Introduction

A new group of parasiticides has recently been introduced to veterinary medicine. Afoxolaner, fluralaner, sarolaner and lotilaner are new insecticide-acaricide molecules from the isoxazoline family that act on the insect aminobutyric acid receptor (GABA) and glutamate receptors, inhibiting GABA and glutamate-regulated uptake of chloride ions resulting in excess neuronal stimulation and death of the arthropod.

Afoxolaner (NexGard®)

Afoxolaner [1-Naphthalenecarboxamide, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}] is one of the members of the isoxazoline family. Afoxolaner has been demonstrated to be a highly effective and safe form of flea and tick control.

Demodex

Afoxolaner has been shown to be highly effective for treatment of demodicosis in case reports (Chavez 2016; Mueller 2017) and one controlled study (Beugnet 2016). The controlled published report evaluated eight dogs diagnosed with generalised demodicosis and compared the efficacy with a topical combination of imidacloprid/moxidectin. Afoxolaner was administered at the recommended dose (at least 2.5 mg/kg) on Days 0, 14, 28 and 56 and the topical combination of imidacloprid/moxidectin was given at the same intervals at the recommended concentration. Clinical examinations and deep skin scrapings were performed every month to evaluate the effect on mite numbers and the resolution of clinical signs. The percentage reductions of mite counts were 99.2%, 99.9% and 100% on Days 28, 56 and 84, respectively, in the afoxolaner-treated group, compared to 89.8%, 85.2% and 86.6% on Days 28, 56 and 84 in the imidacloprid/moxidectin-group. Mite reductions were significantly higher on Days 28, 56 and 84 in the afoxolaner-treated group compared to the imidacloprid/moxidectin-treated group (Beugnet 2016).

In a large series of clinical case evaluations at a referral dermatology practice, 102 cases of generalized demodicosis were treated with excellent results. Of the 102 cases, 68 were dogs with adult-onset demodicosis. The product was administered at 2.5 mg/kg PO, initially used every two weeks in the first ten dogs. With the high degree of efficacy seen in those dogs, the dosage was reduced to monthly in the remaining cases. Ninety percent of the cases were negative after two months of treatment, the remaining dogs after three months. The only dog needing every two-week administration was a dog on immunosuppressive therapy for pemphigus foliaceus, that became mite positive when the interval was increased to four weeks, but remained mite negative when afoxolaner was administered every two weeks (Mueller 2017).

Sarcoptes

Afoxolaner administered at the minimum dose of 2.5 mg/kg PO once a month for two treatments is effective for the treatment of infestation with Sarcoptes scabiei with a rapid and complete cure of mite infestation in one month and resolution of clinical signs in one to two months (Beugnet 2016).

Otodectes

A single oral administration of afoxolaner at the minimum dose of 2.5 mg/kg PO is effective (>98%) in treating dogs with induced O. cynotis infestations with significantly fewer (p<0.05) live mites present in the afoxolaner-treated group compared to the untreated group on Day 28. In this study, however, two out of eight afoxolaner-treated dogs were still infested with one and four ear mites, respectively on Day 28 (Carithers 2016).

Adverse Reactions

Adverse reactions are rare. In a U.S. field study, vomiting was seen in 17/415 (4.1%) cases. Five dogs experienced anorexia during the study, and two of those dogs experienced anorexia with the first dose but not subsequent doses.

Fluralaner (Bravecto®)

Fluralaner (4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2- trifluoroethyl)amino]ethyl]-benzamide) is rapidly absorbed after single-dose oral administration, has a long elimination half-life, long mean residence time, relatively high apparent volume of distribution, and low clearance. For optimal absorption, bioavailability and efficacy, the drug should be administered with food. Numerous studies have demonstrated that a single fluralaner dose administered orally as chewable tablet provides flea and tick control for twelve weeks in dogs.

