Next Article in Journal
Validating Morphometrics with DNA Barcoding to Reliably Separate Three Cryptic Species of Bombus Cresson (Hymenoptera: Apidae)
Previous Article in Journal
Resolving the Taxonomic Status of Potential Biocontrol Agents Belonging to the Neglected Genus Lipolexis Förster (Hymenoptera, Braconidae, Aphidiinae) with Descriptions of Six New Species
Open AccessReview

Recent Advancements in the Control of Cat Fleas

Department of Entomology, University of California, Riverside, CA 92521, USA
Insects 2020, 11(10), 668; https://doi.org/10.3390/insects11100668
Received: 29 August 2020 / Revised: 25 September 2020 / Accepted: 26 September 2020 / Published: 29 September 2020
The cat flea Ctenocephalides felis felis is the most important pest of domesticated cats and dogs worldwide. This review covers the recent advancements in the control of cat fleas. Over the years, there has been an interest in using ecologically friendly approaches to control fleas. To date, no biological, natural, or cultural means have been discovered that mitigate flea infestations. The recent registration of novel topical and oral therapies promises a new revolution in the control of fleas and ticks and the diseases associated with them.

Abstract

With the advent of imidacloprid and fipronil spot-on treatments and the oral ingestion of lufenuron, the strategies and methods to control cat fleas dramatically changed during the last 25 years. New innovations and new chemistries have highlighted this progress. Control strategies are no longer based on the tripartite approach of treating the pet, the indoor environment, and outdoors. The ability of modern therapies to break the cat flea life cycle and prevent reproduction has allowed for the stand-alone treatments that are applied or given to the pet. In doing so, we have not only controlled the cat flea, but we have prevented or reduced the impact of many of the diseases associated with ectoparasites and endoparasites of cats and dogs. This review provides an update of newer and non-conventional approaches to control cat fleas.
Keywords: Ctenocephalides felis felis; isoxazolines; essential oils; insecticide resistance Ctenocephalides felis felis; isoxazolines; essential oils; insecticide resistance

1. Introduction

One of the most important pests of domestic cats and dogs is the cat flea, Ctenocephalides felis felis (Bouché). Several reviews concerning the biology and control of cat fleas and new therapeutics have been published [1,2,3,4,5,6]. However, it has been over 20 years since the topic of alternative measures to control cat fleas has been reviewed [7]. Numerous advancements resulting from the development of new spot-on and oral therapeutics have occurred since then. These advancements have changed our thinking and approach to managing fleas on pets and in the indoor environment.
Even though there has been an increased awareness in so-called “green pest management” in the urban environment, limited progress in controlling ectoparasites with natural products or biological agents has been made. With the advent of the spot-on treatments of fipronil and imidacloprid and the systemic use of lufenuron in the mid-1990s, a paradigm shift in our thinking regarding flea control occurred. In the last decade, treatment of the pet with many of the new therapies has made it possible to interrupt the life cycle of the cat flea and prevent reproduction, thereby eliminating the need to spray interior and exterior environments with insecticides to effectuate control.
The objectives of this review are to update the status of flea control and to provide additional insights into strategies to control cat fleas, especially new therapies and their impacts on other arthropod ectoparasites, and problems associated with cat fleas.

2. Biological Control

Even though some studies with bacteria and fungi have demonstrated activity against cat fleas, the research into biological control of cat fleas has been limited [6]. In a recent study, adult cat fleas were exposed to fungal spores, Beauveria bassiana (isolates 4849, 2MG), exposed to different lighting conditions to stimulate conidiation. Spores produced under a red LED light and fluorescent lighting produced the fastest mortality, killing 100% of adult cat fleas within 36 h [8]. It remains uncertain how this might be exploited to control fleas.

3. Vaccines

The search for a vaccine to protect cats and dogs from cat fleas has persisted over the past four decades. Vaccines have the advantages of not contaminating the environment, avoiding the development of insecticide resistance, targeting a broad, but selective range of vector species, and reducing vector competence [9]. Despite these benefits, developing a vaccine has been problematic. Obstacles to developing a vaccine include the lack of natural immunity of cats and dogs to flea infestations, difficulties in obtaining large quantities of flea extracts, and the presence of a serine proteinase in the flea midgut [10]. To date, there is no vaccine available against insect ectoparasites.
The identification of 97 distinct expressed sequence tags that encoded proteins of the cat flea hindgut and Malpighian tubules may provide molecular targets for flea control strategies in the future [11]. Vaccination of cats with recombinant antigens resulted in an antibody response. Efficacy was defined by determining flea mortality and fertility, oviposition, and viability of the flea eggs. It reduced cat flea egg hatchability and fertility, resulting in a 32–46% efficacy [12].
To relieve the effects of flea allergy dermatitis (FAD) in cats, a co-immunization study using DNA encoding flea saliva antigens and proteins suppressed T cell reactions was conducted. It ameliorated many of the clinical symptoms of FAD in cats and showed utility in a clinical study [13].
Despite these findings, it seems like a vaccine to control fleas is a long way in the future, but an anti-allergic vaccine may be available sooner.

4. Botanical Based Compounds

In the past decade, there has been an increased interest in the use of essential oils (EOs) to control insects of urban and veterinary importance [6,14]. Several products containing d-limonene were registered and tested against cat fleas [1,2]. Researchers continue to identify natural products and EOs that are toxic to fleas. Deposits of carvacrol and nootkatone applied inside glass vials were toxic to adult oriental rat fleas, Xenopsylla cheopis [15]. Extracts from incense cedar, Port Orford Cedar, and western juniper were toxic to adult X. cheopis when applied to the inner surfaces of glass vials [16]. Extracts of California pepper tree (Schinus molle) applied to filter paper were toxic to adult C. f. felis but failed to kill flea eggs [17]. Adult fleas exposed to filter paper strips treated with EOs from Ocimum gratissimum (clove basil) and Cinnamomum spp. (cinnamon) were killed. Filter papers treated with clove oil at 25 μg/cm2 killed 100% of adult fleas at 24 h. The EOs were also active against larvae and eggs [18]. The only study involving pets and EOs reports on various infusions or preparations of six plants, mugwort, lemon, juniper, lavender, lemon balm, and cedar, against fleas, but the paper lacks experimental validation [19].
Plant-derived flea products have been reported to have some adverse effects, especially when applied to cats. Topical applications of tea tree oil (Australian tea tree Melaleuca alternifolia) to cats and dogs resulted in depression, weakness, incoordination, and muscle tremors [20]. In another case, Melaleuca oil applied to three cats resulted in death and severe reactions and toxicosis [21]. About 5–9% of the cats treated with spot-on products that included EOs such as peppermint oil, cinnamon oil, lemongrass oil, and clove oil experienced conditions, such as higher agitation, hypersalivation, seizures, and lethargy [22]. Addie et al. [23] recommend that some EOs should only be used after consultation with a veterinarian.
Several studies have examined EOs as repellents. The European Medicine Agency [24] defines a repellent effect as “a product with a repellent effect will cause the parasite to avoid contact with a treated animal completely and/or to leave a host.” A choice bioassay on filter papers treated with EOs provides a rapid laboratory determination of repellency to adult fleas. Essential oil from Cinnamomum osmophloeum (leaves), Taiwania cryptomerioides (heartwood) and Plectranthus amboinicus (leaves) exhibits repellent activity against cat fleas in a dose dependent manner [25]. Extracts of the seeds of monk’s pepper (Vitex agnus castus) repelled cat fleas for about 6 h [26]. It is unclear how these EOs might be used in a control program to deter flea infestations, especially considering their potential negative impacts on cats.

5. Chemical Treatments

Several reviews have covered the development and efficacy of various therapies to control cat fleas [1,2,6,27]. In recent years, the research and development focus has been on treating the pet, rapidly killing adult fleas, and preventing the flea life cycle from maintaining itself.

5.1. Aminoglycosides

Spinosad is an insecticidal compound derived from natural products from the fermentation of the bacterium Saccharopolyspora spinosa. Given orally to dogs, it provides >95% kill of C. f. felis for several months. Spinetoram, an analogue of spinosad, is even more active than spinosad [6]. A laboratory study with dogs indicated that 30–60 mg/kg of spinetoram provided excellent kill of adult fleas for 2–3 months [28]. In a laboratory and field study conducted in Europe, topical application of spinetoram to cats provided 99.1% reductions of C. f. felis at day 60 whereas fipronil + methoprene provided a 92.3% reduction [29]. Topical applications of spinetoram provided 96% reductions through day 37, providing about the same speed of activity against adult fleas as imidacloprid and fipronil + methoprene [30].

5.2. Insect Growth Regulators

The use of insect growth regulators (IGRs), such as methoprene and pyriproxyfen to inhibit egg hatching and larval development in the environment, and oral applications of lufenuron to interfere with egg viability, have played important roles in developing our understanding of successful cat flea pest management. Combination treatments with adulticides and IGRs interrupted the flea life cycle and controlled fleas inside residences [6,31,32].Other IGRs, such as chlorfluazuron and dicyclanil (0.78 and 0.3 ppm lethal concentration [LC95] in larval rearing medium), are as active as methoprene and pyriproxyfen against cat fleas, and may be promising candidates [33]. Interestingly, pyriproxyfen synergized the activity of methoprene against larval cat fleas with a combination of pyriproxyfen:methoprene (10:1) being twice as active (LC50 0.20 ppm in larval rearing medium) as either methoprene or pyriproxyfen alone [34]. The synergism permitted lower concentrations of each IGR to be applied and still be effective.
The combination of imidacloprid and methoprene and imidacloprid and pyriproxyfen were synergistic against larval fleas [35]. Some combinations of fipronil and methoprene or fipronil and pyriproxyfen were synergistic, but in some cases, they were antagonistic. Synergistic combinations allow the concentrations of the adulticide and IGR to be reduced, and still provide the same activity as higher concentrations of the adulticides alone. In a laboratory study, cats topically treated with fipronil + methoprene + pyriproxyfen were allowed to contact carpets. Pieces of carpet were removed and provisioned with flea rearing medium and cat flea eggs. The plugs of treated carpets prevented 86–98% egg development over a 15-week period, effectively interrupting the life cycle [36].
In 2013, a spot-on to treat dogs containing fipronil and novaluron was registered [37]. To date there are no published results concerning its efficacy.

