Evidence-based veterinary dermatology: a systematic review of interventions for malassezia dermatitis in dogs

Evidence-based veterinary dermatology: a systematic
review of interventions for Malassezia dermatitis in dogs
Amélie Negre*, Emmanuel Bensignor† and
Jacques Guillot‡
*Veterinary Clinic, 7 rue de l’Hôtel de Ville, le Châtelet-en-Brie, France†Veterinary Dermatology Referral Service, Veterinary Clinic, Paris and Cesson-Sévigné, Veterinary Hospital, Nantes, France Introduction
‡Department of Parasitology and Mycology, UMR INRA, AFSSA, ENVA BIPAR, Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France The lipophilic yeast Malassezia pachydermatis is part of Correspondence: Jacques Guillot, ENVA, 94704 Maisons-Alfort, the normal cutaneous microflora of many warm-blooded vertebrates. It is commonly found on healthy dogs in the Sources of Funding
ear canals, on the lips, axillae folds, interdigital spaces, This study is self-funded.
Conflict of Interest
anal sacs, rectum and less commonly in the nose and vagina.1–4 This yeast may become a pathogen wheneveralterations in the skin surface microclimate or host defenceoccur, and it is now widely accepted that Malassezia Abstract
dermatitis is a common skin disease of dogs. The change The aim of this systematic review was to evaluate the
in opinion in the importance of this disease in veterinary efficacy of antifungal treatments for Malassezia
dermatology is illustrated by the number of articles on dermatitis in dogs and, when possible, to propose
Malassezia dermatitis in the literature since the first recommendation for or against their use.
description by Dufait in 1983.5 Cases of zoonosis caused Electronic searches were carried out using PubMed
by M. pachydermatis have also been suspected.6,7 Malassezia MEDLINE®, CABDirect and CONSULTANT database.
dermatitis can occur in dogs of any sex, age and breed The volumes of Advances in Veterinary Dermatology,
with some breeds appearing to be predisposed, for example the proceedings of ESVD/ECVD and AAVD/ACVD con-
West Highland white terriers, Basset hounds, poodles, gresses were hand-searched for studies relevant to
Australian silky terriers and American cocker spaniels.1,5,8–10 this review. All articles and book chapters discussing
Malassezia dermatitis in dogs may be localized or generalized.
treatment of Malassezia dermatitis were scanned for
Skin lesions usually occur on the face (ear canal, perioral additional citations. Lastly, a request was sent to the
and periocular skin, ventral neck) or in cutaneous folds Vetderm Listserv to share recent clinical trials. The
(axillae, groin, interdigital skin and claw folds). Clinical analysis evaluated study design, methodology
signs are variable: erythema, mild to severe pruritus, alopecia, quality, subject enrolment quality, type of interventions
greasy exudation and scaling are generally observed.
and outcome measures.
Secondary lesions include excoriations, lichenification, The searches identified 35 articles, and 14 trials that
hyperpigmentation and exudation. In generalized cases, fulfilled the following selection criteria: (i) in vivo clin-
an offensive and rancid odour is commonly reported. A ical trials, (ii) dogs showing clinical lesions of Malas-
reddish-brown staining of the claws is visible in case of sezia dermatitis and (iii) enrolment of at least five
Malassezia paronychia. Finally, otitis externa has also been dogs. Among these, only eight studies fulfilled the fol-
associated with the presence of these yeasts.1,11–14 lowing additional criterion: (iv) prospective in vivo
The role of M. pachydermatis, as a pathogen, has been clinical trials reporting clinical and mycological out-
debated for a long time. Dufait, and then Mason, first come measures. A total number of 14 different treat-
established the yeast as a disease-causing agent.5,15 The ment protocols included four blinded, randomized and
proliferation of yeasts is suspected to be promoted by controlled trials (quality of evidence grade A), four
excessive sebum production or disruption of the epidermal controlled studies lacking blinding and/or randomiza-
barrier such as may be occurring in hypersensitivity diseases tion (grade B), five open uncontrolled trials (grade C)
(atopy, adverse cutaneous food reactions, flea bite hyper- and one descriptive study (grade D).
sensitivity and contact allergy), cornification disorders, This systematic review allowed us to recommend,
ectoparasite infection, bacterial pyoderma and endocrine with good evidence, the use of only one topical treatment
diseases (hyperadrenocorticism, hypothyroidism, diabetes of Malassezia dermatitis (2% miconazole nitrate +2%
mellitus).9 Long-term glucocorticoids may also increase chlorhexidine, twice a week for 3 weeks) and with fair
Malassezia populations,1,16 whereas all authors do not consider evidence the use of two systemic treatments with
antibiotic administration as a predisposing factor.10,17 azole derivatives (ketoconazole, 10 mg kg–1 day–1 and
Diagnostic criteria for Malassezia dermatitis in dogs are itraconazole, 5 mg kg–1 day–1 for 3 weeks).
still not clearly defined. It has been proposed that the 2008 The Authors. Journal compilation 2008 ESVD and ACVD. 20; 1–12
Negre et al.
diagnosis can be established when a dog with an abnormal ject enrolment quality, type of interventions and outcome measures.
high population of M. pachydermatis on lesional skin Data were presented in tables and compared. When differences shows a good clinical and cytological response to between assessments of authors were noted, they were discussedand reconciled.
appropriate antifungal therapy.18 The diagnosis is obtainedby the direct observation of the yeasts, by cytological,cultural and histopathological techniques. Unfortunately, at this time, there are no clear guidelines on what constitutes Assessment of methodological quality. To determine the risk forbiased estimates of treatment success, three parameters were evalu- a high population of yeasts. Moreover, a diagnosis based ated: randomization, masking of clinicians and/or owners and intention- on the assessment of yeast numbers does not take into to-treat (ITT) analyses. Based on previous systematic reviews,20–22 account that some yeasts could possess unusually potent these parameters were graded as adequate, unclear or inadequate.
