Demodex canis Control in Dogs

NAVC CONFERENCE, JANUARY 2008 Demodex canis Control in Dogs Ralf S. Mueller, DVM, Prof., DACVD, FACVSc, DECVD * Faculty of Veterinary Medicine, Ludwig Maximilian University, Munich, Germany LOCALIZED DEMODICOSIS Localized demodicosis is a mild disease that usually heals spontaneously in 6 to 8 weeks but may wax and wane in a localized area for months (Figure 1). Anecdotally, there is no difference between treated and untreated cases. If therapeutic intervention is desired, mupirocin or benzoyl peroxide gel can be massaged gently into the alopecic area once daily. Thus, treating localized demodicosis is in most cases not a problem. Because any stress on the immune system such as endoparasites or concurrent systemic disease may predispose dogs to demodicosis, possible endoparasites should be treated and the patient s general health status checked very carefully. Although most dogs with localized demodicosis will go into remission, in some dogs the disease will develop into the generalized form. Therefore, patients with localized demodicosis should be reevaluated after a few weeks to months. During return visits, the veterinarian can determine whether there are any indications of generalized demodicosis. 1 I do not treat the localized form at all with ectoparasiticides. Abstinence from miticidal treatment allows identification of those patients with progression to generalized disease. The reason to differentiate dogs with localized disease from those with the generalized form is that young dogs with generalized demodicosis have a strong genetic predisposition for the disease. Breeding with such dogs is strongly discouraged, as they would pass on this genetic trait and their offspring may be more likely to get the disease. I advise all owners of dogs with generalized demodicosis to neuter their pets. GENERALIZED DEMODICOSIS Although the prognosis for dogs with demodicosis has improved dramatically in recent decades, successful treatment may still be a *Corresponding author: R. Mueller, Faculty of Veterinary Medicine, Ludwig Maximilian University, Veterinärstrasse 13, 80539 Munich, Germany; phone, +49 (0) 89 2180 2650; fax, +49 (0) 89 2180 6240; email, ralf.mueller@ med.vetmed.uni-muenchen.de. Dogs with generalized demodicosis need to be reevaluated typically every 2 to 4 weeks, and skin scrapings need to be obtained to monitor success of therapy. challenge in some cases. About 90% of patients can be cured, but it may take up to 12 months of treatment. 2 However, the average time to clinical and microscopic remission in reported studies is approximately 2 to 4 months. 2 The most common reason for treatment failure is premature cessation of therapy. 1 Dogs with juvenile-onset disease (Figure 2) may not always need miticidal therapy. However, there are no good studies evaluating how many young dogs with generalized demodicosis recover spontaneously, and anecdotal estimates vary widely, from 0% to 50%. In intact females, ovariohysterectomy is strongly recommended because the dogs may deteriorate or the disease may recur. 3 In dogs older than 1 to 2 years of age or those with adult-onset generalized demodicosis (Figure 3), systemic disorders can be the cause of demodicosis and the reason for an unfavorable treatment response. Some dogs may recover without miticidal therapy if the underlying disease is treated successfully, although for ethical reasons I am usually not bold enough to withhold anti-mite therapy for several weeks or months in dogs with adultonset demodicosis while treating the underlying disease. Dogs with generalized demodicosis need to be reevaluated typically every 2 to 4 weeks, and skin scrapings need to be obtained to monitor success of therapy. 2 To determine treatment efficacy, skin scrapings should always be taken from the same sites. If there is no clinical improvement or if skin scrapings show the same high number of mites especially immature stages such as nymphs, larvae, or eggs a change in treatment should be considered. Up to 70% of dogs that do not respond well to one treatment will improve and go into remission once the mode of therapy is changed. 2 Secondary pyoderma is almost always present in dogs with demodicosis. 1 The most common bacterial isolate is Staphylococcus intermedius. Empirical therapy for 3 to 8 weeks is usually appropriate. The most common gram-negative bacteria found in canine demodicosis are Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis. If rods predominate, bacterial culture and sensitivity is rec- Supplement to Compendium: Continuing Education for Veterinarians Vol. 30, No. 6(B), June 2008 1