5.3. Isoxazolines

An exciting new class of insecticides, the isoxazolines, was registered in 2014 and emerged on the ectoparasiticide market in 2015 [27]. Isoxazolines are potent inhibitors of γ-aminobutyric acid (GABA)-gated channels and affect l-glutamate-gated chloride channels to a lesser extent [38,39,40,41]. They are second-generation non-competitive antagonists of GABA receptors. Isoxazolines circumvent resistance by attacking new binding regions on the chloride channels [39]. No cross-resistance exists with other non-competitive antagonists, such as fipronil or the macrocyclic lactones such as abamectin and emamectin benzoate [42,43]. Enough differences between insect and mammalian receptors occur to make them selective to insects, and Acari, and excellent candidates as ectoparasiticides. The toxic effects may also extend to Crustacea, as lotilaner was shown to be a powerful antagonist GABA chloride channel of sea lice [38]. Laboratory studies and field trials of new isoxazoline compounds, and combination products published prior to 2017 have been reviewed by Rust [6]. To date afoxolaner, fluralaner, lotilaner, and sarolaner are commercialized.
In addition to killing adult cat fleas, the isoxazolines also kill mites, ticks, lice, triatomine bugs, mosquitoes, biting flies, and sea lice. Some endoparasites also appear to be affected. This remarkable breadth of activity against Insecta, Arachnida, and Crustacea will revolutionize the control of endo- and ectoparasites on cats and dogs. In a study in Sicily and southern Italy, a topical treatment of fipronil + permethrin and an oral dose of afoxolaner + milbemycin oxime was provided to each dog. In addition to killing fleas and ticks, the combination treatment provided a broad spectrum of protection against Anaplasma spp., Borrelia spp., Ehrlichia spp., and dog heartworm [44].
The Project Lake Survey of veterinarians and dog owners regarding their experiences with isoxazoline products indicated that 48.2% of the 2751 respondents had used them [45]. Of the 1768 positive respondents, 66.6% indicated that the dogs had responded with adverse events to the treatment ranging from hair loss to death. As the authors indicate, there are a number of limitations in evaluating voluntary survey data. Palmieri et al. [45] write, “However, FDA (Food and Drug Administration) and EMA (European Medicine Agency) AE (adverse event) reports and Project Lake Survey evidence consistently demonstrate in three separate, distinct data sets that the neurotoxicity is not arthropod-specific, and that post-marketing serious AE are much higher than in the IND (Investigational New Drug) submission studies.” Clearly, additional investigations and surveys are warranted.

5.3.1. Afoxolaner

Afoxolaner first appeared on the market in 2014 as an oral chewable dose for dogs. A chronology of the development of afoxolaner for dogs is provided by Letendre et al. [46]. In addition, afoxolaner also was topically active against fleas and ticks. In a laboratory study with cats, a single oral dose of afoxolaner provided 100% kill of adult fleas within 48 h and 99.5 and 95% reductions for 42 and 63 days, respectively [47]. In a laboratory study, the number of fleas on dogs orally dosed with afoxolaner was reduced by 100% for at least 22 days [48]. An oral dose of afoxolaner + milbemycin oxime to naturally infested dogs provided ≥96.1% reductions of fleas at day 30 [49]. In a field trial with 37 naturally infested dogs in Tampa FL, USA, dogs were provided an oral dose of afoxolaner. Within 7 days, there was a 93% reduction in the number of fleas counted on the dogs and a 99.9% reduction at 30 days. There was a 100% reduction in the number of adult fleas emerging within the residences at 60 days [50].
In a laboratory study, there was 100% kill of the tick Haemaphysalis elliptica on dogs treated with afoxolaner, and it protected them from contracting Babesia rossi [51]. In a laboratory study with dogs, fipronil + permethrin spot-on provided faster knockdown and greater repellency of ticks that did an oral application of afoxolaner. Both treatments provided >90% anti-attachment of Rhipicephalus sanguineus for at least 14 days [48]. An oral dose of afoxolaner + milbemycin oxime provided ≥94.4% reductions of ticks on naturally infested dogs at day 30 [49].

5.3.2. Fluralaner

In a simulated home environment, where natural environmental infestations could reinfest pets, a single topical application of fluralaner provided nearly 100% reductions of fleas on cats and dogs for 12 weeks [52]. In a laboratory study with cats infested with a field isolate of C. f. felis not controlled by fipronil, a spot-on application of fluralaner + moxidectin provided nearly 100% control for the entire 93-day study, whereas a topical application of fipronil + methoprene provided from 65.6 to 30.6% reductions over the same period [53]. In a laboratory study with short haired cats, a single topical application of fluralaner or three topical applications monthly of selamectin + sarolaner provided >94.6% kill of adult cat fleas for 90 days [54].
Topical fluralaner applied to naturally infested cats from 18 different veterinary clinics across 11 USA states provided 99.0% reduction of C. f. felis at week 12. Topical applications of fipronil + methoprene provided a 75.4% reduction [55]. In a similar study with dogs, topically applied fluralaner and fipronil + methoprene provided 99.9 and 93.0% reductions of cat fleas at week 12 [56]. A single topical application of fluralaner to naturally infested cats provided 100% reductions of C. f. felis for up to 84 days [57].
In a large study with 707 cats from 332 households in Germany and Spain, a single spot-on application of fluralaner + moxidectin on cats provided 97 and 98% reductions in ticks and fleas, respectively, throughout the 12-week study. A topical fipronil applied for three consecutive months provided 74.5% reductions at 12 weeks [58].

5.3.3. Lotilaner

An oral dose of lotilaner given to dogs provided 100% kill of adult fleas within 24 h. There was a 98.5% reduction in the number of eggs laid at 24 h and no eggs were laid any period afterwards. When the dogs were challenged with adult fleas, there was a 100% kill for 30 days [59]. An oral dose of lotilaner to cats with an existing C. f. felis infestation provided 100% kill within 24 h. In a second study, 97.4% of the fleas were killed within 8 h. When cats were challenged with adult cat fleas, lotilaner provided 98.6% kill for at least 35 days [60].
Several studies have been conducted to determine the speed at which fleas are killed by lotilaner. In a laboratory study with dogs with existing infestations of C. f. felis, lotilaner provided 64 and 99.6% reductions in the number of fleas counted at 2 and 8 h, respectively [61]. An oral dose of lotilaner to dogs provided 89.9% kill of existing cat flea infestations at 4 h and 100% kill at 12 h. When treated, dogs were challenged with adult fleas for up to 35 days, there was >97% kill at 4 h [62].
Client-owned dogs from 10 veterinary clinics in the USA were dosed with lotilaner or afoxolaner. Lotilaner reduced the number of fleas by 99.3, 99.9, and 100% at 30, 60, and 90 days, respectively. Afoxolaner provided 98.3, 99.8, and 99.8% reductions at 30, 60, and 90 days, respectively. On day 90, all the dogs dosed with lotilaner were flea free and 93% of dogs were flea free when treated with afoxolaner [63].
In a laboratory study, an oral dose of lotilaner to dogs provide 100% kill of Ixodes ricinus within 8 h. Treatment provided protection for 35 days [64]. Similarly, in laboratory studies with four common species of ticks, an oral dose of lotilaner provided greater than 98% efficacy against Dermacentor variabilis, R. sanguineus, Amblyomma americanum, and Ixodes scapularis for at least 4 weeks [65]. Similarly, a single oral dose of lotilaner to dogs provided >98% efficacy against I. ricinus, R. sanguineus, and Dermacentor reticulatus for at least 35 days [66]. In a laboratory study, a single oral dose of lotilaner provided >97% reduction in the number of Haemaphysalis longicornis attached to dogs at 48 h [67].

