Fleas be gone: Current treatment strategies (Proceedings)

Flea allergy continues to be a common condition affecting dogs and cats despite the major advances in the understanding of flea biology, the immune mechanisms of flea allergy and the availability of newer chemicals providing more optimal flea control. Dependency of the proven "on-the-animal" residual adulticides remain the mainstay of treatment for the flea allergic animal, although chemical newcomers to the world of flea control provide additional options such as long acting oral medication. Repeated use and chronic exposure of the flea to some of the respective chemicals may ultimately be leading to the development of tolerance through aggressive use and genetic selection. Fleas are remarkably resilient and adaptive requiring an ongoing need for new molecular development. There has been a growing scientific body of evidence that some of the currently marketed veterinary flea and tick topicals are demonstrating reduced flea adulticidal efficacy. The Companion Animal Parasite Council was established in 2002 to aid in the monitoring of parasiticide efficacy and the possible development of tolerance. This consortium of veterinarians, parasitologists, thought leaders with industry support to advance information on protecting pets from parasites and zoonotic diseases with the recommendation to administer year round flea and/or tick control to companion animals (Website: www.capcvet.org). The evolvement of more novel chemicals is reality with data suggesting the ability to manage the reemerging flea problem with both safety and efficacy (acute and residual) data very appealing.

Agents Used in Flea Control

Traditional Insecticides

What is often referred to as the "traditional insecticides" include many of the over the counter products and similar prescription products used by veterinarians. They typically include pyrethrin products &/or pyrethroids (e.g. permethrin) sometimes in addition to insect growth regulators such as methoprene or pyriproxyfen. Although the natural botanical pyrethrins pose minimal threat to our habitat, the lack of residual effectiveness, as also seen with their synthetic counterpart the pyrethroids, make them limited in the overall control of flea problems. Permethrin has continued to be used as adjunctive treatment in combination with newer chemicals in situations of heavy flea infestations and breakthrough of the residual products.

Insect Growth Regulators (IGR's) and Insect Development Inhibitors (IDI's)

IGR's and IDI's were popularized as a direct result from the knowledge that the adult flea represents only about 1-5% of the total life cycle with the majority in the form of eggs, larvae or pupae present in the environment. The logic of implementing treatment strategically at the most vulnerable pre-adult stages (eggs & larvae) provided further appeal to this approach of flea control. Yet, breakdown of this treatment philosophy has been encountered since there was little affect on preventing or controlling an active flea infestation if an animal were to be exposed to a sufficient flea population to elicit a clinical problem.

Methoprene, a popular synthetic growth hormone, was developed with application to both premise and on-the-animal treatment. The appeal was the high safety profile and successful effect on terminating egg & larvae development. Pyriproxyfen (Nylar) is another IGR that was popularized. It, like methoprene, is incorporated in a number of premise application products in combination with an adulticide, typically a pyrethroid (permethrin). Pyriproxyfen is currently available in a spray, spot-on and collar formulations. The popularity of these products however, was diminished with the introduction of lufenuron, an insect development inhibitor with the convenience of systemic administration. Lufenuron is a chitin inhibitor and hence limits the insect development. It is available as a stand alone product (Program, Novartis Animal Health, Inc.) or in combination with milbemycin oxime (Sentinel, Novartis Animal Health, Inc.) for combined activity against a spectrum of internal parasites including heartworm prevention and intestinal parasite control. An injectable formulation is available for cats. While initial popularity of lufenuron was observed, the introduction of newly developed long acting, safe and effective on-the-animal products led to the favoring of these products over lufenuron. In ideal circumstances effective flea control can be successful with the exclusive use of an IDI or an IGR. Limitations include the need for all animals in the household plus regular visitors to be treated on a regular basis. The circumstance most vulnerable for breakdown was the pet with flea allergy having intermittent exposure to adult fleas from other habitats or animals, resulting in an allergic dermatitis despite the faithful administration of lufenuron. The time necessary to satisfactorily interrupt the life cycle in a heavy flea infested situation despite conscientious therapy has also resulted in a search for other methods of treatment.

Commonly Used Flea Products

Fipronil

Fipronil is a phenylpyrazole with both insecticide & acaracide properties and was originally introduced as a 0.29% spray at a dosage of 3 ml per pound body weight. (Frontline Spray, Merial, Inc.). It was subsequently developed into a 9.7 % solution for spot-on administration for dogs & cats. The spot-on treatment is administered as a minimum target dose of approximately 10mg/kg. Residual efficacy has demonstrated greater than 95% flea control is accomplished with either product for 37 days or longer. In the clinical setting it is perceived that the spray has a higher residual effect in comparison to the spot-on therapy. The ease of spot-on application has led to its high popularity with pet owners. Although residual activity may be diminished with water exposure and bathing, studies conducted by the manufacturer demonstrates excellent tolearance with minimal disruption of the insecticidal effectiveness. Extra label use of fipronil has demonstrated efficacy in the treatment of canine scabies. Safety of fipronil is exceptional with minimal adversity noted.

