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DOI: 10.1111/j.1365-3164.2009.00790.x Treatment of canine generalized demodicosis with a ‘spot-on’ formulation containing 10% moxidectin and 2.5% imidacloprid (Advocate, Bayer Healthcare) Ralf S. Mueller*, Daniela Meyer*, Emmanuel Bensignor† and Carola Sauter-Louis‡ * Medizinische Kleintierklinik, Ludwig Maximilian University, Munich, Germany † Veterinary Referral Service, Paris, France ‡ Clinic for Ruminants, Ludwig Maximilian University, Munich, Sonnenstr. 16, 85764 Oberschleißheim, Germany Correspondence: Ralf S. Mueller, Medizinische Kleintierklinik, Ludwig Maximilian University, Munich, Germany. E-mail: ralf.mueller@ med.vetmed.uni-muenchen.de Source of Funding Bayer HealthCare. Conflict of Interest This study was designed by the authors and supported by Bayer HealthCare. Participating veterinarians received reimbursement only for costs of patient care; study dogs were treated at no cost to the owner. The authors have no financial interest in Bayer HealthCare. In the past 5 years, R. Mueller has been receiving support and ⁄ or funding for research studies and consulting activities from Bayer Animal Health, Boehringer Ingelheim, Novartis Animal Health, Pfizer Animal Health, Procter and Gamble Pet Care, Royal Canin and Virbac and E. Bensignor has been receiving support and ⁄ or funding for research studies and consulting activities from Bayer Animal Health, Janssen Animal Health, LDCA, Sogeval, Pfizer Animal Health, Vetoquinol and Virbac. D. Meyer served as Study Monitor and was supported by Bayer during the study. Abstract In this multicentre study, the efficacy of a spot-on formulation containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer HealthCare) was evaluated for the treatment of dogs with generalized demodicosis. The spot-on was applied every 2 weeks. Secondary bacterial infections were diagnosed by clinical examination, cytology and bacterial culture as appropriate and treated with oral antibiotics. Improvement or deterioration was determined monthly by clinical scores and by assessing mite numbers on microscopy of skin scrapings. Seventytwo dogs were included in the study. Fifty-two dogs had juvenile-onset demodicosis (mean of 11 months, range 2–24 months) and 20 dogs were adults at onset of disease (mean of 8.6 years, range 3.5–14 years). Twenty-six dogs went into remission, three with adult-onset demodicosis, 23 with juvenile-onset. The latter group showed significantly higher remission rates (P = 0.0252). Time until remission varied from 4 to 32 weeks (mean of 12.5 weeks). Dogs with a clinical score of <45 at the beginning of the study showed a significantly better response to the treatment (P = 0.0004), with a remission rate of 71%. In contrast, only 24% of those dogs with a score >45 went into remission. Adverse effects were not observed. One of the dogs responding to treatment showed recurrence of the disease during a follow-up period of 12 months. This study shows a better success rate of Advocate in dogs with mild clinical signs, versus those with moderate to severe clinical signs. Accepted 19 May 2009 Introduction Canine generalized demodicosis is a disease regularly seen in small animal practice. The localized form of the disease occurs most commonly in young dogs, is characterized by focal erythema and alopecia on face and distal limbs and is self-resolving in most dogs.1 The lesions of generalized canine demodicosis are variable and range from generalized erythema and alopecia, comedones, follicular papules to pustules and scales. More severely affected cases have deep folliculitis and furunculosis with severe haemorrhagic exudation and thick crusting.1,2 Lymphadenopathy is common. Secondary bacterial infection is invariably present in these dogs. Staphylococci are the most frequently involved bacteria, but Gram-negative organisms such as Pseudomonas aeruginosa or Proteus mirabilis also occur.3 Pain and pedal oedema may be present, particularly in large dogs. Successful treatment of generalized demodicosis has been reported in a number of publications and has been the topic of an extensive review.3 Amitraz rinses are approved for the treatment of generalized canine demodicosis in many countries in various concentrations. In general, higher concentrations are associated with better success rates but also more pronounced adverse effects.4,5 Injectable formulations of ivermectin and moxidectin approved for large animals have been used daily