The District of Columbia Academy of Veterinary Medicine

January 2003
Dermatology

Daniel O. Morris, DVM, DACVD
University of Pennsylvania, Philadelphia, Pennsylvania

Otitis Externa and Media: Diagnosis and management
in the age of antibiotic resistance

The systematic approach to otitis should consider several different levels of disease. Acute otitis externa, chronic/recurrent otitis externa, and otitis externa/otitis media. The following is one potential "roadmap" to guide you through the pitfalls of diagnosis and management.

rule out physical causes
1. conformational defects
  1. stenotic otic canals -- congenital/hereditary in some breeds
  2. pendulous pinnae -- a desirable characteristic in many breeds
  3. hirsute canals/concave pinnae -- hereditary in some breeds
2. environmental effects
  1. excessive moisture -- "swimmers ear"
  2. high humidity
3. treatment effects
  1. irritating cleansers
  2. cotton-tip trauma
  3. superinfections
4. obstructive masses
  1. polyps, tumors
  2. foreign material -- plant awns, fox tails, etc.
rule out underlying diseases
1. parasitic etiologies
  1. otodectes cynotis
  2. sarcoptic/notoedric mange
  3. demodicosis
  4. Otobius megnini (the spinous ear tick)
  5. Eutrombicula (chiggers)
  6. stomoxys calcitrans (stable flies -- "fly strike")
2. hypersensitivities
  1. atopy and/or food allergy
  2. contact allergy
  3. drug eruptions
3. diseases of altered cornification and/or lipid production
  1. hyperadrenocorticism
  2. hypothyroidism
  3. sex-hormone imbalances
  4. glandular disorders (apocrine or sebaceous glands)
  5. idiopathic seborrhea (Cocker Spaniels, Bassett Hounds)
4. autoimmune diseases
  1. lupus erythematosus
  2. pemphigus complex
  3. bullous pemphigoid
5. other systemic diseases that result in
  1. pyrexia, catabolic states
  2. immune suppression
assess the degree of progressive pathology
1. external ear canal: hyperkeratosis, fibrosis, calcification, glandular hyperplasia
2. concurrent otitis media: ruptured tympanum +/-- destructive osteomyelitis of the tympanic bullae. This assessment necessitates:
  1. otoscopic examination -- may require general anesthesia
  2. may require radiographic imaging or CT scan in order to assess bullae
3. Must answer question: Is this a medically salvageable ear, or does it require surgical intervention?
diagnose the secondary infection
1. cytology of ear exudate -- smear on glass slide, heat fix, stain
  1. cocci -- Staph. intermedius, Streptococcus spp.
  2. rods -- E. coli, Pseudomonas spp., Proteus spp., Klebsiella spp., Corynebacterium spp.
  3. yeast -- Malassezia pachydermatis and Candida albicans (rare)
  4. include a swab of exudate in mineral oil to look for parasites (otodectes, demodex, etc.)
2. Is an otitis media involved?
  1. No -- cytology is sufficient (in acute otitis cases)
  2. Yes -- collect a swab for culture/sensitivity before cleaning the ear!
    1. Carefully pass a sterile culturette through the operating otoscope to sample the middle ear.
    2. If the tympanum is intact, but exudate is visible on the other side, perform a myringotomy
  3. unsure/can't see it because of secondary swelling
    1. approach treatment as if it is ruptured
    2. treat the dog with a systemic steroidal anti-inflammatory for 1 to 2 weeks and try again
  4. What about an intact tympanum in a chronic otitis case?
    1. recent studies have shown that up to 80% of chronic otitis canals with what appear to be intact tympanic membranes have a concurrent otitis media! A myringotomy should be performed in these chronic cases for culture/sensitivity testing
3. skin biopsy -- underutilized in the work-up of otic disease
  1. helpful in the diagnosis of otic demodicosis, allergic otitis, idiopathic seborrhea, sebaceous adenitis
formulate a treatment strategy
1. diagnose/treat the underlying disease if one is present
2. treat the infection itself
3. topical antibacterial preparations for otic use:
  1. Neomycin (Panalog, Animax, Tresaderm
    Broad spectrum, low potency, may be ototoxic
  2. Gentamicin (Gentocin otic, Topagen, Otomax)
    Broad spectrum, high potency, may be ototoxic
  3. Chloramphenicol (Liquichlor, Chlormycetin Otic)- no longer available.
    Broad spectrum, high potency, aplastic anemia a concern in humans
  4. Polymyxin B [Otobiotic, Cortisporin otic (includes neomycin)]
    Narrow spectrum (Gram neg. rods), high potency, use for gentocin resistant rods
  5. Polymyxin E [Coly-Mycin S. (includes neomycin)]
  6. Silver sulfadiazine powder or 1% cream. The cream is available as a generic or by the trade name SilvadeneÒ. The powder is available through Aldrich chemical. Also available in combination with enrofloxacin in Baytril otic (Bayer). Narrow spectrum, high potency: use for polymyxin B-resistant rods, or with any chronic Pseudomonas otitis. Mix cream 1:3 with water (or more dilute) for otic use. I commonly use BurOticHC or Epi-otic as a carrier. The powder can be reconstituted at a 1% or lower concentration. In-vitro studies have shown 0.1% solution to be effective against Pseudomonas.
  7. Enrofloxacin: Baytril otic (Bayer) or use the injectible product in a carrier solution. Gram neg. spectrum + Staph., high potency. Use for severe, refractory Gram neg. infections when all else fails, or when you are forced to use systemic fluoroquinolones (based on C/S) for a concurrent otitis media.
  8. Amikacin injectible (dilute 250mg/ml solution to 50mg/ml) High potency for some strains of gentamicin-resistant Gram neg. rods. Works best in an alkaline environment - compatible with chlorhexidine
  9. Tobramycin [Tobrex ophthalmic and Nebcin injectible (dilute injectible with 150cc sterile water to 8mg/ml)]
4. topical antifungals for otic use
  1. Thiabendazole (Tresaderm) -- efficacy is variable
  2. Nystatin (Panalog, Animax) -- for Canidida, but not Malassezia
  3. Iodine preparations (Xenodyne) -- excellent efficacy, but stains!
  4. Domboro's solution (HB-101, Hydroplus, Otic Domboro, BurOtic) -- drying agent, and acidifier
  5. the Imidazoles: Miconazole 1% (Conofite Lotion) -- very effective Clotrimazole 1% (Veltrim, Otomax) -- some resistance Ketoconazole 2% (Nizoral Lotion) -- very effective
5. therapy of acute otitis externa
  1. yeast alone -- your choice