Imidacloprid

Imidacloprid (Advantage, Bayer Animal Health, Inc.) is also a popular on-the-animal adulticide with residual activity (Table 1). It is currently marketed as a 9.1 % solution and is a member of the nitroguanidine subclass of neonicotinoid insecticides, which is applied as a spot therapy with subsequent translocation over the body within 24 hours. The target dose of imidacloprid is 10 mg/kg. Greater than 95% efficacy for 28 days has been documented in dogs with slightly less in cats. Imidacloprid has a high safety profile and is labeled for use as often as once weekly. Limitation of residual activity is anticipated when used on dogs or cats with rigorous bathing schedules and may need to be reapplied earlier than conventionally used. Imidacloprid has a rapid rate of flea kill. The combination of imidacloprid with permethrin resulted in the product AdvanTix with both insecticidal properties and acaracidal properties. The appeal of both of these products from Bayer Animal Health is their safety and ability for more flexible application interval.

Selamectin

Selamectin is a semi-synthetic compound belonging to the avermectin group and is derived from doramectin. It is marketed as a liquid (6 or 12% active) for spot-application (Revolution, Pfizer Animal Health, Inc.) It is recognized as an endectocide as it has activity against both ectoparasites and endoparasites with its primary positioning for heartworm prevention and flea control. It also has acaracidal properties (Sarcoptes, Otodectes and ticks) as well as other intestinal parasites (Toxocara cati & Ancylostoma tubaeforme). Although the response to treatment for fleas is slower than other compounds, treatment of dogs with flea allergy dermatitis with selamectin has been shown to be successful. The safety of selamectin is good and it has been shown to be comparably safe in ivermectin sensitive breeds such as the collie. The advantage of selamectin is in the broad-spectrum external & internal parasiticidal activity simplifying the approach to treatment, particularly in the cat. It should be emphasized that treating an animal in a heavily flea infested area may give the misperception of ineffectiveness as a consequence of the relatively slower flea kill rate as opposed to fipronil or imidacloprid.

Nitenpyram

Nitenpyram is a neonicotinoid similar to imidacloprid (Capstar, Novartis Animal Health). Unlike Advantage, Capstar is administered orally at a target dose of 1 mg/kg. Nitenpyram is a systemic adulticide, which is a concept that had been used years back with cythioate which was an organophosphate. Nitenpyram is highly effective at rapid removal of adult fleas on pets administered the drug. Ninety five percent of the fleas are eliminated within 4-6 hours after treatment. Peak levels of the drug is reached within 1 hour after treatment and is eliminated within 24 hours, mostly by urinary excretion with no residual activity. Nitenpyram is safe and poses minimal long term risks due to its rapid metabolism and excretion. The utility of this drug is for the short term effect of complete and relatively rapid elimination of fleas on infested pets. This producthas great attributes for use as an integrated product in situations of heavy flea burden and in areas where know exposures are anticipated or has taken place.

Newly Developed Products

The next generation of flea control has included the development of newer chemicals with the same principles of ideal flea control products including safety, acute and residual efficacy, ease of administration and cost effectiveness.

Metaflumizone

Metaflumizone is a novel semicarbazone with derivation from the pyrazole chemistry. It acts by binding the voltage dependent sodium channels in insects. The result is a relaxed paralysis in a broad range of pest insects including the flea. It is marketed as ProMeris® for cats (20% w/v) and with the inclusion of metaflumizone (15% w/v) and amitraz (15 % w/v) for tick control as ProMeris/ProMeris Duo® for dogs by Fort Dodge Animal Health. Efficacy data has demonstrated an acute flea kill with excellent residual efficacy demonstrating greater than 45 days in some studies although it is recommended as a monthly spot application. The combination of amitraz has demonstrated efficacy for tick control exceeding four weeks. In addition, there have been some investigations demonstrating acaricidal activity in the dog with beneficial results observed in the treatment of demodectic acariasis and canine scabies. While cheyletiellosis has not been evaluated, the likelihood would be acceptable control. Both ProMeris for cats and ProMeris for dogs has demonstrated excellent activity in cases of flea allergy dermatitis. Metaflumizone has a very low acute and dermal toxicity and is very well tolerated for the target species of the respective products. The LD50 of metaflumizone is greater than 5000mg/kg for rats making it an exceptionally safe and environmentally acceptable chemical. Due to the fact that the chemistry of this compound is novel and has not been used on fleas, there is no know resistance. The addition of amitraz for the dog formulation enhances the application in tick infested environments with some potential application as a demodicide or scabicide. The usage of metaflumizone and amitraz every 14 days resulted in 99 % reduction of mites in a 3 month treatment program. Monthly application resulted in 94% reduction in three months and success rate based on zero mite counts was observed on day 84 were 43% for dogs treated monthly and 62.5 % for those treated every two weeks. Scabicidal activity when used monthly for two treatments was successful in 75% of the dogs treated and 83% of those treated every 14 days for four treatments. Egg production in cats has been evaluated on animals that have been treated with metaflumizone. Efficacy was noted with >99.6% efficacy against adult fleas from day 3 to day 45 post application. Ova production fell by 52% within 24 hours and over 99% within 48 hours. Egg production continued to be negligible out to day 38 with 99% reduction compared to control cats. Metaflumizone had no effect on the hatching or maturation of flea eggs not eliminated.

