Clinical Consensus Guidelines Demodicosis

Page 1 of 44 Guideline for Treatment of Canine Demodicosis
1 WAVD Clinical consensus guidelines for demodicosis

2
3 Ralf S. Mueller*, Wayne Rosenkrantz†, Emmanuel Bensignor‡, Joanna Karaś-Tęcza §,

4 Tara Paterson ¶, Michael A. Shipstone**
5
6 * Centre for Clinical Veterinary Medicine, LMU Munich, Veterinaerstraße 13, 80539
7 Munich, Germany
8 † Animal Dermatology Clinic, 2965 Edinger Ave, Tustin, California 92780, USA
9 ‡ Dermatology Referral Service, 75003 Paris, 35510 Rennes-Cesson and 44000 Nantes
10 and 13008 Marseille, France
11 § Dermawet Dermatology Service for Dogs and Cats, Odyńca 37 lok.1/2, 02-606
12 Warszawa, Poland
13 ¶ Small Animal Medicine & Surgery Department, School of Veterinary Medicine, St.
14 George's University, PO Box #7, St. George’s, Grenada, W.I.
15 ** Dermatology for Animals, 263 Appleby Road, Stafford Heights, QLD 4053, Australia
16
17
18 Conflict of interest
19 Ralf Mueller has been a consultant, lecturer, or has received financial support for studies
20 from Bayer Animal Health (manufacturer of Advocate®), Elanco Animal Health
21 (manufacturer of Interceptor® and Lotilaner®), Merial (manufacturer of Ivomec® and
22 NexgardTM), MSD (manufacturer of Bravecto®), Novartis (manufacturer of Interceptor®),
23 and Zoetis (manufacturer of Mitaban®, Simparica® and Stronghold®/ Revolution®).
24 Wayne Rosenkrantz has been a consultant, lecturer, or has received financial support
25 for studies from Merial (manufacturer of Ivomec® and NexgardTM), Merck Animal Health
26 (manufacturer of Bravecto®), Elanco Animal Health (manufacturer of Interceptor® and
27 Lotilaner®), and Zoetis (manufacturer of Mitaban®, Simparica® and Stronghold®/
28 Revolution®).
29 Emmanuel Bensignor has been a consultant, lecturer, or has received financial support
30 for studies from Merial (manufacturer of Ivomec® and NexgardTM), Merck Animal Health
31 (manufacturer of Bravecto®), Elanco Animal Health (manufacturer of Interceptor® and
32 Lotilaner®), and Zoetis (manufacturer of Mitaban®, Simparica® and Stronghold®).

33 Joanna Karaś-Tęcza has lectured for Bayer Animal Health (manufacturer of
34 Advocate®), MSD (manufacturer of Bravecto®), Zoetis (manufacturer of Mitaban®,
35 Simparica® and Stronghold®/ Revolution®).
36 Tara Paterson has received financial support for studies from Bayer Animal Health
37 (manufacturer of Advocate®).
38 Michael Shipstone has been a consultant, lecturer, or has received financial support for
39 studies from Merck Animal Health (manufacturer of Bravecto®), Elanco Animal Health
40 (manufacturer of Interceptor® and Lotilaner®), and Zoetis (manufacturer of Mitaban®,
41 Simparica® and Stronghold®).
42
43 Contributions
44 Ralf Mueller wrote the introduction, the sections about the pathogenesis, general
45 treatment considerations, lotilaner, miscellaneous drugs and treatment of feline
46 demodicosis, collected the contributions of the other authors, and edited, formatted and
47 finalised the manuscript. Emmanuel Bensignor wrote the sections on diagnosis and
48 milbemycin oxime, Joanna Karaś-Tęcza those on breeding considerations, fluralaner
49 and sarolaner, Tata Paterson the sections about moxidectin and ivermectin, Michael
50 Shipstone those about clinical signs and doramectin, and Wayne Rosenkrantz initiated
51 these clinical consensus guidelines and contributed the sections on amitraz, afoxolaner
52 and the future outlook.
53
54 Acknowledgements
55 The authors would like to thank the WAVD for supporting this initiative, the many
56 colleagues that published studies evaluating demodicosis in various species and its
57 treatments and thus indirectly contributed to this manuscript, and Dr. Sonya Bettenay for
58 her input on the manuscript.
59
60 Introduction
61 In the last couple of decades, position papers1 and guidelines2 have become very
62 popular in human medicine. This trend has also reached the veterinary field, where such
63 papers are published with increasing frequency.3-5 One of the negative results of this
64 trend is that sometimes conflicting guidelines on the same topic can be published by
65 different groups or associations.6,7 Additionally, papers written by experts in the field
66 may contain recommendations not feasible or understandable for lay people and
67 general practitioners.
68 With the clinical consensus guidelines, the World Association of Veterinary
69 Dermatology has made an effort to provide up-to-date and relevant information about
70 certain topics in veterinary dermatology, written by international panels reflecting expert
71 opinions from different regions of the world and publish them as open access providing
72 worldwide distribution.8,9 The process of development of these clinical consensus
73 guidelines were developed is unique, as input from other specialists and practitioners
74 with expertise and interest in the topics are sought in addition to the authors and
75 reviewers. The drafts of these papers are presented at national and international
76 meetings and made available for comments from members of various dermatology
77 organizations prior to final publication of the manuscript. The authors are proud to be
78 part of this laudable effort and sincerely hope that these clinical consensus guidelines
79 for demodicosis will be of help to many veterinarians all over the world.
80
81 Pathogenesis
82 Demodicosis is a common disease in canine practice10,11 caused by a
83 proliferation of Demodex mites. Those mites are normal commensal organisms in the
84 hair follicles of many mammals,12-18 that are transmitted during the first days of life from
85 the dam to the puppies.19 In most species, demodicosis only occurs when patients are
86 immunocompromised due to other diseases or undergoing immunosuppressive
87 therapies. Demodicosis in immunosuppressed individuals has been reported in humans,
88 dogs and cats amongst others.20-26 With the exception of Demodex (D.) gatoi in the cat,
89 the dog is the only species where young and otherwise healthy animals develop
90 demodicosis. This juvenile demodicosis has been presumed to be due to a cell-
91 mediated deficiency.27
92
93 Immunology
94 Early studies showed a normal humoral response, but decreased lymphocyte
95 blastogenesis in young dogs with naturally occurring demodicosis.28,29 Treatment of
96 puppies with anti-lymphocyte serum led to generalized demodicosis in eight puppies
97 while their untreated littermates remained healthy.30 Subsequently, a T cell exhaustion
98 characterized by low numbers of circulating CD4+ T cells,31 together with increased
99 serum concentrations of IL-5,32 and the immunosuppressive cytokines IL-1033,34 and
100 TGF-beta32 were reported in a number of studies comparing dogs with generalized
101 demodicosis to healthy controls.16,33-35 In contrast, the proinflammatory cytokine TNF-
102 alpha was reduced in dogs with demodicosis.34 The CD4/CD8 ratio was lower and the
103 number of CD8 positive cells was reported to be increased in dogs with generalized
104 demodicosis.35 Histologically, demodicosis is characterized by a mural folliculitis with
105 infiltrating CD8+ cytotoxic T cells, which resolves quickly with resolution of the
106 demodicosis.36 MHC class II receptors are upregulated in the skin of dogs with
107 demodicosis, particularly in keratinocytes.37
108 An immunosuppression as the cause of the demodicosis is further supported by a
109 severe combined immunodeficiency (SCID) mouse model. SCID mice, which have no B
110 and T cells, received skin grafts from dogs which were later infected with D. canis
111 collected from a dog with demodicosis. Within one to three months mites proliferated in
112 the grafted canine skin, but not the surrounding murine skin.38 In another
113 immunodeficient double knock-out mouse model lacking CD28 (a co-stimulatory
114 molecule involved in T cell activation) and STAT6 (essential for a pathway that plays a
115 role in IL-4 signal transduction and Th2 differentiation), mice developed a severe
116 dermatitis due to a proliferation of Demodex mites.39
117 Initially there was debate as to whether the secondary bacterial infection seen
118 with generalised demodicosis was contributing to, or in some way causing those
119 immunological changes.40,41 However, based on the published data this seems less
120 likely42,43 and at least the decreased lymphoblastogenesis seems to be a consequence
121 rather than a cause of the disease.43 Not surprisingly, demodicosis is accompanied by
122 an increase in markers for oxidative stress.44