  2. cocci or cocci/rods -- neomycin, gentamicin
  3. rods only - neomycin, gentamicin
  4. treat BID for 14 days
  5. dose liberally -- small dogs get 4-6 drops, large breeds get 10-12
  6. mix products "in vivo" if using a combination of antibacterial/anti-yeast
6. therapy of chronic otitis externa
  1. history of previous treatment
  2. thorough otoscopic exam
  3. cocci or cocci/rods -- gentamicin or silver sulfadiazine
  4. refractory rods -- polymyxin B, silver sulfadiazine, fluoroquinolones
  5. treat for 21 days minimum, recheck at 7 days, and again before stopping treatment
  6. Always try the less aggressive antimicrobials first
  7. Use concurrent systemic antibiotics if there is pinnal involvement.
  8. NB! The author NEVER uses a topical fluoroquinolone in an ear unless the pet is also receiving systemic fluoroquinolone treatment, due to the potential for rapid development of resistance if the tympanum is compromised and sub-therapeutic concentrations reach the middle ear cavities!
7. pre-soaks for refractory Pseudomonas infections
  1. TRIS-EDTA -- 6gm salt EDTA + 1.2 gms TRIS. qs to 1 liter with distilled water, adjust pH to 8.0 with Hcl (compounding pharmacy) Commercial products: Triz-EDTA (Dermapet); T8 solution (DVM)
  2. 2-5% Acetic acid (white vinegar) -- mix 1:1 to 1:3 with water
8. H. cleaning/flushing of the ear canal - the most important aspect!!
  1. ceruminolytics -- surfactants and detergents that soften and solubilize waxy organic debris for removal [Clear-X (DVM pharm.), Cerulytic (Allerderm/Virbac), Cerumene (Evsco), Surfac (Amer. Hoechst), Panotic (Pfizer)]
  2. combination cleaning/drying agents -- for use in the clinic and at home for routine cleaning and prophylaxis in the recurrent otitis patient. These acidify the ear canal and kill microbes. [Epi-Otic (A/V), Oticalm (DVM), Oti-clens (Beecham), OtiRinse (DVM), AloCetic (DVM); DermaPet cleanser]. Advanced pHormula by EVSCO maintains a pH <5 for up to 18 hours.
  3. antiseptics - Typically utilize chlorhexidine alone or in combination with another antifungal agent. Chlorhexiderm flush (DVM), Hexadene flush (A/V), Malaseb flush (DVM), etc….
  4. flushing solutions
    1. tepid water or saline +/- mixed with a mild ceruminolytic
    2. dilute povidone-iodine (1:50 in water -- weak tea in color)
    3. chlorhexidine (2% diluted to 1:40 in water)
    4. acetic acid (dilute 1:1 to 1:3) -- higher conc. can be irritating
9. I. corticosteroids in otic preparations
  1. antipruritic, and antiinflammatory
  2. decrease glandular secretions (cerumen)
  3. decrease pain and swelling
  4. decrease scarring and hyperproliferation
  5. may be systemically absorbed! Dose-dependent suppression of the hypo-thalamic/pituitary/adrenal axis (iatrogenic Cushing's disease). May influence diagnostic tests such as: CBC, serum chemistry, urinalysis, thyroid profile, and intradermal skin test, beyond the duration of therapy.
special considerations for otitis media
1. definition: inflammation of the tympanic bulla
  1. source of debris, infection, and pro-inflammatory toxins
  2. eventual dystrophic mineralization
  3. exudate is difficult to reach with topical antimicrobials
2. therapy of otitis media
  1. otitis externa is assumed, and you will be treating this based on a cytology anyway
  2. concurrently, treat the otitis media with systemic antibiotics based on a bulla culture/sensitivity for 45 to 60 days minimum
  3. systemic corticosteroids are often indicated to decrease inflammation and swelling: Predniso(lo)ne, 0.5 mg/kg, Bid for 7 days, then Qd for 7 days, then Eod for 7 doses, for antiinflammatory effects
  4. recheck at 1 to 2 weeks, then PRN to assess progress/end-point.
3. guidelines for treating the ear with a ruptured tympanum
  1. no heavy oils/ointments
  2. caution with aminoglycosides (ototoxicity): although recent studies have shown that gentamycin (at concentrations available in commercial products) is not ototoxic to normal dogs, ample anecdotal reports exist to support that it is still a concern in diseased ears.
  3. systemic antibiotic based on C/S: recent studies suggest that antibiotic choice should be based upon MIC's rather than Kirby-Bauer susceptibility testing.
  4. oral ketoconazole (Nizoral) or itraconazole (Sporanox) for yeast - 10mg/kg Qd x 28days minimum.
4. cleaning the ear when the tympanum is compromised: thorough cleansing of the tympanic bulla often makes the difference between resolution and continued chronic otitis media.
  1. water or saline
  2. very dilute povidone-iodine (Betadine solution 1:50)
  3. avoid foaming agents and ceruminolytics (such as DSS and peroxides) unless you can thoroughly rinse them from the bullae.
  4. flush with warm water using a rubber ear bulb syringe or a rubber feeding tube with a 12cc syringe attached
  5. fiberoptic (rigid) endoscopic otoscopes allow excellent visualization and flushing via a rigid Tom-cat catheter. Suction is also enhanced.
  6. NB! Aggressive flushing of the bullae should never be performed without an endotracheal tube in place…risk of aspiration!!
Surgical therapy of otitis
1. Lateral ear canal resection (Zepp procedure):
  1. Useful in dogs with congenitally stenotic ear canals (Shar Peis are notorious).
  2. Allows for easier cleansing/treatment by owners, and better aeration.
  3. Must be performed before proliferative otitis externa has begun!
    1. Useless in most Cocker Spaniels.
  4. Does NOT cure allergic otitis, or otitis due to idiopathic seborrhea.
2. Vertical canal ablation
  1. Used only in select cases when the horizontal portion of the external ear canal is medically salvageable (hearing is maintained).
3. Total ear canal ablation with bulla osteotomy (TECA-BO)
  1. A bulla osteotomy should always be performed for culture and curettage of epithelium and impacted debris.
  2. This procedure should only be performed by trained/experienced surgeons.
  3. Owners are invariably upset about hearing loss.
    1. Most dogs in need of a TECA have very poor hearing in the first place.
    2. This cures the problem! Many dogs act like puppies again - no more chronic ear ache!
    3. Low incidence of side-effects in the hands of a well-trained surgeon (facial nerve paralysis - temporary; abscessation if an infected nidus is retained).

