Canine and feline demodicosis - Veterinary Medicine
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Canine and feline demodicosis
You know demodectic mange frequently occurs in dogs. Now it appears to be more common in cats than previously thought, and new species have been discovered. Find out the latest on diagnosing and treating this frustrating skin disease.


VETERINARY MEDICINE


TREATING LOCALIZED CANINE DEMODICOSIS

Fortunately, juvenile-onset localized demodicosis resolves spontaneously within one or two months in most dogs. Thus, miticidal therapy is not required unless the disease generalizes. It is important not to use mite-specific therapy in cases of localized disease in order to determine which patients progress to generalized disease. By not treating localized cases with miticidal therapies, dogs developing generalized disease can be identified and eliminated from breeding programs given the genetic basis of this disease. Furthermore, mite-specific therapy has potential side effects and presents an unnecessary risk in patients with potentially self-curing disease.

Localized demodectic lesions may benefit from topical antimicrobial agents such as mupirocin, benzoyl peroxide, chlorhexidine, or ethyl lactate when secondary pyoderma is present. The use of any glucocorticoid-containing product is contraindicated and could favor disease generalization. Evaluate the patient's overall health with special consideration to conditions affecting the immune system such as poor husbandry, poor nutrition, inoculation status, and internal parasitism. A clinical examination with skin scrapings two to four weeks after initial diagnosis is indicated to monitor for disease resolution or progression.

TREATING GENERALIZED CANINE DEMODICOSIS


Table 1: Treatment Summary for Generalized Demodicosis in Dogs
Generalized demodicosis can be one of the most frustrating skin diseases you will ever treat (Table 1). Counsel owners on the time (possibly up to a year or longer) and financial commitment required to treat this potentially life-threatening dermatosis. Premature treatment cessation by owners is a central reason for treatment failure. Since clinical signs often improve before parasitologic cure, it is paramount owners understand the need for regularly scheduled follow-up visits to ensure a successful outcome. A client handout may be helpful in educating clients about demodicosis.

Clinical and microscopic observation

Some dogs less than 1 year of age with mild generalized disease may spontaneously recover. Clinical and microscopic observation over several weeks with no mite-specific therapy is an option if signs are mild. Elective sterilization to avoid disease propagation in the gene pool can be performed once any secondary pyoderma is controlled; however, the stress of anesthesia and surgery may promote disease progression.8

If clinical signs progress or mite numbers increase, miticidal therapy is indicated. A complete blood count, serum chemistry profile, and urinalysis are useful, particularly in adult dogs to exclude predisposing conditions or when deep pyoderma is a confounding factor. This minimum database taken in context with presenting clinical signs may lead to other diagnostic testing such as hormonal assays and stimulation studies. Treatment success is directly related to identifying and controlling underlying conditions. Nevertheless, demodicosis may precede an undiagnosed predisposing disease.

Antibiotic therapy for pyoderma


Table 2: Recommended Antibiotic Therapy for Staphylococcal Skin Infection in Dogs
Superficial staphylococcal pyoderma is treated empirically by using a beta-lactamase-stable antibiotic for a minimum of four weeks (Table 2). In dogs with unresponsive superficial pyoderma or deep pyoderma or when rod-shaped bacteria are identified on cytologic examination, select antibiotic therapy based on bacterial culture and antimicrobial sensitivity testing. Continue antibiotic therapy until the pyoderma is clinically and cytologically resolved.

Adjunctive topical therapy with an antibacterial shampoo may hasten clinical resolution. Common antibacterial shampoo ingredients include benzoyl peroxide, chlorhexidine, and ethyl lactate. Benzoyl peroxide-based shampoos are often recommended because of their keratolytic and supposed follicular flushing activity.9

Miticidal therapy


Table 3: Reasons for Treatment Failure in Dogs with Demodicosis
All recognized Demodex mites in dogs appear to respond similarly to mite-targeted therapy. Treatment failure is rarely due to resistant mites. More frequent causes of treatment failure in canine demodicosis include poor pyoderma control, premature discontinuation of therapy, unsuccessful control of underlying conditions, and the use of concomitant glucocorticoids (Table 3). However, if a patient does not respond to the initial miticide, switch to another treatment option.10