123 As the overwhelming majority of affected juvenile dogs do not suffer from a
124 recurrence following successful therapy,45 it seems likely that the presumed cell-
125 mediated deficiency is a temporary problem.
126 The first clinical signs of juvenile demodicosis in dogs occur typically in the first 18
127 months of life.27 Adult-onset demodicosis also exists and is comparable to the
128 demodicosis seen in other species. In the dog, this was reported to be associated with
129 diseases or drugs leading to a compromised immune system such as leishmaniasis,46
130 hyperadrenocorticism,22,47 hypothyroidism,22 neoplasia,22 babesiosis,48 ehrlichiosis,48
131 and glucocorticoid treatment or chemotherapy.22 One report mentioned atopic dermatitis
132 as a frequent concurrent disease, but many dogs received glucocorticoid therapy.49 In
133 cats, demodicosis has been reported in association with feline immunodeficiency
134 virus,26,50,51 xanthoma,52 and diabetes mellitus.53 The localised form has been described
135 in lesions of feline squmous cell carcinoma in situ.54,55 In humans, demodicosis is
136 described as a primary immunosuppressive disorder based on a hereditary T cell
137 defect56 or as a consequence of immunosuppression.25
138
Consensus Statement 1: Generalised demodicosis is most likely a consequence of
temporary immunodeficiency in young dogs and is often associated with an
immunosuppressive condition or treatment in older dogs.
139 Genetics of juvenile demodicosis

140 For decades, strong breed predilections were reported for canine juvenile
141 demodicosis. In early reports those lists were largely anecdotal. More recently, one
142 larger study identified an at least four-fold increased risk to develop generalised
143 demodicosis for the Affenpinscher, Briard, Bullnese, Dogue de Bordeaux, English
144 Bulldog, French bull terrier, Pit bull terrier, Presa canario, Pug and West Highland White
145 Terrier.49,57 A further multi-centered and well-powered study in the United States
146 identified the American Staffordshire terrier, Staffordshire bull terrier and Chinese shar-
147 pei as predisposed breeds.57
148 Those breed predilections and the frequent occurrence of juvenile demodicosis in
149 certain lines, sibling puppies and related dogs make a hereditary basis very likely. In
150 addition, there is anecdotal evidence that preventing affected dogs from breeding
151 decreases the frequency of the disease.27 However, to the authors' knowledge only one
152 study has been published evaluating the genetic basis in more detail. In this study using
153 microsatellite markers, a significant association was found between generalised
154 demodicosis and the DLA haplotypes FH2002, FH2975 and FH2054 in Argentinian
155 mastiffs and Boxers.58
156 Demodicosis in juvenile dogs shows a wide variety of clinical signs, from mild,
157 localised alopecia to severe generalised forms with prominent systemic signs. These
158 variations may be seen within the same litter of puppies. In addition, patients respond
159 differently to the various therapeutic approaches. Thus, it is likely that several genes are
160 involved in the pathogenesis and more and larger studies are needed to elucidate the
161 genetic background of the disease. Further support for a multi-gene involvement is the
162 above mentioned immunodeficient double knock-out mouse strain lacking CD28 and
163 STAT6.39 In contrast to the double knock-out mice, single knock-out siblings kept in
164 close contact and lacking either CD28 or STAT6 did not show any clinical signs.39
165
Consensus Statement 2: In young dogs, demodicosis has a genetic basis and most
likely multiple genes are involved.
166
167 Demodex species in the dog and cat
168 Several mite species have been reported in dogs and cats. In the dog, initially
169 three different species were reported. D. canis is the most common demodectic mite of
170 dogs. A longer-bodied mite was also reported59-62 and named D. injai ("inja" being the
171 Zulu name for "dog").59 The female adult mites were approximately 50% longer and
172 males 100% longer than adult D. canis mites respectively. A short-bodied mite was
173 named D. cornei by some authors because it was supposedly found more
174 superficially.63-66 Genetic comparisons67,68 revealed only one67 or two68 different species
175 of Demodex in the dog: D canis and D injai. The short-bodied mite is now considered a
176 morphological variant of D canis.68 In one report it was suggested that D. cornei are
177 dead or near dead D. canis mites further supporting that only two species of mites
178 exist.69
179 There are 3 different species of Demodex mites in the cat: D. cati,70 D. gatoi71
180 and a third unnamed species.21,72 The unnamed species had a longer gnathosoma and
181 a shorter opisthotoma than D. cati. The length:width ratio of the opisthosoma was
182 approximately 2:1 whereas in D. cati it is approximately 5:1.21 In contrast to D. cati, D.
183 gatoi is contagious and usually causes intense pruritus.73,74 It was considered a very
184 regional disease, predominantly diagnosed in the Southeastern United States.74
185 However, more recently there have been reports from other areas of the world. 73,75,76
186
187
Consensus Statement 3: In dogs, two Demodex species occur, the shorter D. canis and
the longer D. injai. In cats, the shorter D. gatoi has a more regional occurence and
different clinical signs than the classical D. cati.
188 Clinical signs in dogs

189 The signs develop after clinically relevant mite proliferations have occurred and
190 the clinical signs can depend on the degree of the mites’ proliferation and vary greatly.
191 Initially there may be a non-inflammatory hypotrichosis/alopecia and/or an inflammatory
192 dermatitis with mild erythema, comedone formation, scaling and associated
193 hypotrichosis/ alopecia. The lesions may be focal or multifocal to coalescing involving
194 large areas of the body. Dilation and hyperpigmentation of follicular ostea may be
195 present and if seen, is a clinical clue for the disease (Figure). In more inflammatory
196 presentations, follicular-oriented papules may develop (Figure). Pruritus is generally not
197 thought to be characteristic of milder presentations, however it is more common if the
198 short-bodied morphological variant of D. canis63,64 is present and/or if secondary
199 bacterial infection develops. Follicular casts (scale adherent to the hair shafts) may be
200 present. With more severe or advanced disease, secondary bacterial infection may lead
201 to follicular pustules, furunculosis with scale, crust, exudation and ulceration with
202 draining tracts. Severe, generalised pustular demodicosis may be painful and
203 associated with hyperpigmentation, lymphadenopathy, lethargy and fever. In those
204 severely affected dogs, septicaemia due to the invariably present secondary bacterial
205 infection is possible. Pedal demodicosis commonly causes quite marked
206 hyperpigmentation (of both follicles and surrounding skin) and may present with
207 significant interdigital inflammation, oedema and pain.

208 D. injai has been reported in several dog breeds but seems over-represented in
209 terrier breeds and their crosses.62 Whilst it may cause erythema, comedone formation,
210 hyperpigmentation and alopecia, similar to D. canis, the most striking and consistent
211 clinical feature is marked greasiness of the dorsal trunk.
212
213 Clinical Signs in cats
214 D. cati can cause localised or generalised disease and lesions include erythema,
215 hypotrichosis/alopecia, scale and crusting (Figure). Pruritus is variable but may be
216 intense in some individuals. Generalised disease is commonly associated with an
217 underlying disease such as feline immunodeficiency virus,26,50,51 xanthoma,52 or
218 diabetes mellitus.53. In some cats, no other disease may be identified. Demodex mites
219 have also been reported to proliferate within the scaly alopecic lesions of bowenoid in
220 situ carcinoma (BISC).54,55
221 D. gatoi is a contagious mite that inhabits the stratum corneum (like Sarcoptes)
222 and the most common clinical feature is pruritus ranging from mild to very intense. Skin
223 lesions aside from traumatic alopecia and scale are secondary hyperpigmentation,
224 superficial erosion and ulceration. The changes are predominantly truncal with the
225 ventral abdomen having been reported as a site of predilection.73,74
226
Consensus Statement 4: Demodicosis in dogs is characterised by follicular papules and