Demodex

Fluralaner is effective for treatment of generalised demodicosis. In one study comparing a single dose of fluralaner to topically applied Advocate® (imidacloprid/moxidectin) administered once a month; a reduction of 99.8% and 98% in mite numbers was achieved on Day 28 respectively. Skin scrapings were negative in all dogs treated with fluralaner after 56 days. The excellent response of the dogs in this study receiving the imidacloprid and moxidectin spot-on after one month suggests that these dogs may not be comparable to the dogs presented with generalised demodicosis in Europe or North America (Fourie 2015).

In a larger clinical study, 163 dogs of various breeds with generalised demodicosis (63% with juvenile- and 37% with adult- onset of the disease) were treated with fluralaner once at a single dose of 25 mg/kg. The majority of dogs (87%, all of the dogs with juvenile-onset and most with adult-onset demodicosis) had negative skin scrapings after one month and all dogs were negative on scraping after two months. Adverse effects were not seen (Karaś-Tęcza 2015).

Most interesting was the management of breeding bitches of 16 different breed types: German shepherd, pug, Great Dane, Shih Tzu, shiba, malamute, Italian greyhound, Rhodesian ridgeback, mix breed that had produced repeated litters of puppies with generalized demodicosis. In this trial, all bitches were treated with 25 mg/kg fluralaner ten days prior to scheduled mating and three months later with a second dose. Fourteen bitches gave birth to litters that were clinically unaffected by demodicosis, although two puppies from one litter developed localised demodicosis (Karaś-Tęcza 2016).

A recent study that included 67 dogs also demonstrated that fluralaner, when given at the recommended dose for flea and tick prevention, is also effective for the treatment of canine generalized demodicosis. In 46 individuals with adult-onset demodicosis, 63%, 85% and 100% cure rates were observed after two, three and four months, respectively. In 21 dogs diagnosed with juvenile-onset demodicosis, in this same study, 81% and 100% cures were observed after two and three months, respectively (Duangkaew 2017).

Sarcoptes

Fluralaner at a dose of 25 mg/kg once a month for a single treatment is effective for the treatment of infestation with Sarcoptes scabiei with a rapid and complete cure of mite infestation in one month and resolution of clinical signs in one to two months (Taenzler 2016).

Otodectes

A single oral administration of fluralaner at a dose of 25 mg/kg is effective for dogs with experimental O. cynotis infestations with no mites present in the fluralaner-treated group compared to the untreated group on Day 28. In this study, however, two out of eight fluralaner-treated dogs were still infested with one to two ear mites on Day 14 (Taenzler 2016).

Adverse Reactions

Adverse reactions in fluralaner-treated dogs were evaluated in studies evaluating its use for flea and tick control and were uncommon to rare. Transient gastrointestinal-related signs including vomiting and anorexia have been reported in 2% of dogs. Fluralaner can be used without additional risk for collies and other sensitive herding breeds that have the MDR1 mutation. No adverse events were observed subsequent to fluralaner treatment of ABCB1 (-/-) collies at three times the highest expected clinical dose. Fluralaner seems to be an effective, safe and convenient treatment option for all breeds of dogs with generalized demodicosis.

Sarolaner (Simparica®)

Sarolaner (1-(5’-((5S)-5-(3,5-dichloro-4-fluorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3’-H-spiro(azetidine-3,1’-(2) benzofuran)-1-yl)-2-(methylsulfonyl) ethanone) has a very similar spectrum of activity, efficacy, pharmacokinetics and safety to the other isoxazoline molecules.

Demodex

In a recent study, 16 dogs with generalised demodicosis were treated either with monthly oral sarolaner at 2 mg/kg or with a spot-on containing imidacloprid and moxidectin (Advocate®) every 7 days. The sarolaner-treated dogs and the dogs treated with the spot-on had a reduction of over 99% and 96% in mite numbers after one month and negative scrapings after one month and after 11 weeks, respectively. There were no treatment-related adverse events observed. The excellent response of the dogs in this study receiving the weekly spot-on suggests that these dogs may not be comparable to the dogs presented with generalised demodicosis in Europe or North America (Six 2016).