NINTH INTERNATIONAL PARASITE CONTROL SYMPOSIUM Figure 1. One-year-old female German shepherd dog with periocular dermatitis caused by Demodex mites. Figure 2. One-year-old female German shepherd mix with generalized demodicosis. ommended, as the resistance pattern of these organisms is more unpredictable. While waiting for results of the bacterial culture and sensitivity, the infection is treated symptomatically with an antibiotic that is frequently effective for such infections. Fluoroquinolones such as enrofloxacin may be chosen initially. I dispense a small amount sufficient for 7 to 10 days of treatment and then additional medication depending on the results of the sensitivity testing. In addition to systemic antibiotics, antibacterial shampoo therapy is frequently used to remove crusts and treat bacteria topically. Benzoyl peroxide shampoo is most commonly recommended because of its presumed follicular flushing activity. 4 At this time, the cure rate of demodicosis is around 90%. Commonly used therapies include amitraz and macrocyclic lactones such as ivermectin, moxidectin, and milbemycin oxime. 2 COMPOUNDS USED TO TREAT DEMODICOSIS Amitraz Amitraz is licensed in Europe and Australia as a concentration to prepare a therapeutic wash application for the treatment of generalized demodicosis. Amitraz is a monoaminooxidase inhibitor and α 2 - adrenergic agonist that inhibits prostaglandin synthesis. It is available as Mitaban in the United States and Canada and as Ectodex in Europe. Amitraz is also available in a 9% anti-tick collar; unfortunately, this collar is ineffective for the treatment of generalized demodicosis. 1 Some studies using amitraz in various formulations show clinical cure rates up to 90% with special protocols. 5,6 Dogs with medium or long coats should be clipped to allow the solution to come in contact with the skin and better penetrate the hair follicle. All crusts should be removed. Before using amitraz, the dog should be thoroughly washed with a medicated shampoo designed to kill bacteria and remove scales. Amitraz is then applied by wetting and sponging. The solution must be applied to the entire body. Adverse effects such as respiratory problems have been observed in humans, 1,7 so the washing procedure should be performed outside or in a wellventilated area and protective gloves should be worn. In addition, if the dog is placed under anesthesia, it is important to remember that amitraz is an α 2 -adrenergic agonist and that synergistic toxicity with α 2 -adrenergic sedatives such as benzodiazepine or xylazine is possible. The recommended treatment protocol in the United States is 0.025% amitraz in a wash every 2 weeks. Higher concentrations and/or frequencies seem to be associated with a higher success rate. Daily therapy with 0.125% amitraz on alternating halves of the body was reported to be efficacious for 73% of 32 dogs with generalized demodicosis resistant to conventional therapy. 8 Recently, amitraz at 1.25% weekly was used successfully to treat generalized demodicosis in eight dogs that had failed to respond to the drug at lower concentrations. 9 These dogs were premedicated with atipamezole at 0.1 mg/kg IM once and yohimbine 0.1 mg/kg/day PO for a further 3 days in an attempt to counteract the α 2 -adrenergic activity of amitraz, which results in bradycardia, a decrease in rectal temperature, and hyperglycemia. In some of these patients, a transient erythematous rash was observed after rinsing. To maximize the efficacy of amitraz, it is important that rinsed patients do not get wet between rinses. This is particularly difficult in rainy climates and in dogs whose paws are affected. In patients with pododemodicosis or demodectic otitis externa, a mixture of amitraz and paraffin or mineral oil has been recommended topically daily to every 3 days. 2 Adult-onset demodicosis may respond less favorably to therapy. In a recent analysis of studies evaluating treatments for demodicosis, the success rate in adult-onset disease was approximately 30%. 2 2 Supplement to Compendium: Continuing Education for Veterinarians Vol. 30, No. 6(B), June 2008

