Derm Jeopardy -"How to make fleas flee" (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 has predominated the market place as the mainstay of treatment for the flea allergic animal, although chemical newcomers to the world of flea control provide additional attributes in the way of long acting oral medication (Comfortis®, Elanco). Repeated use and chronic exposure of the flea to some active ingredients may 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 and thought leaders with industry support to advance information on protecting pets from parasites and zoonotic diseases, recommends the administration of year round flea and/or tick control to companion animals (Website: www.capcvet.org). Certainly this is a necessity in Southeastern U.S.. 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). The current problem is not the limitation of products but the application and acceptance with pet owner compliance. The pet owner's defiance of acceptance of their pet's affliction of flea allergy can be so powerful that they have convinced themselves that the problem does not exist. Client education or better yet client acceptance of flea problems remain the greatest challenge. Some methods of persuasion are effective including flea allergy testing, indirect recognition of a flea infestation from other co-habitating animals or the environment, or flea fras, tape worm segments, etc.. Many flea allergic animals simply do not carry noticeable flea burdens to the observation of the pet owner. Financial constraints may also limit the ability to satisfactorily control the problem in multipet households. The magic of the custodial flea comb comes in handy except when you come up empty handed and get the "see, I told you so" response. The "prove me wrong" approach has been of some benefit where the pet owner agrees to follow your explicit instructions with the high hopes you are wrong. When the recheck appointment comes up in 21 days and the dog is 65% improved, the owner is usually quick to remind you it probably didn't have anything to do with the flea products. Flea allergy is like scabies: if you suspect it...you treat it. Compliance breakdown and dose splitting is a constant problem. Regardless of how good a treatment plan you have there is frequently a loop hole. A young Jack Russell Terrier with substantial flea allergy dermatitis returned for a reevaluation for a problem that should have been nearly resolved but wasn't. My first thought was a breakdown in compliance which was emphatically denied. My second thought was "where are all the fleas coming from?". I went back over the owner completed history form and looked at the item which asked "Do you have any other pets?" with the response "No". She confirmed the JRT was her only pet. It was by circumstance that her daughter was with her that day and spoke up by saying, "Mom, what about the two cats?" Her mother replied, "the question asked me if I had any other pets and I do not; Those cats belong to you! The reply, "Yes mom, but they all live in the same house!!!"

Today, fleas can be controlled by treating only the hosts in most circumstances where in decades gone by the inclusion of premise treatment was highly advocated. In highly infested environments, the inclusion of premise treatment to eradicate the source of fleas was often necessary and the integration of a systemic IDI such as lufenuron was an integral part of the integrated approach to flea control and provides a good "safety net" today. All fleas must feed once leaving the cocoon and thus must find a host. If there is assurance that there is a parasiticidal effect from contact/feeding on the host then the flea will neither replicate or survive. The weakness is that ALL animals in the area also need to be treated. There are no flea control products that eliminate flea feeding no matter how fast they have an effect. Repellancy of the flea is not attainable even with some of the more potent chemicals although some marketing gimmicks would want you to believe that systemic therapeutics are ineffective because they require the consumption of the chemical. Having been in a situation with a pet owner with 38 dogs and 14 cats with minimal financial resources, the problem becomes insurmountable. The lessons learned include the need for a complete history to enhance the therapeutic effect. The recipe for optimal flea control include the following points.

Obtain a comprehensive history

• Number and species of pets

• Animal's habitat

• Frequent and infrequent visitors (includes uninvited)

• Owner's visualization of flea infestation

• Identification of flea allergic animals (many are atopic)

• Validation of current flea control efforts

• (Specific products, application rate, target animals, etc.)

• Concern for other ectoparasites (ticks, scabies, demodex)

• Strategic use of flea control products:

• Awareness of flea life cycle and pupal window

• Systemic versus topical

• Combined endoparasiticide and ectoparasiticide products (selamectin, moxidectin) may compromise residual activity of flea control

• Client education of treatment concepts and specific active ingredients chosen for their purpose

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. I continue to recognize that the majority of pet owners do not have the perception of either the problem or the most advantageous method of controlling it. Most are in some level of flea denial or they are convinced that their method of treatment has resolved the problem ("I apply that product on my dog every 3 months and put granules in the yard").