According to a review of treatment protocols for canine demodicosis, amitraz, ivermectin, milbemycin oxime, moxidectin, and doramectin are all recommended for treating canine demodicosis.10 This same review found evidence that ronnel, lufenuron, and levamisole should not be used to treat canine demodicosis. Improper study design factors including patient selection, age of onset stratification, definition of cure, time to cure, and follow-up time were major limiting factors in evaluating the efficacy of some treatments. Thus, there was insufficient evidence for or against the use of many other treatments. Because of the safer therapeutic options available, organophosphates should not be used to treat demodicosis.

Amitraz. Topical amitraz is FDA-approved for treating generalized demodicosis in dogs older than 4 months of age. Amitraz, a miticide and insecticide, is a monoamine oxidase inhibitor (MAOI), prostaglandin synthesis inhibitor, and an alpha2-adrenergic agonist.10 Per the product label, amitraz liquid concentrate (Mitaban—Pfizer Animal Health) is to be used as a 0.025% (250 ppm) dip every two weeks for three to six topical treatments until no live mites are found.


Table 4: Protocol to Maximize Amitraz Dip Efficacy in Dogs
Not all dogs can be cured with amitraz administered per the label protocol. Consequently, investigators have found greater cure rates by using various regimens of increased dip concentrations or frequencies.10,11 Overall, topical amitraz at 0.025% to 0.05% every seven to 14 days is recommended. A suggested protocol for amitraz is listed in Table 4.

Pododemodicosis and demodectic otitis can be treated with an extralabel mixture of amitraz and mineral oil (1:9), although this mixture may irritate the otic epithelium in certain individuals.12 Before using an extralabel protocol, it is important to recognize that amitraz is a pesticide registered with the Environmental Protection Agency (EPA). This status makes it a federal violation to use amitraz in a manner contrary to its label. If the label protocol proves to be ineffective, it may be more acceptable to use a macrocyclic lactone instead of extralabel amitraz. Amitraz collars are not recommended for treating demodicosis.10

Amitraz dips are not without risk to dogs and their handlers. Many patients experience mild toxicosis seen as excessive lethargy for one or two days after dipping.8 More overt signs of toxicosis are similar to those seen with the use of alpha2-adrenergic agonists, including sedation, hypothermia, bradycardia, and hyperglycemia. Hyperglycemia is a potential concern in diabetic dogs and clients.13 The use of alpha2-adrenergic antagonists can reverse signs of toxicosis and can be used before dipping in patients with a history of adverse effects.13,14 Atipamezole (50 g/kg intramuscularly) can reverse the signs of toxicosis within 10 minutes.13 Avoid antidepressants and MAOIs, such as selegiline, in dogs receiving amitraz. Animal handlers administering amitraz should wear protective clothing and apply it in a well-ventilated area. Personnel should be aware of the potential risk for drug interactions. Those with respiratory problems or diabetes should not use amitraz.15

A new spot-on formulation containing metaflumizone and amitraz (ProMeris—Fort Dodge Animal Health) is available in the United States to control fleas and ticks on dogs. This product was recently evaluated as a topical treatment for generalized demodicosis in a small study involving 16 dogs older than 1 year of age.16 Dogs were divided into two equal groups and treated with the spot-on at the proposed minimum dose rate (20 mg/kg of both metaflumizone and amitraz, 0.133 ml/kg) on days 0, 28, and 56 or days 0, 14, 28, 42, 56, and 70. Five sites were scraped for mites throughout the study. Clinical signs improved and mite numbers decreased for both treatment groups. For dogs that received three treatments every 28 days until day 56, 42.9% had negative test results for live mites and eggs. For dogs that received six treatments every 14 days until day 70, 62.5% had negative test results for live mites and eggs. Although the spot-on did improve clinical signs and reduce mite numbers, the study excluded dead mites and mite segments from evaluation. It is also unknown whether dogs cleared of mites relapsed after the study because skin scrapings were not obtained after the treatment was discontinued. The use of a spot-on is an exciting concept, but more critically evaluated trials are needed to substantiate this drug's efficacy in the long-term control of generalized demodicosis. It is important to recognize that ProMeris is registered with the EPA. This status makes it a federal violation to use it in a manner inconsistent with its label.

