Isoxazolines for canine demodicosis

Introduction

A new class of ectoparasiticides, isoxazolines, were first released in Canada in 2014, with afoxolaner and fluralaner tablets initially licensed only for the treatment of fleas and ticks in dogs. Anecdotal reports soon suggested that the new drugs were also effective against other ectoparasites, but scientific evidence for any proven efficacy of isoxazolines when used off-label in dogs suffering from other parasitic conditions – such as demodicosis – was slow to emerge, although this is now changing. This paper offers a brief overview of the new class of drug and its efficacy against canine Demodex mites.

Canine demodicosis

Demodicosis is caused by the proliferation of Demodex spp. mites and is a common disease in canine practice worldwide, with a variety of diagnostic and therapeutic options. Background information can be found in the WAVD Clinical Consensus Guidelines * which provide current information on the pathophysiology, diagnosis and treatment of commonly encountered dermatological conditions 1. Until recently, the drug of choice for many clinicians when faced with demodicosis was ivermectin, which was far from ideal as a first-line therapy.

However, this has changed since the introduction of isoxazolines. We all have memorable patients, and this was certainly the case with Kenny, a 6-month-old intact male Australian Shepherd who presented in September 2015 with severe dermatological signs and was diagnosed with demodicosis. His cutaneous lesions were predominantly facial (Figure 1), although there was also a significant secondary bacterial pyoderma caused by methicillin-resistant Staphylococcus pseudintermedius. The severe pruritus induced by the pyoderma required Kenny to wear an Elizabethan collar 24/7, as he had self-traumatized to the point that there was total hair loss on his muzzle and periocular region. I was skeptical that a single dose of an oral medication administered to a dog with demodicosis could lead to a parasitological and clinical cure when it usually took several weeks of daily oral ivermectin to achieve remission. Nevertheless, considering the patient’s age and – most importantly the breed, which is well known to be sensitive to ivermectin – this was an excellent opportunity to treat my first case of canine demodicosis with a single dose of oral fluralaner. When I saw Kenny for subsequent rechecks, the results were astonishing. By day 44 there was complete resolution of the skin lesions (Figure 2), and there was no doubt that the drug was both effective and well tolerated. This then raised two important questions. Was it finally possible to relegate the use of titrated ivermectin and its occasional but alarming adverse effects to the history books? Were isoxazolines truly going to be a game changer for the treatment of canine demodicosis, especially for animal shelters and in communities with limited access to veterinary care? The answer to both questions was “yes” – and since then these drugs have shown impressive results in controlling canine demodicosis, such that they are likely to be the mainstay therapy for many years to come. Our bottle of ivermectin we had at the time ended up expiring at the back of a shelf. 

* https://wavd.org/continuing-education/consensus-guidelines

Isoxazolines: a new class of drug

This new class of ectoparasiticide now encompasses various compounds, including afoxolaner, fluralaner, lotilaner, and sarolaner 2. These molecules have a novel mode of action, specifically blocking insect and acarine ligand-gated chloride channels. They act on the gamma-aminobutyric acid receptor (GABA) and glutamate receptors, inhibiting GABA and glutamate-regulated uptake of chloride ions, resulting in excess neuronal stimulation and rapid parasite death 3.

Isoxazolines are now commercially available either as oral or topical spot-on medications, with the original products containing a single active ingredient. In most countries these products are labelled only for the treatment, prevention and control of fleas and ticks, although some countries now have license indications that include other canine diseases, such as demodicosis, scabies, and otoacariasis. More recently, combination products containing an isoxazoline and a macrocyclic lactone (sometimes also with pyrantel embonate) have also become available and are labelled for the treatment and prevention/control of fleas and ticks, as well as other important endo- and ectoparasites. 

