New drugs in veterinary dermatology (Proceedings)

This lecture will familiarize you with the use of some of the new drugs for used for common dermatologic diseases in veterinary medicine.

Itraconazole (Sporonax ®-Janssen Pharmaceuticals- 100 capsules and 10 mg/ml oral solution)) is a member of the azole family of antifungal agents. Imidazoles (Imidazole family (thiabendazole, clotrimazole, ketaconazole, miconazole and enilconazole) and triazoles (itraconazole and fluconazole) make up this family of drugs. All azoles are potent inhibitors of ergosterol synthesis (a main membrane lipid of fungi) via inhibition of a microsomal cytochrome P450 enzyme (14 α sterol demethylase) (see table 1). Since mammalian cytochrome P450 is involved in glucocorticoid and sex hormone synthesis (androgens), depending on which azole, the dog's cortisol and androgen levels may decrease during therapy. This is more of a potential problem w/ketaconazole then w/itraconazole (ITZ) because ITZ is more selective for the fungal enzyme than the mammalian form. Itraconazole has been used in veterinary dermatology for many years to treat subcutaneous (eg Sporotrichosis) or systemic (eg cryptococcus, histoplasmosis) mycotic infections. More recently it has been used for treating cats (and occasionally dogs) for dermatophyte infections. It has also been found to be very effective for the management of Malassezia dermatitis. For cats w/dermatophytosis the author uses "pulse" therapies (i.e., daily therapy for 1 week, then one week off, then one week on, etc) at a dosage of 5-10 mg/kg/day. It is better absorbed if given with food. Side effects of itraconazole in dogs or cats include anorexia, GI disturbances, hepatopathies and in dogs (when using higher doses (10 mg/kg)) vasculitis. It is teratogenic so it is not to be used in pregnant animals. For dog's w/Malassezia dermatitis, 5 mg/kg, 2 consecutive days/week is as effective as daily administration.

Fluconazole (Diflucan®, Pfizer Pharmaceuticals) is another alternative for the systemic treatment of Malassezia but until recently had been more expensive than either ketoconazole or itraconazole. The dosage is similar to ketoconazole 5-10/kg once daily- GI absorption is unaffected by food intake. The residual effect of fluconazole is similar to itraconazole. Fluconazole is eliminated primarily via the kidneys so administering this drug to a dog w/hepatic disease could be advantageous over the other azoles. Dosage adjustments for dog's w/renal compromise are necessary.

Terbinafine (Lamisil): This anti-fungal agent, now available in generic, can be effective in treating dermatophytosis when given at 30-40 mg / kg / day. A study performed at University of Florida determined that terbinafine persists in hair at concentrations above the MIC for at least 5 weeks after stopping the medication, even after short-term therapy (14 days). However in this study So far clinical studies have not shown it to be more effective than itraconazole.

Imiquimod (5%, Aldara®, 3M Pharmaceuticals) is a topical immunomodulator that has potent antiviral and antitumor activity that is at least partially due to stimulating the production of a variety of cytokines, including α interferon, γ interferon and IL-12. In humans it has been used in the treatment of genital warts, common warts, herpes simplex, keloid, actinic keratoses (AK), basal cell carcinomas and Bowen's disease (squamous cell carcinoma in situ). Most recently it has been reported to be effective for the patch and plaque stages of CTCL in people. In veterinary medicine it has been used for the treatment of Bowen's disease and cutaneous herpes virus infection in cats, AK, warts caused by papilloma virus, sarcoid and aural plaques (in horses). It is applied 2-3 times weekly, usually beginning w/2 times weekly and if tolerated increasing it to 3 times weekly. Side effects may include localized irritation.

Calcineurin inhibiting drugs such as topical tacrolimus (0.1 percent, Protopic®, Fujisawa) and orally administered modified cyclosporine systemically (Atopica®. Novartis Animal Health) first binds an immunophilin (which is an intracellular protein that binds immunosuppressive drugs). This complex binds to calcineurin (a calcium dependent phosphatase that is activated following T cell surface receptor activation). Calcineurin dephosphorylates NFAT (Nuclear Factor of Activated T-cells), which then translocates to the nucleus and activates specific genes. By inhibiting calcineurin, tacrolimus prevents T cell activation and the transcription of proinflammatory genes. It also inhibits the activation of mast cells, eosinophils, lymphocytes, Langerhans' cells, and keratinocytes. Lastly, it also activates transcription of genes responsible for the secretion of immune inhibiting proteins such as TGF-β (transforming growth factor), which is a family of immunosuppressive cytokines. Two of these inhibitors used in veterinary medicine are

Tacrolimus (0.1 percent, Protopic®, Fujisawa) in animals it has been used topically to treat perianal fistulas, KCS, DLE, focal lesions localized immune-mediated disease such as w/pemphigus erythematosus or foliaceus, vasculitis lesions (pinnal, post vaccine), idiopathic sterile granuloma/pyogranuloma syndrome, alopecia areata, vitiligo and focal lesions associated w/atopy. It is applied bid until effect and then taper. Side effects are limited to local irritation.