The ACVD Task Force on Canine Atopic Dermatitis:
What and who can we really believe?

In 2001, a committee of the American College of Veterinary Dermatology published a series of position papers (Olivry T, ed. The ACVD task force on canine atopic dermatitis. Veterinary Immunology and Immunopathology (special issue), vol. 81, 2001), for which members reviewed all of the literature regarding canine atopic dermatitis, and scrutinized it for scientific evidence, merit, and "believability". Rating levels of evidence is the accepted standard in medicine for accepting or rejecting studies published in the medical/veterinary literature. While not surprising to many veterinary dermatologists and allergists, the report does suggest that much of the "art" employed in the diagnosis and treatment of canine atopic dermatitis has not been scientifically substantiated to date.

Background:

Allergy testing: Any method by which sensitization to environmental (or in some cases, dietary) allergens are detected. Such testing usually implies the specific intent to use the information for allergen avoidance or allergen-specific immunotherapy (ASIT). In the practice of human allergy, several testing modalities are employed which may include: skin prick testing (SPT), intradermal testing (IDT), atopy patch testing (APT), and serological methods such as ELISA and RAST. In the practice of veterinary allergy, the SPT and APT are rarely (if ever) used, however the latter may deserve further investigation. Skin tests assay the ability of an allergen to bind to mast cell and basophil-bound IgE or IgG4 (humans)/IgGd (dogs) and provoke degranulation of mast cells which release vasoactive substances that produce an inflammatory response (wheal/flare). Serological tests assay for increased levels of circulating allergen-specific IgE, which may or may not be functional in the allergic reaction.

Intradermal testing in dogs and cats: This is the preferred method used by most veterinary allergists, although it is far from perfect.
1. Air-borne allergens indigenous to the geographic area are selected (pollens, molds) along with common indoor allergens (dust mite and other insect allergens, natural fibers, human and animal epidermals) and biting insects (flea, ant, mosquito, etc.). The most common allergen for human and canine AD patients in the U.S. and Europe is the house dust mite (Dermatophagoides spp.)
2. 0.05 to 0.1cc of each allergen is injected intradermally, and the wheal and flare responses are graded on a scale of 1+ to 4+ as compared to a negative control (saline - always assigned a score of 0) and a positive control (histamine phosphate - always assigned a score of 4+). Most allergists limit the number of allergens tested to less than 60 due to technical reasons.
3. Disadvantages:
  - False positives - even non-atopic animals are capable of reacting to occasional allergens that are present in their environments. Cross-reactivity between biting insects (flea, ant) and arachnids (scabies, house dust mites) may also be a problem. Because of this potential, results must be interpreted in light of the patient's history and the clinical distribution of lesions (ie, flea bite allergy vs. scabies vs. atopy distribution patterns).
  - False negatives - IDT can be affected by exogenous antiinflammatory drugs, stress of the patient ("adrenalin rush"), the presence of secondary infections, and testing patients at the peak of their allergic season or too long after the allergen has disappeared.
  - Cats are especially difficult, as the elasticity of their skin limits the size and turgidity of wheals that are formed. The author uses intravenous fluorescein dye and a Wood's lamp to evaluate feline IDT reactions. Dye dosage: 10mg/kg I.V.
  - Withdrawal periods for antiiflammatory drugs include:
    *oral and topical steroids: 4 weeks
    *injectable steroids: 8 to 12 weeks (may be shorter in some cats)
    *antihistamines: 14 days
    *Omega3/Omega6 fatty acids: 10 days
    clipping an area for testing is necessary, and sedation of the patient is recommended with rare exception.
    expense: the veterinarian must be able to test at least a couple of animals/week to maintain stock allergens in a cost effective manner.
4. Advantages:
  - The organ that is expressing the disease is the one tested
  - Better specificity than serologic tests (see below)
  - If IgGd plays a role, it will be involved in the reaction
  - Higher percentage of "excellent" responses to immunotherapy based upon IDT vs. serologic tests?? This is reported anecdotally but scientific evidence has not been presented.
In-vitro allergy tests (RAST, ELISA, VARL): all serologic tests, regardless of methodology, measure the level of "allergen-specific" IgE in the serum, but cross-reactivity with IgG is known to be a potential problem with most. The newer IgE receptor-based ELISA (Heska Corp., Fort Collins, CO.) is very specific for IgE. RASTS are no longer routinely available in veterinary medicine.