virulence factors, or the hosts could be unusually sensitive Finally, an overall grade of evidence quality, defined by the same to this organism (e.g. Malassezia hypersensitivity). In both authors, was assigned to each study as follows: (i) blinded rand- of these cases, signs of Malassezia dermatitis would likely omized controlled trial (control with either active drug or placebo); (ii) develop in the presence of low numbers of organisms.
controlled trial lacking either blinding or randomization; (iii) open,uncontrolled trial; and (iv) cohort study, case–control analytic study, Current therapeutic options for canine Malassezia dermatitis are reported to include systemic therapy with Studies were also classified according to size of study groups: (i) ketoconazole or itraconazole and/or topical therapy with > 50 subjects per group, (ii) 20–50 subjects per group, (iii) 10–19 azole derivatives or other agents such as selenium sul- subjects per group, and (iv) < 10 subjects per group.
phide and chlorhexidine.15,19 Evidence-based medicineprinciples can be used to carefully appraise the quality of Assessment of subject enrolment quality. For each study, the quality clinical trials and to systematically review and evaluate the of the diagnosis of Malassezia dermatitis was evaluated as follows: efficacy of anti-Malassezia interventions. Such a low bias • ‘Well defined’ was used when animals showed clinical signs of analysis has already been applied to the evaluation of skin inflammation and pruritus associated with the documentation treatment protocols of canine demodicosis, leishmaniosis of abnormally high cutaneous Malassezia yeast populations.
• ‘Poorly defined’ was used when subject selection criteria were The aim of the present study was to systematically review vague and/or when Malassezia yeast presence was documented the efficacy of antifungal interventions for Malassezia dermatitis and when possible, to propose recommenda- • ‘Fairly defined’ was used for intermediate situations.
Assessment of outcome measuresThe following main clinical and laboratory outcome measures were taken • Clinical response expressed with the following scales: (i) Electronic searches were carried out using the MEDLINE database complete remission of signs (90% or greater remission from with the following keywords: [dog OR dogs OR canine] and [malassezia pre-treatment assessment), (ii) partial remission (50% or greater OR pityrosporum] and [treatment OR antifungal OR therapy] (see remission of signs), and (iii) Insufficient remission or worsening ). Using a similar strategy, additional searches were performed to complete the retrieval of veterinary clinical trials using • Mycological outcome expressed with the following scales: (i) complete mycological recovery (90% or greater reduction of yeast/colony count), (ii) partial mycological recovery (50% or greater The five volumes of Advances in Veterinary Dermatology, the reduction of yeast/colony count), and (iii) insufficient mycological proceedings of the European College of Veterinary Dermatology/ recovery (less than 50% reduction of yeast/colony count).
European Society of Veterinary Dermatology congresses and the proceedings of the American Academy of Veterinary Dermatology/AmericanCollege of Veterinary Dermatology meetings were hand-searched for Study design, patient enrolment quality, nature of treatment, clinical Bibliographies of all articles and book chapters discussing treatment of and laboratory outcome and side-effects were reported in tabular Malassezia dermatitis were scanned for additional pertinent citations.
forms. Pharmacological interventions specific to Malassezia otitis Lastly, a request was sent to the Vetderm Listserv to identify recent clinical were discussed in a separate section.
trials that would have not been published before the writing of this article.
Recommendation statements for the use of these drugs for the treatment of Malassezia dermatitis were adopted from that proposed by Olivry and Mueller,22 they were as follows: This review concerns in vivo trials, which assessed the clinical efficacy ofan intervention for treatment of Malassezia dermatitis in dogs. Eval- • When more than one study, including at least one blinded randomized uations of antifungal agents against M. pachydermatis in healthy dogs with- controlled trial, supported the high efficacy of the drug tested, out dermatitis were excluded. Similarly, in vitro studies were not reviewed.
there was ‘good ’ evidence ‘for’ recommending the use of this drug.
Clinical trials were selected if they included more than five dogs.
• When at least one blinded randomized controlled trial provided The search was limited to trials published in peer-reviewed veterinary or support of medium to high efficacy of the drug investigated, medical journals without limitation of publication date. There were no there was ‘fair’ evidence ‘for’ recommending the use of this drug.
restrictions based on language of publication as long as an English • When blinded randomized controlled trial were not available, or when multiple studies yielded controversial evidence oftreatment effect, there was ‘insufficient’ evidence ‘for/against’ The authors independently reviewed all studies that satisfied inclusion • When at least one blinded randomized controlled trial or several criteria. Analysis concerned study design, methodology quality, sub- less detailed studies provide evidence of lack of efficacy, or efficacy 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
Interventions for Malassezia dermatitis in dogs
is associated with common harmful events, there is ‘fair’ evidence clinical recovery’ but mycological follow-up was not ‘against’ recommending the use of this drug.
• When at least one blinded randomized controlled trial or several ITT analyses were not performed, except for one study.27 less detailed studies, supported the lack of efficacy of the Adverse effects, vomiting and decreased appetite, medication tested, or supported any efficacy but with unacceptableside-effects, there was ‘good’ evidence ‘against’ recommending were relatively rare (four of 49 cases).
Ketoconazole. Despite the widespread practice use ofketoconazole to treat Malassezia dermatitis, only four studies evaluated the efficacy of this azole derivative in In November 2007, our search strategy identified 35 vivo. One study was randomized and controlled,23 one articles, of which eight trials (Table 1) fulfilled our selection was randomized and controlled but ketoconazole was criteria: (i) in vivo trials, (ii) dogs showing clinical lesions of administered with cefalexin,24 one was a controlled study Malassezia dermatitis, (iii) enrolment of at least five dogs, lacking blinding25 and one was a descriptive study.26 and (iv) reporting of clinical and mycological outcome Together, these four studies enrolled 57 dogs with measures. Six other studies fulfilled the first three criteria Malassezia dermatitis diagnosed clinically and by cytology but the outcome measures were incomplete (i.e. mycological recovery not specified) and/or were not prospective (Table 2).
