CVC Highlight: Clearing it all up: A review of new dermatology drugs

In veterinary dermatology, the need for more effective and convenient drugs with fewer side effects is continuous. Here are some of the newer drugs available, as well as a few older preparations with new indications.

Patrick Hensel

ANTIMICROBIALS

A variety of veterinary-approved antimicrobials are available to treat pyodermas in small-animals. To minimize the development of antibiotic-resistant microorganisms, it is strongly recommended to use only veterinary-approved antibiotics. Beyond antimicrobial selection, important reasons for treatment failure include inadequate antibiotic dosing or duration and lack of owner compliance. Cephalexin is still a first-choice antibiotic for simple pyodermas, but under certain circumstances newer generations of cephalosporin may be indicated. Treatment duration varies based on the severity of infection and should be continued until one to two weeks beyond clinical resolution.

Cefovecin sodium

Cefovecin sodium (Convenia—Pfizer Animal Health) is a semisynthetic third-generation cephalosporin with a bactericidal effect. It is indicated to treat skin infections caused by Staphylococcus species and Streptococcus canis in dogs and Pasteurella multocida in cats. Occasionally, gastrointestinal signs (diarrhea, vomiting) can be seen with the use of this drug.

Cefovecin is administered subcutaneously (8 mg/kg) and can be repeated in seven to 14 days, making it convenient for noncompliant clients. However, care must be taken to ensure that the infection is completely cleared before stopping treatment. Even though the convenience of this drug is tempting, it is not recommended for superficial pyodermas, which are likely to respond well to cephalexin. Instead, it should be reserved for deeper infections.

Cefpodoxime proxetil

Another third-generation cephalosporin, cefpodoxime proxetil (Simplicef—Pfizer Animal Health), is also available for treating skin infections in dogs. This drug is well-tolerated, although gastrointestinal signs may occasionally occur. It is administered orally once a day (5 to 10 mg/kg), making it a convenient choice. And since it is provided as a tablet and not a gelatin capsule, it is a good choice for dogs that are undergoing a hypoallergenic elimination diet trial to rule out cutaneous adverse food reaction.

Chloramphenicol

One nearly forgotten antibiotic is chloramphenicol. Because contact with this drug can cause an irreversible aplastic anemia in a small percentage of people, it is no longer routinely used in human medicine. Because of the rare use of chloramphenicol, methicillin-resistant Staphylococcus species infections have often been susceptible to this drug so far. However, these infections are invariably secondary to an underlying condition, so beyond treatment of the infection, the primary problem must be identified and addressed. Treatment of methicillin-resistant Staphylococcus species should also always be based on a culture and sensitivity.

Chloramphenicol has good tissue penetration, but since it is bacteriostatic, appropriate dosing and duration of treatment must be achieved. Drawbacks to its use are that it must be given orally (30 to 50 mg/kg) three times a day, and owners need to be advised about the human health risks and wear gloves whenever handling the drug to avoid exposure.

TOPICAL THERAPY

Topical agents have been recognized as a important form of adjunct treatment to enhance resolution of various cutaneous skin diseases, especially skin infections.

Third-generation Tris-EDTA

Third generation Tris-EDTA (Tricide—Molecular Therapeutics) is a chelating agent that removes divalent cations from the outer membrane of bacteria and fungi, causing physical damage to ("poking holes" in) the membrane. Studies have shown that Tris-EDTA is also effective in damaging the cell walls of yeast, which is useful when treating Malassezia otitis.1 It is completely nonirritating, is extremely stable, and can be stored for extended periods.

Tris-EDTA in combination with an appropriate antimicrobial can greatly increase efficacy, even against resistant microorganisms.2-4 It can be mixed with many injectable antimicrobial drugs and then used topically. At the time of use, the appropriate antibiotic or antifungal can be added (e.g. 0.5 to 2 mg enrofloxacin, amikacin, or gentamicin added per ml Tricide; 0.1 to 0.5 mg fluconazole or miconazole/ml Tricide). In this manner, it can be used to topically treat resistant infections or areas where more medication application (such as flushing deep wounds) is needed.

Potentiated silver

SilvaKlenz (Molecular Therapeutics) is a skin and wound cleanser that does not contain alcohol, triclosan, or benzoyl chloride and, thus, does not inhibit wound healing. As with Tricide, this topical product may have a potentiated antibacterial efficacy and may be effective in breaking down bacterial biofilm (even methicillin-resistant Staphylococcus aureus biofilm), a significant barrier to effective treatment of infections. A sister product, Silvion (Molecular Therapeutics), is a spray-on topical antimicrobial skin and wound moisturizer.