5.3.4. Sarolaner

The development of sarolaner and supporting studies are discussed by Woods and McTier [68]. Sarolaner was about 10 times more toxic to C. f. felis than afoxolaner or fluralaner in membrane feeding studies. Oral doses of sarolaner provided 100% reduction in the number of fleas retrieved from dogs for up to 35 days. The activity of sarolaner was not negatively affected by the dieldrin resistant mutation at CfRDL-S285 channel [68,69]. In a laboratory study with dogs, topical applications of sarolaner to dogs provided 100 and 87% kill of fleas at day 1 and 28, respectively, after a six-hour challenge. The treatment with fipronil + methoprene + pyriproxyfen provided 88.8 and 83% reductions of fleas at days 1 and 28, respectively [70].
In a field study in USA, 479 dogs in 293 households were given oral doses of sarolaner or spinosad monthly for 3 consecutive months. At day 90, sarolaner and spinosad provided 99.9 and 99.8% reduction in the number of fleas on dogs, respectively [71]. In a field study conducted in west Central Florida, 26 dogs were orally dosed with sarolaner or a spinosad chewable. Both treatments provided >99% reduction of fleas for at least 60 days. The number of fleas trapped in the structures was reduced by 100% in sarolaner and 99.8% in the spinosad treated dogs [72].
The combination of selamectin + sarolaner topically applied to cats in Europe provided a 99.4% reduction in flea counts at day 90. A comparative treatment of imidacloprid + moxidectin provided a 96.3% reduction in the number of cat fleas [73]. In another study, topical application of selamectin + sarolaner provided a 99.8% reduction of C. f. felis at day 90. Clinical signs of flea allergy dermatitis (FAD) were reduced in 86.7 to 100% of the cats. A topical treatment of imidacloprid + moxidectin provided 95.5% reductions in the number of fleas counted at day 90 and 66.7 to 100% reduction in clinical signs of FAD [74]. In a field study in Japan, 67 cats were topically treated with selamectin + sarolaner or fipronil + methoprene. The selamectin + sarolaner provided 99.5 and 99.9% reduction in numbers of fleas on the cats at days 14 and 30, respectively. Fipronil + methoprene provided 97.6 and 98.6% at days 14 and 30, respectively [75]. In Australia, 104 cats were enrolled in clinical studies. A topical application of selamectin + sarolaner for 3 consecutive months provided 98, 100, and 100% control of cat fleas at days 30, 60, and 90, respectively [76].
In a laboratory study with dogs, an oral dose of sarolaner provided 86.2 and 96.5% reductions in Ixodes holocyclus at 8 and 12 h, respectively whereas an oral dose of afoxolaner provided 21.3 and 85.0% reductions at 8 and 12 h, respectively. When treated dogs were challenged at day 35, sarolaner and afoxolaner provided 65.2 and 21.0% efficacy at 12 h, respectively [77]. Oral doses of sarolaner, moxidectin, and pyrantel to laboratory dogs provided 99.7% reductions in C. f. felis for at least 35 days with no eggs being laid during the 35 days. The treatment began killing fleas within 4 h and all the fleas were dead at 8 h. When moxidectin and pyrantel were applied to dogs, they had no effect on fleas [78].
A clinical field trial of 150 dogs dosed with sarolaner + moxidectin + pyrantel provided a 99.0% reduction in cat flea counts at day 30 and a 99.7% reduction at day 60. Clinical signs of FAD declined from 45.7 to 6.9%. Similarly, in a field study with dogs in Europe and the USA, an oral dose of sarolaner + moxidectin + pyrantel provided ≥97.9% reductions in flea counts at day 30 [79]. In a large multi-location study in the USA, oral doses of sarolaner + moxidectin + pyrantel provided 99.0 and 99.7% at days 30 and 60, respectively [80].
In laboratory studies on dogs, an oral dose of sarolaner + moxidectin + pyrantel provided 98.9% kill of existing infestations of the five most common ticks in the USA. At day 28, >88% kill was achieved 48 h after exposing the ticks to the treated dogs [81]. In a laboratory test, an oral dose of sarolaner + moxidectin + pyrantel provided 100% efficacy of existing infestations of African yellow dog ticks, H. elliptica, on dogs and weekly re-infestations for 35 days [82]. Similarly, sarolaner + moxidectin + pyrantel provided 100% efficacy for 21 days against H. longicornis and ≥97.4% efficacy for 35 days [83]. In another study, sarolaner + moxidectin + pyrantel provided 99.4% kill of black legged tick I. scapularis at 24 h and provided a 94.2% reduction of ticks for at least 28 days [84].
In a field study in Japan, 67 cats were topically treated with selamectin + sarolaner or fipronil + methoprene. Selamectin + sarolaner provided 97.5 and 97.7% reductions of the number of the tick H. longicornis at days 14 and 30, respectively. Fipronil + methoprene provided 91.5 and 93.4% reduction in ticks at days 14 and 30 [75]. In a field study with naturally infested dogs, and an oral dose of sarolaner + moxidectin + pyrantel provided ≥94.8% reduction of ticks at 30 days. An oral dose of afoxolaner + milbemycin oxime provided ≥94.4% reduction in the number of ticks at day 30. The ticks included in the test were I. ricinus, Ixodes hexagonus, R. sanguineus, and D. reticulatus [85].

5.3.5. Additional Uses

The label directions and control claims for each of the isoxazoline insecticides registered vary. In addition to controlling fleas and ticks, isoxazolines in combination with endoparasiticides (i.e., macrocyclic lactones) allow the broader spectrum to intestinal nematodes and heartworm.
In a recent review, the use of isoxazolines to control Demodex mites in dogs was concluded to be effective, with few adverse side effects [86]. Oral doses of afoxolaner or afoxolaner + milbemycin oxime to dogs provided 98.1% reduction in the number of Demodex mites at day 84. At day 84, 62.5% of the dogs were considered mite free. Skin lesions and pruritus were significantly reduced in the treated dogs [87]. In another study, a single oral dose of afoxolaner + milbemycin oxime to dogs provided >95% reduction in the number of Demodex mites by day 28. The most significant decreases in mites and lesions occurred during the first 7 days [88]. In a study of healthy dogs with populations of Demodex mites, cutaneous populations of Demodex over the 90-day period were not affected by a treatment of fluralaner or afoxolaner [89]. It was suggested that isoxazoline treatments may not completely eliminate Demodex mites, but only return them to a more natural population level.
An oral dose of afoxolaner to dogs provided 99.4% reduction of ear mites Otodectes cynotis at day 28 [90]. Topical applications of fluralaner to cats provided 100% control of the ear mite by day 7 and provided protection for at least 84 days [57]. A single application of selamectin + sarolaner provided 94.4% reduction of O. cynotis within 30 days compared with a 72% reduction when treated with imidacloprid + moxidectin [74]. An oral dose of afoxolaner to cats naturally infested with ear mites provided 100% efficacy for at least 35 days [91].
Oral doses of afoxolaner or afoxolaner + milbemycin oxime provided >98% reduction in the number of Sarcoptes mites from skin scrapings from dogs for 2 months [92].
An oral dose of afoxolaner or fluralaner to dogs provided 100% kill of the bug Triatoma infestans (a principal vector of Chagas disease) for 51 days. Less blood was consumed by bugs feeding on dogs treated with afoxolaner than fluralaner for some unknown reason [93].
Yellow-fever mosquitoes, Aedes aegypti, were allowed to feed on dogs dosed with afoxolaner. Mosquitoes readily fed on the dogs indicating that the treatment was not repellent. At 24 h after feeding, 98 and 75.3% of the female mosquitoes were killed when exposed to dogs on day 2 and 29 after the dogs were dosed, respectively [94].
The use of systemic insecticides to control phlebotomine fly vectors has been reviewed by Gomez and Picado [95]. The flies are responsible for transmission of zoonotic visceral leishmaniasis. An oral dose of fluralaner to dogs provided 60–80% mortality of phlebotomine flies for 30 days, but moxidectin, spinosad, and afoxolaner did not increase mortality of the flies [96]. In a laboratory study, dogs dosed with afoxolaner provided 100, 95.9 and 75.5% mortality of Phlebotomus perniciosus within 48 h after feeding [97]. Flies fed on both treated and untreated dogs and the afoxolaner was not repellent.
An indirect effect of treating pets with isoxazolines is the prevention of dog tapeworm transmission by infected adult fleas. An oral dose of afoxolaner + milbemycin oxime provided indirect protection to dogs from ingesting adult cat fleas infected with cysticercoid larvae of Dipylidium caninum [98]. Topical or oral fluralaner treatments prevented dogs from acquiring dog tapeworm [99].
An oral dose of sarolaner + moxidectin + pyrantel or afoxolaner + milbemycin oxime to dogs naturally infected with ascarid nematodes and hookworms provided >99% reduction of fecal egg counts [79]. A topical dose of selamectin + sarolaner prevented the development of feline heartworm Dirofilaria immitis in cats [100].
Dogs naturally infested with canine screwworm myiasis were treated with five different insecticides or drugs. Nitenpyram killed all fly larvae within 6 h, and spinosad + milbemycin oxime killed them within 7 h. Within 24 h, all fly larvae were killed with afoxolaner + milbemycin oxime. There was a synergism between spinosad and milbemycin oxime [101].
The rapid prevention of adult flea feeding has been shown to be important in reducing the effects of FAD. Fluralaner and afoxolaner both provided dramatic improvement of FAD in dogs [102]. Similarly, a topical application of fluralaner decreased all the FAD signs on cats beginning at day 7 and continuing until day 84 [56]. An oral dose of fluralaner resolved 90% of 20 cases of FAD at day 84 and 94% of 16 cases at day 168 [103]. FAD symptoms were dramatically reduced in dogs treated with sarolaner or spinosad at day 90 [70]. Oral applications of sarolaner or spinosad provided 62–67% reduction in FAD as measured by the Canine Atopic Dermatitis Extent and Severity Index-4 scale [71]. Spinetoram was better at reducing FAD compared with the fipronil + methoprene treatment [28]. The topical application of fluralaner provided significant reduction in clinical signs of FAD in cats [104]. Oral doses of sarolaner + moxidectin + pyrantel or afoxolaner + milbemycin oxime dramatically reduced the symptoms of FAD in naturally infested dogs within 30 days [48]. In a multiple location study in the USA, an oral dose of sarolaner + moxidectin + pyrantel or afoxolaner dramatically reduced the clinical signs of FAD with dogs [79].

5.4. Formulations

The use of pet collars has been popular for decades even though there was little published evidence that they controlled flea populations on pets [6]. However, collars containing 10% imidacloprid + 4.5% flumethrin provide effective control of fleas for up to 8 months [105,106,107,108]. In vitro lab studies have shown that the combination of imidacloprid and flumethrin synergizes their toxicity against fleas and ticks [109]. Collars containing imidacloprid + flumethrin provided a 100% reduction in flea numbers on dogs at days 120 and 210, whereas deltamethrin collars provided only 76.7 and 66.7% reduction at days 120 and 210, respectively [110]. The use of an imidacloprid + flumethrin collar on cats on the Isles of Lipari and Vulcano reduced flea infestations by 79.4, 100, and 93.6% at 210, 270, and 360 days, respectively [111].
In addition to controlling fleas and ticks, collars containing either imidacloprid + flumethrin or deltamethrin, provided 88.3 and 61.8% efficacy in preventing the transmission of Leishmania infantum by phlebotomine sand flies. In a study with cats, the imidacloprid + flumethrin collar prevented 75% of feline Leishmania infection [112]. In another study, imidacloprid + flumethrin collars provided a preventive effect of 71.5% in the transmission of Bartonella in cats [113]. The collar provides an effective measure to reduce the risks of both diseases.