In the different treatment protocols evaluated, ketoco- Among the 14 studies, there were 11 articles written in nazole was always used at least orally, with or without English, two in French and one in Korean. The 14 trials adding a shampoo or a cream containing it. The length of reported 12 different treatments protocols. There were treatment varied between 3 and 4 weeks or until clinical four blinded, randomized and controlled trials (quality of recovery. No other antifungal agent was used as control evidence grade A), four controlled studies lacking blinding treatment in these four studies. In one trial, the author and/or randomization (grade B), five open uncontrolled compared two different doses of ketoconazole.23 trials (grade C) and one descriptive study (grade D).
One study23 showed that there was no significant difference in efficacy between 5 and 10 mg kg–1 day–1 of Azole derivatives
ketoconazole administrated once daily for 3 weeks. Three Eleven studies assessing the efficacy of azoles derivatives studies,23,25,26 of which one was a randomized and con- trolled trial,23 reported that ketoconazole administrated at5–10 mg kg–1 day–1 led to partial or a complete improve- Enilconazole. Only one retrospective study of 12 cases of ment of signs in all cases. A complete or nearly complete generalized Malassezia dermatitis reported treatment clinical remission was observed in 50 to 100% of cases.
with a 0.2% enilconazole lotion (frequency of application When cytological results were available, a complete not detailed) in association with ketoconazole.26 Although a complete mycological recovery was described, no Despite all these good results, another randomized specific report of clinical improvement was available.
controlled trial24 reported a complete cytological improve-ment but insufficient clinical efficacy of ketoconazole at 5 Itraconazole. Our literature search identified four clinical to 10 mg kg–1 twice a day along with cefalexin (22–30 mg kg–1 trials investigating the efficacy of itraconazole for treatment twice a day) for 3 weeks: there was no significant of Malassezia dermatitis. One of them was a randomized decrease of either clinical index or pruritus scores during and controlled trial,27 two were controlled studies lacking the trial. However, in this study, a partial improvement was blinding and/or randomization28,29 and one was an open quoted for all the dogs treated (more than 50% of uncontrolled trial.30 These reports included a total of 100 improvement for 37.5% of dogs (three of eight dogs).
dogs with 49 treated with itraconazole. Therapeutic doses ITT analyses were adequate only in two trials.23,26 were variable: 5 mg kg–1 once or twice a day, each day or Adverse reactions were reported only in one trial:23 two consecutive days a week with or without selenium vomiting (two of 10 dogs), anorexia (one of 10) and apathy sulphide shampoo. In two trials, itraconazole was compared (one of 10) were found in rare patients.
with ketoconazole27,29 and in a third one, two differenttreatment regimens were compared.28 Treatment was carried Miconazole. Miconazole was a component of the treatment out for 3 or 4 weeks or until resolution of clinical signs.
protocol in three studies: one randomized and controlled A greater than 50% remission of signs was obtained in trial,31 one controlled study lacking blinding and randomi- two trials, both with 50 to 100% mycological improvement.
zation,32 and one open uncontrolled trial.33 These studies There were no significant differences in any results involved 80 dogs, of which 59 were treated with micona- between itraconazole pulse therapy and the daily adminis- zole always associated with another antifungal agent tration of ketoconazole.27 The improvement of clinical and (topical or systemic drug). Miconazole was used in cream cytological scores, both superior to 50%, were not signif- or shampoo (2% miconazole nitrate + 2% chlorhexidine; icantly different between daily and pulse administrations 2% miconazole nitrate + 2% chlorhexidine + 0.25% selenium of itraconazole.28 Some results of these trials have to be sulphide; or 1% miconazole nitrate + 2% chlorhexidine + 1% interpreted with caution, however. For example, in one study, selenium sulphide). These three shampoos were compared the cytological response was not assessed and the clinical together or versus a 0.25 to 10% selenium sulphide shampoo.
remission (89% of good clinical responses) was evaluated The length of treatment was approximately 3 to 4 weeks, according to the owners’ satisfaction during a follow-up or it was not reported. The frequency of application of telephone call.30 In another study, the trial continued ‘until miconazole was only reported in the randomized and 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
Negre et al.
Table 1. Results (in vivo prospective studies on the treatment of Malassezia dermatitis reporting clinical and mycological outcome)
outcome assessorIntention-to-treat analyses of study subjectsNo. of dogs entered in trial 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
mean clinical score (CADESI) D0: 72; D21: 21 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
Table 1. Continued
14% (one of seven dog with an increase in the cytological counts after treatment) Interventions for
Itraconazole 5 mg kg–1 SID for two consecutive days a week (10 dogs) Ketoconazole 10 mg kg –1 day–1 (10 dogs) Malassezia
dermatitis in dogs
BID, twice daily; SID, once daily; NR, not reported: complete is defined as more than 90% of improvement; partial as less than 90% of improvement.
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Table 2. Results (continued: studies on the treatment of Malassezia dermatitis: either retrospective or lacking clinical or mycological outcome)
Atopy (four of 12), flea allergy (two of 12) hypothyroidism (one of 12) ‘Significant improvement’ on clinical ‘Not negatively influencing’ cytological 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
BID, twice daily; SID, once daily; NR, not reported.