as an oral treatment of canine generalized demodicosis with good success, but are not licensed for the use in small animals at doses effective against Demodex mites.3,6,7 In sensitive dogs, these treatments will lead to neurological adverse effects such as tremors, lethargy, ataxia, and coma with a possible fatal outcome.8,9 Milbemycin oxime is licensed for use in France and Sweden for the treatment of canine generalized demodicosis but the dosage needed (1–2 mg ⁄ kg ⁄ day for up to 12 months) in large dogs is expensive. Recently a spot-on formulation containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer) has been approved ª 2009 The Authors. Journal compilation ª 2009 ESVD and ACVD, Veterinary Dermatology, 20, 441–446. 441 Mueller et al. for the control of canine demodicosis in all European Union countries with a dose of 2.5–6 mg ⁄ kg moxidectin monthly. The aim of this multicentre study was to evaluate the success rate of this spot-on in the treatment of canine generalized demodicosis. Materials and methods Study participants This study was an uncontrolled field study involving cases referred to dermatology specialist practices in Belgium, France, Italy, Germany, Switzerland and Canada. Inclusion criteria Owners with dogs of any breed, body weight and either sex demonstrating microscopic and clinical evidence of generalized demodicosis (according to the judgement of the board certified dermatologists examining the dogs) were invited to participate. Owners provided written informed consent. The study compound was a registered treatment for canine demodicosis at the time of this study. Diagnosis was confirmed with three positive deep skin scrapings from the sites worst affected by papules, pustules or crusts showing in total at least three Demodex canis mites. If no papules, pustules or crusts were present, the areas with the worst erythema or alopecia were scraped. Generalized demodicosis was defined as affecting more than four small areas (<100 cm2) on the body, affecting at least one area of more than 100 cm2 or at least one paw. Exclusion criteria Puppies less than 7 weeks old, dogs weighing less than 1 kg, pregnant or lactating females and dogs with leishmaniosis were excluded from the study. Glucocorticoids were discontinued immediately at the beginning of the study, if the dog had received a short course of prednisolone at anti-inflammatory doses (<0.5 mg ⁄ kg ⁄ day for less than 4 weeks) in the month prior to the study. If higher doses or longer courses had been administered, corticosteroids were discontinued 4 weeks prior to inclusion in the study. Immunosuppressive drugs and additional ectoparasiticidal drugs were not permitted during the study. Antipruritic drugs such as fatty acid therapy and antihistamines were only permitted if they had been administered for at least 2 weeks prior to the trial, and were continued at the same dose and frequency for the duration of the trial. Topical glucocorticoids were not permitted. Drugs with no known ectoparasitic or immunosuppressive activity (such as medications for cardiac diseases, neurologic disorders, i.e. epilepsy, or anti-diabetic medications) were permitted. Post-inclusion removal criteria Dogs deteriorating on treatment were removed from the study. These dogs were assessed as treatment failures. Similarly, dogs not improving on treatment administered every 2 weeks for two subsequent visits were excluded from the study and considered treatment failures. Further reasons for exclusion during the study were serious deviations from the protocol, loss of follow-up or euthanasia. If these occurred before the second evaluation and the dogs had thus received only one treatment, their data were excluded from the statistical evaluation. Dogs were considered treatment failures if euthanasia or loss of follow-up occurred after two or more complete data sets were obtained. Study intervention The dogs were treated with a spot-on preparation containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer HealthCare, Leverkusen, Germany) administered on the dorsal trunk onto the skin in the shoulder region after parting of the hair. The dose of each individual treatment depended on body weight and is detailed in Table 1. In dogs heavier then 25 kg it was recommended to apply the spot-on in several locations along the dorsal midline of the dog. 442 Table 1. Dosing of Advocate (10% imidacloprid and 2.5% moxidectin) administered during the study Weight of the dog (kg) Advocate (mL) Imidacloprid (mg) Moxidectin (mg) 1–4 4 – 10 10 – 25 25 – 40 40 – 65 0.4 1.0 2.5 4.0 6.5 40 100 250 400 650 10 25 62.5 100 162.5 Study protocol Clinicians evaluated the cases every 4 weeks. On each visit, cytology and at least three deep skin scrapings were performed. A small area of approximately one square centimetre was scraped until capillary bleeding was present; where possible the skin was squeezed during the scraping. The skin scraping sites were noted and were taken from the same location on revisits. The average mite number of the three skin scrapings was recorded at each visit. Erythema, comedones ⁄ papules ⁄ pustules, and scales ⁄ crusts were evaluated on 36 different body sites and graded between 0 (normal) and 6 (severe). A clinical score for that day was achieved by adding the individual scores. In animals with adult-onset generalized demodicosis, diagnostic evaluation for underlying diseases was recommended. A panel consisting of a general blood screen, urinalysis, radiographs of the thorax and abdominal ultrasonography at the initial visit and a urine cortisol– creatinine ratio and T4 ⁄ TSH assay at the first or second revisit as appropriate was recommended as part of the protocol. The initial stage of the protocol called for monthly treatments. If there was a clinical or microscopic deterioration at the next visit or no improvement (either clinical or microscopic) on two consecutive visits, the frequency of administration was increased to every 2 weeks. If again there was deterioration (or lack of improvement in clinical scores and ⁄ or the number of mites on skin scrapings at two subsequent visits), the dog was classified as a treatment failure. Because of insufficient success rates with monthly administration, for ethical reasons the protocol was adjusted after inclusion of the first 19 dogs and application of Advocate every 2 weeks was permitted at the first visit. When negative skin scrapings and clinical remission on two consecutive monthly visits were obtained, the therapy was regarded as successful and treatment was discontinued. If, after a follow-up period of 12 months, a dog was still in remission, it was considered cured. Appropriate antibacterial therapy was based on cytologic examination. If rod-shaped organisms were identified, a bacterial culture was obtained and antibiotic therapy was then chosen based on that susceptibility testing. If cocci were observed, therapy with cefalexin at 20–30 mg ⁄ kg twice daily was begun. Failure to respond to this antibiotic therapy resulted in a bacterial culture and a subsequent change of antibiotic therapy based on susceptibility testing. If an anti-bacterial shampoo was used, shampooing was not permitted during the first 48 h after application of the spot-on. Statistics The proportion of cured cases was determined for juvenile and adultonset demodicosis and compared by using Fisher’s exact test. Dogs were divided into two groups depending on their clinical score and the best cut-point was chosen using receiver operating characteristic (ROC) curve analysis. The proportions of cured cases in the group of dogs with milder disease and of cured cases in the more severely affected group were compared by using Fisher’s exact test. The mean number of mites per skin scraping and the clinical score were determined for dogs responding to therapy and for treatment failures and the two groups were compared by use of a Mann–Whitney U-test. The dose of moxidectin per month in dogs responding to therapy was compared to that of the dogs failing to respond, also using a Mann–Whitney test. P < 0.05 was considered significant. A logistic ª 2009 The Authors. Journal compilation ª 2009 ESVD and ACVD, Veterinary Dermatology, 20, 441–446. Moxidectin spot-on for canine demodicosis regression analysis was used to evaluate the correlation between the number of mites and the outcome being a failure. Results Study participants Seventy-two dogs were enrolled in the study. Fifty-two dogs had juvenile-onset demodicosis with a mean age of onset of 11 months (range 2–24 months) and 20 dogs were adults at onset of disease (mean of 8.6 years, range 3.5–14 years). Twelve dogs were pugs, seven were English bulldogs, five were West Highland white terriers, three were French bulldogs, doberman pinschers, dogues de Bourdeaux, Jack Russell terriers and Yorkshire terriers, respectively, and two were shi tzus, German shepherd dogs, Chihuahuas and shar peis. Of the remaining 25 dogs, the