to attach to a non-haired, thin-skinned area such as around the face. As blood feeders the feeding activity of numerous ticks can lead to anaemia but commonly it is the wound created by the tick bite that leads to local irritation particularly if the tick is removed after it has attached and the mouth warts are left in the skin. With the increase of reports in the veterinary literature of tick-borne disease in the UK over the last few years, tick control has become a much more important part of routine ectoparasite control. Ticks are known to carry a range of bacterial, rickettsial, viral and protozoal diseases. The most common tick-borne disease in the UK is Lyme disease (Borrelia burgdorferi) transmitted by Ixodes ticks, however babesiosis (Babesia canis) has been recognised very recently _ in June 2020 _ (MRCVS Online) in the south of England in dogs with no history of travel abroad. The babesia parasite was thought to be transferred by D. reticulatus ticks. While ticks can be manually removed, this relies on them being identified at an early stage, which is not always possible in a dog or cat with a thick pelage and, therefore, prophylactic therapy as part of a holistic ectoparasite programme is preferable. Many of the earliest tick treatments such as fipronil, avermectin (selamectin), milbemycin (moxidectin) and pyrethroid derivatives (permethrin, deltamethrin, flumethrin) are still available and are useful against ticks in dogs. Although many are also licensed for cats, including flumethrin as a component of a flea and tick collar, other pyrethrin and pyrethroids are toxic in this species and are best avoided. Drugs such as the isoxazolines represent newer licensed products with excellent tick activity.

Harvest mites (Neotrombicula autumnalis)
The parasitic larva of the harvest mite (Neotrombicula autumnalis) is responsible for causing an irritating pruritic eruption on ground-skin contact areas in dogs, it can also be found around the ears of outdoor cats. The larva is usually picked up by the pet while out for a rural walk or while out hunting in the autumn. Little is licensed to treat harvest mite infestations and although many products have good efficacy against the parasitic larvae, few produce prolonged residual protection. This means during high-risk periods animals can become quickly re-infested once they return to a contaminated environment. Selamectin has been shown to be useful for therapy of harvest mites in dogs and cats.³ Fipronil, in a combination product with permethrin⁴ has been used in dogs. Anecdotally, the author’s preference for prevention and treatment of harvest mites is the oral isoxazolines. Although not licensed for use, they do seem protect against and reduce re-infestation.

Lice (Trichodectes canis, Linognathus setosus)
Lice are highly host-specific parasites. The two species found on dogs in the UK are the biting louse, Trichodectes canis and the sucking louse Linognathus setosus. Feline lice infestations are rare but when they occur are caused by the biting louse Felicola subrostratus. Lice infestations are uncommon in the UK and when they occur, animals may be asymptomatic or highly pruritic leading to marked signs of self-inflicted trauma. Products that are licensed for the treatment of flea infestations can be used in the treatment of lice. Selamectin, fipronil and imidocloprid are specifically licensed for the treatment of biting lice, although isoxazolines should also be useful.

Browsing mite (Cheyletiella spp.)
Cheyletiella spp. is a browsing mite that feeds on the surface of the skin leading to mild pruritic dermatitis, usually manifesting a dorsal scaling with erythema and crust. Cheyletiella yasguri is the species often found on dogs, and Cheyletiella blakei on cats. However, the mite is not host specific and Cheyletiella parasitovorax may also be identified on pets. Few products are licensed for the treatment of Cheyletiella, so flea products with acaricidal activity in the form of sprays, spot-ons or oral drugs are therefore usually employed. Selamectin, moxidectin and fipronil have been shown to be useful treatments. The selection of therapy often depends on the age of the animal and the thickness of the coat. The biggest treatment challenges are generally found in puppies and kittens where the minimum age and weight of administration of a licensed product influences treatment choice.  

