Topical therapy has an important role in managing canine atopic dermatitis (CAD). Topical therapies can moisturise and soothe the skin, treat and prevent secondary bacterial and yeast infections, and remove adherent scale, grease, allergens and debris. They can be used as sole therapy or combined with other therapeutic strategies.
Most topical treatments are safe with minimal cutaneous or systemic toxicity or other effects. Their use can therefore offset the need for systemic treatments that are expensive and/or have greater potential for adverse effects. Shampoos are the most common topical treatment modality. However, while most dogs accept bathing, this can be time-consuming and requires adequate facilities. This can be off-putting to owners, which can limit the frequency and effectiveness of treatment.
Non-rinsing wipes, foams and spot-on preparations have therefore been developed to facilitate topical application and improve compliance.
This review looks at the topical therapy options for CAD. It focuses on the general principles of topical therapy, using some specific agents to illustrate the scientific evidence for safety and efficacy. It is beyond the scope of this article to discuss topical pharmacological preparations, which are reviewed elsewhere (Olivry et al, 2010; 2015; Mueller et al, 2012).
General principles of topical therapy in CAD
There are three main factors to consider when choosing a topical therapy product. First, the active ingredients should be appropriate for the patient's skin condition. Next, the choice of the formulation or delivery system will depend on the extent of the skin lesions; the type and depth of the skin lesions; the length and density of the coat; whether residual activity is required; ease of use for the owner; and tolerance by the dog. Finally, owner preferences in the colour, scent and feel of a preparation can affect acceptance and compliance with treatment.
Shampoos are most commonly used to treat large areas, especially involving haired skin. Bathing also cleans the skin and coat, removing debris, scales, grease and allergens. Rinsing may remove the active ingredients, which may therefore only be in contact with the skin for a relatively short time. However, persistent antimicrobial activity on hair has been shown after bathing with chlorhexidine products (Kloos et al, 2013). Many dogs tolerate bathing well, but it is not universally accepted. In addition, thorough bathing requires time, plus adequate facilities for washing and drying. These may not be available in all households, and all-year round treatment may not be feasible if one or more steps have to be done outside. Some owners may only be able to bathe their dog every 1–2 weeks, which can limit efficacy. Bathing can be performed by professional groomers or veterinary practices, but this increases the costs.
Other delivery systems have been developed to help overcome some of these problems. These are generally quicker and easier to apply and do not need rinsing.
- Foams can be used to treat large areas and can be massaged into haired skin. They tend not be as wetting as shampoos, but owners can be sensitive to the look and feel of the coat after application (clumped, greasy etc.)
- Sprays, soaks and rinses are similar, although it may be more difficult to massage these into haired skin and they are more wetting
- Options for local treatment of less-haired skin include wipes, lotions, gels, creams and ointments
- Spot-on preparations can be used to passively diffuse the active ingredients across the skin from one or more application sites.
These non-rinsing approaches should lead to persistent activity of the active ingredients, which has been shown for chlorhexidine foams and rinses (Mesman et al, 2016; Ramos et al, 2019). However, with the possible exception of wipes, none will have the same cleansing activity as bathing.
Advantages and disadvantages of topical therapy in CAD
The obvious advantage of topical therapy is that it delivers the active ingredients directly to the skin. In most cases this avoids systemic side effects. Topical antimicrobial therapy also avoids treatment of non-target microbiomes (for example in the gut), which may reduce the selection pressure for antimicrobial resistance in these sites.
However, anything applied topically (especially to inflamed skin) can cause irritation or contact dermatitis. In addition, systemic exposure can occur through percutaneous absorption, grooming, or direct oral ingestion. Finally, using topical treatments increases human exposure and the possibility of adverse effects among owners. It was recently reported that 26% of tested leave-on topical products for dogs contained the preservatives methylisothiazolinone and methylchloroisothiazolinone, which are potential allergens banned in human products (Loeb, 2019). Labelling regulations are weaker for animal products and ingredients such as these may not be listed — the same report stated that 6/62 evaluated products had little to no labelling of their ingredients.
Safety is an important consideration in selecting products, and clinicians should monitor treatment. If there is any cutaneous flare or other problems after starting topical treatment then the product should be discontinued and the patient rinsed in lukewarm water to remove any remaining traces from treated skin. Cases should be reviewed to determine whether the worsening was the result of the underlying or a new skin condition. Suspected adverse reactions should be reported to the manufacturer and Veterinary Medicines Directorate. Owners that have suspected reactions after handling a product should be referred to their medical practitioner.