NAVC CONFERENCE, JANUARY 2008 cure rates varied from 15% to 92%, depending on the dosage used and the age at onset of disease. Several studies have shown a better success rate with higher doses. 11,13 Dogs with adult-onset disease respond more poorly to treatment than dogs with juvenile-onset disease. Some rare adverse effects have been reported; these include ataxia, stupor, and trembling in two dogs given a dosage of 3.8 mg/kg/day; lethargy; and transient vomiting. Figure 3. Twelve-year-old spayed Boston terrier with generalized demodicosis. Adverse effects with amitraz therapy were ataxia, depression, diarrhea, polyphagia/polydipsia, sleepiness, and vomiting. With 1.25% amitraz, generalized erythema, scaling, and an unpleasant odor were noted. 9 Macrocyclic Lactones Milbemycins (e.g., milbemycin oxime, moxidectin) and avermectins (e.g., ivermectin, doramectin) are antiparasitic agents produced by the fermentation of various actinomycetes. They bind selectively to glutamate-gated chloride channels, resulting in increased cell permeability for chloride ions, and cause neuromuscular blocking, resulting in paralysis and death of the parasite. They also interact with γ- aminobutyric acid (GABA) sites. These compounds have a wide margin of safety in mammals because the mammalian peripheral nervous system doesn t have glutamate-gated chloride channels. In addition, GABA is a central nervous system neurotransmitter in mammals, and these compounds cross the blood brain barrier at a very low level. 10 Milbemycin Milbemycin oxime, a fermentation product of Streptomyces hygroscopicus subsp aureolacrimosus, is used as a heartworm preventive and endoparasitic agent. In Europe, milbemycin is registered as an oral formulation against demodicosis and is licensed for use as a monthly heartworm and intestinal parasite preventive in dogs at an oral dosage of 0.5 mg/kg. A variety of dogs of all breeds, including those that are sensitive to high doses of ivermectin, and various ages at onset of both diseases and therapy were treated with milbemycin at dosages varying from 0.5 to 3.8 mg/kg/day. 7,11 14 The mean duration of treatment needed to achieve negative skin scrapings was 8 to 26 weeks; mean treatment duration was 12 to 30 weeks. 2 Clinical Moxidectin Moxidectin was used in three studies at oral dosages ranging from 0.2 to 0.4 mg/kg/day. 26 28 In these studies, 52 dogs with generalized demodicosis, 41 dogs with juvenile-onset disease, and 11 dogs with adult-onset disease were treated with oral moxidectin. Thirty-one (76%) of the dogs with juvenile-onset demodicosis were in remission after 8 to 14 weeks, and seven were lost to follow-up. Of the 11 dogs with adult-onset demodicosis, nine were in remission after 8 to 16 weeks. All dogs were cured, but details on long-term follow-up were unavailable. Transient side effects included anorexia, ataxia, lethargy, stupor, and vomiting. 26 More studies with longer follow-up periods are needed to identify potential benefits and disadvantages of the oral use of moxidectin. Moxidectin as part of a combination with imidacloprid spot-on approved for the treatment of many endo- and ectoparasites including demodicosis has recently become available in many countries. In one multicenter study, this product administered monthly showed a success rate comparable to that of oral milbemycin. 