ELISAs and RAST use a solid phase in which specific allergens are bound to plastic. Antibodies in patient serum may then bind the allergen, and when excess (unbound) patient Ab is washed away, an anti-antibody tagged with either a fluorescent marker (ELISA) or radioactive marker (RAST) is added to "detect" the bound patient antibodies. A liquid phase test currently available in North America is the Veterinary Allergy Reference Laboratory (VARL) Liquid Goldâ test (Pasadena, CA) which guarantees "no false positives" due to the use of Western blot technology to identify the patient antibodies that are captured by the specific allergen in liquid phase, which "eliminates non-specific IgE binding". No scientific evidence to substantiate these claims have been published.
1. Disadvantages:
  - False positives are a very concerning problem, regardless of the laboratory. This is probably due to non-specific binding by non-allergen specific IgE and IgG. Dogs have extremely high base-line levels of IgE as the result of chronic exposure to endo- and ectoparasites. The IgE receptor-based ELISA by Heska Corp. (Fort Collins, CO) may correlate better with IDAT than other serologic tests, according to the manufacturer.
  - Attempts to improve specificity have led to concerns about false negatives: there is good evidence in humans and horses that local IgE production (in the skin and lungs respectively) may be an important part of allergic skin and airway disease. Therefore, IgE levels in the serum might not correlate with the level of allergen-specific IgE in the target organ. Also, it has been shown that serum levels of allergen-specific IgE decrease in the "off season" when constant exposure is absent, while tissue levels are more durable.
2. Advantages:
  - No need for sedation or clipping. Drug withdrawal has traditionally not been thought to be as important as with IDAT. This may not be true with Heska's IgE receptor-based ELISA, which recommends steroid withdrawal similar to IDT. In addition, despite its claims of superior specificity, the Heska test doesn't assay for IgGd. While it is unknown how large a role is played by IgGd in canine and feline atopy, I commonly have negative Heska tests when the IDT is positive.
Allergen-specific immunotherapy (tail of newt, eye of frog…): An attempt to modify the immune response toward specific allergens (based upon allergy testing) in patients with clinical signs present for more than 4 months/year that cannot be controlled with non-steroidal regimens.
1. Mechanism of effect: Despite being in use for nearly 100 years in the treatment of human allergy, the specific mechanisms of effect remain incompletely known. Many theories exist regarding mechanism of effect: ¯ IgE? ¯ reactivity of mast cells/basophils? ¯eosinophil degranulation? Immunization (IgG blocking antibody)? Shift from Th2 to Th1 helper T-cell population? Currently unknown - maybe a combination of factors. In human medicine, ASIT is more efficacious for allergic respiratory diseases, and use in atopic dermatitis patients is limited.
2. Protocols: There is very little standardization between institutions or practices. No prospective, controlled studies have been conducted in veterinary medicine to suggest the most appropriate doses or protocols for administration, and different clinicians will use different dose/frequency protocols based upon their training backgrounds and personal experiences.
  
  Most veterinary allergists agree upon the following:
  - aqueous allergens should be used
  - 12 to 15 allergens per vial max (to avoid over-dilution of individual ingredients). Maximum of 2 vials per dog (to avoid overloading the patient)
  - select allergens for injection that are thought to be most clinically significant based upon the history/seasonality
  - subcutaneous injections are given starting with a very dilute concentration (vial 1 = 100-200 protein nitrogen units (PNU)/cc) and progressing through mid-level (vial 2 = 1,000- 2,000PNU/cc) to the highest concentration (vial 3 = 10,000 - 20,000 PNU/cc) for maintenance.
  - Maintenance frequency is determined by the dog's pruritic interval - some need "boosters" as frequently as Q7days.
3. Advantages: very limited/rare side-effects which may include itching after the shot (decrease dose 50% and gradually increase by 0.1 increments to reach the highest tolerable dose & pre-treat with antihistamines); hives (return to more dilute vial and observe closely after each shot - pretreat with antihistamines); anaphylaxis (virtually unheard of in dogs - discontinue use).