Interventions for Malassezia dermatitis in dogs
controlled trial, which reported more than 90% of marked detected in the assessed trials. Deviations from protocol clinical and cytological response with a 2% concentrated and/or loss to follow-up can introduce attrition bias which shampoo.31 Mason and Atwell32 observed only 50% reduces the statistical power of the study.37 Violation of marked clinical improvement with a less concentrated eligibility criteria and non-adherence to treatment are shampoo. In the other study, a clinical improvement was possible reasons of deviation from protocols and these reported, however, mycological data were not available.33 were not clearly discussed in the assessed trials. Loss to ITT analysis was adequate only in the randomized and follow-up refers to drop-out by refusing to participate, because of the impossibility of re-evaluating patients, and No adverse reaction was reported after miconazole because of withdrawal for adverse drug reactions or other health concerns.37 ITT analyses can reduce the bias due toheavy loss to follow-up, but after evaluating all trials, the ITT analyses were adequate in only half of the studies.
Terbinafine. The efficacy of terbinafine was assessed in In summary, clinical inference from study results must two trials: one randomized and controlled but with inadequate be evaluated in light of the high selection and detection ITT analysis24 and one controlled trial lacking blinding and biases and an unknown attrition rate.
randomization.29 These studies involved 64 dogs (18 ofthem were treated with terbinafine). In the study by Rosales et al.,24 treatment was carried out for 3 weeks, at The external validity of this review can be decreased by 30 mg kg–1 day–1 along with cefalexin at 22–30 mg kg–1 the enrolment criteria, the nature and duration of the twice a day, and this led to an insufficient remission of clinical treatments, and the assessed modalities of outcome.22 signs with only partial mycological improvement. In the other Quality of inclusion of study subjects was good in half of study, terbinafine was administrated at 2.5 mg kg–1 day–1 the studies and fairly defined in the other. In strict cases with 1% terbinafine cream and a 2.5% selenium sulphide of Malassezia dermatitis, a distinction had been made shampoo.29 Clinical improvement was complete but between the increase of Malassezia populations and that treatment length was double that with ketoconazole.
of Staphylococus intermedius. It is noteworthy that Furthermore no mycological evaluation was available for despite the high frequency of Malassezia dermatitis in analysis. No adverse reactions were reported.
dogs, there are no guidelines for the diagnosis of thisdisease. Diagnoses are made principally on suggestive clinical signs and support of yeast proliferation, both Chlorhexidine. Topical treatment with chlorhexidine was criteria being highly imprecise. Furthermore, relying on the used in four studies: one randomized and controlled,31 one number of Malassezia could be meaningless, as numbers controlled study lacking blinding and randomization32 and do not take into account the possibility that some very two open uncontrolled trials.33,34 In one trial, a 3% chlo- virulent strains of yeast may exist, and/or that some sensitive rhexidine shampoo applied three times a week for 3 weeks hosts could exhibit signs with low numbers of yeasts.
led to complete clinical and cytological improvement Furthermore, in some trials, the cytological diagnosis was without any side-effects.34 In the three other studies, not clearly described, and we are left to assume that chlorhexidine was always associated with one or two bacterial proliferation was not a criterion of exclusion.24 Certain products (such as chlorhexidine or miconazole) Selenium sulphide,29,31–33 piroctone olamine35 and also exhibit an antibacterial activity, and it is difficult to benzalkonium chloride36 were tested in low grade trials determine the relative importance of the reduction in and always in association with one or more other product(s).
yeast and bacterial populations and their role in the clinicalimprovement reported by the authors in these trials.
Pharmacological intervention, length and frequency of Discussion
administration were very different from one trial to another.
This systematic review of clinical trials evaluating the For example, ketoconazole was used at 5 mg kg–1 once a efficacy of treatment of Malassezia dermatitis in dogs led day,25 10 mg kg–1 once a day26,27 and 10 mg kg–1 twice a to recommendations for and against different protocols.
day;24 terbinafine was tested at 2.5 mg kg–1 once a day29 Nevertheless, the results obtained from this analysis must and at 30 mg kg–1 once a day.24 The frequency of application be assessed for their internal and external validity.
of topical treatments was usually two or three times aweek. Trials lasted 3 to 4 weeks or, sometimes, until clinical recovery. However, type, dosage, frequency, route The internal validity of this study can be reduced by and length of administration of the drugs used in the trials several biases, such as selection, detection, performance studied reflected most of the times reported ‘standard of and attribution.37 Lack of appropriate randomization schemes care’ protocols used in specialty referral practices and/or could lead to selection bias, which may have occurred in recommended in veterinary dermatology textbooks.
this review because only six trials were randomized.
In one third of the studies assessed in this review, clinical Detection bias is the result of lack of blinded design.37 The and/or cytological improvements were not reported,25,29,32 or investigators and/or dog owners were aware of the they were subjectively evaluated by the outcome assessor pharmacological intervention in 11 trials, which may have without precise values available, or they were based on influenced the assessment of outcome. Performance bias the owners’ satisfaction.30,33 In the majority of trials, (e.g. one group of dogs was treated preferentially with improvement was assessed by a lesional score and/or a medications in addition to that being evaluated) was not cytological yeast count. However, we were only able to 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
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find eight prospective studies reporting clinical and myco- double advantage of being simple and of reducing the cost logical improvement following treatment. Furthermore, it of treatment.27 The absorption of itraconazole is better is not clearly determined in most studies if the clinical when combined with food and is enhanced in an acid improvement was due to reduced numbers of yeast environment or in the presence of fat. Adverse reactions organisms, to other effects like antibacterial activity of include anorexia and may be related to hepatic toxicosis.28 some topical products or to the potential anti-inflammatory Vasculitis has also been observed, resulting in an ulcerative properties of systemically administered azole derivatives.19,38 When treatment protocols associated different Ketoconazole and itraconazole are believed to inhibit the molecules26,29,31–33 or when a concurrent disease was fungal P450 enzyme system. However this inhibition is simultaneously treated,29 it was very difficult or impossible not specific (especially with ketoconazole) and the canine to discern the relative efficacy of each product, e.g. in the P450 enzyme system may also be affected. As a consequence, study comparing ketoconazole and terbinafine combined the drugs can affect the metabolism of other drugs. Keto- conazole is the most widely used systemic drug for the In conclusion, the external validity of this systematic treatment of Malassezia dermatitis for its valuable clinical review may have been affected by different factors such efficacy and convenience of oral administration.1,12,14,26,42–44 as the imprecise selection of subjects enrolled in the trials, Ketoconazole is an expensive drug in some countries but treatment associating several products (with different is usually much more affordable than itraconazole. Neither types of activity) and limited evaluation of outcome measures.