Given that a variety of isoxazolines are now available in most countries, a short literature review of the most common compounds used to treat canine demodicosis may be helpful. 18 recently published studies have been identified that review the four commercially available isoxazolines, and the results in eradicating Demodex spp. mites are very encouraging. The efficacy of oral afoxolaner has been evaluated in 253 dogs in seven studies 456 78910, whilst oral and topical fluralaner has been assessed in 371 dogs in eight studies 111213 1415161718, with the details summarized in Tables 1 and 2 respectively. There are also reports on two of the other products in this drug category. Oral lotilaner has been evaluated in one study, where ten dogs treated three times 28 days apart (20 mg/kg PO) were all being mite-free at day 70, with no adverse effects noted 19. Two controlled studies have also investigated the efficacy of oral sarolaner. In one study 8 dogs were treated three times 30 days apart (2 mg/kg PO) with sarolaner alone, whilst another 8 dogs were treated with a weekly spot-on containing imidacloprid and moxidectin 20. All dogs were mite-free at day 44 and there were no adverse effects, but the oral sarolaner was reported to have performed better than the spot-on. The second non-inferiority study compared the same two products 21; 53 dogs were treated 30 days apart (2-4 mg/kg PO) with all dogs being mite-free at day 150, whilst another 28 dogs were treated weekly or monthly with the imidacloprid-moxidectin spot-on. There were no adverse effects with oral sarolaner, and again this drug performed better than the spot-on product.

Guidelines for treating demodicosis

The clinician should always follow the recommended labelled dosage for flea prevention/control/treatment when prescribing an isoxazoline for demodicosis, and conform to the minimum age and bodyweight requirements on the label. For certain oral products the drug bioavailability may be compromised if a dog is fasted before dosing, so fluralaner and lotilaner should be administered with food; the plasma levels of afoxolaner and sarolaner are the same regardless of whether the drug is given with or without food. My current preferred therapeutic option for a dog with demodicosis is to administer a single oral or topical dose of fluralaner, for two reasons. Firstly, there is a higher level of evidence for efficacy, as to date there are more controlled studies with this compound than the other products, and secondly the sustained 12-week duration of action has been linked to better owner compliance compared with the use of monthly treatments 22. However, there are alternatives. One is to give a single oral dose of afoxolaner (or the afoxolaner/milbemycin oxime combination) once a month for three months. This regime is also suitable if using oral sarolaner (or the sarolaner/moxidectin/pyrantel embonate combination) or lotilaner. In most cases systemic antibiotics will not be needed; topical antibacterial therapy combined with good miticidal agents will be sufficient unless a severe bacterial infection is present 1.

However, it is prudent to sound some words of caution when treating Demodex infection with these compounds. Geographical differences exist in the availability and licensure of isoxazoline drugs for use in dogs, and the clinician must consider the relevant regional prescribing recommendations. If prescribing an isoxazoline to treat canine demodicosis represents an extra-label use, some national or regional legislation will permit such therapies only where a drug licensed to treat canine demodicosis has either failed or is contraindicated 1. In addition, adult-onset generalized demodicosis may be associated with an immunosuppressive condition or concurrent treatments for other medical conditions, so recurrences are possible regardless of the product used. Animals being treated for generalized demodicosis should be monitored clinically and microscopically every month until the second negative skin scraping, and a follow‐up of at least 12 months after treatment cessation has been recommended before we can say a dog is cured 1. Finally, although isoxazolines are generally very safe, they can occasionally have potential side effects, including vomiting, diarrhea, anorexia, lethargy, and seizures; in particular, if using this class of drug in a dog with a history of seizures or other neurological disorders the clinician should always proceed with caution. Essentially, isoxazolines should only be used in suitable patients and always under veterinary supervision.

Conclusion

The recent introduction of isoxazoline ectoparasiticides has resulted in an apparently effective and safe therapy for canine demodicosis – a condition that has been traditionally difficult and frustrating to treat – with low frequency of administration. It seems that ivermectin can now be discarded and the clinician can be more confident in selecting a product that will benefit canine patients, although given that this class of drug may not have a national license for use in demodicosis, appropriate precautions should still be taken when prescribing it.