4. Disadvantages: animals on ASIT need frequent and expert monitoring. They cannot be sent home on ASIT and forgotten. Secondary pyoderma and Malassezia dermatitis are very common, even in dogs with excellent responses. Owners will perceive pruritic infections as "immunotherapy failure"! Most pets require adjunctive anti-pruritic therapies - especially during the first 6 to 12 months of therapy. Even the best responders may have their more difficult seasons. If you are unwilling/unable to diagnose secondary infections and manage these patients carefully, don't waste your client's time and money with ASIT.
Newer therapies for the adjunctive therapy of atopic dermatitis
1. Pentoxifylline (Trentalâ): A methylxanthine derivative with multiple immunomodulatory effects, that has been used for a myriad of human diseases, including diseases of the skin.
  - Suppresses pro-inflammatory cytokines while increasing anti-inflammatory cytokines. Inhibits chemokine production and inflammatory cell migration. Down-regulates integrin expression on endothelial cells. Inhibits T-cell/keratinocyte and T-cell/endothelial cell binding.
  - Useful for contact allergy in dogs at a dosage of 10mg/kg Bid.
  - A double-blinded/placebo controlled/cross-over study in dogs showed that a dosage of 10mg/kg Bid produced a statistically significant decrease in erythema and pruritus in 10 dogs when compared to placebo, but the clinical over-all clinical effect is disappointing . However, pentoxifylline is synergistic with glucocorticoids (lower the gcc dose necessary?)
  - Since pentoxifylline predominantly inhibits the late-phase reaction, blocking the immediate reaction with antihistamines may also produce synergy (studies not done to evaluate this hypothesis).
2. Cyclosporine A (oral): a macrolide immunosuppressants which suppresses cytokine production and proliferation of T-cells. This effect is non-selective for allergen-specific T-cells, therefore secondary infections and tumorigenesis are concerns.
  - Dose: Dependent upon indication: 5mg/kg (2.5mg/kg in combo with ketoconazole) for atopic dermatitis or perianal fistulas in dogs, up to 20mg/kg for AI disease. Administration with generic ketoconazole to dogs is usually recommended (when possible), to decrease the total CycA dose needed for clinical effect and decrease the cost of therapy. For eosinophilic granuloma complex in cats: 10mg/kg (50mg/cat). Cats often tolerate ketoconazole poorly. For organ transplant patients and AI disease patients, monitoring of trough plasma or whole blood is necessary to adjust dosing. This is generally not done for atopy patients unless specific problems so indicate.
  - Products available: Sandimmune is the original formulation, and bioavailability is unpredicatable. A newer microemulsion, Neoral, has a faster rate and degree of absorption, and is preferred by most clinicians. Supplied as 10mg, 25mg, 50mg gel caps and 100mg/ml oral solution. Generic available.
  - Side-effects: G.I. disturbances, anorexia, gingival hypertrophy, papillomatosis, excessive shedding and hypertrichosis. Secondary infections and neoplasia in long-term cases. The renal and hepatic toxicity seen in humans is only produced in dogs/cats with extremely high plasma levels or with pre-existing renal or hepatic insufficiency. $$$
  - Monitoring: Caution in patients with hepatic compromise - especially in combination with ketoconazole (also potentially hepatotoxic). Monitor liver enzymes as clinically indicated, +/- trough drug levels.
3. Tacrolimus 0.1% gel (topical): excellent efficacy in human patients. A 0.3% lotion produced a good effect on erythema but not pruritus in one canine study. However, limiting the amount used may have affected the efficacy in this report.
4. Mycophenolate mofetil (Cellceptâ): A very low toxicity
  immunosuppressant which is becoming increasingly more popular in veterinary medicine. Developed as an organ transplant drug, with toxicity studies performed originally in dogs, it may be useful for a wide array of autoimmune and other immune-mediated diseases (IMHA, RA, pemphigus, glomerulonephritis, etc…). Excellent efficacy reported with human AD.
  - Side effects: primarily gastrointestinal (diarrhea) which usually resolves with decreased dosage. Mild lymphopenia which does not prohibit therapy, is typical. $$$$
  - Monitoring: CBC after 1 month, then quarterly.
5. Misoprostol (Cytotecâ): A PGE1 analog with efficacy in Type-1 hypersensitivity. A dosage of 3-6mcg/kg Tid produced a significant reduction in pruritus and skin lesions (30% greater than placebo) in 20 dogs. Adverse effects: vomiting/diarrhea, $$$
6. Leukotriene inhibitors: as leukotrienes play an important role in allergic inflammation in human AD, leukotriene inhibitors have been tested for clinical efficacy. While some are useful in human beings, no good examples of efficacy have been demonstrated in dogs or cats to date.