pustules that in more severely affected dogs may develop into alopecia and crusting with
secondary bacterial infections and systemic signs. D. injae occurs more often in terrier
breeds and additionally causes excessive greasiness. In cats, D. cati shows similar
clinical signs, while in contrast infestations with the contagious D. gatoi often lead to
trunkal pruritus.
227
228 Diagnosis
229 Deep skin scrapings
230 At this time, deep skin scrapings are the diagnostic tool of choice in most patients
231 with suspected demodicosis.77 Samples may be collected with curettes, spatulae, sharp
232 or dull scalpel blades. Placing a drop of mineral oil on the sampling instrument or directly
233 on the skin is helpful for better adherence of the sampled debris to the instrument.
234 Multiple scrapings of approximately 1 cm2 of affected skin should be performed in the
235 direction of the hair growth and importantly the skin should be squeezed constantly or
236 intermittently during scraping to extrude the mites from the depth of the follicles to the
237 surface. Squeezing the skin has been shown to increase the number of mites found.78
238 Primary lesions such as follicular papules and pustules should be selected in order to
239 obtain the best yield. Ulcerated areas are not suited as it is less likely to find parasites in
240 such areas. The skin is scraped until capillary bleeding occurs indicating sufficient depth
241 of the scraping. If necessary in a long- or medium-haired dog, gently clipping the area
242 (in the direction of hair growth) to be scraped will minimize the loss of the scraped
243 material into the surrounding hair. Debris is then transferred to a slide, mixed with
244 mineral or paraffin oil and examined with a cover slip under the microscope at low
245 magnification (x40 or x100). Magnification occurs with both the ocular lens (typically
246 x10) and the objective lenses (x4 or x10). Recognition of mites is easier with a lowered
247 microscope condensor and decreased light to increase the contrast in the microscope
248 field (Figure).
249 As Demodex mites are part of the normal microfauna, one mite identified on
250 several deep skin scrapings could be a normal but uncommon finding. However, more
251 than one mite is strongly suggestive of clinical demodicosis.3 Different life stages (eggs,
252 larvae, nymphs and adults) and their numbers should be recorded and compared from
253 the same sites at each visit to objectively measure the treatment success.
254
255 Trichograms
256 Trichograms have been reported as an alternative to deep skin scrapings78,79 and
257 are particularly useful in areas that are difficult to scrape, such as periocular and
258 interdigital areas. An area of 1cm2 should be plucked with a forceps in the direction of
259 the hair growth and placed in a drop of mineral or paraffin oil on a slide. The use of a
260 coverslip allows more thorough and rapid inspection of the specimen (Figure). To
261 increase the chance of a positive trichogram, a large number of hairs (50-100) should be
262 plucked. When performed properly, trichograms have a high diagnostic yield. However,
263 negative trichograms should be followed by deep skin scrapings before ruling out
264 demodicosis. Positive trichograms in healthy dogs are rare.80
265
266 Tape strips (“scotch tests”)
267 Tape strips have also been reported as an excellent diagnostic method for canine
268 demodicosis.81 While squeezing the skin, the acetate tape is pressed onto the skin with
269 the sticky surface down. This technique was initially reported to be more sensitive than
270 deep skin scrapings.81 However, follow-up studies have shown contradicting results.82,83
271
272 Skin biopsies
273 In some rare cases, skin scrapings, trichograms and tape preparations may be
274 negative and skin biopsies may be needed to detect the Demodex mites in the hair
275 follicles or in foreign body granulomas observed as a consequence of furunculosis. This
276 may be more likely in certain body locations such as the paws and certain breeds such
277 as the Shar Pei.3
278
279 Other methods of mite detection
280 Direct examination of the exudate from pustules or draining tracts may reveal
281 mites in some patients. Specimens can be collected by squeezing the exudate onto a
282 glass slide, and visualized by adding mineral oil and a coverslip.3 In one study, exudate
283 was collected from dogs showing exudative lesions with the blunt side of a second
284 scalpel blade after gently removing the crusts and squeezing the lesion.84 In this
285 particular study, the exudate sampling was compared to deep skin scrapings and
286 trichograms and was positive in all dogs sampled. However, this technique is only
287 possible in dogs with more severe forms of demodicosis. Cytological specimens stained
288 with Diff Quik may also reveal Demodex mites (more easily recognised with the
289 condensor lowered for searching). Although this is not a very sensitive method for the
290 diagnosis, it is not uncommon to find mites on the evaluation of cytology samples of
291 dogs with exudative forms of demodicosis.
292
Consensus Statement 5: Deep skin scrapings (currently the diagnostic method of

choice), trichograms, tape strips and examinations of exudate may be useful in
identifying Demodex mites. More than one mite on any given test is an indication of
clinically relevant demodicosis.
293
294 Diagnosing bacterial infections
295 Frequently, generalized demodicosis is associated with secondary bacterial
296 infections. Particularly in severe cases involving furunculosis, a bacterial septicemia is
297 possible. When clinical signs of possible bacterial infection such as pustules or draining
298 tracts are present, an impression smear should be obtained, stained and evaluated for
299 an increased number and/or intracellular location of bacterial organisms. Most
300 commonly, Staphylococcus pseudintermedius will be present,45 but in some patients,
301 particularly those with furunculosis, Gram-negative rods such as Escherichia coli or
302 Pseudomonas aeruginosa may dominate. For these cases a culture and sensitivity
303 testing is indicated.
304
305 Breeding considerations
306 Canine generalized demodicosis is a relatively frequent and often very severe
307 parasitic skin disease. As many as 0.58 % of the dogs in the USA suffer from the
308 generalized form of the disease.57 Multiple risk factors are involved in the development
309 of canine demodicosis and one of the most important recognised risk factors is breed
310 predisposition. Juvenile demodicosis is more common in purebred dogs of particular
311 breeds. Selective breeding in order to obtain a certain set of desired characteristics in a
312 particular breed can lead to a reduction of genetic variation within a breed. This may
313 facilitate the clinical expression of recessive genes and in turn can result in a greater
314 susceptibility to certain diseases. Knowledge about breed predispositions for certain
315 diseases such as demodicosis is useful not only while creating a list of differential
316 diagnoses and when advising clients which breed to purchase, but also when advising
317 breeders. Implementing appropriate prophylactic strategies can markedly reduce the
318 prevalence of generalized juvenile demodicosis in the dog.27 Excluding bitches from
319 breeding that have given birth to puppies with demodicosis will lead to a prominent
320 decrease of puppies affected with demodicosis.27 As early as 1981, the American
321 Academy of Veterinary Dermatology adopted a resolution recommending ‘neutering all
322 dogs who have had generalized demodicosis so that the incidence of the disease is
323 decreased and not perpetuated’.85 Today, it is consensus among veterinary
324 dermatologists worldwide that affected dogs or there parents should not be used for
325 breeding.3
326
Consensus Statement 6: Dogs with generalised demodicosis should not be bred.
327
328 Treatment
329 General considerations
330 Demodicosis varies from mild localised to severe generalised disease. Mild
331 localised disease will spontaneously resolve in most cases. How many dogs with more
332 severe disease would also spontaneously resolve without treatment is unclear. Although
333 a study has attempted to evaluate the proportion of dogs with the generalised form of
334 the disease that undergo spontaneous remission,86 such studies are difficult to conduct
335 and robust data is lacking to answer this question. In addition, in most countries it is
336 considered unethical to withhold treatment of dogs with severe demodicosis and owners
337 of such dogs usually will not consent to observation instead of interventional (and
338 typically efficacious) acaricidal therapy. Nevertheless, there is some evidence that
339 spontaneous remission can occur in a subset of dogs with generalised disease. 86,87
340 In juvenile dogs, treatment of the demodicosis and possibly the secondary
341 bacterial infection, if present, is typically sufficient without the need for further diagnostic
342 work-up. In contrast, for those cats and dogs with adult-onset disease, the possibility of
343 an underlying, immunosuppressive disease should be investigated. In one dog with
344 adult-onset demodicosis, treatment of the primary disease resulted in resolution of the
345 demodicosis.59 In another study evaluating dogs with adult-onset demodicosis,22 4/9
346 dogs in which the primary disease was diagnosed and treated successfully were cured.
347 In contrast, only 3/25 dogs in which no underlying disease was diagnosed or the
348 concurrent disease could not be treated were cured. However, even a thorough work-up
349 for underlying diseases will not always be successful in identifying a cause for the
350 demodicosis. In one larger study, 30% of the adult dogs had idiopathic demodicosis.22
351 Regardless of the specific miticidal therapy, treatment success is monitored both
352 clinically and by repeated skin scrapings. Generally, it is recommended to examine dogs
353 and cats with demodicosis monthly.3 At each recheck, skin scrapings are taken from the
354 same sites as in previous visits. In addition to clinical improvement, the numbers of
355 mites and immature stages should decrease with each visit. If clinical improvement does
356 not occur and mite numbers fail to improve, a change in therapy should be considered.45
357 Clients need to be informed that their pets may look better before the mites have been
358 eliminated, thus the need to comply with monthly evaluations until the patient is deemed
359 parasitologically cured. They also need to be educated about the potentially slow
360 improvement in clinical signs over several weeks to months. Miticidal therapy should be
361 continued four weeks beyond the second set of negative monthly scrapings to decrease
362 the risk of a disease recurrence.3,45 In dogs that responded very slowly to therapy,
363 treatment may be extended even further.3 In a systematic review of 124 dogs reported to
364 have failed the initial therapy, two thirds responded to a change of therapy.45 Similarly,
365 of 40 dogs with recurring demodicosis within 12 months after initially responding to
366 therapy, more than two thirds went into remission after another treatment course with
367 the same or an alternative medication.45 A follow-up of at least 12 months after
368 treatment cessation has been recommended before calling a dog cured, although in
369 some studies the disease recurred after more than 12 months of remission in a few
370 dogs.45
371
Consensus Statement 7: Treatment for generalised demodicosis should be monitored

clinically and microscopically every month until the second negative skin scraping.
372
373 In most dogs with demodicosis, a secondary bacterial infection will develop with
374 time. In the past, systemic antibiotic therapy was recommended for all dogs in which a
375 secondary bacterial infection could be demonstrated clinically and cytologically. 3
376 However, in a randomised controlled trial evaluating 58 dogs with generalised