Modified cyclosporine (Atopica®, Novartis) is a calcineurin inhibitor that is administered orally. To increase absorption, only modified cyclosporine should be used. The dosage for dogs is 5 mg/kg sid, while the feline dose (off label use) is 5.0- 7.5 mg/kg sid (off label- be sure to retrovirus test prior to administration in cats). There may be a 4-6 week delay before seeing full effectiveness so you can give glucocorticoids during the first 3 weeks to help keep the dog comfortable during this lag time. Side effects in dogs are very limited and are primarily GI. Other side effects reported include cutaneous papillomatosis and hyperplastic gingivitis. In order to minimize the most limiting factor of CSA (vomiting) I use Cerenia® for the first 4 days and administer Atopica® with a meal. An important drug interaction is ketaconazole (KCZ). KCZ inhibits the enzyme responsible for CSA metabolism (cP450 3A4) thereby increasing concentrations and prolonging elimination of CSA. Because of the cost of CSA, coadministration with ketaconazole has been used by some authors in DOGS. This combination with KCZ can lower the amount of CSA that needs to be administered. Doses suggested are 2.5 mg/kg of CSA and 7.5 mg/kg of KCZ sid. Please note failure to respond to this combination doesn't mean that a full dose of CSA will be ineffective. The author therefore rarely begins therapy w/this combination. I use this drug in dogs with atopic dermatitis the dog is moderately to severely pruritic and I want to avoid steroids. It is also used (off label use) for the treatment of perianal fistulas, sebaceous adenitis, feline eosinophilic plaques/granulomas/indolent ulcers and feline atopic dermatitis

Cefpodoxime proxetil (Simplicef®, Pfizer) and cefovecin (Convenia®, Pfizer) are 2 new antibiotics available for small animal practice.

Cefpodoxime (Simplicef®, Pfizer) is a 3rd generation cephalosporin effective for most of the Staphylococcus infections that occur in dogs. This once a day antibiotic is useful in cases where the owner has difficultly administering capules not only because it is once a day but it seems that these pill are easier to give. When doing a food trial it is best to avoid gelatin (animal protein) so that giving cefpodoxime tablets would fill this need. Also it seems like there is less GI disturbances than there is w/cephalexin. An additional reason to dispense Simplicef is the veterinary drug companies must be supported so that they have the resources to continue R &D. However consider when dispensing cefpodoxime there are some Staphylococcus infections that will be resistant to cefpodoxime but susceptible to cephalexin. Also the supposed advantage that a once a day treatment may not be such- a study revealed there is no difference in compliance w/sid vs bid. Lastly there are numerous studies showing that sid cephalexin at 30-40 mg /kg sid is as effective as splitting this dose, however this is NOT my recommendation but that missing 1dose of cephalexin is not catastrophic. Also see comments about 3rd generation cephalosporin use below.

Cefovecin (Convenia®, Pfizer) is a parenterally administered 3rd generation cephalosporin that will be of tremendous value when used selectively. I feel that for now this drug should be reserved for cases where the owner is unable to medicate the dog or cat. I am concerned that I that therapeutic drug concentrations after the first injection are maintained for only 7-14 days depending on the infectious agent while tissue levels persist for up to 65 days. The question is whether this prolonged subtherapeutic blood (tissue?) level will encourage the incidence of methicillin resistant Staphylococcus. Will adverse reactions require prolonged treatment due to the prolonged systemic drug clearance? What are the long-term effects on injection sites especially in cats? How clinically significant is the in vitro finding that cefovecin increases free concentrations of carprofen, furosemide, doxycycline, and ketoconazole. Will drugs w/a high degree of protein-binding (e.g. cardiac, anticonvulsant, and behavioral medications) compete enough with cefovecin-binding to adverse reactions.

In regards to 3rd generation cephalosporins and any fluoroquinolones, in the BSAVA Guide to the Use of Veterinary Medicines, prudent use of antimicrobial agents it is stated that in all species fluoroquinolones and third- and fourth-generation cephalosporins should be used judiciously and never considered as first-choice options.

Also the European Medicines Agency states (EMEA/CVMP/215997/2006) "Following advice given by the CVMP Scientific Advisory Group on Antimicrobials (SAGAM), the CVMP agreed the following statements should be included in section 4.5 of the SPC (special precautions for use) "It is prudent to reserve third generation cephalosporins for the treatment of clinical conditions, which have responded poorly, or are expected to respond poorly, to other classes of antimicrobials or first generation cephalosporins." and "Use of the product should be based on susceptibility testing and take into account official and local antimicrobial policies".

Baths -Topical therapy has been always been a component of treating dermatologic diseases in veterinary medicine. The increasing incidence of resistant bacterial infections in the skin has brought this well known but underutilized therapy to the forefront. Antimicrobials (antiseptics and topical antibiotics) are becoming the foundation of the treatment of bacterial pyoderma in the dog. There are numerous cases in which the author, pending culture results of a pustule, instituted topical antimicrobial therapy. In some of these cases when the owner was contacted concerning the culture results and an oral antibiotic was recommended, the owner would question whether they needed to add oral therapy to the treatment since the dog was significantly better!