disease was diagnosed in 10 mixed breeds and only once in dogs of 15 further breeds. Of the dogs with adult-onset demodicosis, five were West Highland white terriers, all other breeds occurred only once. Thirty-nine dogs were females of which 6 were spayed; there were 33 males and 2 of those were castrated. The mean clinical score of the included cases was 99 (range 9–518) and the mean number of mites per skin scraping was 27 (range 1–149). Exclusions Sixty-three dogs completed the study. Six dogs were lost to follow-up and three died or were euthanized. Of these nine dogs, six only received one treatment and thus were excluded from the statistical evaluation, including the three dead dogs. Thus, 66 dogs were evaluated. Of the three diseased dogs, a young pug was euthanized by the referring veterinarian after 1 month of treatment due to prominent lymphadenopathy and suspected lymphoma, although a prior lymph node aspirate at the referral centre had revealed reactive lymph nodes and no further tests were conducted. An adult pug was euthanized 2 weeks after the second monthly treatment due to lethargy and lack of improvement. A Boston terrier died after a few days of lethargy 4 weeks after the first and only treatment; the owner refused a necropsy. Treatment outcome Twenty-six dogs (39.4%) went into remission, three with adult-onset demodicosis, 23 with juvenile-onset. The latter showed significantly higher remission rates (Fisher’s exact test, P = 0.0252). Time until remission varied from 4 to 32 weeks (mean of 12.5 weeks). In a Labrador retriever with lymphoma, Demodex canis mites could always be found on microscopy of skin scrapings, but clinical signs could be controlled with treatment. The mean score of dogs included in the study was 123. The cut-point for dividing clinically more and less severe disease was a clinical score of 45. Dogs with a clinical score of <45 at the beginning of the study showed a significantly better response to the treatment (Fisher’s exact test, P = 0.0004), with a remission rate of 71% (15 ⁄ 21). In contrast, only 24% of those dogs (11 ⁄ 45) with a score >45 went into remission. The mean score of dogs responding to therapy was 74 [95% confidence interval (CI) 44–105], that of dogs failing to improve was 153 (95% CI 114–192); this difference was significant (Mann–Whitney test, P = 0.0004). The mean numbers of mites found per skin scraping on the first visit in dogs achieving remission with treatment was 20 (95% CI 14–26). The mean number of mites in dogs considered as treatment failures was 30 (95% CI 22–38). This difference was also significant (Mann–Whitney test, P = 0.0082). The number of mites was significantly correlated with the outcome being a failure (logistic regression analysis, P = 0.0094). The odds ratio for the factor mites was 1.056. A number of different logistic regression methods were performed to check the interaction between age and score (categorical as well as numerical). There was no interaction between the two variables. The average dose of moxidectin in dogs responding to therapy was 6.1 mg ⁄ kg ⁄ month and almost identical to the 6.7 mg ⁄ kg ⁄ month of the dogs failing to respond (Mann–Whitney test, P = 0.325). Adverse effects were not seen. One of the dogs responding to treatment showed recurrence of the disease during a follow-up period of 12 months. In seven of the dogs with adult-onset demodicosis, a diagnostic evaluation for underlying disease was refused. Of the remaining 13 dogs, one dog had cardiac and renal insufficiency, another dog had only cardiac insufficiency, one was hypothyroid, one had hyperadrenocorticism, one dog had lymphoma and one had testicular tumour. In seven dogs, an underlying disease could not be identified. Of the five West Highland white terriers with adult-onset demodicosis, one was hypothyroid, in two dogs evaluation failed to detect an underlying disease, in a further dog more diagnostic tests were refused by the owner and the last of these dogs was lost to follow-up. All dogs with an identified underlying disease failed to achieve remission, and only the hypothyroid dog was treated adequately for the underlying disease and later on responded to alternative treatment. Discussion In this study, the efficacy of a spot-on formulation containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer HealthCare) for the treatment of generalized canine demodicosis had a better success rate in dogs with less severe disease (as assessed by clinical