of these agents has a marketing authorization for thetreatment of Malassezia dermatitis in dogs. In some coun- Implications for clinical practice tries legislative issues may direct veterinary clinicians to As it was shown in the clinical trials scrutinized in the consider itraconazole rather than ketoconazole therapy present study, treatment of Malassezia dermatitis in dogs because the former is licensed for use in the cat.
can be topical, systemic or both. The choice of the phar- This systematic review demonstrated that at this time, macological intervention should be adapted to the severity there is insufficient evidence for recommending the use of the dermatitis and the achievability of the intervention.
of oral terbinafine or topical treatments comprising Topical treatments are adapted to local lesions but also to miconazole, enilconazole, chlorhexidine, piroctone olamine generalized dermatitis, depending on their formulation.
Nevertheless, before prescribing a shampoo, clinicians have Treatment of chronic relapsing cases of Malassezia to take into account the body size, the type of coat and dog’s dermatitis can be frustrating and may be limited due to behaviour as well as owner compliance, availability and financial considerations. Identification and treatment of underlying causes are essential. When predisposing From the data analysed in this systematic review (Table 3), factors cannot be controlled, regular topical treatment or and according to the criteria outlined at the method section, pulse oral therapy is described to be useful in keeping the there is good evidence for recommending the use of 2% dermatitis controlled so that relapses are minimal.1,13,18 miconazole nitrate + 2% chlorhexidine gluconate shampoo Because of lower risk for toxicity, topical treatments are twice a week for 3 weeks.31,33 In fungal cells, the fixation preferred to systemic treatments for long-term therapy.
of miconazole on cytochrome P450 inhibits the synthesisof ergosterol, triglycerides, phospholipids, chitin and oxidative and peroxidative enzymes. All these modifications perturb Trials assessing the in vivo efficacy of antifungal treatments numerous functions of the yeast membrane, leading to for Malassezia dermatitis in dogs are very few in number.
accumulation of hydrogen peroxides, which asphyxiate This is quite surprising if we consider that Malassezia the fungal cell.39,40 Chlorhexidine is usually used as gluconate dermatitis is a very common condition in veterinary salts forms, which are the most soluble in water or alcohol.
medicine. From our data, only one topical treatment can Chlorhexidine is a good antiseptic with a broad activity be recommended with ‘good evidence’ and two systemic spectrum (staphylococci, Pseudomonas).41 treatments with ‘fair evidence’. For the topical product, When topical treatment is not possible, the use of trials often evaluated associations of miconazole and ketoconazole (5 to 10 mg kg–1 once daily for 3 weeks) or chlorhexidine so we cannot estimate the individual efficacy itraconazole (5 mg kg–1 once daily, two consecutive days of each product. Further studies are needed in order to a week for 3 weeks) can be recommended with fair evidence evaluate the efficacy of these topical agents, one by one, of efficacy (Table 3). Ketoconazole at 5 mg kg–1 day–1 as well as to determine the optimal frequency of administration.
seems as effective as 10 mg kg–1 day–1 2,3 and therefore Indeed, it would be very useful to evaluate the efficacy of the lowest dosage may be considered on a first-line basis, topical applications of miconazole alone, in particular for as it is cheaper and potentially less likely to induce adverse countries where the 2% miconazole + 2% chlorhexidine effects. Ketoconazole may cause anorexia, vomiting, diarrhoea, malaise, and more rarely, hepatic toxicity and For forthcoming studies, we recommend in vivo randomized, controlled and double-blinded studies following the CON- In a randomized, controlled and blinded study com- SORT reporting guidelines (reader should refer to the Con- paring the efficacy of ketoconazole and a pulse administration of itraconazole, there were no differences in clinical scores, comparable results, we propose that all new studies on pruritus and Malassezia population counts in the two treatment of Malassezia dermatitis follow the same groups.27 Itraconazole pulse therapy is possible due to the clinical and mycological criteria of subject inclusion and persistence of the drug in the horny layer and has the the same clinical scoring for the follow-up. Each subject 2008 The Authors. Journal compilation 2008 ESVD and ACVD.
2008 The Authors. Journal compilation 2008 ESVD and ACVD.
Table 3. Recommendations for treatment of Malassezia dermatitis in dogs
Ketoconazole 5 mg kg–1 SID + 2% ketoconazole shampoo twice a week + 2% ketoconazole cream BID Ketoconazole 10 mg kg–1 SID + 0.2% enilconazole lotion Itraconazole 5 mg kg–1 SID for two consecutive days a week Itraconazole 5 mg kg–1 SID for two consecutives days a week Itraconazole 5 mg kg–1 SID + 2.5% selenium sulphide shampoo twice a week Terbinafine 30 mg kg −1 + cefalexin 22–30 mg kg–1 BID Terbinafine 2.5 mg/kg SID + 1% terbinafine cream + 2.5% selenium sulphide shampoo twice a week 1% miconazole nitrate, 1% chlorhexidine and 1% selenium sulphide shampoo 3% chlorhexidine shampoo three times a week Piroctone olamine and ammonium lactate shampoo once a week + piroctone olamine and salicylic acid Interventions for
Menthol, hamamelis, benzalkonium chloride and PCMX spray dilution BID 1 = When more than one study, included at least one blinded randomized controlled trial, supports the high efficacy of the drug tested, there is ‘good’ evidence ‘for’ recommending the use of this drug.
