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Synergy Between Dinotefuran and Fipronil Against the Cat Flea

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Synergy Between Dinotefuran and Fipronil Against the Cat Flea Delcombel et al. Parasites & Vectors (2017) 10:341 DOI 10.1186/s13071-017-2272-8 RESEARCH Open Access Synergy between dinotefuran and fipronil against the cat flea (Ctenocephalides felis): improved onset of action and residual speed of kill in adult cats Romain Delcombel1, Hamadi Karembe1, Bakela Nare3, Audrey Burton3, Julian Liebenberg2, Josephus Fourie2 and Marie Varloud 1* Abstract Background: The cat flea, Ctenocephalides felis felis (C. felis), is a cosmopolitan hematophagous ectoparasite, and is considered to be the most prevalent flea species in both Europe and the USA. Clinical signs frequently associated with flea bites include pruritus, dermatitis and in severe cases even pyodermatitis and alopecia. Ctenocephalides felis is also a vector for several pathogens and is an intermediate host for the cestode Dipylidium caninum. Treatment of cats with a fast-acting pulicide, that is persistently effective in protecting the animal against re-infestation, is therefore imperative to their health. In addition, a rapid onset of activity (“speed of kill”) may also reduce the risks of disease transmission and flea allergic dermatitis. The aim of this study was to evaluate the in vitro insecticidal activity and potential synergism between dinotefuran and fipronil against C. felis. A further aim was to evaluate the onset of activity and residual speed of kill of the combination in vivo on cats artificially infested with C. felis. Methods: In the first study, the insecticidal activity of dinotefuran and fipronil separately and dinotefuran/fipronil (DF) in combination, at a fixed ratio (2:1), was evaluated using an in vitro coated-vial bioassay. In the second study, the onset of activity against existing flea infestations and residual speed of kill of DF against artificial flea infestations on cats was assessed in vivo. Onset of activity against existing flea infestations was assessed in terms of knock-down effect within 2 h post-treatment and onset of speed of kill assessed at 3 h, 6 h and 12 h post-treatment. Residual speed of kill was evaluated 6 h and 48 h after infestation, over a period of six weeks post-treatment. Results: In vitro results revealed that the DF combination was synergistic and more potent against fleas than either compound alone. The combination also proved effective when tested in vivo. Efficacy was > 97% [geometric mean (GM) and arithmetic mean (AM)] at 3 h after treatment, and ≥ 99.8% (GM and AM) at 6 h and 12 h post-treatment. At 6 h after flea re-infestations, the efficacy of DF remained ≥ 90.8% (GM and AM) for up to 28 days, and at 42 days post- treatment persistent efficacy was still ≥ 54.3% (GM and AM). At 48 h after flea re-infestations, DF remained almost fully effective for up to 28 days, with efficacies ≥ 99.4% (GM and AM) and was persistently ≥ 93.0% (GM and AM) effective for up to 42 days post-treatment. (Continued on next page) * Correspondence: [email protected] 1Ceva Santé Animale, 10 avenue de la Ballastière, 33500 Libourne, France Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Delcombel et al. Parasites & Vectors (2017) 10:341 Page 2 of 10 (Continued from previous page) Conclusions: The combination of dinotefuran and fipronil in a single formulation exhibited strong synergistic insecticidal activity against C. felis in vitro, and also proved effective on artificially infested cats. This activity had a rapid onset that persisted for 6 weeks against re-infestations of C. felis on cats. The rapid curative insecticidal effect was observed as early as 3 h after treatment, and as early as 6 h after re-infestations for up to 6 weeks post-treatment. The insecticidal activity profile of DF makes it an optimal candidate for the protection of cats against flea infestations, and possibly also associated diseases. Keywords: Dinotefuran, Fipronil, Synergy, Efficacy, In vitro, In vivo, Fleas, Ctenocephalides felis Background cats with a fast-acting pulicide, with a persistent efficacy The cat flea, Ctenocephalides felis felis (C. felis)isa against re-infestation, is therefore imperative to their hematophagous ectoparasite that infests cats and other health. Whilst the efficacy of pulicidal products has domestic animals worldwide [1]. Both outdoor and indoor generally been evaluated 48 h after treatment against domestic animals are affected. A recent epidemiological existing flea infestations or re-infestation [17], some of study conducted in several European countries, indicated them, especially spot-on formulations, are expected to that 15.5% of cats