Metaflumizone studies of distribution have been investigated demonstrating minimal absorption of the active ingredient while hair samples revealed wide spread distribution of the active in cats post treatment. Findings in the dog which had reached residual metaflumizone present after day 56 had reached a maximum level between day 2 and 7. Metaflumizole plasma levels were detectable but not quantifiable. The dosage in cats is approximately 40 mg/kg while that for dogs provides a minimum of 20 mg/kg and 20 mg/kg of amitraz. It is approved for use in cats 8 weeks and older.

Dinotefuran

Dinotefuran is derived from chemical structure of acetylcholine (not nicotine) Structure unique among neonicotinoids representing the third generation. Its mode of action similar to that of 1st - and 2nd -generation neonicotinoids but it binds poorly to insect ACh receptors of other neonicotinoids, suggesting novel site of action. Selective toxicity against insects demonstrating highly selective against their ACh receptors. This novel 3rd -generation neonicotinoid is not an analogue of other neonicotinoids being a highly efficacious insecticide with wide margin of safety and comparable acute toxicity to the insect with superior residual activity. It is a non-carcinogen and it is based on acetylcholine and is a non-chlorinated, non-aromatic compound which limits breakdown into toxic byproducts making it environmentally friendly. Dinotefuran stands out with exceptional long-term safety based on chronic NOAEL. The NOAEL is the Chronic no-observed-adverse-effect level which is the amount of chemical administered daily over an average lifetime (2 years in rat) without causing any adverse effects. Dinotefuran has rapid efficacy with 59% of fleas killed in 2 hours leaving a residual of 30 days. Safety studies in puppies (from 7 weeks of age) and adult dogs up to 5 times the recommended dose was applied at two weekly intervals with no significant adverse effects. A community safety study carried out using 240 dogs confirmed the safety of Vectra 3D™ and good efficacy. Dinotefuran is currently available for dogs by Summit Vet. Pharm. as Vectra 3D® with the combination of other active ingredients including permethrin for tick control and pyriproxyfen as an insect development inhibitor. The availability of Vectra 2D for cats is expected in the future. The cat formulation will exclude the permethrin because of toxicity issues utilizing dinotefuran and pyriproxyfen.

Spinosad (Comfortis®)

Spinosad (Comfortis®, Eli Lilly) is an insecticide developed for use in dogs as an oral chewable tablet designed to provide 30 days of efficacy against the flea. It is a rapid acting chemical with the similar acute effect as nitenpyram. The primary target is the activation of nicotinic acetylcholine receptors and is the first in this class of compound for animal application. Spinosad does not interact with known insecticidal binding sites of other nicotinic or GABAergic insecticides such as neonicotinoids, milbemycins, fiproles or cycodienes. The end effect is the activation of the nicotinic receptor gated calcium channels with some secondary effects on GABA receptors to contribute to the insecticidal activity. The administration should be performed with a meal for maximum absorption and should be restricted for dogs 14 weeks or older. Reproductive studies in the dog has not demonstrated any adversity. Insecticidal activity begins within 30 minutes of administration and has 100 per cent flea kill in 4 hours in laboratory studies. High dose studies of 100 mg/kg once daily for 10 days has been performed. Vomiting was the most predominant adversity in 5 of the 6 dogs treated in at this dosage. Other adversities noted with regular administration include vomiting, decreased appetite, lethargy, decreased activity, diarrhea and others. Studies performed on flea ova production shows 100 % elimination within 3 days of application. The product is dispensed in packaging for administration at 30 mg/kg with six tablets per package. Five body weight ranges are represented in the distribution packages. Efficacy for the treatment of flea allergy dermatitis has been demonstrated. The attribute of using a rapid acting systemic with the residual of 30 days is evident and may be of particular usefulness in the treatment of animals that have high water exposure or remain outside in the weather to avoid loss of topical application activity with some animals. The increased safety of using a systemic instead of topical application may be an incentive for pets that spend time with small children. An adjunct to the use of a systemic is the opportunity to integrate topical therapy without the loss of parasiticidal activity when bathing and other topical treatment is desired.