Topical treatment options in CAD
The main aim of topical therapy in CAD is to reduce pruritus and inflammation. It is likely that CAD involves a poor skin barrier; abnormal skin inflammation; reactions to environmental and/or food allergens; and secondary staphylococcal and/or Malassezia spp. yeast infections (Nuttall et al, 2019). Topical therapy can therefore be beneficial by removing allergens from the skin and coat; repairing the skin barrier; antipruritic or anti-inflammatory activity; and/or reducing microbial colonisation. The International Committee for Allergic Diseases in Animals (ICADA) treatment guidelines for CAD (Olivry et al, 2010; 2015) state that bathing at least once weekly with a non-irritating shampoo and lukewarm water can provide a direct soothing effect to the skin; physically remove allergens and microbes; and increase skin hydration (Figures 1 and 2).
Topical spot-on emollients in CAD
There have been limited clinical trials investigating topical spot-on emollient formulations in CAD. Sphingolipid extracts increased ceramide levels and lamellar lipid structures in a keratinocyte/collagen matrix in vitro canine skin model (Cerrato et al, 2016). Adelmidrol, which is a topical analogue of palmitoylethanolamide (PEA), significantly reduced Ascaris suum extract-induced wheals and mast cell numbers in experimentally sensitised Beagles (Cerrato et al, 2012). In another study, adelmidrol increased PEA expression and inhibited release of the pro-inflammatory chemokine MCP-2 by canine keratinocytes, human keratinocytes and human embryonic kidney cells in vitro (Petrosino et al, 2016). A spot-on preparation of ceramides, cholesterol and free fatty acids (Allerderm®; Virbac SA, Carros, France) was shown to help restore ultrastructural lipid abnormalities in a small number of atopic dogs (Piekutowska et al, 2008; Popa et al, 2012). Clinical trials resulted in a modest but significant reduction in lesion scores but not pruritus scores (Fujimara et al, 2011; Marsella et al, 2013). Similar results were seen using an essential fatty acid/essential oil spot-on (Dermoscent Essential 6; LDCA, Tarn, France) (Blaskovic et al, 2014), although this was not confirmed in a later randomised controlled trial (RCT) (Hobi et al, 2017). It is possible that spot-on emollients may be more beneficial after bathing, although larger RCTs are required to confirm their efficacy.
Shampoos and foams in CAD
Despite the ICADA recommendation, there have been few well-conducted studies on the safety and efficacy of shampoos in CAD. Moreover, it is difficult to differentiate between the effects of the individual active ingredients and the vehicle. In one double-blinded RCT, twice-weekly bathing either with a shampoo containing lactoferrin, chlorhexidine, piroctone olamine, chitosan, essential fatty acids and glycerine (DermaTopic®; Almapharm, Wildpoldsried, Germany), or a placebo vehicle, significantly reduced pruritus but not lesion scores (Schilling and Mueller, 2012). In another RCT, an emollient shampoo containing lipids, complex sugars and piroctone olamine (Allermyl®; Virbac), significantly reduced pruritus (Löflath et al, 2007). Further studies showed equivalent efficacy between this shampoo and combined use of phytosphingosine, raspberry oil and lipid-containing shampoos, foams and sprays (Douxo® Calm; Ceva Sante Animale; Libourne, France) (Bourdeau et al, 2007; Bensignor et al, 2013). The intensity of bathing also proved to be important, as in one study both the trial shampoo and placebo control were more effective used in a whirlpool bath compared to a shower (Löflath et al, 2007). However, the effect of these products was modest and short-lived. The effect could be extended by using foam preparations, as using the Douxo® Calm products in a 3-week cycle of one shampoo followed by foam applications every 2–3 days reduced lesion scores by 76% using the validated Canine Atopic Dermatitis Extent and Severity Index (Olivry et al, 2014); CADESI-4 mean scores were 44 at day 0 and 10.6 at day 21 (Gatellet et al, 2019). In comparison, the standard Douxo® Calm protocol of weekly shampoos and twice-weekly foam applications reduced the lesion scores by 40% (CADESI-4 mean scores of 39 at day 0 and 23.4 at day 21).
Ophytrium-containing shampoo and foam in CAD
The ideal topical product for CAD should be emollient; lipid barrier sparing; microbiome balancing (i.e. prevent bacterial and yeast dysbiosis or infection); easy to apply and welltolerated; and have some residual activity on the skin. Recently, a range of ophytrium (a root extract from Japanese mondo grass, Ophiopogon japonicus) containing products have been developed to achieve these aims (Douxo® S3 range; Ceva Sante Animale). These include emollient/soothing (Douxo® S3 Calm), anti-bacterial/anti-fungal with 3% chlorhexidine (Douxo® S3 Pyo) and anti-scaling/seborrhoea with a Punica granatum (pomegranate) extract (Seboliance/Douxo® S3 Seb) formulations. The safety and efficacy of these products were demonstrated using in vitro reconstructed canine and human epidermis (RCE/RHE) models, healthy dogs and clinical trials.