were infested with fleas [2]. Moreover, act much sooner. This property, referred to as speed of C. felis was the most prevalent flea species in this study. kill, represents the rapid onset of activity, thus freeing Similarly, C. felis has recently been reported to be the cats from their fleas. Rapid speed of kill may also reduce most prevalent flea species in the USA [3]. In this the risks of disease transmission and FAD [18]. epidemiological survey conducted by Blagburn and colla- Dinotefuran is a furanicotinyl insecticide belonging to borators in 2016, 96% of the fleas collected countrywide the third generation of neonicotinoids [19]. It acts were identified as C. felis. specifically on the nervous system of fleas by inhibiting a Fleas are highly efficient in acquiring a host by leaping nicotinic subclass of acetylcholine receptors. Dinotefuran from their immediate environment onto such an animal is a contact pulicide and has a rapid speed of kill against [4]. In addition, when more than one animal is accommo- fleas, as early as 2 h [20] to 6 h post-treatment on dated in a household, an infested host can transmit live infested cats [21]. Moreover, it has been demonstrated and prolific fleas to its congeners, and this inter-host that dinotefuran has a residual efficacy lasting for transfer can occur within an hour after contact [5]. Imme- 30 days, when evaluated against 4 consecutive weekly diately after a host has been acquired, fleas start feeding infestations with fleas [22]. The activity of this com- and continue to take numerous blood meals daily [6–9]. pound is, however, limited to insects and no acaricidal Consequently, symptoms associated with flea infesta- activity has been demonstrated, except at high concen- tions can soon be observed. For instance, allergenic pro- trations and after a week of exposure [23, 24]. Fipronil teins contained in C. felis saliva, may result in immediate on the other hand, is a proven insecticide and acaricide. hypersensitivity resulting in flea allergic dermatitis (FAD) This compound acts on insects and acarines by blocking [10]. Cats with FAD suffer from intense discomfort caused the action of gamma-aminobutyric acid. It also acts by by severe pruritus and dermatitis characterized by contact and because it accumulates in the skin and seba- excoriation, scaling, crusting, miliary lesions and papules. ceous glands, remains active for at least 4 weeks against If untreated, the disease can lead to pyodermitis and fleas and ticks [25]. alopecia. Although the threshold in unknown, a small In order to strengthen and extend insecticidal activity, number of flea bites are expected to induce a resurgence a combination of active ingredients with different modes of the symptoms in cats already sensitized to flea allergens of action and potency in a single spot-on formulation [11]. The detrimental effects of flea infestations are, how- has been proposed [26, 27]. Moreover, if compounds in ever, not limited to sensitized animals, but can be respon- combination are synergistic, the same insecticidal sible for skin irritation in non-flea allergen sensitized efficacy can be achieved as when they are administered hosts, resulting in intense grooming and itching, and can separately, but at lower active ingredient concentrations. even induce anemia in susceptible cats [11]. This is likely to improve the safety profile of such Ctenocephalides felis is also a vector of several patho- products. In this study, dinotefuran and fipronil were gens, namely viruses such as feline leukemia virus [12], combined in a single solution, taking advantage of their bacteria such as Rickettsia felis [13], Haemoplasma different mechanisms of action. It was anticipated that species [14] and Bartonella species [15]. Fleas also act as this novel combination would provide a more complete intermediate host for intestinal helminths such as the topical protection of cats against ectoparasites, a rapid cestode Dipylidium caninum [16]. Effective treatment of onset of efficacy to alleviate flea bite dermatitis and a Delcombel et al. Parasites & Vectors (2017) 10:341 Page 3 of 10 long lasting residual speed of kill effect, aiding in the Table 1 Details on age and gender of cats included in the protection of cats against FAD and flea-borne pathogens. study The aim of this study was to evaluate the insecticidal Group Treatment Age in years Gender n activity and potential synergism between dinotefuran and Mean Min Max Female Male fipronil against C. felis in vitro, when tested separately or in 1 Untreated 4.0 0.9 9.0 5 3 8 combination, and also to evaluate the onset of activity and 2 DF 5.2 3.9 7.0 6 2 8 residual speed of kill in vivo on artificially infested cats.
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