scores). However, in dogs with more severe disease, the spot-on did not achieve the success rates reported in the literature for other therapies.3 In dogs with adult-onset demodicosis, the remission rate was lower than in juvenile demodectic dogs. In the literature, it is occasionally stated that some dogs with generalized onset of juvenile demodicosis recover spontaneously.1 To the authors’ knowledge, there is no scientific data available confirming such statements. As most dogs presented in referral practice have quite extensive disease, it would be unethical to include a control group treated with placebo. Furthermore, it would be difficult to convince owners to participate in such a study. Presumably for these two reasons, a placebo control had ª 2009 The Authors. Journal compilation ª 2009 ESVD and ACVD, Veterinary Dermatology, 20, 441–446. 443 Mueller et al. not be included in previous studies on this disease.3 It is possible that similar to previous studies some juvenile dogs included would have recovered without miticidal therapy. Most previous reports regarding the treatment of generalized demodicosis evaluate amitraz rinses4,10,11 and daily oral administration of macrocyclic lactones such as ivermectin,6,12–14 milbemycin oxime15–17 and moxidectin.7,18 Amitraz rinses are laborious, require total body clipping in dogs with medium or longer coat, and have been associated with a number of adverse effects in the treated case. It is recommended to perform the rinses in well-ventilated areas to prevent inhalation of active ingredients by the personal and subsequent adverse effects such as headaches.3 Injectable formulations of ivermectin and moxidectin approved for large animals given orally daily have been reported as successful treatments for canine generalized demodicosis.7,18 However, such a use of these drugs is not covered by registration and dogs sensitive to macrocyclic lactones may develop neurological adverse effects such as lethargy, ataxia, tremors and potentially fatal coma.8,9 Milbemycin oxime is registered in some countries as an oral daily treatment for canine demodicosis,19 but is costly and difficult to obtain in many others. Thus, an effective and safe spot-on treatment for canine demodicosis is of great benefit to the small animal practitioner. Monthly administration of a spot-on containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer HealthCare) was recently reported to be as efficacious as milbemycin oxime in the treatment of canine generalized demodicosis20 and is registered for the control of this disease in Europe. The success rate in that study was over 80%, which compares favourably with most studies published previously.3 After registration, this current study was initiated by Bayer to confirm this efficacy in a larger, multicentre study involving veterinary dermatologists in five European countries. However, administration every 2 weeks is an off-label use for this product. The percentage of dogs achieving remission in our study was much smaller. There are a number of possible reasons for this discrepancy. The population of this current study consisted of dogs referred to veterinary dermatologists, and thus more dogs with severe skin disease may have been included. Unfortunately, a different body score was used in the two studies, making comparison of disease severity difficult. However, the better success rate of dogs with a lower clinical score compared to dogs with more severe clinical disease supports this. The number of mites per skin scraping was not specifically evaluated in the former study. Higher mite numbers were seen in our study in the dogs not responding to treatment. Furthermore, with amitraz and milbemycin oxime it is known that the success rate in dogs with adult-onset demodicosis is lower than that in juvenile dogs affected with demodicosis.3,19 In our study, the dogs with adultonset demodicosis did not respond as well as juvenile dogs, providing further evidence for the difficulty to cure adult dogs developing generalized demodicosis. Although the age range of included dogs was given in another study evaluating topical imidacloprid ⁄ moxidectin and indicates participants with adult-onset demodicosis, it is not known, how many of the participants were adult dogs.20 444 Although there was a significant difference between the mean clinical scores of responders and treatment failures, some of the dogs cured by the moxidectin ⁄ imidacloprid spot-on had clinical scores