2 = When at least one blinded randomized controlled trial provides support of medium to high efficacy of the drug investigated, there is ‘fair’ evidence ‘for’ recommending the use of this drug.
3 = When blinded randomized controlled trial are not available, or when multiple studies yield controversial evidence of treatment effect, there is ‘insufficient ’ evidence ‘for/against’ recommending the use of this drug.
4 = When at least one blinded randomized controlled trial or several less detailed studies provide evidence of lack of efficacy, or efficacy is associated with common harmful events, there is ‘fair’ evidence ‘against’ recommending the use of this drug.
Malassezia
BID, twice daily; SID, once daily; NA, not applicable; NR, not reported.
dermatitis in dogs
Negre et al.
involved in the study should be retained in statistical populations in dogs with pruritic skin disease. Journal of Small analyses for ITT analyses. Treatment protocol (doses and frequency of administration) should be clearly detailed.
10. Plant JD, Rosenkrantz WS, Griffin CE. Factors associated with and prevalence of high Malassezia pachydermatis numbers on Results should include clinical and mycological dog skin. Journal of the American Veterinary Medical Association In conclusion, our systematic review allowed us to 11. Bond R, Lloyd DH. Skin and mucosal population of Malassezia recommend with good evidence only one topical treatment pachydermatis in healthy and seborrhoeic Basset Hounds.
of Malassezia dermatitis (2% miconazole nitrate + 2% Veterinary Dermatology 1997; 8: 101–6.
chlorhexidine, twice a week for 3 weeks) and with fair 12. Mason KV. Cutaneous Malassezia. In: Griffin CE, Kwochka KW, evidence two systemic treatments with azole derivatives MacDonald JM, eds. Current Veterinary Dermatology. St Louis,MO: Mosby Year Book, 1993: 44–8.
(ketoconazole, 5 to 10 mg kg–1 day–1 and itraconazole, 13. Morris DO. Malassezia dermatitis and otitis. Veterinary Clinics of 5 mg kg–1 day–1). Future studies are needed to evaluate North America – Small Animal Practice 1999; 29: 1303–10.
the efficacy of azole derivatives and of other traditional 14. Muse R. Malassezia dermatitis. In: Bonagura R, ed. Current treatments and also of alternative products. This review Veterinary Therapy XIII. Small Animal Practice. Philadelphia, PA: did not include an analysis of in vitro assays, which are more difficult to correlate to clinical features. Significant 15. Mason KV, Evans AG. Dermatitis associated with Malassezia pachydermatis in 11 dogs. Journal of the American Animal differences in the in vitro susceptibility to antifungal drugs Hospital Association 1991; 27: 13–20.
have been demonstrated among Malassezia species.46–48 16. White SD, Bourdeau P, Blumstein P et al. Comparison via cytology Most M. pachydermatis isolates were proved to be suscep- and culture of carriage of Malassezia pachydermatis in atopic and tible to amphotericin B, azole derivatives, nystatin and healthy dogs. In: Kwochka KW, Willemse T, Von Tscharner C, eds.
terbinafine. However, some isolates seemed to be resistant Advances in Veterinary Dermatology, vol. 3. Oxford, UK: Butterworth to fluconazole49 or to flucytosine.50 In a recent study, Cole et al.51 demonstrated that ketoconazole had a stronger in 17. Matousek JL, Campbell KL. Malassezia dermatitis. Compendium on Continuing Education for the Practicing Veterinarian 2002; 24: vitro activity than clotrimazole and miconazole but similar to itraconazole.51 The treatment of Malassezia otitis was 18. Bond R. Malassezia pachydermatis and canine skin disease.
also excluded, because the ecosystems of ear canal and body skin are different. Those topics should be the subject 19. Mason KV, Stewart LJ. Malassezia and canine dermatitis. In: Ihrke PJ, Mason IS, White SD, eds. Advances in Veterinary Dermatology,Vol. 2. Oxford: Pergamon Press, 1993: 399 –402.
20. Mueller RS. Treatment protocols for demodicosis: an evidence- Acknowledgements
based review. Veterinary Dermatology 2004; 15: 75 –89.
21. Noli C, Auxilia ST. Treatment of canine Old World visceral leishmaniasis: The authors would like to thank Thierry Olivry and Aiden a systematic review. Veterinary Dermatology 2005; 16: 213–32.
Foster for helpful discussion on the protocol and corrections 22. Olivry T, Mueller RS and the International Task Force on Canine Atopic Dermatitis. Evidence-based veterinary dermatology: asystematic review of the pharmacotherapy of canine atopicdermatitis. Veterinary Dermatology 2003; 14: 121–46.
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and Kirk’s Small Animal Dermatology, 6th edn. Philadelphia, PA: 24. Rosales MS, Marsella R, Kunkle G, Harris BL, Nicklin CF, Lopez J. Comparison of the clinical efficacy of oral terbinafine and 2. Bond R, Lloyd DH, Plummer JM. Evaluation of a detergent scrub ketoconazole combined with cephalexin in the treatment of technique for the quantitative culture of Malassezia pachydermatis Malassezia dermatitis in dogs – a pilot study. Veterinary Derma- from canine skin. Research in Veterinary Science 1995; 58: 133– 25. Sai JP, Madhavi SL, Satish KK. Therapeutic studies on seborrheic 3. Guillot J, Bond R. Malassezia pachydermatis: a review. Medical dermatitis in dogs associated with Malassezia pachydermatis.