6. Insecticide Resistance

A review of insecticide resistance indicates widespread resistance to certain carbamates, organophosphates, and pyrethroids [114]. More than 3000 C. f. felis populations were collected from 10 different countries from 2002 to 2017. Of the 1837 isolates that were tested, there was no evidence of a decreased susceptibility to imidacloprid [115]. In another study an isolate of C. f. felis collected from three dogs in which fipronil + methoprene spot-on had not performed well was reared and tested in the laboratory. The field-collected isolate was tested on cats and dogs treated with fipronil + methoprene. The fipronil + methoprene provided >97.6% reductions in fleas on dogs and >85.6% on cats for at least 29 days. The authors concluded that the reported failures in earlier trials were probably due to factors other than insecticidal resistance [116]. To date, there is little evidence suggesting that resistance has developed to many of the new topical and oral insecticides being used.
Populations of C. f. felis from goat farms in Turkey had >90% frequency of the kdr gene (L1014F) and super kdr gene (T929V) in response to intensive use of cypermethrin [117]. This study supports the claim that pyrethroid resistance is widespread in C. f. felis [112].

7. Control Strategies

Strategies to control cat fleas have evolved over the past two decades with the advent of new chemistries and therapies. Treatment of the pet, the indoor environment, and the outdoor environment was the standard practice prior to advent of modern topical and oral treatments in the mid-1990s [1,2]. In recent years, the reduction in the ability of cat fleas to lay viable eggs has become an important factor when considering the efficacy of topical and oral treatments of pets [118,119]. By interrupting flea reproduction, these topical and systemic flea products are capable of controlling flea populations in the indoor premises.
Of the 759 pet-owners surveyed from 84 different veterinary clinics from 2002 to 2012, 71% of the dog owners and 50% of the cat owners had used a flea control product in the previous 12 months. Pet owners preferred spot-on, on-animal sprays, and pills as treatment options. Some common causes of failures to control fleas were a lack of knowledge about the flea life cycle, misapplication of the product, and noncompliance of treatment schedules by the pet owners [120].
There has been a trend to market therapies having a combination of products that protect or control various ectoparasites and endoparasites. Products with active ingredients to control fleas and ticks include drugs like moxidectin (antihelminthic activity against heartworms) and pyrantel (anti-parasiticide against pinworms and roundworms). This might be in part explained by a recent survey of 24 veterinary hospitals across the country. About 96% of these veterinarians recommended 12-month flea and tick control. Of the 559 dog owners surveyed, 73% also felt 12 months control necessary. However, pet owners typically apply flea and tick control products for only 4 to 4.6 months [121]. When purchasing patterns of 650 veterinary clinics were examined from 2014 to 2017, some 201,565 dogs were prescribed either fluralaner (29.1%), afoxolaner (58.9%), or spinosad (26.9%). Approximately 80% of the dogs were from southern and Midwestern states. Dog owners purchased more months of protection by selecting longer duration products like fluralaner than shorter length treatments like afoxolaner or spinosad. However, the months of protection obtained by the dog owner was less than that recommended by a veterinarian by 53% for fluralaner, 62% for afoxolaner, and 71% for spinosad [122]. Purchasing products with longer lasting activity against endo- and ectoparasites is clearly a strategy that pet owners are likely to adopt.
Two distinctly different approaches to use of isoxazolines have developed. Pfister and Armstrong [123] provide a review and discussion of the merits of a cutaneous application (permethrin) and a systemic application (fluralaner). When they considered the following four factors, owner adherence to the recommended treatment protocol, rapid onset of activity following administration, uniform efficacy over all areas of the treated dog at risk for parasite attachment, and maintenance of high efficacy throughout the retreatment interval, they felt the systemic treatment provided the optimal outcome. If sarolaner or fluralaner had been chosen as the cutaneous treatment instead of permethrin, possibly their assessment might change.
There has been a reluctance in some regulatory agencies to consider oral or topical treatments of pets as a stand-alone treatment. However, evidence is accumulating that the treatment of all pets within a home, with many of the newer therapeutics, can break the lifecycle and completely control an indoor infestation [118]. A topical application of imidacloprid reduced the number of fleas on pets by 98.8% on pets and the number of fleas trapped in the homes by 99.9%. An oral dose of lufenuron combined with pyrethrin sprays reduced the number of fleas on animals by 99.2% and the number trapped in homes by 99.7% [31]. Three monthly topical applications of fipronil or imidacloprid to cats and dogs provided 96.5 and 99.5% reductions on animals and the number of fleas trapped within homes was reduced 98.6 and 98.6%, respectively [124]. In Australia, pets were treated with nitenpyram + lufenuron or imidacloprid. Nitenpyram + lufenuron provided 90–100% reduction of fleas on animals over the year and 100% reduction of fleas in the home [125]. Topical treatments with imidacloprid varied over the 1-year study. There was an 84.2–97.2% reduction of fleas on animals over 16 weeks. After the rainy season, control ranged from 70.5 to 87.8% reductions. The number of fleas trapped ranged from 0.0 to 93.6%. A single topical application of indoxacarb or monthly applications of fipronil + methoprene provided 99.1 and 54.8% reductions of fleas on dogs at day 60. Light trap counts in the homes decreased by 97.7% with indoxacarb and 84.6% with fipronil + methoprene at day 60 [126].
Similar results have been reported with isoxazoline compounds. Oral doses of afoxolaner for dogs reduced the number of fleas on dogs by 99.3 and 100% at days 7 and 30, respectively. The number of fleas caught in light traps in the residence decreased by 97.7 and 100% at 30 and 60 days, respectively [50]. Oral doses of fluralaner or afoxolaner provided 100% reduction in the number of fleas collected from treated dogs at day 86. Fluralaner and afoxolaner provided 100 and 98.9% reductions in the number of fleas caught in light traps in homes [102]. A single topical application of fipronil + pyriproxyfen on cats prevented flea egg development for 15 weeks in a simulated indoor environment [36]. Carpet disks from rooms with fipronil + pyriproxyfen treated cats prevented egg development. The treatment successfully interrupted the life cycle. Oral doses of sarolaner or spinosad to dogs resulted in >99.8% reduction in the number of fleas trapped within structures at 60 days [79]. Similarly, Dryden et al. [127] reported that a single topical application of fluralaner reduced the flea count on cats by 100% and the number of fleas in light traps by 99.9% by day 86.

8. Future Directions

The use of RNAi delivery systems to control insects of veterinary importance is an exciting new direction for the future of flea control. The delivery system allows for the knockdown of very specific targeted gene expression in both insects and acarines. Edwards et al. [128] were able to demonstrate the transfer of RNAi to cat fleas through a membrane feeding system, and resulted in 96% knockdown of GSTσ, a detoxification enzyme, within 2 days and sustained at least 7 days. The RNAi response to ingested dsRNA in C. f. felis was not impaired by gut enzymes of the flea. Another exciting delivery system that involves the use of nanoparticles is also being actively researched [129].
Even though there is little evidence to suggest widespread insecticide resistance in cat fleas to the modern arsenal of treatments available, it is important that flea populations be continually monitored to rapidly detect any changes in their populations. The maintenance of susceptible populations of C. f. felis is essential [112].
The control of C. f. felis in feral animals remains a problem. Feral animals provide for a reservoir of fleas in the environment. Currently, there is a lack of effective control measures to use outdoors to control these feral populations. Possibly baits to feed to feral animals containing actives such as the isoxazolines might be developed to control fleas, especially those associated with sylvatic plague.

9. Conclusions

The development of therapies that can reduce cat flea reproduction, prevent cat flea development, and rapidly kill adult fleas on the pet has dramatically altered our approaches to controlling cat fleas in the urban environment. The need for environmental treatments, especially indoors, has been greatly reduced. The costs of some of these new treatments may be prohibitive for universal adoption, but other adulticides containing IGRs are still effective and maybe more economical. The arsenal of potential topical and oral therapies to control cat fleas is impressive.

Funding

This research received no extramural funding.