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 and currently incorporated in a flea control product. 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 along with the integration of newer parasiticideds (Vectra, Summit Vet Pharm). 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 products has replaced the dependency on 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 marketed as Frontline Plus® (Merial, Inc.) with the inclusion of S-Methoprene as an IGR. Residual efficacy initially demonstrated excellent results (greater than 95% flea control) with the observation of less effectiveness in clinical settings within the last several years. While this may not be a general observation throughout all areas in North America, it appears to be quite evident in Southeastern U.S.. Geographic areas including the Gulf Coast area may be more affected by loss of efficacy as a consequence of a greater flea populations and more intense chemical use. Extra-label use is often required to have sufficient control of flea infestation flea allergic dog as often as every 10-14 days in some locations.

Imidacloprid

Imidacloprid (Advantage®, Advantage Multi®, and Advantix®; Bayer Animal Health, Inc.) is also a popular on-the-animal adulticide with some residual activity. Greater than 95% efficacy for 28 days has been documented in dogs although in SE United States, particularly with routine bathing, two weeks residual may be maximal. The frequency of Advantage® administration should not exceed once weekly according to manufacturer's recommendation. Application every two weeks in cats has been noticeably more effective. 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 but should never be used on cats. Advantage Multi combines moxidectin for additional parasiticidal effect as an end-ectocide.

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 where higher concentration of active ingredient occurs. 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 others with a more rapid onset.

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 product has the limitation of minimal residual efficacy while the virtues of a systemic treatment with rapid effect.

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 residual efficacy as a monthly spot application although clinical conditions may result in less effective long term control. The combination of amitraz has demonstrated efficacy for tick control exceeding four weeks and now approved for the treatment of demodicosis. Both ProMeris for cats and ProMeris for dogs has demonstrated activity in cases of flea allergy dermatitis. The addition of amitraz for the dog formulation enhances the application in tick infested environments with application as a demodicide and likely a scabicide. Metaflumizone studies of distribution have been investigated showing minimal absorption of the active ingredient while hair samples revealed wide spread distribution of the active in cats post treatment.

The limitations of ProMeris® continues to be the large volume, disagreeable odor and current observations of a pemphigus foliaceous-like eruption that has occurred in a small percentage of dogs treated. The reaction is typically at the application site but may have a distribution pattern similar to conventional spontaneous idiopathic PF. Breed predilection has been observed with the PF like adversity. Resolution is usually more rapid than non-drug induced PF once therapy is discontinued. On-going therapy has not been necessary for the PF associated with ProMeris® if the drug is withdrawn.

Dinotefuran

Dinotefuran is derived from chemical structure of acetylcholine (not nicotine) 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 and shows a wide margin of safety and comparable acute toxicity to the insect. 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 growth regulator. The availability of Vectra 2D for cats is formulated to 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. The advantages of Comfortis® include its effectiveness for effectively treating flea allergy dermatitis with a long acting systemic in a convenient, user friendly application, particularly in multi-dog household. It does not rely on translocation and eliminates the potential for irritancy with topical spot therapy and also the concern for human exposure or sensitive animals. In addition to the rapid flea kill it also eliminates flea egg production. It has a 98%+ flea control with monthly treatments and is eliminated through the feces in an environmentally friendly form (produced from the fermentation of a bacterium-Saccharopolyspora spinosa). Its limitations are the lack of tick control, the low incidence of vomition with no activity on ticks. It should not be used in dogs receiving higher dose ivermectin for demodicidal therapy. Because of the unique activity of the active ingredient, however, it can be used with other parasiticides selected for tick control in areas or situations where a tick problem prevails. Newer introductions using the spinosy class of pesticide is Spinetoram, a topical approved for flea control in cats marketed as Assurity®. It alters the function of nicotinic and GABA-gated ion channels and does not interact with know bindingsites of other classes of insecticide such as neonicitinoids. The inclusion of milbemycin oxime with spinosad is marketed as Trifexis by Elanco to include heartworm preventative with hookworm, roundworm and whipworm control as well as spinosad for flea control for use in dogs. While this product does not provide tick control it can be combined with a permethrin containing product in dogs to achieve that goal. Trifexis is provided in the same convenient package sizes for dosaging dogs from 5 to 120 pounds.

Selected Veterinary Flea Control Products