above 200, indicating that other factors besides disease severity influence treatment outcome. Similarly, a number of dogs responding to treatment had very high mite numbers despite the difference in mean mite numbers on skin scrapings between successfully treated dogs and treatment failures. For the evaluation of treatments for canine generalized demodicosis, a follow-up period of 12 months is typically recommended to identify the recurrence rate. In studies evaluating amitraz therapy for generalized demodicosis and providing data on follow-up, the overall recurrence of dogs responding to treatment was 11%.3 With milbemycin oxime, the recurrence rate was over 20%, and the recurrence rate seen with ivermectin was between those of the latter two drugs.3 Only one of the dogs in our study showed recurrence of demodicosis within 12 months after cessation of therapy, indicating that a high rate of recurrence is not likely with this therapy. In previous studies evaluating daily moxidectin orally, the success rate has been comparable to that seen with ivermectin or amitraz.3 The oral bioavailability of moxidectin in the dog compared with other species has been reported as very high.21 It has a half life of approximately 2 days in the dog.22,23 Thus, daily administration will increase serum concentrations for quite some time and those high serum concentrations may be responsible for its excellent therapeutic effects observed in canine generalized demodicosis.7,18 However, oral moxidectin is not approved for the treatment of demodicosis and adverse effects such as lethargy and ataxia have been reported.7 The therapeutic acaricidal effects of moxidectin in the spot-on combination with imidacloprid used in this study resulted in lower treatment success than that reported for oral administration. This may be due to less frequent administration and lower systemic absorption and subsequent serum concentration compared to oral administration. Moxidectin serum and skin concentrations have been shown to increase proportional to frequency of application of the imidacloprid ⁄ moxidectin spot-on (Bayer HealthCare, data on file). Possibly, more frequent application of the spot-on results in increased success rates. Supporting this, the initial protocol of monthly administration, that was only to be changed to administration every 2 weeks in dogs not responding to treatment, had to be abandoned in favour of treatments every other week from the start due to ethical concerns following the low response rate of the first dogs included in the study. Further study is under progress to determine, if weekly administration would further increase the success rate for canine generalized demodicosis. Although breed predispositions could not be evaluated statistically due to the involvement of a number of centres, the frequent occurrence of demodicosis in bulldogs, terriers and doberman pinschers confirms previous reports in the literature.1 Pugs were the most common breed in this study and may be predisposed in Europe. All five West Highland white terriers included in the study developed demodicosis as adult dogs. All other breeds in ª 2009 The Authors. Journal compilation ª 2009 ESVD and ACVD, Veterinary Dermatology, 20, 441–446. Moxidectin spot-on for canine demodicosis the group of adult dogs were represented only once. Thus, West Highland white terriers may be predisposed to adult onset demodicosis. In summary, a satisfactory outcome was achieved in the majority of dogs with mild to moderate generalized demodicosis when treated with a spot-on containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer). Dogs with severe clinical disease did not respond as well and may require additional therapy or a change of treatment. Acknowledgements The authors would like to thank participating investigators for their contribution of cases to this study: Luc Beco (Spa, Belgium); Emmanuel Bensignor (Cesson Sevigne, France); Patrick Bourdeau (Nantes, France); Eric Guaguere (Lomme, France); Monika Linek (Hamburg, Germany); Christine Löwenstein (Hofheim, Germany); Ralf Mueller (Munich, Germany); Daniela Meyer (Munich, Germany, Study Coordinator); Chiara Noli (Peveragno, Italy); Manon Paradis (Montréal, Canada); Pascal Prélaud (Maisons Alfort, France); Petra Roosje (Bern, Switzerland). References 1. Scott DW, Miller WH, Griffin CE. Small Animal Dermatology, 6th edn. Philadelphia, W. B. Saunders, 2001: 457–74. 2. Mueller RS. Dermatology for the Small Animal Practitioner. Jackson, Teton New Media, 2000: 58–68. 