Tacrolimus

Tacrolimus (Protopic 0.1% ointment—Astellas) is an option for topical therapy of localized immune-mediated diseases such as atopy, discoid lupus erythematosus, pemphigus erythematosus, and pemphigus foliaceus and for maintenance of patients with perianal fistula. Although used orally in people, it has not been used orally in veterinary medicine because of the high frequency of side effects.5 It has a similar mode of action to that of cyclosporine but is more potent. Inform owners that a transient increase in local erythema and irritation can occur after starting therapy. Tacrolimus ointment is applied topically to the affected skin once daily. Based on study data, it appears to be both safe and effective.6

IMMUNE-MODIFYING DRUGS

Treatment of immune-mediated skin diseases generally requires immunosuppressive drugs, such as corticosteroids. However, some medications are now available to lessen that need or to replace corticosteroids for long-term management of these conditions. While generic products for some of these medications are available, their bioavailability is not always equivalent to that of the parent product. The cost of the branded product is the most common reason why clients wish to use a generic form. It is recommended to initiate therapy with a branded product and, once full effect has been achieved, then a generic product may be used if requested by the client. The client must be informed that these generic drugs may not work as well and dosing may need to be adjusted.

Cyclosporine

Cyclosporine (Atopica—Novartis Animal Health) has both anti-inflammatory and immunosuppressive properties. It targets cell-mediated immunity, and with its other properties, it results in fewer side effects than corticosteroids. It is used to treat perianal fistulas and canine atopic dermatitis and can also be an effective maintenance drug for patients with autoimmune diseases such as pemphigus foliaceus. A double-blinded, randomized study of 29 cats comparing the efficacy of once-daily dosing of cyclosporine (1 mg/kg) to prednisolone (5 mg/kg) in cats with atopic dermatitis concluded that there was no significant difference in response.7 Atopica has just been FDA-approved as an oral solution for cats.

Given that this drug is metabolized in the liver, take caution when using it in patients with liver disease. Many other drugs use the same enzyme system in the liver, and their use can reduce the metabolism of cyclosporine. For example, giving 5 mg/kg/day ketoconazole orally can help to reduce the cyclosporine dose by up to 50%. By reducing the dose, the risk of side effects is also reduced. The most common side effects associated with cyclosporine include vomiting, diarrhea, and anorexia.

Cyclosporine is generally given without food, resulting in rapid absorption and the risk of gastrointestinal side effects. Giving with food, freezing the capsules, splitting the dose (twice daily), or giving with metoclopramide or ketoconazole, which allows a further reduction in dose, may be effective in reducing the risk of adverse effects. Long-term management requires finding the lowest effective dose, and patients should have blood work evaluated every three months during the treatment of active disease and, once stable, at least once a year.

Pentoxifylline

The human product pentoxifylline (Trental—Sanofi-Aventis) is a vasoactive agent with anti-inflammatory properties. It has been used to treat vasculitis, atopy, and dermatomyositis in dogs. It can take several weeks of treatment with pentoxifylline to be effective. One study in dogs with familial canine dermatomyositis showed a median response time to treatment of six weeks.8

This medication should be given with food, and the side effects, while rare, include vomiting, diarrhea, and central nervous system excitement.

Trilostane

Trilostane (Vetoryl—Dechra Veterinary Products) is indicated for treating Cushing's disease. This synthetic steroid analogue reduces the synthesis of cortisol, aldosterone, and adrenal androgens. This inhibition is reversible and dose-dependent. Trilostane significantly reduces the production of progesterone, so it should not be used in breeding animals.

In addition to treating Cushing's disease, trilostane has been used effectively in the treatment of alopecia X. While this is not considered a severe disease but more of a cosmetic problem, owners may elect to treat it. In one study involving 18 Pomeranians with alopecia X given a high dose of trilostane (11 mg/kg/day), 85% demonstrated improvement of clinical signs within four to eight weeks, and no adverse effects were reported.9

The clinical dose for the treatment of alopecia X ranges from 2 to 6.7 mg/kg given orally once daily with food. The recommended initial dose is 2 mg/kg given once or twice daily. Response may take several months, at which time the dose should be tapered to the lowest effective dose. Side effects are rare and can include diarrhea, vomiting, and lethargy. Patients receiving trilostane should be monitored with regular ACTH simulation tests.

