Evaluation of Fluralaner As an Oral Acaricide to Reduce Tick Infestation
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Pelletier et al. Parasites Vectors (2020) 13:73 https://doi.org/10.1186/s13071-020-3932-7 Parasites & Vectors RESEARCH Open Access Evaluation of furalaner as an oral acaricide to reduce tick infestation in a wild rodent reservoir of Lyme disease Jérôme Pelletier1,2,3*, Jean‑Philippe Rocheleau2,4, Cécile Aenishaenslin1,2,3, Francis Beaudry5, Gabrielle Dimitri Masson1,2, L. Robbin Lindsay6, Nicholas H. Ogden2,7, Catherine Bouchard2,7 and Patrick A. Leighton1,2,3 Abstract Background: Lyme disease (LD) is an increasing public health threat in temperate zones of the northern hemisphere, yet relatively few methods exist for reducing LD risk in endemic areas. Disrupting the LD transmission cycle in nature is a promising avenue for risk reduction. This experimental study evaluated the efcacy of furalaner, a recent oral aca‑ ricide with a long duration of efect in dogs, for killing Ixodes scapularis ticks in Peromyscus maniculatus mice, a known wildlife reservoir for Borrelia burgdorferi in nature. Methods: We assigned 87 mice to 3 furalaner treatment groups (50 mg/kg, 12.5 mg/kg and untreated control) administered as a single oral treatment. Mice were then infested with 20 Ixodes scapularis larvae at 2, 28 and 45 days post‑treatment and we measured efcacy as the proportion of infesting larvae that died within 48 h. At each infesta‑ tion, blood from 3 mice in each treatment group was tested to obtain furalaner plasma concentrations (C p). Results: Treatment with 50 mg/kg and 12.5 mg/kg furalaner killed 97% and 94% of infesting larvae 2 days post‑treat‑ ment, but no signifcant efect of treatment on feeding larvae was observed 28 and 45 days post‑treatment. Mouse Cp did not difer signifcantly between the two tested doses. Mean Cp decreased from 13,000 ng/ml in the 50 mg/kg group and 4000 ng/ml in the 12.5 mg/kg group at Day 2 to < 100 ng/ml in both groups at Day 45. Conclusions: We provide the frst evidence that furalaner is efective for killing immature ticks in Peromyscus mice, a frst step in evaluating its potential for treating wild rodents as a public health intervention to reduce LD risk in endemic areas. Keywords: Lyme disease, Mice, Isoxazolines, Fluralaner, Ticks, Ixodes scapularis, Peromyscus spp. Background alone [3]. In southern Canada, Lyme borreliosis is cur- Lyme disease (LD), caused by the spirochete Borrelia rently emerging, associated with the northward spread burgdorferi [1], is the most important tick-borne dis- of the tick Ixodes scapularis, with the number of annual ease in Europe and North America [2]. In the USA, reported cases increasing from 144 in 2010 to 2025 the annual incidence rate was 7.2 reported cases per in 2017 [4–6]. Because LD is a signifcant burden for 100,000 people with 33,000 reported cases in 2018 public health, diferent strategies have been developed to prevent disease transmission to humans, including promoting the adoption of personal preventive meas- *Correspondence: [email protected] 1 Département de pathologie et microbiologie, Faculté de médecine ures and reducing tick density in the environment. vétérinaire, Université de Montréal, Saint‑Hyacinthe, QC, Canada Tick control measures include the direct application of Full list of author information is available at the end of the article acaricides in the environment or the treatment of the © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pelletier et al. Parasites Vectors (2020) 13:73 Page 2 of 9 main tick hosts, such as the white-tailed deer, with oral this product in mice, and specifcally in wild mice of the or topical acaricides [7]. Another potential intervention genus Peromyscus. Peromyscus mice are considered to be approach is to treat key reservoirs of B. burgdorferi, the primary wildlife reservoirs for Borrelia burgdorferi in such as Peromyscus spp. mice, to decrease the density much of North America [32, 33]. of ticks in the environment and/or the prevalence of In the present study, we administered furalaner to Per- infection in questing ticks, both of which contribute to omyscus mice and then infested mice with larval Ixodes the density of infected ticks in the environment which scapularis ticks in a controlled trial in a laboratory envi- is the main measure of the acarological risk of LD [7– ronment as a frst step to evaluate the potential of fu- 9]. Oral vaccination of mice against B. burgdorferi’s ralaner, and