377 demodicosis half of the dogs were treated with systemic antibiotics in addition to
378 miticidal therapy with daily ivermectin and topical weekly benzoyl peroxide shampoo, the
379 other half received only shampoo and ivermectin.88 In this study, there was no significant
380 difference between groups in the time to cytological resolution of the bacterial
381 pyoderma, the time to negative skin scrapings and clinical remission, indicating that with
382 appropriate miticidal therapy systemic antibiotics may not be needed in many dogs with
383 demodicosis.88 In dogs with severe disease, previous antibiotic treatment or dogs with
384 bacterial infections caused by rods, a bacterial culture and sensitivity should be
385 recommended as a basis for the selection of appropriate antibiotic therapy. As the
386 prevalence of skin infections with multiresistant bacteria is increasing, antibiotic
387 stewardship with a judicial use of systemic antibiotics is recommended,9 and topical
388 antibacterial therapy alone should be considered for the majority of dogs with
389 demodicosis.
390
391
Consensus Statement 8: In dogs with demodicosis systemic antibiotics will typically not
be needed and topical antibacterial therapy combined with good miticidal agents will be
sufficient unless severe bacterial infection is present.
392 Amitraz
393 Amitraz as a leave-on rinse has been the approved mainstay treatment for canine
394 generalized demodicosis in many countries for decades. It is a diamide, N’-(2,4-
395 dimethylphenyl)-N-[(2,4-dimethylphenyl) imino]1-8 methyl]-N-methylmethanidamide.89
396 Amitraz is a monoamine oxidase inhibitor, an alpha 2-adrenergic agonist and inhibits
397 prostaglandin synthesis.89 In addition to the rinse, amitraz is also available in a 9% tick
398 preventive collar, reported as a sole therapy90 and as a spot-on product in combination
399 with other ectoparasiticides.91 However, amitraz tick collar efficacy for canine
400 demodicosis is controversial. Pilot studies of the spot-on products (in combination with
401 metaflumizone92-94 and with fipronil95) reported successful treatment of canine
402 generalised demodicosis. However, pemphigus foliaceus-like drug reactions were
403 reported with both products.96,97 The manufacturer has discontinued the production of
404 the amitraz-metaflumizone product but it may still be available in some parts of the
405 world.
406 The amitraz rinse has been shown to be an effective treatment option in many
407 studies.91,92,94,95,98-111 This evidence for efficacy was confirmed by systematic reviews.3,45
408 Amitraz rinses require adequate skin contact for optimal efficacy. Therefore it is
409 recommended to clip the hair coat in medium- and long-haired dogs.112 The hair should
410 be kept short throughout the treatment period. The rinse should be applied with a
411 sponge and the skin soaked thoroughly and allowed to dry without rinsing. Dogs should
412 not get wet between rinses, to avoid washing off the amitraz. Gentle removal of crusts
413 and surface debris with a shampoo is recommended before application of the amitraz
414 rinse.112 Dogs should be lightly towel-dried after shampooing and water rinsing prior to
415 the application of the amitraz rinse.
416 Rinses should be performed in a well-ventilated area and protective clothing
417 should be worn by the handler, as adverse effects such as respiratory problems have
418 been observed in humans.27,45 Care should be taken to avoid inappropriate ingestion or
419 excessive exposure. In addition to respiratory adverse effects, many other side effects
420 have been reported in humans associated with amitraz poisoning. A systematic review
421 in humans analyzed 32 studies describing 310 cases of amitraz poisoning. 113 The most
422 commonly reported clinical features of amitraz poisoning were altered sensorium,
423 miosis, hyperglycemia, bradycardia, vomiting, respiratory failure, hypotension and
424 hypothermia.113 Diabetic (humans) should avoid all contact with amitraz. Reported
425 adverse effects of amitraz in dogs included depression, sleepiness, ataxia, pruritus,
426 urticaria, oedema, skin irritations, polyphagia, polydipsia, hypotension, bradycardia,
427 hyperglycaemia, vomiting and diarrhoea.27,45 Severe reactions or intoxications in dogs
428 can be treated with yohimbine, atipamezole, and other appropriate supportive
429 measures. Smaller breed dogs, in particular toy-breed dogs, such as Pomeranians and
430 Chihuahuas, are at increased risk for toxicity and deaths have been reported.114
431 Chihuahuas are specifically excluded on the label. Amitraz should be used with caution
432 in very young, geriatric and/or debilitated animals. Since amitraz is an α 2-adrenergic
433 agonist, sedating agents that are also α-adrenergic agonists (e.g. benzodiazepines,
434 xylazine) should be avoided due to possible synergistic toxicity.27
435 The recommended concentration varies from 0.025 to 0.06% once weekly to
436 every two weeks. Clinical efficacy increases with increasing concentration and shorter
437 treatment intervals.103,104 Intensive protocols with daily rinsing of alternating body halves
438 at a concentration of 0.125% 106 or weekly treatment with an amitraz concentration of
439 1.25%103 have been reported in dogs not responding to conventional therapies. In the
440 latter report, each time, dogs were treated once with atipamezole (0.1 mg ⁄ kg intra-
441 muscularly) followed by oral yohimbine (0.1 mg ⁄ kg) once daily for 3 days to minimize
442 systemic adverse effects with each weekly treatment.103 Treatment of pedal
443 demodicosis with amitraz rinses may be especially problematic in wet environments
444 because it is difficult to maintain sufficient amitraz on the pedal skin in these
445 circumstances. Daily treatment of the paws27 or using other treatment modalities may be
446 needed. As many as 20% of dogs with generalised demodicosis do not attain negative
447 scraping results or experience a recurrence when treatment with amitraz is
448 discontinued.104 The success rate of amitraz rinses was reported to be lower in dogs
449 with adult-onset demodicosis.45
450 Combining amitraz with other miticidal therapies has been previously reported but
451 is currently rarely used because of the high efficacy of other therapies. There is a report
452 of potentiated neurotoxicity in a dog treated with ivermectin and amitraz. 112
453
Consensus Statement 9: Weekly amitraz rinses at 0.025-0.05% are effective for canine
demodicosis, long-haired animals should be clipped.
454
455 Ivermectin
456 Ivermectin is derived from the fermentation of molecularly synthesized
457 Streptomyces avermitilis.115 Since its introduction as a broad-spectrum parasiticide in
458 1981, it has become widely used in veterinary medicine. For almost two decades,
459 ivermectin was the most commonly used macrocyclic lactone in the treatment of canine
460 demodicosis. However, it is only approved in dogs for the prevention of the heartworm
461 Dirofilaria immitis - all other applications are considered extra-label.116
462 Preliminary studies using ivermectin for the treatment of demodicosis evaluated
463 various dosages and routes of administration. Initial results indicated that daily oral
464 administration of ivermectin was the most efficacious protocol whilst weekly
465 subcutaneous administration at 0.4 mg/kg108 or use of a 0.5% ivermectin topical pour-on
466 three times weekly117 yielded poor results. Several studies have examined the use of
467 oral ivermectin at varying dosages with contrasting results. Oral administration at 350
468 μg/kg118 and 400 μg/kg119 daily demonstrated poor efficacy with only 30% and 48% rates
469 of cure, respectively. However small sample size and concurrent administration of other
470 drugs may have negatively impacted the results of these trials. In contrast, the cure rate
471 was 85% in another study when ivermectin was administered orally at 300 μg/kg
472 daily;120 similar results were achieved using 500-600 μg/kg.121-123 The currently
473 recommended protocols generally employ 300-600 μg/kg orally once daily until four to
474 eight weeks beyond parasitological cure.3
475 Despite its frequent successful use in the treatment of demodicosis, it is unlikely
476 that ivermectin will ever become labeled for this purpose due to its potential toxicity.
477 Dogs treated with ivermectin should be closely monitored for potential neurotoxicity,
478 especially ivermectin-sensitive breeds such as collie breeds, Australian shepherds,
479 Shetland and Old English sheepdogs or dogs treated with high doses of ivermectin.
480 Clinical signs of toxicosis may include mydriasis, lethargy, vomiting, ataxia, tremors and
481 temporary blindness which may rapidly progress to seizures, stupor, coma, respiratory
482 failure and death.45,124,125 Mydriasis is typically the first clinical sign of ivermectin toxicity
483 and the last to resolve. There is no specific antidote for ivermectin toxicosis. Depending
484 on their severity, the clinical signs typically resolve within days to weeks following
485 cessation of the drug along with supportive care. In the case of an acute oral overdose,
486 repeated doses of activated charcoal may be administered in an effort to disrupt
487 enterohepatic recirculation.116 Intravenous lipid emulsion therapy has been shown to be
488 effective in the treatment of adverse reactions to all lipophilic drugs including
489 ivermectin.126 Its effect is thought to be due to the lipid sink mechanism whereby the
490 drug is drawn out of the tissues and sequestered into a lipid phase within the
491 intravascular space thereby decreasing CNS tissue concentrations.126 Physostigmine, a
492 parasympathomimetic alkaloid and reversible cholinesterase inhibitor, has been shown
493 to cause short-term improvement in neurologic signs but is not recommended for
494 prolonged use due to its significant cholinergic effects and only temporary action.125
495 Flumazenil, a GABA-antagonist, has been shown to reverse the effects of ivermectin in
496 experimental models in rodents.125,127 However, its clinical efficacy in dogs has yet to be
497 demonstrated.
498 Ivermectin toxicity can occur as a result of acute overdose, elevated serum
499 concentration following long-term administration or associated with genetic susceptibility
500 which is seen most commonly in herding breeds such as collie breeds, Australian
501 shepherds, Shetland and Old English sheepdogs and their crosses but has also been
502 recognised to occur in other breeds.124,128-130 Not uncommonly, this results in a severe
503 and sometimes fatal idiosyncratic neurotoxicosis. Ivermectin-sensitivity occurs in
504 individuals that carry a frame shift deletion mutation of the ABCB1 gene (formerly multi-
505 drug resistance gene, mdr1), which is responsible for producing P-glycoprotein (P-gp) –
506 an ATP-dependent transmembrane transporter protein which plays an important role in
507 the blood-brain barrier.129 The deletion mutation causes P-gp synthesis to terminate