Isoxazolines and Demodicosis

With the advent of these new treatments for demodicosis, as well as chronic use of these treatments as flea and tick preventatives, come new concerns about their impact on normal canine cutaneous Demodex populations. Demodex mites are considered part of the microbiota of most mammals, including dogs. Under normal circumstances, they appear to live as commensals, feeding on their host’s sebum and are only opportunistically pathogenic.

A recent study, however, to investigate if healthy dogs treated with the isoxazolines, afoxolaner and fluralaner at the labelled dose for flea and tick prevention maintain a normal population of Demodex mites as part of their cutaneous microbiota demonstrated that after 30 and 90 days of treatment, healthy dogs have continued presence of Demodex mites in numbers similar to the population of healthy dogs not receiving these treatments (Zewe 2017).

These conclusions suggest that dogs on isoxazoline treatment maintain Demodex populations as part of their cutaneous microbiota, despite the apparent ability of these medications to resolve clinical demodicosis. Tested isoxazolines at the labelled dose do not appear to completely eradicate Demodex mites from the skin, but simply reduce Demodex populations to normal numbers in affected dogs. To date, no studies have been performed to detect Demodex DNA post-treatment in dogs with demodicosis. More studies are needed to characterise the response of the Demodex populations in dogs with clinical disease to isoxazolines, independently and in comparison to other treatments for demodicosis.

References

1.  Beugnet F, Halos L, Larsen D, et al. Efficacy of oral afoxolaner for the treatment of canine generalised demodicosis. Parasite. 2016;23:14.

2.  Carithers D, Crawford J, de Vos C, Lotriet A, Fourie J. Assessment of afoxolaner efficacy against Otodectes cynotis infestations of dogs. Parasit Vectors. 2016;9(1):635.

3.  Chavez F. Case report of afoxolaner treatment for canine demodicosis in four dogs naturally infected with Demodex canis. Intern J Appl Res Vet Med. 2016;14:123–127.

4.  Duangkaew L, Larsuprom L, Anakkul P, et al. Efficacy of oral fluralaner for the treatment of generalized demodicosis in dogs from Bangkok, Thailand. North American Veterinary Dermatology Forum. 2017;432.

5.  Fourie JJ, Liebenberg JE, Horak IG, et al. Efficacy of orally administered fluralaner (Bravecto) or topically applied imidacloprid/moxidectin (Advocate(R)) against generalized demodicosis in dogs. Parasit Vectors. 2015;8:187.

6.  Karaś-Tęcza J, Dawidowicz J. Efficacy of fluralaner for the treatment of canine demodicosis. Vet Dermatol. 2015;26:307.

7.  Karaś-Tęcza J. Update on the diagnosis and treatment of canine demodicosis. World Congress Veterinary Dermatology 8. Bordeaux, France, 2016 Demodex Workshop report.

8.  Mueller RS, Shipstone MA. Update on the diagnosis and treatment of canine demodicosis. Adv Vet Dermatol. 2017;8:206–209.

9.  Six RH, Becskei C, Mazaleski MM, et al. Efficacy of sarolaner, a novel oral isoxazoline, against two common mite infestations in dogs: Demodex spp. and Otodectes cynotis. Vet Parasitol. 2016;222:62–66.

10.  Taenzler J, Liebenberg J, Roepke RK, Frénais R, Heckeroth AR. Efficacy of fluralaner administered either orally or topically for the treatment of naturally acquired Sarcoptes scabiei var. canis infestation in dogs. Parasit Vectors. 2016;9(1):392.

11.  Taenzler J, de Vos C, Roepke RK, Frénais R, Heckeroth AR. Efficacy of fluralaner against Otodectes cynotis infestations in dogs and cats. Parasit Vectors. 2017;10(1):30.

12.  Zewe CM, Altet L, Lam AT, Ferrer L. Afoxolaner and fluralaner treatment do not impact on cutaneous Demodex populations of healthy dogs. Vet Dermatol. 2017;28:1.