more broadly the new isoxazoline family of outer surface protein A (OspA) is reported in the litera- ectoparasiticide drugs, to kill ticks on wild rodents as a ture as an efective way to reduce the prevalence of the public health intervention. spirochete among host seeking ticks [10, 11]. Te appli- cation of topical acaricides to wild rodents using treat- Methods ment stations has also been used to efectively reduce Animals tick density in the environment [12–16]. Eighty-seven healthy Peromyscus maniculatus mice In 2014, a novel ectoparasiticide family called isoxa- from Rocky Mountain Laboratory (Hamilton, MT, USA) zolines reached the veterinary drug market. Isoxazo- were used in this experiment. Peromyscus maniculatus lines are non-competitive inhibitors of y-aminobutyric is a competent reservoir for B. burgdorferi and permis- acid (GABA)- and l-glutamate-gated chloride chan- sive host for I. scapularis, and closely phylogenetically nels (GABACl and GluCl), a target that they share with related to P. leucopus the primary reservoir for LD in other ectoparasiticides like fpronil, dieldrin and aver- many parts of North America [32]. Te group was com- mectins [17, 18]. More specifcally, isoxazolines mostly posed of 40 male and 47 female adult mice (> 1 year-old) act on the GABACl channel by blocking ion channel with an average weight (± standard deviation, SD) of opening [17–20]. Isoxazolines, like sarolaner and afox- 20.1 ± 2.7 g. Mice were individually housed in cages with olaner, have been shown to kill adult ticks and prevent 580 cm2 foors, environmental enrichment, commercial B. burgdorferi transmission in dogs [21, 22]. Fluralaner, food (Charles River rodent diet, Charles River Labora- another member of this new family, is noted for its abil- tory, Wilmington, MA, USA) and tap water during the ity to kill ticks rapidly and for its long efcacy period entire experimentation period. All animals were housed following a single oral administration, when used in in the same room at a temperature between 22–25 °C, a dogs [23, 24]. Wengenmayer et al. [24] showed that, relative humidity between 50–70%, and a 12:12 h light/ in dogs, furalaner (BravectoTM chewable formula- dark photocycle. Behaviour was visually assessed daily, tion) killed 98% of infesting adult Ixodes ricinus ticks and mouse weight was assessed during each manipula- within 24 hours following a single oral administra- tion. Mice were euthanized at the end of the experiment tion up to 12 weeks post-treatment. A pharmacology or when limit points were reached. study in dogs supported the clinical observations of a long duration efect by measuring a furalaner half-life Experimental design of 12–15 days and a quantifable plasmatic concentra- Mice were randomly allocated to three equal groups of tion for up to 112 days [25]. Tese two characteristics, 29 animals: one control group and two treatment groups. high efcacy and long duration of efect, are attractive Each mouse received a 250 mg peanut butter bait: fu- features for treatment of wildlife where providing an ralaner (BravectoTM chewable formulation, Merck Ani- efective dose to a signifcant proportion of the host mal Health, Madison, NJ, USA) was mixed with peanut population can be both difcult and costly. In addi- butter baits in the two treatment groups, while pure pea- tion, isoxazolines have been shown to be safe when nut butter was given to the control group. Te frst treat- applied at many times the recommended dose in both ment group received a dose of 50 mg/kg, which is 2 times mammals (dogs and rats [26–28]) and birds (chickens the minimal targeted treatment dose used for dogs, and [29, 30]). Some toxicological data about furalaner and the second treatment group received a dose of 12.5 mg/ related compounds like afoxolaner and sarolaner exist kg, which is half the minimal targeted treatment dose for for laboratory mice (Mus musculus) but they are lim- dogs [23, 24]. Te 50 mg/kg dose was chosen since we ited to genotoxicity and mutagenicity [20, 29, 31]. anticipated more rapid clearance of the molecule by Pero- Despite the potential of rodent-targeted interventions myscus mice compared to dogs. Te 12.5 mg/kg dose was for reducing LD risk in the environment and the unique included to evaluate the potential clinical efect of a dose pharmacological properties of furalaner and other isox- below the targeted range, which is likely to occur under azolines, there are currently no data on the efcacy of feld conditions.