Ophytrium is safe for treated animals and their owners (Anon, 2019; Kolasa et al, 2019a; 2019b; Ollivier et al, 2019a). Ophytrium and the ophytrium-based products did not induce any toxic effects in RHE and RCE models, which maintained thickness, layers and differentiation. Penetration was limited to the skin, with no systemic absorption. No adverse effects were seen in dogs treated in excess of normal use (one shampoo with four double-quantity foam applications per week for 3 weeks).
Cytokine-stressed RHE and RCE models were used to demonstrate efficacy on skin barrier, inflammation and microbiome pathways. Ophytrium limited adhesion and biofilm formation by Staphylococcus pseudintermedius and S. aureus on the surface of the stressed models, compared to controls (Ollivier et al, 2019b). Treatment with ophytrium blocked structural changes (cell dissociation, spongiosis, and fewer and smaller keratohyaline granules); decreased pro-inflammatory cytokine expression (IL-8 and thymic stromal lymphopoietin); decreased permeability and transepidermal water loss; and increased claudin-1, filaggrin, natural moisturising factor (NMF) and ceramide production (Anon, 2019; Ollivier et al, 2019c). Treatment therefore blocked inflammatory pathways and allowed the stressed RHE to retain normal morphology and epidermal barrier function.
Clinical efficacy has been assessed in atopic humans and dogs. In a single-blind placebo-controlled RCT in 90 children and 144 adults with mild-to-moderate atopic dermatitis, twice-daily application of an Ophiopogon japonicus-derived product reduced lesion scores, improved quality of life measures, and reduced the relapse rate (Mainzer et al, 2019). In an open pilot study of Douxo S3 Calm®, 24 atopic dogs were shampooed once and then received foam applications every 48–72 hours for 3 weeks (Gatellet et al, 2020a). The mean CADESI-4 scores decreased significantly, from 24.7 to 9.8 between day 0 and day 21, with a >50% decrease in 69.6% of dogs. On day 21, 52.2% of dogs had a CADESI-4 score <10. The mean pruritus score decreased by 40.6% after 21 days, with a >50% decrease in 52.2% of the dogs. The attending veterinary surgeons considered the improvement as satisfactory, good or excellent in 69.5% of cases. Pet owners were satisfied with the efficacy of the protocol in 73.9% of cases.
Topical antimicrobial therapy in CAD
Chronic cutaneous dysbiosis is common in CAD (Nuttall et al, 2019). Recurrent staphylococcal and/or Malassezia spp. infections initiate flares of inflammation and pruritus (Figure 2). Regular antibiotic treatment (pulse or ‘weekend’ therapy) has been used previously to ameliorate flares associated with staphylococcal infections. However, repeated courses of broad-spectrum antibiotics are a major driver of antimicrobial resistance, and pulse therapy is not now recommended (Nuttall, 2012). Similar pulse therapy with ketoconazole or itraconazole is used to control Malassezia spp. infection, but azole-resistant Malassezia spp. isolates have recently been isolated (Angileri et al, 2019). Using topical antimicrobial therapy to reduce systemic antimicrobial use is therefore important in antimicrobial stewardship.
Topical antimicrobial agents
A wide variety of topical anti-bacterial and anti-fungal agents have been used in dogs (Mueller et al, 2012). These include acetic acid, boric acid, povidone iodine, chlorhexidine, sodium hypochlorite, hypochlorous acid, benzoyl peroxide, ethyl lactate, nisin, phytosphingosines, topical azoles, triclosan and tris-EDTA. Despite this, there are relatively few studies of efficacy and safety of these agents. A systematic review revealed a lack of double-blind RCTs demonstrating in vivo efficacy of shampoo therapy and the superiority of any one or combination of ingredients (Mueller et al, 2012).
Chlorhexidine has the strongest scientific and clinical evidence supporting its anti-bacterial and anti-fungal efficacy. It has been incorporated into shampoos, surgical scrubs, sprays, wipes and solutions at varying concentrations, with or without other ingredients. A study comparing in vitro activity of anti-bacterial and anti-fungal shampoos against Malassezia pachydermatis and a range of antimicrobial-susceptible and resistant staphylococcal, Escherichia coli and Pseudomonas spp. isolates showed that the chlorhexidine-containing shampoos were highly effective irrespective of antimicrobial resistance, whereas the non-chlorhexidine shampoos showed only limited antimicrobial activity (Young et al, 2012). A similar in vitro study showed that chlorhexidine-impregnated wipes were effective against M. pachydermatis, Staphylococcus spp. and E. coli isolates, although efficacy was limited against antimicrobial-resistant E. coli and Pseudomonas spp. isolates (Rafferty et al, 2019). Chlorhexidine shampoos and sprays (although not wipes) show residual anti-bacterial and anti-fungal activity on treated dog hairs (Kloos et al, 2013; Mesman et al, 2016; Rafferty et al, 2019; Ramos et al, 2019). Twice-weekly bathing with 2–4% chlorhexidine shampoos can be as effective as systemic amoxicillin-clavulanate in canine superficial staphylococcal infections (Borio et al, 2015) and in meticillin-resistant staphylococcal infections (Murayama et al, 2010). Based on this evidence, topical treatment, particularly with chlorhexidine-containing products, is recommended for first-line treatment of superficial bacterial and Malassezia spp. skin infections in dogs (Mueller et al, 2012; Brissot et al, 2016).