Sarcoptic mange (Sarcoptes scabiei)
This is a common highly pruritic, contagious ectoparasitic disease of dogs. It is a zoonosis and can be passed from dog to owner. These obligate parasites burrow through the skin causing intense irritation, dramatic scaling and usually severe self-inflicted trauma. The severity of the lesions is thought in part to be due to a hypersensitivity reaction to mite allergens in the skin. Lesions tend to be located on relatively hairless areas such as the ear tips and the extensor aspects of the joints. S. scabiei is known to be highly prevalent in the fox population, as the mite is viable for several weeks off their host, fomite spread from fox to dog is thought to be a common means of transmission. The most effective ectoparasiticides are those with a systemic mode of action. Selamectin and moxidectin both have proven efficacy and are licensed to treat scabies. The newer isoxazolines in the form of afoxalaner, fluralaner and sarolaner are also licensed for the therapy of S. scabiei.

Demodectic mange (Demodex spp.)
Demodectic mange in the dog is principally caused by the obligate parasite Demodex canis. Other less common canine species of the parasite have been identified as Demodex cornei a short surface-dwelling variant and Demodex injai a long serpent-shaped form. In the cat infestation is caused by Demodex cati and Demodex gatoi. Demodicosis is found in two forms either as localised disease or generalised disease. It is a rare disease in the cat but should still be eliminated as part of any skin investigation. In the dog it can be juvenile onset, which is usually found in dogs less than three years of age and adult onset, which is seen in older dogs and usually associated with some form of immunosuppression. Therapy for demodicosis has evolved rapidly over the last few years. While localised juvenile onset disease will resolve with minimal treatment in most cases, providing the dog or cat is systemically well, the more severe forms of the disease have in the past needed extended course of topical therapy with amitraz. Milbemycins, which includes moxidectin, (not avermectins), have activity against Demodex spp. Several moxidectin products are licensed to treat demodex in the dog. Current recommendations suggest that lime sulphur and amitraz have the biggest evidence base to support their use in feline demodicosis.⁵ Isoxazolines in the form of afoxalaner, fluralaner and sarolaner are licensed indications for the therapy of canine demodicosis and recommended for use in therapy.⁵ Fluralaner and sarolaner as licenced feline ectoparasiticides may also have activity against feline demodicosis.

Classes of ectoparasiticides and their spectrum of activity

Chloride channel activators
This principal ectoparasiticide in this group is selamectin. Selamectin has a broad spectrum of activity against both endo and ectoparasites and has been demonstrated to be safe and efficacious in the control of naturally acquired flea infestations on dogs and cats presented as veterinary patients in Europe.⁶ It has also been shown to be highly effective in the treatment and prevention of flea infestations, without the need for supplementary environmental control measures.⁷ However, its SOK is inferior to some licensed adulticides and would not therefore be the author’s first choice for flea allergic animals. Selamectin is licensed for the treatment of biting lice, ear mites and S. scabiei. In addition, clinical studies have shown it is effective as an off licensed against sucking lice, Neotrombibula autumnalis and Cheyletiella spp.^3,8

Nicotinic acetylcholine receptor agonists
Nicotinic acetylcholine receptor agonists (NARAs) include the neonicotinoids (dinotefuran, imidocloprid and nitenpyam) as well as the spinosyn derivatives (spinosad, spinetoram). All of the products in this group have a rapid SOK and are excellent rapid acting flea adulticides.⁹ Their rapid SOK makes them good choices for flea allergic animals. However, they are relatively narrow spectrum with no acaricidal action, they are therefore often combined with other actives to give a broader spectrum ectoparasitic cover (see Table 1).

Indoxacarb is the flea adulticides within this class of drugs. Indoxacarb has excellent adulticide activity against 

C. felis to control flea infestation and clinical signs in a high proportion of dogs and cats with flea allergy dermatitis (FAD) without the need for other drugs.¹⁰ It also provides superior and effective environmental flea control in heavily infested environments compared to fipronil (S) methoprene topical formulations.¹¹ It has no acaricidal activity as a monotherapy but is available with permethrin for dogs giving an increased licensed indication for ticks.