3. Mueller RS. Treatment protocols for demodicosis: an evidencebased review. Veterinary Dermatology 2004; 15: 75–89. 4. 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. Veterinary Dermatology 2001; 12: 89–92. 5. Kwochka KW, Kunkle GA, Foil CA. The efficacy of amitraz for generalized demodicosis in dogs: a study of two concentrations and frequencies of application. Compendium on Continuing Education for the Practicing Veterinarian 1985; 7: 8–17. 6. Mueller RS, Hastie K, Bettenay SV. Daily oral ivermectin for the treatment of generalised demodicosis in 23 dogs. Australian Veterinary Practitioner 1999; 29: 132–6. 7. Wagner R, Wendlberger U. Field efficacy of moxidectin in dogs and rabbits naturally infested with Sarcoptes spp., Demodex spp. and Psoroptes spp. mites. Veterinary Parasitology 2000; 93: 149–58. 8. Mueller RS, Bettenay SV. A proposed new therapeutic protocol for the treatment of canine mange with ivermectin. Journal of the American Animal Hospital Association 1999; 35: 77–80. 9. Paul AJ, Tranquilli WJ, Seward RL et al. Clinical observations in collies given ivermectin orally. American Journal of Veterinary Research 1987; 48: 684–5. 10. Medleau L, Willemse T. Efficacy of daily amitraz therapy for refractory, generalized demodicosis in dogs: two independent studies. Journal of the American Animal Hospital Association 1995; 31: 246–9. 11. Muller GH. Amitraz treatment of demodicosis. Journal of the American Animal Hospital Association 1983; 19: 435–41. 12. Fondati A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs. Veterinary Dermatology 1996; 7: 99–104. 13. Medleau L, Ristic Z, McElveen DR. Daily ivermectin for treatment of generalized demodicosis in dogs. Veterinary Dermatology 1996; 7: 209–12. 14. Paradis M, Laperriere E. Efficacy of daily ivermectin treatment in a dog with amitraz-resistant, generalized demodicosis. Veterinary Dermatology 1992; 3: 85–8. 15. Garfield RA, Reedy LM. The use of oral milbemycin oxime (Interceptor) in the treatment of chronic generalized canine demodicosis. Veterinary Dermatology 1992; 3: 231–5. 16. Miller WH, Scott DW, Cayatte SM et al. Clinical efficacy of increased dosages of milbemycin oxime for treatment of generalized demodicosis in adult dogs. Journal of the American Veterinary Medical Association 1995; 207: 1581–4. 17. Mueller RS, Bettenay SV. Milbemycin oxime in the treatment of canine demodicosis. Australian Veterinary Practitioner 1995; 25: 122–6. 18. 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: 554–5. 19. Holm B. Efficacy of milbemycin oxime in the treatment of canine generalized demodicosis: a retrospective study of 99 dogs (1995–2000). Veterinary Dermatology 2004; 15: 369–76. 20. 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. Parasitology Research 2005; 97(Suppl 1): 89– 96. 21. Lallemand E, Lespine A, Alvinerie M et al. Estimation of absolute oral bioavailability of moxidectin in dogs using a semi-simultaneous method: influence of lipid co-administration. Journal of Veterinary Pharmacology and Therapeutics 2007; 30: 375–80. 22. Al-Azzam SI, Fleckenstein L, Cheng KJ et al. Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogs. Biopharmaceutics & Drug Disposition 2007; 28: 431–8. 23. Vanapalli SR, Hung YP, Fleckenstein L et al. Pharmacokinetics and dose proportionality of oral moxidectin in beagle dogs. Biopharmaceutics & Drug Disposition 2002; 23: 263–72. Résumé Dans cette étude multicentrique, l’efficacité d’un spot-on contenant 10% d’imidaclopride et 2.5% de moxidectine (Advocate, Bayer HealthCare) a été évaluée dans le traitement de démodécie canine généralisée. Le spot-on était appliqué toutes les deux semaines. Les infections bactériennes secondaires ont été diagnostiquées par des examens clinique, cytologique et bactériologique adaptés et traitées par une antibiothérapie orale. L’évolution était déterminée chaque mois en fonction des scores cliniques et du nombre d’acariens identifiés à l’examen microscopique de produits de raclages cutanés. Soixantedouze chiens ont été inclus dans l’étude. Cinquante deux chiens étaient atteints de démodécie juvénile (moyenne de 11 mois, amplitude de 2 à 24 mois). Vingt chiens étaient adultes au commencement de la maladie (moyenne de 8.6 ans, amplitude de 3.5 à 14 ans). Vingt-six chiens sont entrés en rémission, 3 présentant une démodécie de l’adulte et 23, une démodécie juvénile. Ce dernier groupe a montré des taux de rémission significativement plus élevés (P=0.0252). La rémission intervenait à partir de 4 à 12 semaines (moyenne de 12.5 semaines). Les chiens avec un score clinique <45 au début de l’étude ont montré une réponse au traitement significativement plus élevée (P=0.0004), avec un taux de rémission de 71%. En ª 2009 The Authors. Journal compilation ª 2009 ESVD and ACVD, Veterinary Dermatology, 20, 441–446. 