The ACVD Task Force on Canine Atopic Dermatitis findings:

Regarding serum based tests: "Methodology for these tests varies by laboratory; few critical studies have evaluated performance of these tests, and current inter-laboratory standardization and quality control measures are inadequate." "Allergen-specific IgE serological tests are never completely sensitive, nor completely specific. There is only partial correlation between serum tests and intradermal testing; however, the significance of discrepant results is unknown and unstudied. Variation in test methodologies along with absence of universal standardization and reporting procedures have created confusion, varying study results, and an inability to compare between studies performed by different investigators."
Regarding IDT: "Despite its widespread use by veterinary dermatologists, the usefulness of the intradermal test would be greatly enhanced by the use of standardized allergen extracts and homogenous criteria for the interpretation of results. Irrespective of these shortcomings, intradermal testing is regarded as a valuable tool in the demonstration of allergen-specific hypersensitivity when performed according to accepted guidelines."
Regarding ASIT: "In spite of insufficient evidence derived from randomized controlled trials, multiple open studies and a large body of clinical observations suggest that ASIT is effective in controlling the clinical signs of dogs with AD. As a result of the scarcity of evidence from controlled trials, the true efficacy of ASIT, and the optimal protocols for allergen dose and frequency of injections are currently unknown. ASIT may nevertheless be included in the treatment of canine AD because of its potential advantages and limited disadvantages compared to other forms of therapy."
Regarding the use of antihistamines for the treatment of canine AD: "A critical review of the literature describing antihistamine use in canine AD reveals that the majority of published, peer-reviewed studies are open, uncontrolled or partially-controlled trials. Such studies vary widely in reported efficacy, from perhaps 0 to 75% of patients, even using the same drug. The few blinded placebo-controlled trials available have failed to confirm efficacy of these drugs to relieve the pruritus of canine AD. Some studies indicate that synergistic effects could occur with the concurrent use of essential fatty acid supplements. Consequently, at the time of this writing, there is insufficient evidence to conclude for or against the efficacy of antihistamines for treatment of canine AD".
Regarding the use of essential fatty acids for the treatment of canine AD: "To date, more than 20 trials have been performed, reporting the efficacy of either oral EFA supplements or EFA-rich diets". Due to study design problems and other deficiencies, the task force concludes that: "Consequently, there is presently insufficient evidence to recommend for or against the use of EFA to control clinical signs of canine AD. Evidence of efficacy must await the performance of blinded, randomized and controlled trials for at least 3 months duration in which diets are identical for all of the study subjects".
Regarding the use of non-steroidal antipruritics for the treatment of canine AD: "At the time of this writing, there is fair evidence to support the recommendation for using cyclosporine, misoprostol and pentoxifylline for the treatment of canine AD. This recommendation can be strengthened by the performance of additional blinded randomized controlled trials with larger numbers of dogs. In contrast, there is insufficient evidence to recommend for or against treatment with tacrolimus, leukotriene inhibitors, serotonin-reuptake antagonists and capsaicin".
Regarding the use of steroidal anti-pruritics for the treatment of canine AD: "Recently completed clinical trials were designed with oral GC's used as "standard of care" for treatment of canine AD. These studies provide high quality evidence in favor of the strong efficacy of oral low-dose glucocorticoid formulations to control skin lesions and pruritus…"