Acknowledgments

I would like to thank Byron Blagburn (Auburn University) and Nancy Hinkle (University of Georgia) for the thoughtful and constructive comments.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Dryden, M.W.; Rust, M.K. The cat flea: Biology, ecology and control. Vet. Parasitol. 1994, 52, 1–19. [Google Scholar] [CrossRef]
  2. Rust, M.K.; Dryden, M.W. The biology, ecology, and management of the cat flea. Annu. Rev. Entomol. 1997, 42, 451–473. [Google Scholar] [CrossRef] [PubMed]
  3. Blagburn, B.L.; Dryden, M.W. Biology, treatment, and control of flea and tick infestations. Vet. Clin. Small Anim. 2009, 39, 1173–1200. [Google Scholar] [CrossRef] [PubMed]
  4. Beugnet, F.; Franc, M. Insecticide and acaricide molecules and/or combinations to prevent pet infestation by ectoparasites. Trends Parasitol. 2012, 28, 267–279. [Google Scholar] [CrossRef]
  5. Boase, C.; Kocisova, A.; Rettich, F. Fleas and flea management. In Urban Insect Pests Sustainable Management Strategies; Dhang, P., Ed.; CAB Int.: Reading, UK, 2014; pp. 86–98. [Google Scholar]
  6. Rust, M.K. The biology and ecology of cat fleas and advancements in their pest management: A review. Insects 2017, 8, 118. [Google Scholar] [CrossRef]
  7. Hinkle, N.C.; Rust, M.K.; Reierson, D.A. Biorational approaches to flea (Siphonaptera: Pulicidae) suppression: Present and future. J. Agric. Entomol. 1997, 14, 309–321. [Google Scholar]
  8. Pittarate, S.; Thungrabeab, M.; Mekchay, S.; Krutmuang, P. Virulence of aerial conidia of Beauveria bassiana produced under LED light to Ctenocephalides felis (cat flea). J. Pathog. 2018, 2018. [Google Scholar] [CrossRef]
  9. De la Fuente, J.; Contreras, M.; Estrada-Peña, A.; Cabezas-Cruz, A. Targeting a global health problem: Vaccine design and challenges for the control of tick-borne diseases. Vaccine 2017, 35, 5089–5094. [Google Scholar] [CrossRef]
  10. Nesbit, A.J.; Huntly, J.F. Progress and opportunities in the development of vaccines against mites, fleas and myiasis-causing flies of veterinary importance. Parasite Immunol. 2006, 28, 165–172. [Google Scholar] [CrossRef]
  11. Gaines, P.J.; Brandt, K.S.; Eisele, A.M.; Wagner, W.P.; Bozic, C.M.; Wisnewski, N. Analysis of expressed sequence tags from subtracted and unsubtracted Ctenocephalides felis hindgut and Malpighian tubule cDNA libraries. Insect Mol. Biol. 2002, 11, 299–306. [Google Scholar] [CrossRef]
  12. Contreras, M.; Villar, M.; Artigas-Jerónimo, S.; Kornieieva, L.; Mytrofanov, S. A reverse vaccinology approach to the identification and characterization of Ctenocephalides felis candidate protective antigens for the control of cat flea infestations. Parasites Vectors 2017, 11, 43. [Google Scholar] [CrossRef] [PubMed]
  13. Jin, J.; Ding, Z.; Meng, F.; Liu, Q.; Ng, T.; Hu, Y.; Zhao, G.; Zhai, B.; Chu, H.-J.; Wang, B. An immunotherapeutic treatment against flea allergy dermatitis in cats by co-immunization of DNA and protein vaccines. Vaccine 2010, 28, 1997–2004. [Google Scholar] [CrossRef] [PubMed]
  14. Ellse, L.; Wall, R. The use of essential oils in veterinary ectoparasite control: A review. Med. Vet. Entomol. 2014, 28, 233–243. [Google Scholar] [CrossRef] [PubMed]
  15. Panella, N.A.; Dolan, M.C.; Karchesy, J.J.; Xiong, Y.; Peralta-Cruz, J.; Khasawneh, M.; Montenieri, J.A.; Maupin, G.O. Use of novel compounds for pest control: Insecticidal and acaricidal activity of essential oils components from heartwood of Alaska yellow cedar. J. Med. Entomol. 2005, 42, 352–358. [Google Scholar] [CrossRef]
  16. Dolan, M.C.; Dietrich, G.; Panella, N.A.; Montenieri, J.A.; Karchesy, J.J. Biocidal activity of three wood essential oils against Ixodes scapularis (Acari: Ixodidae), Xenopsylla cheopis (Siphonaptera: Pulicidae), and Aedes aegypti (Diptera: Culicidae). J. Econ. Entomol. 2007, 100, 622–625. [Google Scholar] [CrossRef]
  17. Batista, L.C.; Cid, Y.P.; Almeda, A.P.; Prudêncio, E.R.; Riger, C.J.; Souza, M.A.A.; Coumendouros, K.; Chaves, D.S.A. In vitro efficacy of essential oils and extracts of Schinus molle L. against Ctenocephalides felis felis. Parasitology 2016, 143, 627–638. [Google Scholar] [CrossRef]
  18. Dos Santos, J.V.B.; Siqueria, D.; Alves, M.A.; Riger, C.J.; Lambert, M.M.; Campos, D.R.; Moreira, L.O.; Conceicão, R.; Boylan, F.; Correia, T.R.; et al. In vitro activity of essential oils against adult and immature stages of Ctenocephalides felis felis. Parasitology 2020, 147, 340–347. [Google Scholar] [CrossRef]
  19. Lans, C.; Turner, N.; Khan, T. Medicinal plant treatments for fleas and ear problems of cats and dogs in British Columbia, Canada. Parasitol. Res. 2008, 103, 889–898. [Google Scholar] [CrossRef]
  20. Villar, D.; Knight, M.J. Toxicity of melaleuca oil and related essential oils applied topically on dogs and cats. Vet. Hum. Toxicol. 1994, 36, 139–142. [Google Scholar]
  21. Bischoff, K.; Guale, F. Australian tea tree (Melaleuca alternifolia) oil poisoning in three purebred cats. J. Vet. Diag. Investig. 1998, 10, 208–210. [Google Scholar] [CrossRef]
  22. Genovese, A.G.; McLean, M.K.; Khan, S.A. Adverse reactions from essential oil-containing natural flea products exempted from Environmental Protection Agency regulations in dogs and cats. J. Vet. Emerg. Crit. Care 2012, 22, 470–475. [Google Scholar] [CrossRef] [PubMed]
  23. Addie, D.D.; Boucrant-Baralon, C.; Egberink, H.; Frymus, T.; Gruffydd-Jones, T.; Hartmann, K.; Horzinek, M.C.; Hosie, M.J.; Lioret, A.; Lutz, H.; et al. Disinfectant choices in veterinary practices, shelters and households ABCD guidelines on safe and effective disinfection for feline environments. J. Feline Med. Surg. 2015, 17, 594–605. [Google Scholar] [CrossRef] [PubMed]
  24. European Medicines Agency (EMEA). Guideline for the Testing and Evaluation of the Efficacy of Antiparasitic Substances for the Treatment and Prevention of Tick and Flea Infestation in Dogs and Cats. 2016. Available online: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500210927.pdf (accessed on 14 September 2020).
  25. Su, L.-C.; Huang, C.-G.; Chang, S.-T.; Yang, S.-H.; Hsu, S.-H.; Wu, W.-J.; Huang, R.-N. An improved bioassay facilitates the screening of repellents against cat flea, Ctenocephalides felis (Siphonaptera: Pulicidae). Pest. Manag. Sci. 2014, 70, 264–270. [Google Scholar] [CrossRef] [PubMed]
  26. Mehlhorn, H.; Schmahl, G.; Schmidt, J. Extract of the seeds of the plant Vitex agnus castus proven to be highly efficacious as a repellent against ticks, fleas, mosquitoes and biting flies. Parasitol. Res. 2005, 95, 363–365. [Google Scholar] [CrossRef] [PubMed]
  27. Sojka, P.A. Isoxazolines. J. Exot. Pet Med. 2018, 27, 118–122. [Google Scholar] [CrossRef]
  28. White, W.H.; Riggs, K.L.; Totten, M.L.; Snyder, D.E.; McCoy, C.M.; Young, D.R. Initial evaluations of the effectiveness of spinetoram as long-acting, oral systemic pulicide for controlling cat fleas (Ctenocephalides felis) infestations on dogs. Vet. Parasitol. 2017, 233, 25–31. [Google Scholar] [CrossRef]
  29. Wheeler, D.W.; Trout, C.M.; Thompson, C.M.; Winkle, J.R.; White, W.H. Evaluation of an 11.2% spinetoram topical spot-on solution for the control of experimental and natural flea (Ctenocephalides felis) infestations on cats in Europe. Vet. Parasitol. 2018, 258, 99–107. [Google Scholar] [CrossRef]
  30. Paarlberg, T.; Winkle, J.; Rumschlag, A.J.; Young, L.M.; Ryan, W.G.; Synder, D.E. Effectiveness and residual speed of flea kill of a novel spot on formulation of spinetoram (Cheristin®) for cats. Parasites Vectors 2017, 10, 59. [Google Scholar] [CrossRef]
  31. Osbrink, W.L.A.; Rust, M.K.; Reierson, D.A. Distribution and control of cat fleas in homes in southern California (Siphonaptera: Pulicidae). J. Econ. Entomol. 1986, 79, 135–140. [Google Scholar] [CrossRef]
  32. Dryden, M.W.; Perez, H.R.; Ulitchny, D.M. Control of fleas on pets and in homes by use of imidacloprid or lufenuron and a pyrethrin spray. JAVMA 1999, 215, 36–39. [Google Scholar]
  33. Rust, M.K.; Hemsarth, W.L.H. Intrinsic activity of IGRs against larval cat fleas. J. Med. Entomol. 2017, 54, 418–421. [Google Scholar] [CrossRef] [PubMed]
  34. Rust, M.K.; Hemsarth, W.L.H. Synergism of the IGRs methoprene and pyriproxyfen against larval cat fleas (Siphonaptera: Pulicidae). J. Med. Entomol. 2016, 53, 629–633. [Google Scholar] [CrossRef] [PubMed]
  35. Rust, M.K.; Hemsarth, W.L.H. Synergism of adulticides and insect growth regulators against larval cat fleas (Siphonaptera: Pulicidae). J. Med. Entomol. 2019, 56, 790–795. [Google Scholar] [CrossRef] [PubMed]
  36. Lebon, W.; Franc, M.; Bouhsira, E.; Lienard, E.; Murray, M.; Carithers, D.; Beugnet, F. Prevention of flea egg development in a simulated home environment by Frontline® Gold (fipronil, (S)-methoprene, pyriproxyfen) applied topically to cats. Int. J. Appl. Res. Vet. Med. 2018, 16, 67–73. [Google Scholar]