445 Mueller et al. revanche, seuls 24% des chiens ayant un score clinique > 45 se sont améliorés. Aucun effet secondaire n’a été observé. Un des chiens répondant au traitement a montré une récidive au cours de la période de suivi de 12 mois. Cette étude montre qu’ Advocate a un taux de succès plus élevé chez les chiens présentant des signes cliniques faibles contrairement à ceux présentant des signes cliniques modérés à sévères. Resumen En este estudio multicéntrico se evaluó la eficacia de una formulación tópica conteniendo 10% de imidacloprid y 2,5% de moxidectina (Advocate, Bayer Healthcare) en el tratamiento de perros con demodicosis generalizada. El producto de aplicación única fue administrado cada dos semanas. Se diagnosticaron las infecciones bacterianas mediante examen clı́nico, citologı́a y cultivo bacteriano, según fue necesario, y se trataron con antibióticos por vı́a oral. Se determinó mensualmente la mejora o el deterioro mediante valoración clı́nica y evaluando el numero de ácaros mediante microscopı́a de raspados de piel. Setenta y dos perros se incluyeron en el estudio. Cincuenta y dos perros tenı́an demodicosis juvenil (media de 11 meses, rango de 2-24 meses) y veinte perros eran adultos en el momento de aparición de la enfermedad (media 8,6 años, rango 3,5-14 años). Veintiséis perros entraron en remisión, tres con demodicosis de aparición en adultos, 23 con demodicosis juvenil. Este último grupo mostró grados de remisión significativamente mayores (P=0,0252). El tiempo pasado hasta la remisión varió de 4 a 32 semanas (media 12,5 semanas). Los perros con una valoración clı́nica > 45 al principio del estudio mostraron una respuesta significativamente mayor al tratamiento (P=0,0004), con un ı́ndice de remisión del 71%. Por el contrario, sólo 24% de los perros con una valoración clı́nica inicial >45 entraron en remisión. No se observaron efectos adversos. Uno de los perros que respondió al tratamiento presentó recidiva de la enfermedad durante el periodo de seguimiento de 12 meses. Este estudio muestra una mayor eficacia de Advocate en perros con signos clı́nicos ligeros, en contraste con los animales con signos clı́nicos moderados o severos. Zusammenfassung In dieser Multi-Center-Studie wurde die Wirksamkeit einer Spot-on Formulierung, welche 10%iges Imidacloprid und 2,5%iges Moxidectin enthielt (Advocate, Bayer HealthCare) für die Behandlung der generalisierten Demodikose des Hundes beurteilt. Das Spot-on wurde alle zwei Wochen aufgetragen. Sekundäre bakterielle Infektionen wurden mittels klinischer Untersuchung, Zytologie und falls nötig mittels Bakterienkultur diagnostiziert und mit oralen Antibiotika behandelt. Eine Verbesserung oder Verschlechterung wurde mittels klinischer Werteskala und durch Schätzung der Milbenzahlen in den mikroskopischen Präparaten der Hautgeschabsel monatlich erhoben. Zweiundsiebzig Hunde wurden in die Studie aufgenommen. Zweiundfünfzig Hunde hatten eine juvenile Demodikose (Durchschnittsalter von 11 Monaten, bei einer Breite von 2-24 Monaten) und 20 Hunde waren erwachsen, als die Krankheit auftrat (Durchschnittsalter von 8,6 Jahren, bei einer Breite von 3,5-14 Jahren). Sechsundzwanzig Hunde wurden gesund, 3 davon mit Adulter Demodikose, 23 mit Juveniler Demodikose. Die letztere Gruppe zeigte signifikant höhere Remissionsraten (P=0,0252). Die Zeit bis zur Remission variierte von 4 bis 32 Wochen (durchschnittlich 12,5 Wochen). Hunde mit einer klinischen Bewertung von <45 am Anfang der Studie zeigten eine signifikant bessere Reaktion auf die Behandlung (P=0,0004) mit einer Remissionsrate von 71%. Im Gegensatz dazu gingen nur 24% der Hunde mit einer Bewertung von > 45 in Remission. Nebenwirkungen wurden nicht beobachtet. Einer der Hunde, der auf die Behandlung ansprach, zeigte während einer Folgeperiode von 12 Monaten ein Wiederaufflammen der Krankheit. Diese Studie zeigte eine bessere Erfolgsrate für Advocate bei Hunden mit milden klinischen Symptomen im Gegensatz zu denen mit moderat bis schwerer klinischer Symptomatik. 446 ª 2009 The Authors. Journal compilation ª 2009 ESVD and ACVD, Veterinary Dermatology, 20, 441–446.