Macrocyclic lactones. Macrocyclic lactones include the avermectins (ivermectin and doramectin) and milbemycins (milbemycin oxime and moxidectin). This class of drugs selectively binds to glutamate-gated and gamma-aminobutyric acid (GABA)-gated chloride channels in the mite's nervous system, resulting in cell hyperpolarization, mite paralysis, and, finally, death. Macrocyclic lactones do not readily cross the mature mammalian blood-brain barrier.17 Safety in mammals is due to the lack of glutamate-gated chloride channels in the peripheral nervous system and the restriction of GABA to the central nervous system.


Table 5: Macrocyclic Lactone Dosages for Generalized Demodicosis in Dogs
The ease of oral administration compared with dips makes macrocyclic lactones the first line of therapy for many dermatologists (Table 5). Unfortunately, the use of macrocyclic lactones for generalized demodicosis is considered extralabel, and there is no antidote to the potentially serious and life-threatening side effects. Also, dogs should have negative heartworm disease test results before macrocyclic lactone therapy is implemented. When using macrocyclic lactones for generalized demodicosis, the owner must understand its extralabel use and potential for side effects. Some dermatologists will have the owner sign a consent-to-treat form outlining this information before macrocyclic lactones use.

Ivermectin —For generalized demodicosis, the injectable form of ivermectin is given orally at a dose of 300 to 600 g/kg/day.10,12 The aqueous formulations may be more palatable than are the propylene glycol-based products. Adverse events are sporadic and include lethargy, edematous wheals, mydriasis, muscle tremors, and ataxia. The main concern is the development of signs attributable to severe neurotoxicosis including depression, stupor, coma, ataxia, and seizures; death can also result. Blindness has also been reported in dogs.18


Table 6: Example of Incrementally Increasing the Dose of Ivermectin in a Dog
To better identify ivermectin-sensitive dogs, one report recommends initially dosing ivermectin at 50 g/kg/day and then incrementally increasing the dose by 50 g/kg during the first days of treatment until the target dose is achieved.19 Another way to gradually increase the dose of ivermectin is to calculate the target dose and corresponding volume, and then give 25%, 50%, and 75% of the total volume for several days before reaching the therapeutic volume (Table 6). Because of the long half-life of the drug, ivermectin serum concentrations increase for weeks with daily dosing. Thus, patients need to be monitored for side effects during the first several weeks to months of therapy.10 The pour-on formulation of ivermectin is not effective in treating generalized demodicosis.10


Table 7: Selected P-Glycoprotein Inhibitors*
Signs of ivermectin toxicosis can occur in any breed but are most common in ivermectin-sensitive breeds such as collies and other herding breeds.20,21 Ivermectin sensitivity is derived from a frameshift deletion mutation of the multidrug resistance gene (MDR1; the most recent nomenclature is ABC), resulting in a severely truncated, nonfunctional protein product. The product of the MDR1 gene, P-glycoprotein, is a large ATP-dependent transmembrane protein transporter found in the blood-brain barrier among other tissues.22 P-glycoprotein pumps substrates (e.g. ivermectin and loperamide) within the brain back into the blood. Dogs homozygous for this mutation (MDR1-1 delta) display an ivermectin-sensitive phenotype, developing severe neurotoxicosis after a single dose of ivermectin.22 When ivermectin is deemed necessary for a dog, testing for the MDR1-1 delta genotype before its use is available through Washington State University's Veterinary Clinical Pharmacology Laboratory ( http://www.vetmed.wsu.edu/vcpl/). Dogs without an ivermectin-sensitive genotype can still show signs of toxicosis if ivermectin is given in conjunction with P-glycoprotein inhibitors (Table 7).