29 The efficacy and suitable protocols of this spot-on for treatment of canine generalized demodicosis are currently under further investigation in another multicenter study with dermatologists in four European countries. Preliminary results of this study show that remission was achieved using moxidectin in this spot-on every 2 weeks in approximately two-thirds of the cases with less than 20 mites per scraping. At Ludwig Maximilian University, Munich, Germany, we currently use this spot-on weekly for our patients with generalized demodicosis. Ivermectin Ivermectin is a fermentation product of Streptomyces avermitilis. In the United States and Europe, it is only licensed in small animals for the prevention of dirofilariasis at an oral dosage of 0.006 mg/kg once monthly. To my knowledge, ivermectin is not licensed for treating demodicosis in any country. It was first reported as a treatment for generalized demodicosis in the mid-1980s. Oral dosages usually vary from 0.3 to 0.6 mg/kg/day, and treatment courses range from 35 to 210 days. Published data on the efficacy of ivermectin for canine demodicosis are more limited than that for amitraz, with approximately 100 cases available for review. 3,15 19 The rate of clinical cure varied from 83% to 100% in individual studies. 2 An early protocol, treating with ivermectin at 0.4 mg/kg SC once weekly, did not demonstrate much efficacy. 5 Supplement to Compendium: Continuing Education for Veterinarians Vol. 30, No. 6(B), June 2008 3

NINTH INTERNATIONAL PARASITE CONTROL SYMPOSIUM Daily oral treatment of ivermectin was shown in seven studies that included a total of 120 patients to have a good success rate. The dosages used ranged from 0.3 to 0.6 mg/kg. The mean time to achieve negative skin scrapings was 6.5 to 28 weeks; the mean treatment duration was 10 to 33 weeks. Higher dosing does not seem to influence the time to first negative skin scrapings: An alternate-day protocol, in which dogs received 0.45 to 0.6 mg/kg, seemed equally efficacious as 0.3 mg/kg/day. 20 However, the pour-on formulation of ivermectin, which is very effective in the treatment of nonfollicular mites in dogs and cats, performed very poorly in dogs with generalized demodicosis when it was applied three times weekly at a dosage of 1.5 mg/kg. Only 2 of 12 treated dogs achieved parasitologic cure. 21 Side effects of ivermectin include ataxia, edematous wheals, lethargy, and mydriasis. These develop as late as 10 weeks into treatment. Collies are particularly sensitive. 2 One report recommended gradually increasing the dosage of ivermectin from 0.05 to 0.1, 0.2, and 0.3 mg/kg during the first days of treatment to identify sensitive animals. 22 Because of ivermectin s relatively long half-life, serum concentrations of ivermectin administered daily continue to increase for weeks before reaching equilibrium at much higher levels than with weekly therapy. Thus, chronic toxicity due to cumulative therapy may develop with prolonged daily ivermectin treatment. Today, some veterinary laboratories offer a gene test to recognize dogs with a defect of the MDR-1 gene encoding for the multidrug resistant transport P-glycoprotein. 23 This gene was reported to be associated with ivermectin toxicity in collies. 24 The MDR-1 defect is autosomal recessive. However, a study presented at the North American Veterinary Dermatology Forum in 2007 indicated that most dogs showing chronic toxicity have a normal MDR-1 gene. 25 These dogs did not develop the severe acute toxicity at low doses that is seen in collies but typically showed subchronic toxicity and clinical signs after 4 days to 5 weeks of therapy. Doramectin In one study, 23 dogs were injected weekly with 0.6 mg/kg doramectin SC for 5 to 23 weeks. 30 Ten of the dogs were cured, seven relapsed after 1 to 24 months (two of which responded to repeat doramectin treatment), and six were lost to follow-up. More studies are needed to evaluate the efficacy and optimal dosing of doramectin for the treatment of canine demodicosis. OTHER TREATMENT OPTIONS A number of other drugs have been evaluated as treatment for canine demodicosis, including amitraz collars, 31 closantel, 32 deltamethrin, 33 herbal 34 and homeopathic preparations, 35 muramyl dipeptide, 36 phoxime, 37 vitamin E, 38,39 pour-on ivermectin, 21 levamisole, 40,41 lufenuron, 42 and ronnel, 40,43 but insufficient evidence exists regarding the efficacy of these products. Typically, a follow-up of 12 months is recommended after remission of a dog with generalized demodicosis, as recurrences after cessation of therapy are possible. In a recent meta-analysis, it was concluded that if a recurrence of generalized demodicosis is treated again either with the original medication or a different type of drug, two of three dogs will go into long-term remission and can be cured after the second treatment course. 