508 prematurely resulting in severely truncated, non-functional P-gp molecules.
509 Consequently, transport of certain drugs out of the central nervous system (CNS) is
510 impaired leading to accumulation of drug within the CNS to toxic levels.129 Ivermectin is
511 among the substrates for P-gp and therefore, individuals that are homozygous for this
512 autosomal recessive gene demonstrate the ivermectin-sensitivity phenotype. Dogs can
513 be tested for the ABCB1-1Δ genotype prior to beginning ivermectin therapy through a
514 number of laboratories.125,130 However, dogs without this defect may also show signs of
515 toxicity.131
516 In ivermectin-sensitive individuals, toxicity may be apparent four to twelve hours
517 after oral administration.125 Slow titration up to the therapeutic dose over several days is
518 recommended when instituting ivermectin therapy in all breeds of dogs to enable close
519 monitoring for adverse reactions and early identification of ivermectin-sensitive
520 individuals.124 A starting dose of 0.05 mg/kg on Day 1 is recommended, then 0.1 mg/kg
521 on Day 2 followed by incremental doses of 0.1 mg/kg/day until the final dose is
522 achieved.124 Treatment should cease and an alternate therapy be considered if
523 neurologic signs develop during this titration period.
524 Owing to ivermectin’s long half-life (80 +/- 30 hours),126 serum concentrations rise
525 over weeks until after perhaps 6 weeks a steady-state is reached. Subchronic
526 ivermectin toxicity has also been reported following long-term therapy as serum drug
527 concentrations accumulate to toxic levels.45,119 In a study of 28 dogs that developed
528 subchronic toxicity while being treated for demodicosis with ivermectin or other
529 macrocyclic lactones, only one dog was heterozygous and all others were homozygous
530 for the normal ABCB1 gene.131 Interestingly, 10 dogs in this study were concurrently
531 receiving one or more drugs that are also substrates of P-gp such as ketoconazole,
532 cyclosporine or glucocorticoids. The concurrent use of ivermectin with other P-gp
533 substrates should be avoided whenever possible. In addition, use of spinosad-
534 containing products should be avoided as mild to moderate ivermectin toxicosis has
535 been reported when these drugs are used concurrently.132 Spinosad has been shown to
536 be a potent inhibitor of canine P-gp which accounts for its impact on ivermectin
537 pharmacokinetics.132,133 Under the Animal Medicinal Drug Use Clarification Act
538 (AMDUCA), off-label therapies should only be used in instances where a drug licensed
539 for the purpose of treating demodicosis has either failed or is contra-indicated.
540
541 Milbemycin oxime
542 Milbemycin oxime is the fermentation product of Streptomyces hygroscopus
543 aureolacrimosus. It is approved in many countries as an endoparasiticide. In some
544 countries, oral milbemyin oxime is licensed for the treatment of canine demodicosis at a
545 dose of 0.5-2 mg/kg daily. In studies from the USA and Australia, a clearly higher
546 success rate was seen with the higher dose of 1-2 mg/kg compared to 0.5-
547 1mg/kg.23,134,135 However, these studies were conducted in referral practices with
548 potentially more chronic and severely affected patients. In contrast, a Swedish study
549 showed a good response with the low dose protocol,136 possibly because most dogs in
550 that study were diagnosed early in the disease and had not previously been treated with
551 other miticides. Alternatively, a different genetic background of the dogs or different
552 sensitivity of the mites to milbemycin oxime may have influenced the results. The
553 success rate of milbemycin oxime was shown to be much lower in dogs with adult-onset
554 demodicosis.23,135
555 There seems to be a high safety margin with milbemycin oxime.45 It has been
556 administered to Collies at a dose of 2.5 mg/kg daily for 10 days with no adverse effects
557 observed.137 However, dogs homozygous for the ABCB1-1Δ (MDR-1) mutation
558 developed ataxia with milbemycin oxime at a dose of only 1.5 mg/kg daily, although they
559 tolerated the drug at 0.6 mg/kg/day.128 In herding breeds, it is thus prudent to evaluate
560 the ABCB1-1Δ (MDR-1) genotype and to use lower doses or increase the dose
561 gradually in dogs homozygous for the ABCB1-1Δ (MDR-1) mutation similar to what is
562 recommended for oral ivermectin.124
563
564 Moxidectin
565 Moxidectin, a macrocyclic lactone derived from the fermentation of Streptomyces
566 hygroscopicus aureolacrimosus, has demonstrated comparable efficacy to that of other
567 macrocyclic lactones in the treatment of canine generalized demodicosis. Daily oral
568 administration at 300-400 µg/kg yielded cure rates of 72 to 85%138-140 and 500 µg/kg
569 administered every 72 hours showed similar results.121 When oral administration (500
570 µg/kg) was compared to the subcutaneous route (500-1,000 µg/kg), each administered
571 every 72 hours, rates of cure were 75% and 86%, respectively. Adverse effects were
572 reported in 10 to 37% of dogs in these studies,121,138-140 but were mostly mild and
573 included emesis, salivation, anorexia, lethargy, dyspnoea, and facial oedema. Since
574 these occurred more frequently with subcutaneous administration,140 the oral route is
575 preferable. The efficacy of moxidectin appears to be similar to that of ivermectin, and
576 although neurologic signs such as mydriasis, tremor, ataxia and seizures have been
577 reported with overdoses,125 moxidectin seems to be better tolerated by ivermectin-
578 sensitive individuals than is ivermectin.139 Nevertheless, a gradual dose increase over
579 several days similar to what is recommended for ivermectin124 seems prudent to identify
580 the few dogs intolerant to the drug, before adverse effects become severe and
581 potentially fatal.45
582 Topical application appears to be better tolerated than either of the
583 aforementioned routes. A 2.5% preparation of moxidectin combined with 10%
584 imidacloprid was well-tolerated even in ivermectin-sensitive breeds that were given
585 three monthly applications of up to five times the recommended dose.141 When applied
586 every two weeks, efficacy was greater in dogs with juvenile-onset versus adult-onset
587 disease - similar to studies using other treatment protocols.142 In a study comparing
588 varying application rates of the moxidectin/imidacloprid spot-on, a significant dose-
589 dependent effect was observed resulting in enhanced efficacy with more frequent
590 application than once monthly.123,143 No adverse events occurred in the
591 moxidectin/imidacloprid-treated dogs. In contrast, in the same study, three dogs
592 became toxic while receiving daily oral ivermectin at 500 µg/kg. Although ivermectin
593 was more efficacious than moxidectin/imidacloprid in this study, weekly application of
594 the latter yielded good clinical results and represents a safe therapeutic option.123,143
595 Follow-up data also revealed good long-term effects with no relapse of disease within
596 one year of parasitological cure. Based on the demonstrated dose-dependent efficacy,
597 this product was registered for weekly use in dogs with demodicosis in many countries
598 and should be considered in mild to moderate cases.
599 Further research is required to evaluate the impact of the topical
600 moxidectin/imidacloprid preparation in the prevention of relapse of demodicosis
601 following parasitological cure. One pilot study evaluated the response to once monthly
602 treatment in twelve dogs with relapsing juvenile- and adult-onset generalized
603 demodicosis following parasitologic cure. All but one dog remained in remission during
604 the 12-month trial.144 Since this spot-on is commonly prescribed to young dogs as a
605 monthly agent for the treatment and prevention of other parasitic diseases, its influence
606 on the progression of localised demodicosis to the more generalised form should be
607 evaluated. However, the high rate of spontaneous resolution of localized disease
608 complicates interpretation of such studies.27
609
610 Doramectin
611 Doramectin is a longer-acting macrocyclic lactone that has been reported as a
612 successful treatment for canine demodicosis.145-147 In the first study, twenty-three dogs
613 were injected once weekly with 600 μg/kg subcutaneously for 5–23 weeks.145 Ten of the
614 dogs were cured, seven relapsed after 1–24 months (two of which responded to repeat
615 doramectin treatment) and six were lost to follow-up. None of the animals in this study
616 were reported to show any adverse effects with therapy. In a second study, doramectin
617 was given orally to 29 dogs with generalised demodicosis with good efficacy.146 Ataxia
618 as an adverse effect of doramectin therapy for demodicosis was seen in one Golden
619 retriever.146 The most recent study involved 400 client-owned dogs treated with weekly
620 subcutaneous doramectin injections (0.6 mg/kg), 232 of which successfully completed
621 the protocol. Two-hundred and twenty of these dogs (94.8%) achieved clinical remission
622 with two consecutive negative skin scrapes collected two weeks apart. The time taken to
623 achieve this remission ranged from 4 to 20 weeks (mean duration 7.1 weeks). Three
624 dogs (1.3%) relapsed within a month of treatment cessation but all were successfully
625 treated with a second round of injections. Ten (4.3%) were failures, with no detectable
626 difference in mite numbers seen on follow-up skin scrapings (mean treatment duration
627 6.4 weeks). The treatment was well tolerated and only two adverse reactions were seen,
628 one was a local irritation reaction at the injection site and the other ataxia, both
629 developed under and resolved upon cessation of therapy. There were seventeen adult
630 animals (greater than 4 years), 47% had an underlying concurrent disease diagnosed.
631 The efficacy was lower in this group and only 66.7% achieved remission in 6 to 8 weeks
632 (mean duration 7.1 weeks). Overall this appears to be a well-tolerated and useful
633 therapy for the treatment of canine generalised demodicosis.
634
Consensus Statement 10: Oral ivermectin at 0.03-0.06 mg/kg daily, moxidectin at 0.03-
0.05 mg/kg daily, milbemcyin oxime at 1.0-2.0 mg/kg daily and doramectin injected
subcutaneously every week at 0.06 mg/kg are effective therapies for canine demodicosis,
but an initial gradual dose increase is recommended for systemic moxidectin and
ivermectin to identify dogs sensitive to toxicoses induced by those macrocyclic lactones.
Topical moxidectin/imidacloprid should be considered for mild-moderate cases of canine
demodicosis.
635
636 Isoxazolines
637 Recently, a new group of parasiticides also effective against canine demodicosis
638 has been introduced to veterinary medicine.148 These ectoparasiticides are isoxazolines
639 and include fluralaner, sarolaner, afoxolaner and lotilaner. These molecules have been
640 shown to target a binding site that inhibits insect and acarine ligand-gated chloride
641 channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid

642 (GABA), thereby blocking pre- and post-synaptic transfer of chloride ions across cell
643 membranes.149 Prolonged isoxazoline-induced hyperexcitation results in uncontrolled
644 activity of the central nervous system and death of insects and acarines. The selective
645 toxicity of isoxazolines between insects, acarines and mammals may be inferred by the
646 differential sensitivity of the insects' and acarines' GABA receptors versus mammalian
647 GABA receptors.150,151
648
649 Fluralaner
650 Fluralaner (4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-
651 methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-benzamide) is a rapidly absorbed
652 isoxazoline, that reaches maximum concentrations within 24 hours and is quantifiable in
653 plasma for up to 112 days after a single oral administration.152 Absorption is increased
654 when fluralaner is given with food,153 it is predominately excreted unchanged in the
655 faeces by hepatic elimination.152 It is administered orally every three months. The long
656 interval between treatments may increase owner compliance and thus successful
657 treatment outcome. Fluralaner can be used without additional risk for collies and other
658 sensitive herding breeds that have the MDR1 mutation.154 Following intravenous
659 administration fluralaner exhibits a relatively high apparent volume of distribution, a low
660 plasma clearance, a long terminal half-life of 12-15 days, and a long mean residence
661 time of 15-20 days thereby demonstrating a long persistence of fluralaner in both dogs
662 and cats.155
663 Fluralaner every three months was compared to a spot-on containing
664 imidacloprid/moxidectin administered once monthly.156 A reduction of 99.8% and 98% in
665 mite numbers was achieved after 28 days respectively. Scrapings were negative in all
666 dogs treated with fluralaner after 56 days.156 However, the dogs used in this study were
667 probably not comparable to privately owned dogs in Europe or North America. In a
668 larger clinical study, 163 dogs of various breeds with generalised demodicosis (63% with
669 juvenile- and 37% with adult- onset of the disease) were treated with fluralaner once at a
670 single dose of 25 mg/kg.157 The majority of dogs (87%, all of the dogs with juvenile onset
671 and most with adult-onset demodicosis) had negative skin scrapings after one month
672 and all dogs were negative on scraping after two months. Adverse effects were not
673 seen.157 A recent study that included 67 dogs also demonstrated that fluralaner when
674 given at the recommended dose for flea and tick prevention is also effective for the
675 treatment of canine generalized demodicosis.158 In 46 individuals with adult-onset
676 demodicosis 63%, 85% and 100% cure rates were observed after 2, 3 and 4 months,
677 respectively. In 21 dogs diagnosed with juvenile-onset demodicosis in this same study,
678 81% and 100% cure rates were observed after 2 and 3 months, respectively.
679 Adverse reactions in fluralaner-treated dogs in studies evaluating flea and tick
680 control were uncommon to rare. During a 12-week period only four of 223 fluralaner-
681 treated dogs (2.0%) had an adverse event, this was in all cases transient
682 gastrointestinal-related signs including vomiting and anorexia.159 In toxicity studies, oral
683 administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-
684 week intervals caused no clinical signs, the safety margin in healthy dogs ≥8 weeks of
685 age and weighing ≥2 kg was more than five times the labelled dose.154 Of 224 dogs
686 participating in a 182-day field study, 7.1%, 6.7%, and 4.9% showed emesis, decreased
687 appetite and diarrhoea respectively. Lethargy, polydipsia and flatulence were seen in
688 5.4%, 1.8% and 1.3% of the dogs.160
689 Fluralaner can be used without additional risk for collies and other sensitive
690 herding breeds that have the MDR1 mutation.154 No adverse events were observed
691 subsequent to fluralaner treatment of ABCB1-1Δ (-/-) Collies at three times the highest
692 expected clinical dose. Thus, fluralaner seems to be an effective, safe and convenient
693 treatment option for all breeds of dogs with generalized demodicosis.156,157
694
695 Afoxolaner
696 Afoxolaner [1-Naphthalenecarboxamide, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-
697 4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}]
698 is one of the members of the isoxazoline family. In a variety of studies, afoxolaner was
699 demonstrated to be a highly effective and safe form of flea and tick control.161-164
700 Afoxolaner is a palatable beef-flavoured product that can be given with or without
701 food. After oral administration to dogs, it is rapidly absorbed into the systemic circulation,
702 where the drug becomes active. Afoxolaner is highly protein bound (>99%), the unbound
703 fraction distributes moderately into tissues.165 It is slowly eliminated from the body via
704 biliary excretion of free afoxolaner and via hepatic metabolism and subsequent biliary
705 and renal clearance of afoxolaner metabolites. This slow clearance gives afoxolaner a
706 long half-life in dogs and sustained ectoparasitic activity. In an oral bioavailability study,
707 afloxolaner was rapidly absorbed (Tmax = 2-4 hours), achieved a maximum plasma
708 concentration (Cmax) of 1655 +/- 332 ng/ml, demonstrated a bioavailability of 73.9%
709 and exhibited a terminal plasma half-life (T1/2) of 15 days.165 Company-generated study
710 data showed no differences in pharmacokinetics in fed or fasted dogs supporting that it
711 can be given without food.
712 Adverse reactions in flea and tick studies are rare. In a 90-day US field study
713 vomiting was seen in 17 of 415 dogs (4.1%), 13 (3.1%) showed dry flaky skin, diarrhoea
714 without blood was seen in 13 (3.1%) and lethargy in 7 (1.7%).166 Only five dogs showed
715 anorexia during the study, and two of those dogs experienced anorexia with the first
716 dose but not subsequent doses. Three dogs in this field study had a history of seizures.
717 One dog experienced a seizure on the same day after receiving first and second dosing
718 and a third seizure one week after the third dosing but completed the study. One other
719 dog with a history of seizures had one seizure 19 days after the third dose. The third dog
720 with a history of seizures, had no seizures during the study trial.166 The safety profile of
721 afoxolaner was further evaluated in two studies in 8-week-old Beagle dogs.163 In the first
722 study, 32 Beagle dogs were randomly assigned to receive 1x, 3x or 5x the maximum
723 exposure dose (6.3mg/kg). Treatments were administered at three one-month dose
724 intervals (Days 0, 28 and 56) followed by three fortnightly dose intervals (Days 84, 98
725 and 112). Physical examinations, and blood collections for clinical pathology analysis
726 and afoxolaner plasma concentrations, were performed throughout the study. No
727 afoxolaner related changes were observed in growth, physical variables, clinical
728 pathology variables, or tissues examined histologically. No clinically or statistically
729 significant health abnormalities related to the administration of afoxolaner were
730 observed. Vomiting and diarrhoea were observed sporadically across all groups
731 including the controls.163 In the second study, afoxolaner was combined with
732 milbemycin and the same protocol was repeated as performed in the first study. No
733 treatment-related changes were observed in any of the examinations described above.
734 Vomiting and diarrhoea were observed sporadically across all groups including the
735 control group.167 In the USA, afoxolaner is approved to be given to 8-week-old puppies.
736 The safety of afoxolaner in breeding, pregnant and lactating dogs has not been
737 evaluated.
738 Afoxolaner has been shown to be highly effective for treatment of demodicosis in
739 case reports168,169 and one controlled study.170 The controlled published report looked at
740 eight dogs diagnosed with generalized demodicosis and compared the efficacy with a
741 topical combination of imidacloprid/moxidectin. Afoxolaner was administered at the
742 recommended dose (at least 2.5 mg/kg) on Days 0, 14, 28 and 56 and the topical
743 combination of imidacloprid/moxidectin was given at the same intervals at the
744 recommended concentration. Clinical examinations and deep skin scrapings were
745 performed every month to evaluate the effect on mite numbers and the resolution of
746 clinical signs. The percentage reductions of mite counts were 99.2%, 99.9% and 100%