  37. EPA. Notice of Pesticide Registration. 2013. Available online: https://www3.epa.gov/pesticides/chem_search/ppls/053883-00312-20130628.pdf (accessed on 28 September 2020).
  38. Rufener, L.; Danelli, V.; Bertrand, D.; Sager, H. The novel isooxazoline ectoparasiticide lotilaner (Credelio™): A non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACIs). Parasites Vectors 2017, 10, 530. [Google Scholar] [CrossRef]
  39. Gassel, M.; Wolf, C.; Noack, S.; Williams, H.; Ilg, T. The novel isoxazoline ectoparasiticide fluralaner: Selective inhibition of arthropod γ-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal/acaricidal activity. Insect Biochem. Mol. Biol. 2014, 45, 111–124. [Google Scholar] [CrossRef]
  40. Weber, T.; Selzer, P.M. Isoxazolines: A novel chemotype highly effective on ectoparasites. ChemMedChem 2016, 11, 270–276. [Google Scholar] [CrossRef]
  41. Xu, M.; Long, J.K.; Lahm, G.P.; Shoop, W.L.; Cordova, D.; Wagerle, T.; Smith, B.K.; Pahutski, T.F.; Shapiro, R.; Mahaffey, M.; et al. The discovery of afoxolaner: A new ectoparasiticide for dogs. In Ectoparasites: Drug Discovery against Moving Targets, 1st ed.; Meng, C.Q., Sluder, A.E., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2018; pp. 259–827. [Google Scholar]
  42. Casida, J.E.; Durkin, K.A. Novel GABA receptor pesticide targets. Pest. Biochem. Physiol. 2015, 121, 22–30. [Google Scholar] [CrossRef]
  43. Casida, J.E. Golden age of RyR and GABA-R diamide and isoxazoline insecticides: Common genesis, serendipity, surprises, selectivity, and safety. Chem. Res. Toxicol. 2015, 28, 560–566. [Google Scholar] [CrossRef]
  44. Abbate, J.M.; Napoli, E.; Arfuso, F.; Gaglio, G.; Giannetto, S.; Halos, L.; Beugnet, F.; Brianti, E. Six-month field efficacy and safety study of combined treatment of dogs with Frontline Tri-Act® and NexGard Spectra®. Parasites Vectors 2018, 11, 425. [Google Scholar] [CrossRef]
  45. Palmieri, V.; Dodds, W.J.; Morgan, J.; Carney, E.; Fritsche, H.A.; Jeffrey, J.; Bullock, R.; Kimball, J.P. Survey of canine use and safety of isoxazoline parasiticides. Vet. Med. Sci. 2020, 1–13. [Google Scholar] [CrossRef]
  46. Letendre, L.; Larsen, D.; Soll, D. Development of afoxolaner as a new ectoparasiticide for dogs. In Ectoparasites: Drug Discovery against Moving Targets, 1st ed.; Meng, C.Q., Sluder, A.E., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2018; pp. 273–294. [Google Scholar]
  47. Machado, M.A.; Campos, D.R.; Lopes, N.L.; Bastos, I.B.P.; Alves, M.S.R.; Correia, T.R.; Scott, F.B.; Fernandes, J.I. Efficacy of afoxolaner in the flea control in experimentally infested cats. Braz. J. Vet. Parasitol. 2019, 28, 760–763. [Google Scholar] [CrossRef] [PubMed]
  48. Cvejić, D.; Schneider, C.; Neethling, W.; Hellmann, K.; Liebenberg, J.; Navarro, C. The sustained speed of kill of ticks (Rhipicephalus sanguineus) and fleas (Ctenocephalides felis felis) on dogs by a spot-on combination of fipronil and permethrin (Effitix®) compared with oral afoxolaner (NexGard®). Vet. Parasitol. 2017, 243, 52–57. [Google Scholar] [CrossRef]
  49. Becskei, C.; Fias, D.; Mahabir, S.P.; Farkas, R. Efficacy of a novel oral chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against natural flea and tick infestations on dogs presented as veterinary patients in Europe. Parasites Vectors 2020, 13, 72. [Google Scholar] [CrossRef] [PubMed]
  50. Dryden, M.W.; Smith, V.; Chwala, M.; Jones, E.; Crevoiserat, L.; McGrady, J.C.; Foley, K.M.; Patton, P.R.; Hawkins, A.; Carithers, D. Evaluation of afoxolaner chewables to control flea populations in naturally infested dogs in private residences in Tampa, FL, USA. Parasites Vectors 2015, 8, 826. [Google Scholar] [CrossRef]
  51. Beugnet, F.; Lebon, W.; de Vos, C. Prevention of the transmission of Babesia rossi by Haemaphysalis elliptica in dogs treated with Nexgard®. Parasite 2019, 26, 49. [Google Scholar] [CrossRef]
  52. Ranjan, S.; Young, D.; Sun, F. A single topical fluralaner application to cats and dogs controls fleas for 12 weeks in a simulated home environment. Parasites Vectors 2018, 11, 385. [Google Scholar] [CrossRef]
  53. Fisara, P.; Guerino, F.; Sun, F. Efficacy of a spot-on combinations of fluralaner plus moxidectin (Bravecto® Plus) in cats following repeated experimental challenge with a field isolate of Ctenocephalides felis. Parasites Vectors 2019, 12, 259. [Google Scholar] [CrossRef]
  54. Vatta, A.F.; King, V.L.; Young, D.R.; Chapin, S. Efficacy of three consecutive monthly doses of a topical formulation of selamectin and sarolaner (Revolution® Plus/Stronghold® Plus) compared with a single dose of fluralaner (Bravecto® for cats) against induced infestations of Ctenocephalides felis on cats. Vet. Parasitol. 2019, 270, S52–S57. [Google Scholar] [CrossRef]
  55. Meadows, C.; Guerino, F.; Sun, F. A randomized, blinded, controlled USA field study to assess the use of fluralaner topical solution in controlling feline flea infestations. Parasites Vectors 2017, 10, 37. [Google Scholar] [CrossRef]
  56. Meadows, C.; Guerino, F.; Sun, F. A randomized, blinded, controlled USA field study to assess the use of fluralaner topical solution in controlling canine flea infestations. Parasites Vectors 2017, 10, 36. [Google Scholar] [CrossRef] [PubMed]
  57. Bosco, A.; Leone, F.; Vascone, R.; Pennacchio, S.; Ciuca, L.; Cringoli, G.; Rinaldi, L. Efficacy of fluralaner spot-on solution for the treatment of Ctenocephalides felis and Otodectus cynotis mixed infestation in naturally infested cats. BMC Vet. Res. 2019, 15, 28. [Google Scholar] [CrossRef]
  58. Rohdich, N.; Zschiesche, E.; Wolf, O.; Loehlein, W.; Pobel, T.; Gil, M.J.; Roepke, R.K.A. Field effectiveness and safety of fluralaner plus moxidectin (Bravecto® Plus) against ticks and fleas: A European randomized, blinded, multicenter field study in naturally-infested client-owned cats. Parasites Vectors 2018, 11, 598. [Google Scholar] [CrossRef] [PubMed]
  59. Young, L.; Karadzovska, D.; Wiseman, S.; Helbig, R. Efficacy of lotilaner (Credelio™) against the adult cat flea, Ctenocephalides felis and flea eggs following oral administration to dogs. Parasites Vectors 2020, 13, 25. [Google Scholar] [CrossRef] [PubMed]
  60. Cavalleri, D.; Murphy, M.; Seewald, W.; Nanchen, S. Laboratory evaluation of the efficacy and speed of kill of lotilaner (Credelio™) against Ctenocephalides felis on cats. Parasites Vectors 2018, 11, 408. [Google Scholar] [CrossRef]
  61. Cavalleri, D.; Murphy, M.; Seewald, W.; Drake, J.; Nanchen, S. Assessment of the onset of lotilaner (Credelio™) speed of kill of fleas on dogs. Parasites Vectors 2017, 10, 521. [Google Scholar] [CrossRef]
  62. Cavalleri, D.; Murphy, M.; Seewald, M.; Drake, J.; Nanchen, S. Assessment of the speed of flea kill of lotilaner (Credelio™) throughout the month following oral administration to dogs. Parasites Vectors 2017, 10, 539. [Google Scholar] [CrossRef]
  63. Karadzovska, D.; Chappell, K.; Coble, S.; Murphy, M.; Cavalleri, D.; Wiseman, S.; Drake, J.; Nanchen, S. A randomized, controlled field study to assess the efficacy and safety of lotilaner flavored chewable tablets (Credelio™) in eliminating fleas in client-owned dogs in the USA. Parasites Vectors 2017, 10, 528. [Google Scholar] [CrossRef]
  64. Murphy, M.; Cavalleri, D.; Seewald, W.; Drake, J.; Nanchen, S. Laboratory evaluation of the speed of kill of lotilaner (Credelio™) against Ixodes ricinus ticks on dogs. Parasites Vectors 2017, 10, 541. [Google Scholar] [CrossRef]
  65. Murphy, M.; Garcia, R.; Karadzovska, D.; Cavalleri, D.; Snyder, D.; Seewald, W.; Real, T.; Drake, J.; Wiseman, S.; Nanchen, S. Laboratory evaluations of the immediate and sustained efficacy of lotilaner (Credelio™) against four common species of ticks affecting dogs in North America. Parasites Vectors 2017, 10, 523. [Google Scholar] [CrossRef]
  66. Cavalleri, D.; Murphy, M.; Gorbea, R.L.; Seewald, W.; Drake, J.; Nanchen, S. Laboratory evaluations of the immediate and sustained effectiveness of lotilaner (Credelio™) against three common species of ticks affecting dogs in Europe. Parasites Vectors 2017, 10, 527. [Google Scholar] [CrossRef] [PubMed]
  67. Otaki, H.; Sonobe, J.; Murphy, M.; Cavalleri, D.; Seewald, W.; Drake, J.; Nanchen, S. Laboratory evaluation of the efficacy of lotilaner (Credelio™) against Haemaphysalis longicornis infestations of dogs. Parasites Vectors 2018, 11, 448. [Google Scholar] [CrossRef] [PubMed]
  68. Woods, D.J.; McTier, T.L. Discovery, development, and commercialization of sarolaner (Simparica®), a novel oral isooxazoline ectoparasiticide for dogs. In Ectoparasites: Drug Discovery Against Moving Targets, 1st ed.; Meng, C.Q., Sluder, A.E., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2018; pp. 295–318. [Google Scholar]