2 Thus, treatment of recurrent demodicosis should be recommended and does not necessarily indicate a poor prognosis. However, some dogs will never go into microscopic remission (clinically, these patients appear healthy, but skin scrapings always identify a few mites) and may show frequent recurrence of clinical signs. In these dogs, life-long monthly amitraz rinses or weekly treatment with macrocyclic lactones (the one chosen differs depending on the case) may provide relief and a normal life without clinical skin disease. REFERENCES 1. Scott DW, Miller WH, Griffin CE. Small Animal Dermatology. 6th ed. Philadelphia: WB Saunders; 2001. 2. Mueller RS. Treatment protocols for demodicosis: an evidence-based review. Vet Derm 2004;15:75-89. 3. Mueller RS, Hastie K, Bettenay SV. Daily oral ivermectin for the treatment of generalised demodicosis in 23 dogs. Aust Vet Pract 1999;29:132-136. 4. Mueller RS. Topical dermatological therapy. In: Maddison JE, Page SW, Church D, eds. Small Animal Clinical Pharmacology. London: WB Saunders; 2002:535-545. 5. Scott DW, Walton DK. Experiences with the use of amitraz and ivermectin for the treatment of generalized demodicosis in dogs. JAAHA 1985;21:535-541. 6. Muller GH. Amitraz treatment of demodicosis. JAAHA 1983;19:435-441. 7. Mueller RS, Bettenay SV. Milbemycin oxime in the treatment of canine demodicosis. Aust Vet Pract 1995;25:122-126. 8. Medleau L, Willemse T. Efficacy of daily amitraz therapy for refractory, generalized demodicosis in dogs: two independent studies. JAAHA 1995;31:246-249. 9. Hugnet C, Bruchon-Hugnet C, Royer H, et al. Efficacy of 1.25% amitraz solution in the treatment of generalized demodicosis (eight cases) and sarcoptic mange (five cases) in dogs. Vet Dermatol 2001;12:89-92. 10. Campbell WC, Fisher MH, Stapley EQ. Ivermectin a potent new antiparasitic agent. Science 1983;221:823-828. 11. Garfield RA, Reedy LM. The use of oral milbemycin oxime (Interceptor) in the treatment of chronic generalized canine demodicosis. Vet Dermatol 1992;3:231-235. 12. Holm B. Efficacy of milbemycin oxime in the treatment of canine generalized demodicosis: a retrospective study of 99 dogs (1995-2000). Vet Dermatol 2004;15:369-376. 13. Miller WH, Scott DW, Cayatte SM, et al. Clinical efficacy of increased dosages of milbemycin oxime for treatment of generalized demodicosis in adult dogs. JAAHA 1995;207:1581-1584. 14. Miller WH, Scott DW, Wellington JR, et al. Clinical efficacy of milbemycin oxime in the treatment of generalized demodicosis in adult dogs. JAAHA 1993;203:1426-1429. 15. Medleau L, Ristic Z, McElveen DR. Daily ivermectin for treatment of generalized demodicosis in dogs. Vet Dermatol 1996;7:209-212. 4 Supplement to Compendium: Continuing Education for Veterinarians Vol. 30, No. 6(B), June 2008

NAVC CONFERENCE, JANUARY 2008 16. Fondati A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs. Vet Dermatol 1996;7:99-104. 17. Ristic Z, Medleau L, Paradis M, et al. Ivermectin for treatment of generalized demodicosis in dogs. JAAHA 1995;207:1308-1310. 18. Paradis M, Laperriere E. Efficacy of daily ivermectin treatment in a dog with amitraz-resistant, generalized demodicosis. Vet Dermatol 1992;3:85-88. 19. Guaguere E. Efficacy of daily oral ivermectin treatment in 38 dogs with generalized demodicosis: a study of relapse rates. In: Kwochka KW, Willemse T, Von Tscharner C, eds. Advances in Veterinary Dermatology. Oxford: Butterworth-Heinemann; 1998:453-454. 20. Tapp T, Muse R, Rosenkrantz WS. Efficacy of alternate day oral ivermectin in the treatment of generalized demodicosis. Annu Meet Am Acad Vet Derm Am Coll Vet Dermatol 1998:25. 