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généralisés traités par des dérivés azolés. Pratique Médicale et 5. Dufait R. Pityrosporum canis as the cause of canine chronic Chirurgicale Des Animaux de Compagnie 1996; 31: 297–307.
dermatitis. Veterinary Medicine and Small Animal Clinician 1983; 27. Bensignor E. Oral itraconazole as a pulse therapy for the treat- ment of canine Malassezia dermatitis: a randomized, blinded, 6. Chang HJ, Miller HL, Watkins N et al. An epidemic of Malassezia comparative trial. Pratique Médicale et Chirurgicale de L’animal pachydermatis in an intensive care nursery associated with coloniza- tion of health care workers per dogs. New England Journal of 28. Pinchbeck LR, Hillier A, Kowalski JJ, Kwochka KW. Comparison of pulse administration versus once daily administration of 7. Morris DO, O’Shea K, Shofer FS, Rankin S. Malassezia pachyder- itraconazole for the treatment of Malassezia pachydermatis matis carriage in dog owners. Emerging Infectious Diseases dermatitis and otitis in dogs. Journal of the American Veterinary Medical Association 2002; 12: 1807–12.
8. Maudlin EA, Scott DW, Miller WH, Smith A. Malassezia dermatitis 29. Ashok K, Kitab S, Anshu S. Treatment of dermatitis in dogs associated in the dog: a retrospective histopathological and immunological with Malassezia pachydermatis. Indian Veterinary Journal 2002; study of 86 cases (1990–95). Veterinary Dermatology 1997; 8: 30. Ayoung J, Woophil H, Kidong E, Woo LK, Ho OT. Efficacy of 9. Bond R, Ferguson EA, Curtis CF, Craig JM, Lloyd DH. Factors itraconazole in 18 cases of Malassezia dermatitis in dogs. Journal associated with elevated cutaneous Malassezia pachydermatis of Veterinary Clinics 2005; 22: 90 –3.
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31. Bond R, Rose JF, Ellis JW, Lloyd DH. Comparison of two part II. Journal of the American Academy of Dermatology 1994; shampoos for treatment of Malassezia pachydermatis-associated seborrhoeic dermatitis in basset hounds. Journal of Small Animal 41. Russel AD, Day MJ. Antibacterial activity of chlorhexidine.
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ment of the efficacy of a 3% chlorhexidine shampoo in the control 46. Gupta AK, Kohli Y, Li A, Faergemann J, Summerbell RC. In vitro of elevated cutaneous Malassezia populations and associated susceptibility of the seven Malassezia species to ketoconazole, clinical signs (Malassezia dermatitis) in dogs. Proceedings of voriconazole, itraconazole and terbinafine. British Journal of the 19th Annual Congress of the ESVD ECVD, Tenerife, 2003: 47. Hammer KA, Carson CF, Riley TV. In vitro activities of ketoconazole, 35. Rème C, Cadot P, Holzapfel G, Jasmin P. Efficacy of combined econazole, miconazole and Melaleuca alternifolia (tea tree) oil topical therapy with keratoregulating shampoo and lotion in the against Malassezia species. Antimicrobial Agents and Chemo- management of keratoseborroeic disorders associated with Malassezia proliferation in dogs. Veterinary Dermatology 2003; 48. Velegraki A, Alexopoulos EC, Kritikou S, Gaitanis G. Use of fatty acid RPMI 1640 medium for testing susceptibilities of eight Malassezia 36. Carlotti DN, Rème CA. Efficacy of a soothing astringent topical species to the new triazole posaconazole and to six established spray for the management of Malassezia pododermatitis in dogs: antifungal agents by a modified NCCLS M27–A2 microdilution method a preliminary open-label clinical trial. Proceedings of the 47th and Etest. Journal of Clinical Microbiology 2004; 42: 3589 –93.
Annual British Small Animal Veterinary Association Congress, 49. Lyskova P, Vydrazalova M, Mazurova J. Identification and antimi- crobial activity of bacteria and yeasts isolated from healthy dogs 37. Juni P, Altman DG, Egger M. Systematic reviews in health care: and dogs with otitis externa. Journal of Veterinary Medicine 2007; assessing the quality of controlled clinical trials. British Medical 50. Garau M, Pereiro M, Del Palacio A. In vitro susceptibilities of 38. Marsella R, Kunkle GA, Vaughn DM, MacDonald J. Double-blind Malassezia species to a new triazole, albaconazole (UR 9825), and pilot study on the effects of ketoconazole on intradermal skin test other antifungal compounds. Antimicrobial Agents and Chemo- and leukotriene C4 concentration in the skin of atopic dogs.
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39. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview: In vitro activity of an ear rinse containing tromethamine, EDTA, part I. Journal of the American Academy of Dermatology 1994; benzyl alcohol and 0.1% ketoconazole on Malassezia organisms from dogs with otitis externa. Veterinary Dermatology 2007; 18: 40. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview: Résumé
Le but de cette étude était d’évaluer l’efficacité des traitements antifongiques pour la dermatite à Malassezia chez le chien, et si possible de proposer des recommandations pour ou contre leur utilisation. Des recherches électroniques ont été effectuées en utilisant PubMed MEDLINE®, CABDirect et CONSULT- ANT. Les volumes de Advances in Veterinary Dermatology, les proceedings des congrès ESVD/ECVD etAAVD/ACVD ont été revus pour trouver les “études intéressantes pour cette revue. Tous les articleset chapitres d’ouvrages relatifs au traitement de la dermatite à Malassezia ont été revus pour des citationsadditionnelles. Finalement, une requête a été postée sur la liste Vetderm pour partager les données les plusrécentes en cours de publication. L’analyse s’est intéressée au type d’étude, à la qualité méthodologique,à l’enrolement des sujets, au type d’intervention et aux données mesurées. 35 articles ont été sélectionnés, et seulement 14 études présentaient les critères de sélection suivants: (i) études cliniques in vivo, (ii) chiens présentant des signes cliniques de dermatite à Malassezia, (iii) enrole-ment d’au moins cinq chiens. Parmi ces études, seulement huit présentait le critère supplémentaire: (iv)étude prospective in vivo présentant des données chiffrées quant à l’amélioration clinique et mycologique.