Malassezia dermatitis of dogs, cats and birds

Background: The genus Malassezia is now thought to include 9 distinct species of yeast. Malassezia yeast are characterized by their thick, multi-layered cell wall and unipolar budding process (gives them the appearance of peanuts), as well as their ability to utilize lipids as a source of carbon. Of these, the primary opportunistic pathogen of domestic animals, Malassezia pachydermatis, is unique in that it doesn't show an absolute requirement for lipids in culture media, although it prefers growing in a lipid-rich environment (lipophilic). This characteristic favors its overgrowth in conjunction with seborrheic skin diseases and otitis externa.

Clinical Presentation: Dogs

M. pachydermatis is part of the commensal (normal) microflora of canine skin.
Primary diseases which cause inflammation and increased sebum production provide a cutaneous microenvironment which encourages overgrowth of the organism (increased moisture and surface lipids; disruption of stratum corneum barrier function):
1. Allergies: atopy, food allergy, flea bite hypersensitivity, contact allergy
2. Endocrinopathies and other metabolic diseases: hyperadrenocorticism, hypothyroidism, diabetes mellitus, hepatocutaneous syndrome cutaneous or internal neoplasia
Dermatitis associated with Malassezia overgrowth (Malassezia dermatitis or MD) is typically pruritic.
1. cases of non-pruritic MD are rare and usually associated with endocrinopathy, neoplasia, or zinc-responsive dermatosis.
Primary lesions are limited to erythema. Secondary lesions are common (excoriations, seborrheic plaques, lichenification, maceration and intertrigo).
1. cannot be reliably distinguished from Staphylococcal pyoderma without cytologic examination
2. inflamed skin can either be dry and flaky, or greasy (seborrhea oleosa)
3. Malassezia can cause a folliculitis which mimics Staphylococcal folliculitis.
4. Infundibular cysts, in which massive numbers of the yeast organisms are present in cystic fluid, occur rarely
5. Paronychia (inflammation of the claw beds) may occur with or without more wide-spread Malassezia dermatitis.
  1. Most will be presented for the complaint of claw biting or paw licking.
  2. Physical examination will usually reveal a reddish-brown staining of the proximal claw or a waxy exudate in the claw fold, with inflammation of the surrounding soft tissue.
  3. The majority of cases will also have interdigital pododermatitis associated with the presence of yeast - pedal pruritus caused by the yeast may confuse the clinical evaluation of an atopic dog, especially the response to therapy.
6. Distribution of lesions: face (especially periocular and perioral skin), feet (interdigital spaces and claw folds), intertriginous areas (axillae, groin/inguinum, vulvar and mammary folds) and perineum.
  1. These areas are also commonly associated with atopic and food sensitivity dermatitis (and express a higher moisture level than the skin of the dorsum).
7. Otitis externa: M. pachydermatis is a common cause, but is usually secondary to an underlying allergic otitis or moisture trapping which promote a favorable microenvironment for yeast overgrowth.

Clinical Presentation: Cats

Part of the commensal microflora of feline skin. M. pachydermatis, M. sympodialis have been isolated from normal cats.
Malassezia dermatitis is typically secondary to allergy, endocrinopathy, or neoplasia (reported with thymoma-induced exfoliative dermatitis and pancreatic and/or hepatobiliary paraneoplastic alopecia).
Clinical signs:
In association with allergic disease -- pruritus, erythema, self-excoriations, paronychia, and (less commonly) lichenification.
1. The face appears to be the most commonly affected area.
2. MD is rare in cats (compared to dogs).
3. Malassezia-associated otitis externa is uncommon (compared to dogs).
  In association with neoplastic disease: exfoliative dermatitis in the case of thymoma-associated dermatosis; alopecia with shiny skin in the case of paraneoplastic alopecia

Zoonosis: M. pachydermatis has been implicated as a pathogen in neonatal intensive care units in which health care workers have introduced infection to human neonates from their family pets. Recommendations for immunocompromised clients?? A large epidemiological survey is currently under way to determine how commonly human beings host M. pachydermatis on their hands - whether from normal dogs or allergic dogs with Malassezia dermatitis.