21. Paradis M, Page N. Topical (pour-on) ivermectin in the treatment of chronic generalized demodicosis in dogs. Vet Dermatol 1998;9:55-59. 22. Mueller RS, Bettenay SV. A proposed new therapeutic protocol for the treatment of canine mange with ivermectin. JAAHA 1999;35:77-80. 23. Geyer J, Doring B, Godoy JR, et al. Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: verification in a moxidectin-sensitive Australian shepherd. J Vet Pharmacol Ther 2005;28:95-99. 24. Neff MW, Robertson KR, Wong AK, et al. Breed distribution and history of canine mdr1-1delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci USA 2004:11725-11730. 25. Bissonnette S, Paradis M, Daneau I, et al. Survey of the MDR1 gene for heterozygous mutations in dogs displaying subchronic toxicity signs to systemic macrocyclic lactones following treatment regimen for a generalized demodicosis. North Am Vet Forum 2007:198. 26. Wagner R, Wendlberger U. Field efficacy of moxidectin in dogs and rabbits naturally infested with Sarcoptes spp., Demodex spp. and Psoroptes spp. mites. Vet Parasitol 2000;93:149-158. 27. Bensignor E, Carlotti D. Moxidectin in the treatment of generalized demodicosis in dogs: a pilot study: 8 cases. In: Kwochka KW, Willemse T, Von Tscharner C, eds. Advances in Veterinary Dermatology. Oxford: Butterworth-Heinemann; 1998:554-555. 28. Burrows A. Evaluation of the clinical efficacy of two different doses of moxidectin in the treatment of generalized demodicosis in the dog. Sci Meet Aust Coll Vet Sci 1997. 29. Heine J, Krieger K, Dumont P, et al. Evaluation of the efficacy and safety of imidacloprid 10% plus moxidectin 2.5% spot-on in the treatment of generalized demodicosis in dogs: results of a European field study. Parasitol Res 2005;97(suppl 1):89-96. 30. Johnstone IP. Doramectin as a treatment for canine and feline demodicosis. Aust Vet Pract 2002;32:98-103. 31. Franc M, Soubeyroux H. Le traitement de la demodecie du chien par un collier a 9% d amitraz. Rev Med Vet (Toulouse) 1986;137:583-586. 32. Losson B, Benakhla A. Efficacite du closantel dans le traitement de la gale demodectique du chien. Ann Med Vet 1980;124:521-526. 33. Kamboj DS, Singh KB, Avtar S, et al. Studies on the therapeutic efficacy of amitraz, deltamethrin and ivermectin on canine demodicosis. Indian Vet J 1993;70:61-64. 34. Das SS. Efficacy of Maggacite, an indigenous preparation against demodicosis in dogs and its comparison with deltamethrin. Indian Vet J 1998;75:157-158. 35. Nayak DC, Tripathy SB, Dey PC, et al. Therapeutic efficacy of some homeopathic preparations against experimentally produced demodicosis in canines. Indian Vet J 1998;75:342-344. 36. Kraiss A, Gothe R. Demodikosetherapie mit Muramyl dipeptide und Amitraz. Kleintierpraxis 1983;28:425-426, 429-430. 37. Sikovec J. Demodicosis and sarcoptic mange in the dog: therapy trials with phoxim (Sebacil). Vet Med Rev 1983;2:172-177. 38. Gilbert PA, Griffin CE, Rosenkrantz WS. Serum vitamin E levels in dogs with pyoderma and generalized demodicosis. JAAHA 1992;28:407-410. 39. Figueiredo C, Viana JA, Curi PR. Clinical evaluation of the effect of vitamin E in the treatment of generalized canine demodicosis. In: Ihrke PJ, Mason IS, White SD, eds. Advances in Veterinary Dermatology. Oxford: Pergamon Press; 1993:247-261. 40. Scott DW, Schultz RD, Baker EB. Further studies on the therapeutic and immunologic aspects of generalized demodectic mange in the dog. JAAHA 1976;12:203-213. 41. Mojzisova J, Paulik S, Bajova V, et al. The immunomodulatory effect of levamisole with the use of amitraz in dogs with uncomplicated generalized demodicosis. Vet Med Czech 1997;42:307-311. 42. Schwassmann M, Kunkle GA, Hepler DI, et al. Use of lufenuron for treatment of generalized demodicosis in dogs. Vet Dermatol 1997;8:11-18. 43. Baker BB, Stannard AA, Yaskulski SG, et al. Evaluation of topical application of ronnel solution for generalized demodicosis in dogs. JAVMA 1976;168:1105-1107. Supplement to Compendium: Continuing Education for Veterinarians Vol. 30, No. 6(B), June 2008 5

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