Un nombre total de 14 protocoles différents de traitement incluant quatre études en aveugle, randomiséeset contrôlées (grade A de qualité), quatre études contrôlées mais sans aveugle et/ou randomisation (gradeB), cinq études ouvertes non contrôlées (grade C) et une étude descriptive (grade D). Cette métaanalyse permet de recommander avec un bon degré de preuve, l’utilisation d’un seul traitement topique pour la dermatite à Malassezia (shampooing contenant 2% miconazole nitrate + 2% chlorhexidine, 2fois par semaine pendant trois semaines) et avec un niveau correct de preuve l’utilisation de deux traitementssystémiques avec des dérivés azolés (ketoconazole, 10 mg/kg/jour et itraconazole, 5 mg/kg/jour pendanttrois semaines).
El propósito de esta revisión sistemática fue evaluar la eficacia de tratamientos antifúngicos frente a dermatitis producida por Malassezia en perros, y, cuando fuese posible, proponer recomendacionesen contra o a favor de su uso.
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Negre et al.
Se realizaron búsquedas electronicas utilizando PubMed MEDLINE®, CABDirect y la base de datos CON- SULTANT. Los volumenes Advances in Veterinary Dermatology y los resumenes de conferencias ESVD/ECVD y AAVD/ACVD fueron examinados manulamente en busca de estudios relevantes para esta revisión.
Todos los artículos y capítulos de libros discutiendo tratamientos frente a dermatitis por Malassezia se exam-inaron para obtener referencias adicionales. Por último se envió una petición al grupo de discusion VetdermListserv para compartir datos clínicos recientes. El análisis evaluó el diseño de los estudios, la calidad delos métodos, la calidad de la seleccion de pacientes, el tipo de tratamiento y los resultados del mismo. Las búsquedas identificaron 35 artículos y 14 pruebas clínicas que cumplían los siguientes criterios de selección: (i) pruebas clínicas in vivo, (ii) perros que presentaban lesiones clínicas de dermatitis producidapor Malassezia, (iii) selección de al menos cinco perros. Entre estos, solo 8 estudios cumplieron el siguientecriterio adicional: (iv) pruebas in vivo prospectivas que indicaban los resultados clínicos y micológicos. Untotal de 14 protocolos de tratamiento incluyeron cuatro pruebas ciegas al azar y controladas (calidad deevidencia grado A), cuatro estudios controlados no ciegos ni al azar (calidad de evidencia grado B), cincoestudios abiertos no controlados (grado C) y un estudio descriptivo (grado D).
Esta revisión sistemática nos ha permitido recomendar, con evidencias solidas, el uso de solo un tratamiento tópico frente a dermatitis por Malassezia (2% de nitrato de miconazol+ 2% de clorhexidina, 2 veces ensemana durante tres semanas) y con evidencia menos solida el uso de dos tratamientos sistémicos conderivados de azol (ketoconazol, 10 mg/kg/día e itraconazol, 5 mg/kg/día durante tres semanas.
Zusammenfassung
Das Ziel dieser systematischen Review war es, die Wirksamkeit von antimyko- tischen Behandlungen bei der Malasseziendermatitis des Hundes zu evaluieren und, falls möglich, eineEmpfehlung für oder gegen ihre Verwendung abzugeben.
Eine elektronische Suche wurde mit den Datenbanken PubMed MEDLINE®, CABDirect und CONSULT- ANT durchgeführt. Die Ausgaben von Advances in Veterinary Dermatology, die Proceedings der ESVD/ECVDund AAVD/ACVD Kongresse wurden ‘per Hand’ auf Studien durchsucht, welche für diese Review relevantwaren. Alle Artikel und Buchkapitel, die die Behandlung der Malasseziendermatitis diskutierten, wurden aufzusätzliche Referenzen durchgesehen. Letztendlich wurde ein Aufruf an die Vetderm Listserv geschickt, umüber jüngste klinische Studien zu erfahren. Bei der Analyse wurden Studiendesign, Qualität der Methode,Qualität der registrierten Subjekte, die Art der Interventionen und das Ausmaß der Ergebnisse evaluiert.
Die Literatursuche ergab 35 Artikel und 14 Studien, die die folgenden Auswahlkriterien erfüllten: (i) in vivo klinische Studien, (ii) Hunde, die klinische Veränderungen einer Malasseziendermatitis zeigten, (iii) eineMindestanzahl von fünf teilnehmenden Hunden. Unter diesen erfüllten nur acht Studien die folgendenZusatzkriterien: (iv) prospektive in vivo Studien, die die klinischen und mykologischen Ergebnisse beschrieben.
Insgesamt wurden 14 verschiedene Behandlungsprotokolle gefunden, die vier geblindete, randomisierteund kontrollierte Studien (Qualität der Evidenz Grad A), vier kontrollierte Studien, die nicht geblindet oderrandomisiert waren (Grad B), fünf offene unkontrollierte Studien (Grad C) und eine deskriptive Studie (GradD) beinhalteten. Diese systematische Review erlaubte es uns mit guter Evidenz die Verwendung einer topischen Behandlung für die Malasseziendermatitis (2% Mikonazolnitrat + 2% Chlorhexidin, zweimal wöchentlich,3 Wochen lang) und mit ausreichender Evidenz die Verwendung zweier systemischer Behandlungen mitAzolderivaten (Ketokonazol, 10 mg/kg/Tag und Itrakonazol, 5mg/kg/Tag für drei Wochen) zu empfehlen.
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