Recently, the FDA issued a safety warning stating that some dogs have developed signs of ivermectin toxicity when high extralabel doses of ivermectin are used concurrently with spinosad (Comfortis—Eli Lilly).23 Additional information can be found in the Lilly Companion Animal Health Technical Bulletin (http://elms.xh1.lilly.com/10788_03_tech_Bulletin.pdf). Thus, dogs receiving ivermectin for the treatment of demodicosis should not receive concurrent treatment with spinosad.

Milbemycin oxime —Oral milbemycin oxime (Interceptor—Novartis Animal Health) is recommended at a dose of 1.5 to 2 mg/kg/day, although dose ranges of 0.5 to 3.1 mg/kg/day have been used.10,24,25 Cure rates vary but are better with higher doses. Ivermectin-sensitive breeds generally tolerate milbemycin oxime at the doses outlined above.26 Side effects of daily milbemycin oxime administration are similar to those of ivermectin and include depression, stupor, coma, ataxia, and seizures. The major limitation of this drug is expense.

We have treated demodectic otitis topically with a commercial solution containing 0.1% milbemycin oxime (MilbeMite Otic Solution—Novartis Animal Health); this use is considered extralabel.

Moxidectin —Few studies are available, but moxidectin (Cydectin injectable—Fort Dodge) given orally at 400 g/kg/day can be effective in treating generalized demodicosis.10,27,28 Moxidectin can be started at a lower dose and then gradually increased to 400 g/kg/day similar to ivermectin, as outlined above. Consider treatments other than moxidectin for ivermectin-sensitive breeds.29

Recently, an imidacloprid (10% w/v) and moxidectin (2.5% w/v) spot-on (Advantage Multi—Bayer Animal Health) was introduced in the United States as a heartworm, intestinal parasite, and flea preventive. A similar European product (Advocate—Bayer HealthCare) is labeled to treat and prevent flea infestation, treat ear mite infestation, treat sarcoptic mange, treat demodicosis (caused by D. canis), prevent heartworm disease, and treat gastrointestinal nematodes. This spot-on product was evaluated in the treatment of generalized demodicosis through a multicenter, randomized, blinded field trial during the registration process in Europe.30 Another group of dogs with generalized demodicosis was treated with daily milbemycin oxime and served as the control group. Dogs were treated with the spot-on two to four times, at four-week intervals, with the test product at the recommended dose of at least 0.1 ml/kg. Up to five body sites were scraped each month to look for Demodex species mites. Treatment was discontinued when two subsequent monthly skin scrapings were negative for living mites or at the last examination on day 84. At study end, 87% of the treated dogs and 88% of the control dogs had no live mites on skin scrapings with no difference in clinical response between the groups.

A limitation of the study is the exclusion of dead mites and mite segments from evaluation. It is also unknown whether dogs cleared of mites relapsed after the study because skin scrapings were not obtained after treatment discontinuation. Although this moxidectin spot-on appears to be equally effective when compared with milbemycin oxime in the treatment of generalized demodicosis using the criteria of this study, more long-term studies with stricter evidence for parasitologic cure are needed to corroborate these findings. Based on the experience of our European colleagues, treatment failures with this product are not uncommon.

Doramectin —Doramectin, another avermectin, has been used in a study involving 23 dogs that received weekly subcutaneous injections of 600 g/kg.10,31 None of the animals showed adverse effects with doramectin; however, this drug should not be used in ivermectin-sensitive breeds of dogs. More research is needed to evaluate doramectin for treating demodicosis.10

Monitoring

Clinical signs and microscopic examination of skin scrapings are used to guide treatment for generalized demodicosis. Repeat skin scrapings every two to four weeks during treatment. Sample at least four to six affected body sites including the face and paws at each recheck. Obtain samples from the same body areas to consistently monitor the mite population. Once all scrapings are negative for mites at any developmental stage, including dead mites or mite fragments, a parasitologic cure can be declared.8,12

If eggs or immature mite numbers do not decrease over four to eight weeks, consider altering the dose or frequency of the given treatment. Miticidal treatment continues until two consecutive negative skin scrapings collected two to four weeks apart are obtained. Chronic cases benefit from an additional month of therapy beyond the two negative scrapings. A complete cure is declared if no relapses occur within 12 months from the time of treatment discontinuation.12


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