An investigator-blinded, placebo controlled randomized controlled trial (RCT) in 2009 published in Pediatrics showed that some people with atopic dermatitis benefited from taking regular bleach baths in diluted bleach and lukewarm water along with having topical mupirocin applied in their nares In the study 31 patients (6 months to 17 years old) who had moderate to severe atopic dermatitis and a bacterial skin infection were treated with oral antibiotics for 14 days. Half of these patients also received bleach in their bath water (half a cup per full standard tub). The other half bathed in a placebo. All were instructed to bathe for 5 to 10 minutes twice a week for three months. The research team saw such rapid improvement in the children taking the bleach baths that they ended the study early. However, in addition to the bleach baths, in the treatment group, topical mupirocin was applied in the nares. Because of this and numerous other issues with this study, the author feels that it is a treatment that can be considered in selected cases of dogs with atopic dermatitis and recurrent pyoderma.

There are studies that support the use of topical antiseptics in the treatment of canine superficial bacterial pyoderma. In 2010 Loeffler et al performed a study to assess and compare the clinical and antibacterial efficacy of two shampoos used as sole antimicrobial treatment in dogs with superficial pyoderma. They compared a 3% chlorhexidine gluconate shampoo (Leo Animal Health) with a 2.5% benzoyl peroxide shampoo (Paxcutol, Virbac) in 22 dogs with superficial pyoderma. Owners washed their dogs two to three times weekly with a ten-minute contact time for 21 days. This abstract states that it was a randomized, partially blinded study but did not explain the partial blinding component. Response was measured on days 1, 8 and 22 through clinical scores (owner-assessed pruritus; clinician-assessed pruritus, skin lesions and coat condition, all on a scale of 1-5), total bacterial counts and counts of coagulase-positive staphylococci obtained with a detergent scrub method. Overall response was assessed at the end of the study by the clinician. Overall clinical improvement was seen in 15 (68.2%) dogs with either shampoo. Lesions associated with pyoderma had resolved in three dogs, improved in 12, remained unchanged in 4 and worsened in 1 dog at the end of the 21 day study.

In another study the effectiveness of 2% chlorhexidine acetate (surgical scrub) was evaluated in the treatment of canine superficial bacterial pyoderma. This study had 2 components. The first was to evaluate the clinical efficacy 2% chlorhexidine for the treatment of canine superficial pyoderma. This study was a randomized, double blinded, controlled trial. The dogs were washed twice weekly for 1 week with a 5 minute contact time. At the end of 7 days the owners and investigator rated the clinical appearance as follows- excellent (score 3), having complete disappearance of skin lesions after treatment; good (score 2), having apparent improvement with some lesions remaining after treatment; fair (score 1), having no apparent improvement and some newly developed lesions after treatment; or poor (score 0), having exacerbation during treatment. The control group was bathed with 4% chlorhexidine gluconate. In the 2% group there were 6 dogs rated as good, 3 as fair and 1 as poor, while the 4% there were 7 rated as good and 3 as fair. This suggests that just bathing w/chlorhexidine can improve the clinical appearance of canine pyoderma. The weakness in this study is that they didn't have a placebo controlled group.

The second component was an open trial using 2% chlorhexidine acetate in eight dogs with cefalexin-resistant Staphylococcus intermedius group associated superficial pyoderma. The dogs were bathed every 2 days for 2 weeks. At the end of 14 days the owners and investigators rated the clinical appearance as follows excellent, improvement without the need for antimicrobial administration; good, improvement with some remaining lesions in need of antimicrobial, administration; fair, no apparent improvement with some newly developed lesions after treatment; or poor, exacerbation during treatment. Five of the 8 dogs were completely cured while the other 3 needed systemic antibiotic therapy. Their conclusion was a 2% chlorhexidine shampoo could be a useful and safe topical adjunct therapy for dogs with superficial pyoderma involving cefalexin-resistant Staphylococcus intermedius group. The majority of dogs, however, also required systemic antibiotics to resolve the infection

Lastly the buzz word in veterinary medicine is compliance. In an abstract presented at the 2011 NAVDF described a study in which 10 dogs with a superficial bacterial pyoderma due to a member of SIG were washed with 2% chlorhexidine (Nolvasan Surgical Scrub Fort Dodge Animal Health). Two different contact times (Group 1: 1 min, Group 2: 10 min) were investigated in symmetrical lesions at different sites every two days for 4 times. Sixty and 70% of dogs subjectively evaluated by owners and investigators showed excellent to good improvement in Group 1 and 2. The abstract did not define what excellent and good responses meant but even without those definitions, this study suggests that we can improve compliance by not insisting that the dogs have a 10 minute contact time with the shampoo. But before we reach this conclusion we need to see if this result is reproducible using the non surgical shampoos.