Sodium channel modulators
This group of drugs contain actives such as permethrin, deltamethrin and flumethrin. The latter two drugs are usually used as component of ectoparasiticide collars. While collars may be easy ways to achieve ectoparasite control both actives used in collars have good activity against fleas but a slow onset of action, making them better for routine flea control rather than for flea-allergic animals.¹²

GABA gated chloride channel antagonists
This group of drugs contains the older phenylpyrazoles which includes fipronil and the newer class of isoxazolines containing the actives afoxolaner, fluralaner, lotilaner and sarolaner. Fipronil as a monotherapy has a slow SOK. In one study it achieved a speed of kill of only 46.5% in eight hours⁹ and in another it took a full 12-18 hours to reach 100% efficacy.¹³

The isoxazoline group of drugs was launched in 2014 in the US with afoxolaner. This was closely followed by oral fluralaner, sarolaner, topical fluralaner and lotilaner. While the precise labelling for each product differs in its license applications as far as spectrum of activity, minimum age of administration, method of administration, minimum body weight and dosing interval (see Table 2) all of the products within this group are approved for treatment and prevention of flea infestations and for ticks in dogs and cats. The safety of all of these products and their ability to treat fleas has been well documented. Afoxalaner has been shown to be effective in killing C. felis^14-16 and C. canis.¹⁷ Fluralaner has shown similar benefits as both an oral¹⁸ and topical¹⁹ formulation to control flea infestations and also the signs of flea allergic dermatitis in dogs and cat.^19-21 A study undertaken by Dryden (2016) compared the activity of afoxalaner and fluralaner to control flea populations, reduce pruritus and minimize dermatological lesions in naturally infested dogs and found both were highly efficacious with little difference between the two.²² Sarolaner has been shown to be effective in the treatment of fleas in pets^23,24 and flea allergic dermatitis²⁵ as has lotilaner.^26-28 Isoxazalines are absorbed systemically, the onset of action of all products is two to four hours with close to 100% of fleas killed within eight hours.²⁹ Their speed of kill together with their safety profile and persistence makes these the drugs of choice in the author’s hands for FAD in the dog and cat.

Although there is evidence in the literature that all have good activity against mites only afoxalaner, fluralaner and sarolaner are currently licenced as acaracides.^30-33 However, all four drugs represent on the basis of supporting literature, useful choices for a wide range of ectoparasites in dogs and cats.

Juvenoids
Two form of juvenoids or insect growth regulators (IGRs) are available for the management of flea infestations in the dog. These are the chitin biosynthesis inhibitors (lufenuron) and the juvenile hormone mimetics (methoprene and pyriproxyfen). As numerous studies have shown, products such as the isoxazolines and the NARAs have a rapid and complete SOK before fleas can feed and lay eggs, hence breaking the life cycle, the use of juvenoids as part of a flea control programme may seem superfluous. However recent studies have shown a marked synergism between IGRs and adulticides.³⁴ It would seem that IGRs reduce the time required to control fleas within the environment and also lessen the likelihood that insecticide resistance may develop.³⁵ Several studies have shown that drugs such as lufenuron,³⁶ methoprene and pyriproxyfen³⁷ produce significant increases in adult mortality as well as preventing flea development. Therefore, because of the multiple effects that IGRs have on both immature and adult fleas, the incorporation of an IGR into any treatment regime will increase the efficacy over the use of an adulticide alone.² 

Summary 
The veterinary surgeon has more choice of ectoparasite treatments than ever before. With such a bewildering selection of tablets, collars, sprays and spot-ons, it is difficult to know which are the best products to prescribe. Many aspects should be considered when selecting therapy. As well as the obvious reasons, such as safety and efficacy; features, such as cost, ease of application and convenience, can influence owner compliance, which is important in sustaining a treatment programme. Products such as fipronil and imidocloprid are available as NFA-VPS and still represent good low-cost options for flea control. However, more recent adulticides such as the nicotinic acetylcholine receptors agonists (NARAs) and the isoxazalines with their rapid SOK are superior in the control of FAD. The broad spectrum of action and the convenience of oral dosing also makes the isoxazolines excellent choices for the therapy of mite infestations.

This article refers to the UK situation, which is broadly similar to Ireland.