Diagnosis: The Malassezia organism can be identified on animal skin by cytologic, cultural, and histopathologic techniques.

Cytology: Dry skin scrapings, tape-stripping procedures, cotton-tip swabs, and direct impression smears with glass slides. Apply the material to a glass slide, then heat fix, diff-quik, and observe at 100x power under oil immersion. Look for oval or peanut-shaped (budding) yeast.
1. For dry skin: scrapings, tape-stripping, or adhesive slides work best.
  1. With scrapings, it may be necessary to mix the material with saline and heat fix until dry (in order to adhere the material to the slide).
2. For greasy skin: Direct impression smears allow quantitation of yeast/hpf
  1. How many is too many? 1 yeast per hpf is a general guideline, although the only controlled study published has suggested 1 yeast per 27 hpf may be sufficient to correlate with pathologic effect.
3. Cotton tip swabs are useful for interdigital spaces if they are tacky, as it can be difficult to impress slides directly - especially in small breed dogs. Tape stripping also works nicely.
4. For diagnosis of Malassezia paronychia, the broken end of a wooden cotton-tip swab is used to scrape the claw fold, and exudate is pressed and rolled onto a glass slide.
5. For examination of ear exudate in dogs with ceruminous or exudative otitis externa, rolling of exudate in a thin layer on glass slides with a cotton-tip swab is the preferred method.
Culture: should not be necessary to identify a pathologic number of yeast Most normal dogs will yield a positive growth on culture (false positives).
1. M. pachydermatis may cause a false-positive color change on dermatophyte test media, as it can turn the agar red within 7 days at 37 degrees Celsius - always confirm dermatophytes microscopically by identifying macroconidia.
Histopathology: again, not necessary to make the diagnosis of MD, but often found on biopsies submitted from dogs with pruritic dermatitis.

Treatment: currently rooted in topical and systemic anti-fungal treatments.

For wide-spread infections: systemic therapy.
1. Oral ketoconazole (Nizoralâ; 5 to 10mg/kg Q24h for 21 to 28 days)
2. Oral itraconazole (Sporanoxâ; 10mg/kg Q24h for 21 to 28 days)
3. A low-dose regimen of ketoconazole (5mg/kg Q24h for 10 days, followed by 5mg/kg Q48h for 10 doses) has been reported to be successful in the majority of cases, and lessens the expense of therapy.
  1. Give these drugs with food (fatty meal). Use caution in dogs with hepatic disease. Pre-screen liver enzymes in old/debilitated animals. Use only Itraconazole in cats.
For localized and/or adjunctive therapy: topical treatment
1. Miconazole or ketoconazole shampoos, chlorhexidine shampoo, lime sulfur dip (for generalized disease)
2. Miconazole or clotrimazole spray, lotion, cream for "spot" therapy.
3. Lotions (liquid) are used for otitis externa (eg. Conofite lotion). Otomaxâ contains clotrimazole, but Malassezia yeast appear to develop resistance commonly. Reserve its use for cases with concurrent bacterial otitis.
4. Chlorhexidine soaks of feet for Malassezia pododermatitis
5. For Malassezia paronychia, scrubbing of the claw folds with a tooth brush using miconazole shampoo has been beneficial
Rule out and treat/eliminate primary diseases!!!
Prophylaxis for chronic/relapsing MD:
1. Regular shampoo therapy (weekly or biweekly)
2. Pulse oral ketoconazole (5 to 10mg/kg given 2 consecutive days per week)
  1. Monitor for hepatotoxicity if clinical signs dictate
A commercial Malassezia extract is undergoing licensing by FDA. A large multicenter study should be performed in order to determine its utility as an immunotherapeutic extract.

Malassezia sp. in Psittacine birds

Malassezia sp. have been reported to occur on normal avian skin as commensal organisms. We occasionally see Malassezia yeast on skin samples from necropsied birds with debilitating systemic diseases.
The role of Malassezia sp. in feather picking Psittacine species has been debated but very little evidence has been presented - and none substantiated by peer review.
1. A large survey of normal and feather-picking birds at U Penn has failed to identify Malassezia yeast on any birds.
  - Feather dust stains similarly to yeast organisms, and can be nearly impossible to distinguish from yeast bodies. Culture should be the more reliable method for identification, but does not allow a quick, on-site diagnosis.