TYROSINE KINASE INHIBITORS

Toceranib phosphate

Toceranib phosphate (Palladia—Pfizer Animal Health), a receptor tyrosine kinase inhibitor, has direct antitumor and antiangiogenic activity. It is the first FDA-approved veterinary cancer therapy and is indicated for treating grade II or III mast cell tumors in dogs. Side effects include diarrhea, neutropenia, and weight loss.

Masitinib

Masitinib (Kinavet-CA1—AB Science) is another tyrosine kinase inhibitor useful for treating mast cell tumors in dogs that is currently available in the United States and conditionally approved by the FDA. Masitinib may also be useful in treating atopic dermatitis. A study looking at this application demonstrated a significant reduction in clinical signs.10

ANTIVIRAL DRUGS

Imiquimod

Imiquimod (Aldara 5% cream—3M Pharmaceuticals) is an immune response modifier designed to stimulate a patient's own immune system to release cytokines. This drug is expensive, which can be an impediment to wider use. While considered an antiviral, antitumor drug, it does not have a direct antiviral effect. It has been used to treat papilloma and sarcoids in horses with some success. In small animals, it has been used to treat feline herpesvirus dermatitis, actinic keratosis, and squamous cell carcinoma. Inform owners that it can produce local irritation, pruritus, and oozing. Imiquimod is applied in very small amounts once weekly to every other day to the affected area until the lesion resolves.

Interferon alfa-2b

Interferon alfa-2b (Schering; consult your local distributor) is known to increase cytokine production and is used to treat viral infections and for immunomodulatory purposes. It can be used to treat canine papillomavirus infection and recurrent pyodermas in dogs and indolent ulcers, idiopathic facial dermatitis, dermatitis secondary to feline herpesvirus infection, and atopy in cats. There is a huge dose range for use in dogs (30 to 20,000 IU orally once a day11) and cats (60 to 120 IU/day orally), and it comes highly concentrated (10 million IU/vial), necessitating dilution before use. It can be diluted and stored (frozen) for several months.

Patrick Hensel, Dr.med.vet., DACVD

Department of Small Animal Medicine & Surgery

College of Veterinary Medicine

University of Georgia

Athens, GA 30602

REFERENCES

1. Hensel P, Austel M, Wooley RE, et al. In vitro and in vivo evaluation of a potentiated miconazole aural solution in chronic Malassezia otitis externa in dogs. Vet Dermatol 2009;20(5):429-434.

2. Wooley RE, Ritchie BW, Burnley VV. In vitro effect of a buffered chelating agent and neomycin or oxytetracycline on bacteria associated with diseases of fish. Dis Aquat Organ 2004;59(3):263-267.

3. Weinstein WL, Moore PA, Sanchez S, et al. In vitro efficacy of a buffered chelating solution as an antimicrobial potentiator for antifungal drugs against fungal pathogens obtained from horses with mycotic keratitis. Am J Vet Res 2006;67(4):562-568.

4. Austel M, Hensel P, Wooley RE, et al. Comparison of the effect of tris EDTA (Tricide)-ciprofloxacin-fluconazole-dexamethasone-ear drops with Baytril otic in dogs with acute or chronic bacterial otitis externa (abstr). Vet Dermatol 2009;20: 218.

5. Vaden SL. Cyclosoprine and tacrolimus. Semin Vet Med Surg (Small Anim Pract) 1997; 12(3):161-166.

6. Griffies JD, Mendelsohn CL, Rosenkrantz WS, et al. Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus erythematosus in dogs. J Am Anim Hosp Assoc 2004;40(1):29-41.

7. Wisselink MA, Willemse T. The efficacy of cyclosporine A in cats with presumed atopic dermatitis: a double blind, randomized prednisolone-controlled study. Vet J 2009;180(1):55-59.

8. Rees CA, Boothe DM. Therapeutic response to pentoxifylline and its active metabolites in dogs with familial canine dermatomyositis. Vet Ther 2003;4(3):234-241.

9. Cerundolo R, Lloyd DH, Persechino A, et al. Treatment of canine Alopecia X with trilostane. Vet Dermatol 2004;15(5):285-293.

10. Cadot P, Hensel P, Bensignor E, et al. Masitinib decreases signs of canine atopic dermatitis: a multicentre, randomized, double-blind, placebo-controlled phase 3 trial. Vet Dermatol 2011;22(6):554-564.

11. Thompson LA, Grieshaber TL, Glickman L, et al. Human recombinant interferon alpha-2b for management of idiopathic recurrent superficial pyoderma in dogs: a pilot study. Vet Ther 2004;5(1):75-81.