747 on Days 28, 56 and 84, respectively, in the afoxolaner-treated group, compared to
748 89.8%, 85.2% and 86.6% on Days 28, 56 and 84 in the imidacloprid/moxidectin-group.
749 Mite reductions were significantly higher on Days 28, 56 and 84 in the afoxolaner-
750 treated group compared to the imidacloprid/moxidectin treated group.170 In a large series
751 of clinical case evaluations at a referral dermatology practice 102 cases of generalized
752 demodicosis were treated with excellent results. Of the 102 cases, 68 were dogs with
753 adult onset demodicosis. The product was administered at 2.5 mg/kg per os, initially
754 used every two weeks in the first ten dogs. With the high degree of efficacy seen in
755 those dogs, the dosage was reduced to monthly in the remaining cases. Ninety percent
756 of the cases were negative after two months of treatment, the remaining dogs after three
757 months. The only dog needing every two week administration was a dog on
758 immunosuppressive therapy for pemphigus foliaceus, that became mite positive when
759 the interval was increased to four weeks, but remained mite negative when afoxolaner
760 was administered every two weeks.169
761
762 Sarolaner
763 Sarolaner (1-(5'-((5S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
764 dihydroisoxazol-3-yl)-3'-H-spiro(azetidine-3,1'-(2) benzofuran)-1-yl)-2-(methylsulfonyl)
765 ethanone) was discovered through a targeted synthesis and screening program and was
766 selected for development on the basis of structural uniqueness, potency, mammalian
767 safety, and pharmacokinetic suitability.171 This isoxazoline can be safely used for
768 puppies from 8 weeks of age.172 In an initial in-vivo study in dogs, sarolaner
769 demonstrated robust efficacy (≥99.8%) for 35 days against both fleas and adult ticks.172
770 Sarolaner chewable tablets are generally well tolerated with rare treatment-related
771 adverse reactions. The majority of observed adverse events are typical of those
772 commonly seen in the general dog population. In a 90-day study, vomiting was observed
773 in ten of 315 dogs (3.5%), and lethargy in eight dogs (2.5%).173 Sarolaner is currently
774 authorised as chewable tablet with indications for the treatment of fleas, ticks and ear
775 mites in dogs.
776 In a recent study, 16 dogs with generalised demodicosis were treated either with
777 monthly oral sarolaner or with a weekly spot-on containing imidacloprid and
778 moxidectin.174 The sarolaner-treated dogs and the dogs treated with the spot-on had a
779 reduction of over 99% and 96% in mite numbers after one month and negative
780 scrapings after one month and after 11 weeks respectively.174 In addition, the Demodex-
781 infested dogs showed a marked improvement in their clinical signs. There were no
782 treatment-related adverse events observed. The excellent response of the dogs in this
783 study receiving the weekly spot-on containing imidacloprid and moxidectin after one
784 month suggests that these dogs may not be comparable to the dogs presented with
785 generalised demodicosis in Europe or North America that were treated with this spot-on.
786
Consensus Statement 11: Although not many published studies have evaluated the
efficacy of isoxazolines for canine demodicosis in pet dogs, preliminary data is very
encouraging and makes this drug class a promising treatment option for dogs with
demodicosis.
787
788 Other drugs
789 Various other drugs have been used to treat generalized demodicosis. As
790 described above, an immune aberration seems to contribute to the development of
791 generalized demodicosis.175 Thus it seems logical, that immunomodulatory agents may
792 be beneficial for dogs with demodicosis and a number of those agents were evaluated in
793 several studies.
794 A mycobacterial cell wall component, muramyl dipeptide, was injected
795 subcutaneously at 0.2 mg/kg weekly in dogs with generalized demodicosis either as
796 monotherapy or in combination with amitraz at two different concentrations (0.025 and
797 0.05% twice weekly) and compared to therapy with amitraz alone at 0.025% twice
798 weekly.176 Remission was achieved in all dogs. The study numbers were very small (two
799 dogs per treatment group) and there was no follow-up period, thus it is difficult to
800 ascertain if the muramyl dipeptide was of any benefit. Muramyl dipeptide was also
801 shown in a separate study to increase the lymphocyte response to mitogens in 8 dogs
802 with demodicosis, without reaching the comparative values of healthy dogs.29 Adverse
803 effects were not mentioned.
804 Levamisole at a dose from 3 to 10 mg/kg given at different intervals was used in
805 two studies,175,177 which showed a positive effect on lymphocyte proliferation assays, but
806 did not improve efficacy based on clinical or parasitologic resolution of demodicosis.
807 In another study, 16 dogs with generalized demodicosis were treated either with
808 amitraz rinses at 0.0375% every five days alone or in combination with 2ml of
809 inactivated Parapox virus suis subcutaneously on day 0, 2 and 9.178 The dogs receiving
810 combination therapy achieved remission within 85 days compared to 104 days in the
811 control group (p<0.05), although a power analysis was not presented. To the authors’
812 knowledge, this is the first randomised trial showing a beneficial effect of an
813 immunostimulant as treatment for canine demodicosis.
814 Thirty-six dogs with generalized demodicosis were treated with 1000 mg of
815 vitamin E daily, weekly amitraz rinses at 0.05% or a combination of both therapies.179 All
816 dogs went into remission, the dogs on combination therapy had the shortest time until
817 remission (7.1 weeks vs. 7.3 weeks with amitraz only and 8.5 weeks with vitamin E only)
818 but a statistical evaluation was not performed. Compared to a control group, affected
819 dogs had lower serum vitamin E concentrations. However, it was not known if
820 inadequate dietary intake of vitamin E at the beginning of the study or the disease
821 caused this difference. When the mean serum vitamin E concentration was compared
822 among dogs with pyoderma, generalized demodicosis and normal dogs, no significant
823 differences were found between groups.180
824 Lufenuron is a chitin synthesis inhibitor. As chitin is found in the shells and
825 exoskeletons of all life stages of Demodex spp.181 it was proposed that this compound
826 might interrupt the life cycle of the Demodex mite. However, lufenuron at mean doses of
827 up to 15.8 mg/kg three times weekly for 2–3 months did not lead to improvement of
828 canine demodicosis.182
829 Three dogs with generalized demodicosis were sprayed weekly with a
830 deltamethrin spray at 0.005%. After 3 weekly applications there was no difference in
831 clinical signs or numbers of mites on skin scrapings.110 Deltamethrin at 12.5% was used
832 in another report and compared with an indigenous preparation containing extracts of
833 Mallotus phillipensis, Oleum pinus, Oleum terebinth and Sulphur sublimatum. Topicals
834 were applied twice daily until skin scrapings were negative, which took 7 days in the
835 group treated with the indigenous preparation and 11 days for deltamethrin.183 Dogs had
836 to be restrained for 1 h after the topical application to prevent excessive licking. Skin
837 scrapings were still negative in all dogs one month after cessation of therapy.
838 Homeopathic preparations containing Sulphur 200, Heparsulphuris 200 or
839 Psorinum 200 were given orally at 5 drops daily for 5 weeks to three groups of six
840 puppies experimentally infected with Demodex canis.184 The post-treatment mean
841 demodicosis indices were lower in the groups treated with Sulphur 200 and Psorinum
842 200 compared with the group treated with Heparsulphuris 200 and a control group, but
843 neither complete clinical nor microscopic resolution could be achieved. A herbal
844 preparation containing extracts of Cedrus deodara, Azadirecta indica and Embelia ribes
845 was sprayed on lesions of 14 dogs with apparent generalized demodicosis.185 Dogs
846 were reevaluated after 24 h and if skin scrapings were still positive for D. canis, dogs
847 were retreated once. Subsequent weekly skin scrapings for 6 weeks were negative in all
848 dogs.
849 Closantel ({N 9–5-chloro-4-(4-chlorophenyl cyanomethyl)-2-methylphenyl}-2-
850 hydroxyl 3,5 diiodobenzamide) is an anthelminthic of the salicylanilide family and was
851 used to treat nine dogs with generalized demodicosis at a dose of 5 mg/kg
852 subcutaneously for the first injection and 2.5 mg/kg for subsequent weekly injections.186