In addition to their anti-bacterial and anti-fungal activity, it is likely that these shampoos will benefit CAD by cleansing debris and allergens from the skin surface. However, their effect on skin barrier function and specific pruritic and inflammatory pathways in CAD is not proven (Schilling and Mueller, 2012). Combining chlorhexidine or other antimicrobials with emollients in a single product is attractive, but the potential drying effects of the antimicrobial and/or effects on its efficacy must be considered. In addition, poor labelling can make it difficult to determine the full range of ingredients and potential interactions (Loeb, 2019).
Ophytrium-chlorhexidine containing shampoo and foam
As discussed above, ophytrium blocks inflammatory pathways, preserves normal epidermal morphology and barrier function, and reduces staphylococcal adherence and biofilm formation in vitro. It has been combined with 3% chlorhexidine in a novel shampoo and foam formulation (Douxo® S3 Pyo), which maintains anti-bacterial and anti-fungal efficacy compared to a 3% chlorhexidine/0.5% climbazole/phytosphingosine product (Douxo® Pyo). In an open pilot study, atopic dogs with bacterial overgrowth were treated for 3 weeks with either one shampoo and two foam applications per week (Group 1; 9 dogs) or one shampoo followed by a foam application every 48–72 hours (Group 2; 8 dogs) (Gatellet et al, 2020b). The mean cytological bacterial scores (0–4) decreased from 2.2 to 0.8 in Group 1 (64% decrease) and from 3.0 to 1.3 in Group 2 (56% decrease). Decreases in the extent (49% in Group 1; 46% in Group 2) and severity (53% in Group 1; 44% in Group 2) scores were similar between the two treatment protocols. Overall, mean bacterial overgrowth scores declined by 56% in Group 1 and by 52% in Group 2. This shows that the chlorhexidine-ophytrium products reduced bacterial numbers and improved clinical signs, and that a single shampoo followed by foam application every 48–72 hours in a 3-week period was as effective as a weekly shampoo/foam protocol. This is likely to make treatment easier and facilitate compliance.
Conclusions
There is a need for well-designed and controlled studies to provide support for the efficacy of topical products used in CAD with or without surface and superficial skin infections. The ophytrium-based Douxo® S3 range of products are the first to show in vitro and in vivo evidence of safety and efficacy. Safety for patients and their owners was established using the in vitro RCE and RHE models as well as in subsequent clinical trials. The RCE and RHE models showed that ophytrium has positive effects on skin barrier function, epidermal inflammation and the cutaneous microbiome. These are critical areas in the pathogenesis and management of CAD. This was subsequently confirmed in clinical studies, although double-blind placebo-controlled trials will be necessary to confirm the efficacy. The 3-week shampoo and foam application cycles (Figure 3) will greatly aid compliance with treatment.
Effective topical therapy can make a difference. While these products are not likely to manage a patient by themselves, they can improve the efficacy of treatment programmes using other modalities such as allergen specific immunotherapy and antiinflammatory treatment. Reducing the need for systemic treatment will improve safety and reduce costs. Finally, using effective topical antimicrobials will reduce the need for systemic antimicrobials. This is a vital part of antimicrobial stewardship. The benefits of topical therapy should therefore always be considered in the management of CAD.
KEY POINTS
- Topical therapy can help ameliorate canine atopic dermatitis (CAD) and offset the need for more systemic treatments that may be expensive and/or have more adverse effects.
- Using topical anti-bacterial/anti-fungal therapy to reduce systemic antimicrobial treatment is a vital part of antimicrobial stewardship.
- Topical products need to demonstrate efficacy as well as safety for the treated animal and its owners.
- Shampoos are most effective, but non-rinsing foams, sprays and wipes are easier to use.
- Ophytrium is a novel compound that blocks inflammation, epidermal disruption, and staphylococcal adherence and biofilm formation in human and canine epidermis models.
- Use of 3-week treatment cycles with one ophytrium-based shampoo followed by a foam application every 2–3 days has been shown to help ameliorate CAD (Douxo S3 Calm®; Ceva Sante Animale, Libourne, France) and superficial staphylococcal pyoderma (ophytrium/3% chlorhexidine; Douxo S3 Pyo®)