  69. McTier, T.L.; Chubb, N.; Curtis, M.P.; Hedges, L.; Inskeep, G.A.; Knauer, C.S.; Menon, S.; Mills, B.; Pullins, A.; Zinser, E.; et al. Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs. Vet. Parasitol. 2016, 222, 3–11. [Google Scholar] [CrossRef] [PubMed]
  70. Carithers, D.; Everett, W.R.; Gross, S.; Crawford, J. Comparative efficacy of fipronil/(S)-methoprene/pyriproxyfen (FRONTLINE® Gold) and sarolaner (SIMPARICA®) against Ctenocephalides felis flea infestations on dogs. Int. J. Appl. Res. Vet. Med. 2018, 16, 28–32. [Google Scholar]
  71. Cherni, J.A.; Mahabir, S.P.; Six, R.H. Efficacy and safety of sarolaner (Simparica™) against fleas on dogs presented as veterinary patients in the United States. Vet. Parasitol. 2016, 222, 43–48. [Google Scholar] [CrossRef] [PubMed]
  72. Dryden, M.W.; Canfield, M.S.; Niedfeldt, E.; Kinnon, A.; Kalosy, K.; Smith, A.; Foley, K.M.; Smith, V.; Bress, T.S.; Smith, N.; et al. Evaluation of sarolaner and spinosad oral treatments to eliminate fleas, reduce dermatologic lesions and minimize pruritus in naturally infested dogs in west Central Florida, USA. Parasites Vectors 2017, 10, 389. [Google Scholar] [CrossRef]
  73. Geurden, T.; Becskei, C.; Farkas, R.; Lin, D.; Rugg, D. Efficacy and safety of a new spot-on formulation of selamectin plus sarolaner in the treatment of naturally occurring flea and tick infestations in cats presented as veterinary patients in Europe. Vet. Parasitol. 2017, 238, S12–S17. [Google Scholar] [CrossRef]
  74. Vatta, A.F.; Myers, M.R.; Rugg, J.J.; Chapin, S.; Pullins, A.; King, V.L.; Rugg, D. Efficacy and safety of a combination of selamectin plus sarolaner for the treatment and prevention of flea infestations and the treatment of ear mites in cats presented as veterinary patients in the United States. Vet. Parasitol. 2019, 270, S3–S11. [Google Scholar] [CrossRef]
  75. Yonetake, W.; Fujii, T.; Naito, M.; Hodge, A.; Maeder, S.; Rugg, D. Efficacy of a new topical formulation of selamectin plus sarolaner for the control of fleas and ticks infesting cats in Japan. Vet. Parasitol. 2019, 270, S12–S18. [Google Scholar] [CrossRef]
  76. Packianathan, R.; Pittorino, M.; Hodge, A.; Bruellke, N.; Graham, K. Safety and efficacy of a new spot-on formulation of selamectin plus sarolaner in the treatment and control of naturally occurring flea infestations in cats presented as veterinary patients in Australia. Parasites Vectors 2020, 13, 227. [Google Scholar] [CrossRef]
  77. Packianathan, R.; Hodge, A.; Bruellke, N.; Davis, K.; Maeder, S. Comparative speed of kill of sarolaner (Simparica®) and afoxolaner (NexGard®) against induced infestations of Ixodes holocyclus on dogs. Parasites Vectors 2017, 19, 98. [Google Scholar] [CrossRef] [PubMed]
  78. Kryda, K.; Mahabir, S.P.; Carter, L.; Everett, W.R.; Young, D.R.; Meyer, L.; Thys, M.; Chapin, S.; Holzmer, S.J.; Becskei, C. Laboratory studies evaluating the efficacy of a novel orally administered combination product containing sarolaner, moxidectin and pyrantel (Simparica Trio™) for the treatment and control of flea infestations on dogs. Parasites Vectors 2020, 13, 57. [Google Scholar] [CrossRef]
  79. Beckei, C.; Kydra, K.; Fias, D.; Follis, S.L.; Wozniakiewicz, M.; Mahabir, S.P. Field efficacy and safety of a novel oral chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against naturally acquired gastrointestinal nematode infections in dogs presented as veterinary patients in Europe and the USA. Parasites Vectors 2020, 13, 70. [Google Scholar] [CrossRef] [PubMed]
  80. Kryda, K.; Mahabir, S.P.; Inskeep, T.; Rugg, J. Safety and efficacy of a novel oral chewable combination tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against natural flea infestations in client-owned dogs in the USA. Parasites Vectors 2020, 13, 98. [Google Scholar] [CrossRef] [PubMed]
  81. Kryda, K.; Mahabir, S.P.; Chapin, S.; Holzmer, S.J.; Bowersock, L.; Everett, W.R.; Riner, J.; Carter, L.; Young, D. Efficacy of a novel orally administered combination product containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against induced infestations of five common tick species infesting dogs in the USA. Parasites Vectors 2020, 13, 77. [Google Scholar] [CrossRef]
  82. Fourie, J.J.; Liebenberg, J.E.; Crafford, D.; Six, R. Immediate and persistent efficacy of sarolaner (Simparica™) against Haemaphysalis elliptica on dogs. Parasites Vectors 2019, 12, 431. [Google Scholar] [CrossRef]
  83. Oda, K.; Yonetake, W.; Fujii, T.; Hodge, A.; Six, R.H.; Maeder, S. Efficacy of sarolaner (Simparica®) against induced infestations of Haemaphysalis longicornis on dogs. Parasites Vectors 2019, 12, 509. [Google Scholar] [CrossRef]
  84. Holzmer, S.; Kydra, K.; Mahabir, S.P.; Everett, W. Evaluation of the speed of kill of a novel orally administered combination product containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against induced infestations of Ixodes scapularis on dogs. Parasites Vectors 2020, 13, 76. [Google Scholar] [CrossRef]
  85. Becskei, C.; Liebenberg, J.; Thys, M.; Mahabir, S.P. Efficacy of a novel chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against four common tick species infesting dogs in Europe. Parasites Vectors 2020, 13, 100. [Google Scholar] [CrossRef]
  86. Zhou, X.; Hohman, A.; Hsu, W.H. Review of extralabel use of isoxazolines for treatment of demodicosis in dogs and cats. JAVMA 2020, 256, 1342–1346. [Google Scholar] [CrossRef]
  87. Lebon, W.; Beccati, M.; Bourdeau, P.; Brement, T.; Bruet, V.; Cekiera, A.; Crosaz, O.; Darmon, C.; Guillot, J.; Mosca, M.; et al. Efficacy of two formulations of afoxolaner (NexGard® and NexGard Spectra®) for the treatment of generalized demodicosis in dogs, in veterinary dermatology referral centers in Europe. Parasites Vectors 2018, 11, 506. [Google Scholar] [CrossRef] [PubMed]
  88. Romero-Núñez, C.; Sheinberg, G.; Martin, A.; Romero, A.; Flores, A.; Heredia, R.; Miranda, L. Efficacy of afoxolaner plus milbemycin oxime in the treatment of canine demodicosis. Int. J. Appl. Res. Vet. Med. 2019, 17, 35–41. [Google Scholar]
  89. Zewe, C.M.; Altet, L.; Lam, A.T.H.; Ferrer, L. Afoxolaner and fluralaner treatment do not impact on cutaneous Demodex populations of healthy dogs. Vet. Dermatol. 2017, 28, 468-e107. [Google Scholar] [CrossRef] [PubMed]
  90. Carithers, D.; Crawford, J.; de Vos, C.; Lotriet, A.; Fourie, J. Assessment of afoxolaner efficacy against Otodectes cynotis infestations of dogs. Parasites Vectors 2016, 9, 635. [Google Scholar] [CrossRef] [PubMed]
  91. Machado, M.A.; Campos, D.R.; Lopes, N.L.; Bastos, I.P.B.; Botelho, C.B.; Correia, T.R.; Scott, F.B.; Fernandes, J.L. Efficacy of afoxolaner in the treatment of otodectic mange in naturally infested cats. Vet. Parasitol. 2018, 256, 29–31. [Google Scholar] [CrossRef]
  92. Hampel, V.; Knaus, M.; Schäfer, J.; Beugnet, F.; Rehbein, S. Treatment of canine sarcoptic mange with afoxolaner (NexGard®) and afoxolaner plus milbemycin oxime (NexGard Spectra®) chewable tablets: Efficacy under field conditions in Portugal and Germany. Parasite 2018, 25, 63. [Google Scholar] [CrossRef]
  93. Loza, A.; Talaga, A.; Herbas, G.; Canaviri, R.J.; Cahuasin, T.; Luck, L.; Guibarra, A.; Goncalves, R.; Pereira, J.A.; Gomez, S.A.; et al. Systemic insecticide treatment of the canine reservoir of Trypanosoma cruzi induces high levels of lethality in Triatoma infestans, a principal vector of Chagas disease. Parasites Vectors 2017, 10, 344. [Google Scholar] [CrossRef]
  94. Liebenberg, J.; Fourie, J.; Lebon, W.; Larsen, D.; Halos, L.; Beugnet, F. Assessment of the insecticidal activity of afoxolaner against Aedes aegypti in dogs treated with NexGard®. Parasite 2017, 24, 39. [Google Scholar] [CrossRef]
  95. Gomez, S.A.; Picado, A. Systemic insecticides used in dogs: Potential candidates for phlebotomine vector control? Trop. Med. Int. Health 2017, 22, 755–764. [Google Scholar] [CrossRef]
  96. Gomez, S.A.; Curdi, J.L.; Hernandez, J.A.C.; Peris, P.P.; Gil, A.E.; Velasquez, R.V.O.; Hernandez, P.O.; Picado, A. Phlebotomine mortality effect of systemic insecticides administered to dogs. Parasites Vectors 2018, 11, 230. [Google Scholar] [CrossRef]
  97. Perier, N.; Lebon, W.; Meyer, L.; Lekouch, N.; Aouiche, N.; Beugnet, F. Assessment of the insecticidal activity of oral afoxolaner against Phlebotomus perniciosus in dogs. Parasite 2019, 26, 63. [Google Scholar] [CrossRef] [PubMed]
  98. Beugnet, F.; Meyer, L.; Fourie, F.; Larsen, D. Preventive efficacy of NexGard Spectra® against Dipylidium caninum infection in dogs using a natural flea (Ctenocephalides felis) infestation model. Parasite 2017, 24, 16. [Google Scholar] [CrossRef] [PubMed]