853 All dogs improved, but only six dogs went into microscopic remission after six injections.
854 A follow-up period was not specified.
855 Overall, for almost all of those drugs there is insufficient evidence to be
856 recommended as treatment of canine generalised demodicosis, either due to low
857 numbers of patients in the studies, unclear methods, insufficient efficacy, or prominent
858 adverse effects.45 There is some evidence for efficacy of inactivated Parapox virus suis
859 subcutaneously as a concurrent treatment to amitraz.178
860
861 Treatment of feline demodicosis
862 A number of drugs have been used to treat feline demodicosis, including
863 organophosphate baths,187-190 rotenone,187,191 lime sulfur dips,26,73,74,192,193 amitraz
864 rinses,73,194-196 ivermectin orally and by injection,73 selamectin,73 milbemycin oxime24 and
865 a moxidectin/imidacloprid spot-on.197
866 The two treatments most frequently reported as successful are lime sulphur dips
867 and amitraz rinses. Lime sulphur dips were used at 2% every 5-7 days73,74,192,193,196 and
868 were successful in 22/24 cats. Adverse effects were not seen. Amitraz rinses were
869 typically used at a concentration of 0.0125%73,196 to 0.025%194 up to 0.1%195 weekly and
870 12/14 cats responded to treatment. However, both treatments are not always tolerated
871 well by the affected cats. In a more recent case series, 8 of 13 cats in one household
872 showed pruritic skin disease and skin scrapings were positive for D. gatoi in two of those
873 cats. Weekly administration of a spot-on containing moxidectin/imidacloprid for 10
874 weeks was tolerated well and pruritus resolved in all cats following treatment.197 Thus, at
875 least for D. gatoi, this spot-on may be a more convenient efficacious therapy.
876
Consensus Statement 12: Demodicosis in cats may be treated with weekly lime sulphur
dips at a concentration of 2% or amitraz baths at a concentration of 0.0125%. An easier
alternative may be weekly administration of a spot-on containing moxidectin/imidacloprid.
877
878 Prognosis and future outlook
879 With the advent and widespread use of isoxazoline therapy for flea and tick
880 control, the future incidence of canine demodicosis could be impacted. How prominent
881 this effect will be, remains to be seen in the coming years. Fifteen breeding bitches with
882 a history of producing consistent litters of puppies which developed generalised
883 demodicosis were followed and showed marked reduction in the number of puppies
884 breaking with generalized demodicosis.198 In this trial, all bitches were treated with 25
885 mg/kg fluralaner 10 days prior to the scheduled mating and 3 months later with a second
886 dose. All 15 bitches included in the study gave birth to litters of healthy puppies and 14
887 of those 15 litters did not develop demodicosis in the first 12 months, two puppies of one
888 litter developed localised demodicosis only.198 The obtained result indicates a high
889 efficiency of fluralaner not only as a treatment but also as a preventive strategy in cases
890 of breed predisposed, generalized, juvenile onset canine demodicosis. Although these
891 results are impressive, isoxazoline therapy should not replace the need for withholding
892 affected and carrier dogs from breeding programs.
893 There is also concern about the possible impact of isoxazoline therapy on normal
894 canine cutaneous Demodex populations. Demodex mites are considered part of the
895 microbiota of most mammals, including dogs. Under normal circumstances, they appear
896 to live as commensals, feeding on their host’s sebum and are only opportunistically
897 pathogenic. Similar to bacterial flora found on the skin, follicular mites have been shown
898 to contain immune-reactive lipase,199 which can produce free fatty acids from sebum
899 triglycerides. Therefore, the mites could play a role in the defense of the skin against
900 pathogenic bacteria, particularly against Staphylococcus aureus and Streptococcus
901 pyogenes.200 The investigation of the normal cutaneous Demodex populations has
902 been, until recently, elusive due to the low number of individual mites present on healthy
903 dogs. The development of PCR techniques targeting Demodex-DNA in skin samples
904 has allowed advancement of the study of Demodex populations.201 A previous study
905 using a real-time PCR (RT-PCR) for D. canis detected Demodex-DNA in approximately
906 18% of healthy dogs after sampling hairs from two to five body sites.14 Direct
907 proportionality between the number of positive dogs and the number of sampled sites
908 and hairs was demonstrated clearly, as positive results increased to 100% when the
909 number of sampled sites increased to 20.14 A recent study investigated if healthy dogs
910 treated with the isoxazolines afoxolaner and fluralaner at the labelled dose for flea and
911 tick prevention would maintain a normal population of Demodex mites as part of their
912 cutaneous microbiota. The study demonstrated that after 30 and 90 days of treatment,
913 healthy dogs still had Demodex mites similar to the population of healthy dogs not
914 receiving these treatments.202 However, PCR will also detect antigen from dead mites,
915 the duration of the study was only three months and to the authors' knowledge the
916 maximum time to eliminate dead mites from the follicle is not known although the
917 interfollicular epidermal turnover is faster than three months. This data may thus suggest
918 that dogs on isoxazoline treatment may maintain Demodex populations as part of their
919 cutaneous microbiota, despite the apparent ability of these medications to resolve
920 clinical demodicosis. To date, no studies have been performed to detect Demodex DNA
921 post-treatment in dogs with demodicosis. Isoxazolines may not affect Demodex mites in
922 normal dogs to the same degree or may have no effect at all on normal mite populations
923 in unaffected dogs. More studies of longer duration are needed to characterise the
924 response of the Demodex populations in dogs with clinical disease to isoxazolines and
925 in comparison to other treatments for demodicosis.
926 Currently the isoxazoline derivatives have shown impressive results in controlling
927 demodicosis and are likely to be the mainstay therapy for many years to come. The
928 development of resistance is less likely to occur due to their selective inhibition of insect
929 and acarid GABACls and GluCls. This novel binding site is key to the innovative activity
930 profile, which bypasses the critical cross-resistance observed in other non-competitive
931 antagonists203 and will likely slow development of resistance to this class of molecules.
932 A combination product combining afoxolaner and milbemycin oxime has been released
933 in Europe for flea, tick, nematode infestation and heartworm prevention. 174 No studies
934 are reported to date regarding demodicosis treatment with this product. However, the
935 combined molecules of afoxolaner and milbemycin oxime could have additive effects, as
936 both have efficacy for Demodex mites as sole molecules. In view of these
937 developments, further derivatives and combinations are likely to be approved and more
938 treatment options will be likely be available in the future.
939
940
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1474

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Page 1 of 44 Guideline for Treatment of Canine Demodicosis

1 WAVD Clinical consensus guidelines for demodicosis

3 Ralf S. Mueller*, Wayne Rosenkrantz†, Emmanuel Bensignor‡, Joanna Karaś-Tęcza §,

32 Lotilaner®), and Zoetis (manufacturer of Mitaban®, Simparica® and Stronghold®).

122 an increase in markers for oxidative stress.44

139 Genetics of juvenile demodicosis

188 Clinical signs in dogs

207 significant interdigital inflammation, oedema and pain.

Consensus Statement 4: Demodicosis in dogs is characterised by follicular papules and

Consensus Statement 5: Deep skin scrapings (currently the diagnostic method of

Consensus Statement 6: Dogs with generalised demodicosis should not be bred.

Consensus Statement 7: Treatment for generalised demodicosis should be monitored

376 However, in a randomised controlled trial evaluating 58 dogs with generalised

641 channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid

1034 2017: 1-5.

1269 North America Small Animal Practice 2012; 42: 313-vii.

1410 177. Mojzisova J, Paulik S, Bajova V, et al. The immunomodulatory effect of

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