  99. Gopinath, D.; Meyer, L.; Smith, J.; Armstrong, R. Topical or oral fluralaner efficacy against flea (Ctenocephalides felis) transmission of Dipylidium caninum infection to dogs. Parasites Vectors 2018, 11, 557. [Google Scholar] [CrossRef] [PubMed]
  100. McTier, T.L.; Pullins, A.; Chapin, S.; Rugg, J.; von Reitzenstein, M.; McCall, J.W.; King, V.L.; Vatta, A.F. The efficacy of a novel topical formulation of selamectin plus sarolaner (Revolution®/Stronghold® Plus) in preventing the development of Dirofilaria immitis in cats. Vet. Parasitol. 2019, 270, 56–62. [Google Scholar] [CrossRef] [PubMed]
  101. Han, H.S.; Chen, C.; Schievano, C.; Noli, C. The comparative efficacy of afoxolaner, spinosad, milbemycin, spinosad plus milbemycin, and nitenpyram for the treatment of canine cutaneous myiasis. Vet. Dermatol. 2018, 29, 312-e109. [Google Scholar] [CrossRef]
  102. Dryden, M.W.; Canfield, M.S.; Kalosy, K.; Smith, A.; Crevoiserat, L.; McGrady, J.C.; Foley, K.M.; Green, K.; Tebaldi, C.; Smith, V.; et al. Evaluation of fluralaner and afoxolaner treatments to control flea populations, reduce pruritus and minimize dermatologic lesions in naturally infested dogs in private residences in west central Florida USA. Parasites Vectors 2016, 9, 365. [Google Scholar] [CrossRef]
  103. Crosaz, O.; Chapelle, E.; Cochet-Faivre, N.; Ka, D.; Hubinois, C.; Guiliot, J. Open field study on the efficacy of oral fluralaner for long-term control of flea allergy dermatitis in client-owned dogs in Lle-de-France region. Parasites Vectors 2016, 9, 174. [Google Scholar] [CrossRef]
  104. Briand, A.; Cochet-Faivre, N.; Prélaud, P.; Armstrong, R.; Hubinois, C. Open field study on the efficacy of fluralaner topical solution for long-term control of flea bite allergy dermatitis in client owned cats in Lle-de-France region. BMC Vet. Res. 2019, 15, 337. [Google Scholar] [CrossRef]
  105. Stanneck, D.; Kruedewagen, E.M.; Fourie, J.J.; Horak, I.G.; Davis, W.; Krieger, K.J. Efficacy of an imidacloprid/flumethrin collar against fleas and ticks on cats. Parasites Vectors 2012, 5, 82. [Google Scholar] [CrossRef]
  106. Stanneck, D.; Kruedewagen, E.M.; Fourie, J.J.; Horak, I.G.; Davis, W.; Krieger, K.J. Efficacy of an imidacloprid/flumethrin collar against fleas, ticks, mites and lice on dogs. Parasites Vectors 2012, 5, 102. [Google Scholar] [CrossRef]
  107. Stanneck, D.; Rass, J.; Radeloff, I.; Kruedewagen, E.; Sueur, C.L.; Hellmann, K.; Krieger, K. Evaluation of the long-term efficacy and safety of an imidacloprid 10%/flumethrin 4.5% polymer matrix collar (Seresto®®) in dogs and cats naturally infested with fleas and/or ticks in multicentre clinical field studies in Europe. Parasites Vectors 2012, 5, 66. [Google Scholar] [CrossRef] [PubMed]
  108. Dryden, M.W.; Smith, V.; Davis, W.L.; Settje, T.; Hostetler, J. Evaluation and comparison of a flumethrin-imidacloprid collar and repeated monthly treatments of fipronil/(s)-methoprene to control flea, Ctenocephalides f. felis, infestations on cats for eight months. Parasites Vectors 2016, 9, 287. [Google Scholar] [CrossRef] [PubMed]
  109. Stanneck, D.; Ebbinghaus-Kintscher, U.; Schoenhense, E.; Krudewagen, E.M.; Turberg, A.; Leisewitz, A.; Jiritschka, W.; Krieger, K.J. The synergistic action of imidacloprid and flumethrin and their release kinetics from collars applied for ectoparasite control in dogs and cats. Parasites Vectors 2012, 5, 73. [Google Scholar] [CrossRef] [PubMed]
  110. Brianti, E.; Napoli, E.; Gaglio, G.; Falsone, L.; Giannetto, S.; Basano, F.S.; Nazzari, R.; Latrofa, M.S.; Annoscia, G.; Tarallo, V.D.; et al. Field evaluation of two different treatment approaches and their ability to control fleas and prevent canine leishmaniosis in a highly endemic area. PLOS Negl. Trop. Dis. 2016, 10, e0004987. [Google Scholar] [CrossRef]
  111. Otranto, D.; Dantas-Torres, F.; Napoli, E.; Basano, F.S.; Deuster, K.; Pollmeier, M.; Capelli, G.; Brianti, E. Season-long control of flea and tick infestations in a population of cats in the Aeolian archipelago using a collar containing 10% imidacloprid and 4.5% flumethrin. Vet. Parasitol. 2017, 248, 80–83. [Google Scholar] [CrossRef]
  112. Brianti, E.; Falsone, L.; Napoli, E.; Gagilo, G.; Giannetto, S.; Pennisi, M.G.; Priolo, V.; Latrofa, M.S.; Tarallo, V.D.; Basano, F.S.; et al. Prevention of feline leishmaniosis with an imidacloprid 10%/flumethrin 4.5% polymer matric collar. Parasites Vectors 2017, 10, 334. [Google Scholar] [CrossRef]
  113. Greco, G.; Brianti, E.; Buonavoglia, C.; Carelli, G.; Pollmeier, M.; Schunack, B.; Dowgier, G.; Capelli, G.; Dantas-Torres, F.; Otranto, D. Effectiveness of a 10% imidacloprid/4.5% flumethrin polymer matrix collar on reducing the risk of Bartonella spp. infection in privately owned cats. Parasites Vectors 2019, 12, 69. [Google Scholar] [CrossRef]
  114. Rust, M.K. Insecticide resistance in fleas. Insects 2016, 7, 10. [Google Scholar] [CrossRef]
  115. Rust, M.K.; Blagburn, B.L.; Denholm, I.; Dryden, M.W.; Payne, P.; Hinkle, N.C.; Koop, S.; Williamson, M. International program to monitor cat flea populations for susceptibility to imidacloprid. J. Med. Entomol. 2019, 55, 1245–1253. [Google Scholar] [CrossRef]
  116. Carithers, D.; Dryden, M.; Everett, W.R.; Gross, S.; Crawford, J. Assessment of FRONTLINE® Plus efficacy at 24-hour counts against Tampa 2014 Isolate Ctenocephalides felis flea infestations on cats and dogs on days 1, 7, 14, 21, and 28. Int. J. Appl. Res. Vet. Med. 2018, 16, 52–58. [Google Scholar]
  117. Alak, S.E.; Köseoğlu, A.E.; Kandemir, C.; Taşkin, T.; Demir, S.; Döşkaya, M.; Űn, C.; Can, H. High frequency of knockdown resistance mutations in the para gene of cat flea (Ctenocephalides felis) samples collected from goats. Parasitol. Res. 2020, 119, 2067–2073. [Google Scholar] [CrossRef] [PubMed]
  118. Dryden, M.W.; Broce, A.B. Integrated flea control for the 21st Century. Compend. Contin. Educ. Pract. Vet. 2002, 24, 36–40. [Google Scholar]
  119. Dryden, M.W. Flea and tick control in the 21st century: Challenges and opportunities. Vet. Dermatol. 2009, 20, 435–440. [Google Scholar] [CrossRef] [PubMed]
  120. Peribáñez, M.A.; Calvete, C.; Gracia, M.J. Preferences of pet owners in regard to the use of insecticides for flea control. J. Med. Entomol. 2018, 55, 1254–1263. [Google Scholar] [CrossRef] [PubMed]
  121. Lavan, R.P.; Tunceli, K.; Zhang, D.; Normile, D.; Armstrong, R. Assessment of dog owner adherence to veterinarians’ flea and tick prevention recommendations in the United States using a cross-sectional survey. Parasites Vectors 2017, 10, 284. [Google Scholar] [CrossRef] [PubMed]
  122. Lavan, R.; Armstrong, R.; Tunceli, K.; Normile, D. Dog owner flea/tick medication purchases in the USA. Parasites Vectors 2018, 11, 581. [Google Scholar] [CrossRef] [PubMed]
  123. Pfister, K.; Armstrong, R. Systemically and cutaneously distributed ectoparasiticides: A review of the efficacy against ticks and fleas in dogs. Parasites Vectors 2018, 9, 436. [Google Scholar] [CrossRef]
  124. Dryden, M.W.; Denenberg, T.M.; Bunch, S. Control of fleas on naturally infested dogs and cats and in private residences with topical spot applications of fipronil or imidacloprid. Vet. Parasitol. 2000, 93, 69–75. [Google Scholar] [CrossRef]
  125. Miller, P.F.; Peters, B.A.; Holt, C.A. A field study to evaluate integrated flea control using lufenuron and nitenpyram compared to imidacloprid used alone. Aust. Vet. Practit. 2001, 31, 60–66. [Google Scholar]
  126. Dryden, M.W.; Payne, P.A.; Smith, V.; Chwala, M.; Jones, E.; Davenport, J.; Fadl, G.; Martinez-Perez de Zeiders, M.F.; Heaney, K. Evaluation of indoxacarb and fipronil (s)-methoprene topical spot-on formulations to control flea populations in naturally infested dogs and cats in private residences in Tampa FL. USA. Parasites Vectors 2013, 6, 366. [Google Scholar] [CrossRef]
  127. Dryden, M.W.; Canfield, M.S.; Bocon, C.; Phan, L.; Niedfeldt, E.; Kinnon, A.; Warcholek, S.A.; Smith, V.; Bress, T.S.; Smith, N.; et al. In-home assessment of either topical fluralaner or topical selamectin for flea control in naturally infested cats in West Central Florida, USA. Parasites Vectors 2018, 11, 422. [Google Scholar] [CrossRef] [PubMed]
  128. Edwards, C.H.; Baird, J.; Zinser, E.; Woods, D.J.; Shaw, S.; Campbell, E.M.; Bowman, A.S. RNA interference in the cat flea, Ctenocephalides felis: Approaches for sustained gene knockdown and evidence of involvement of Dicer-2 and Argonaute2. Int. J. Parasitol. 2018, 48, 993–1002. [Google Scholar] [CrossRef] [PubMed]
  129. Whitten, M.M.A. Novel RNAi delivery systems in the control of medical and veterinary pests. Curr. Opin. Insect Sci. 2019, 34, 1–6. [Google Scholar] [CrossRef] [PubMed]
Back to TopTop