a for apoquel

What’s New in Vet Dermatology?

Small Animal Specialist Hospital

Linda Vogelnest BVSc (Hons) MANZCVSc (Feline Medicine)

FANZCVSc (Veterinary Dermatology)Specialist Veterinary Dermatologist

What’s new?

• New Meds– Apoquel® – when and why?, compared to Atopica®– Bravecto® & Nexgard®- demodicosis

• Update on tricky infections– MRSP dermatitis/otitis – diagnosis & treatment options– Malassezia dermatitis/otitis – treatments

Apoquel• Oclacitinib

– New drug and class• Janus Kinase inhibitor

– Enzymes vital to signaling & cell activation– Found in many cell types

» Suppressing activation (i.e. immunosuppressant!)» Lymphocytes (cell-mediated immunity)

• “allergy” cytokines e.g. IL-2/4/7/9/21• “itch” cytokine – IL-31• “anti-viral/anti-tumour” cytokines e.g. IL-10, IFN-γ

» Innate immunity – macrophages, neutrophils etc – IL-12/23

Apoquel• Oclacitinib

– Immunosuppressant• No metabolic effects• No drug interactions

– Indications• Control of pruritus from allergic dermatitis• Control of atopic dermatitis • In dogs ≥ 12 months old

IL-31• Injected into 11 dogs (expt AD) pruritus (lasted 4-24 hours)*

– 2 dogs – placebo; 10 dogs - itch increased 2-10 fold; 1 dog – no itch • Detected in serum*

– in 57% of dogs with ‘natural’ AD(127/223)– in 0% of dogs with expt AD (no itch; 0/24), normal dogs (no itch; 0/87)– in 0% of dogs with flea allergy (itchy; 0/30)

• Detected in human AD; levels correlate with severity of AD

Gonzales et al(2013)* Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis." Vet Dermatol 24(1): 48-53

• 299 dogs client-owned dogs with AD• Enrolled at 19 Dermatology Specialty Practices in USA

0 1 2 7 14 28 56 84 1120

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10OWNER VAS SCORE

Placebo (P) Oclacitinib (O) Open Label (OL)

Day of Study

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AS S

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(cm

)

0 14 28 56 84 1120

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20

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100DERMATOLOGIST CADESI-02 SCORE

Placebo (P) Oclacitinib (O) Open Label (OL)

Day of Study

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-02

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After time 0 Oclacitinib is significantly different from PlaceboAs much as (p < 0.0001)

More Controlled Studies - AUS• Gadeyne C, Little PR, King VL, et al (2014)

– Efficacy of oclacitinib (Apoquel®) compared with prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in client-owned dogs in Australia. Vet Dermatol 25(6), 512-e586

• single-masked, randomized controlled clinical trial • 123 client-owned dogs with allergic dermatitis in GP

0.0 0.2 1.0 6.0 14.0 28.00

102030405060708090

100Delta-Cortef (prednisolone)

APOQUEL (oclacitinib)

Day of Study

Mea

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DOSE:Pred – 0.5-1mg/kg SID up to Day 6, then EOD to Day 28Apoquel – 0.4-0.6mg/kg BID up to Day 14, then SID

More Controlled Studies - AUS• Little PR, King VL, Davis KR, et al (2015)

– A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs. Vet Dermatol, 26(1), 23-e28

• blinded, randomized clinical trial, non-inferiority test at day 28• 226 client-owned dogs with AD from eight specialty derm practices

DOSE:Atopica – 5mg/kg SID Apoquel – 0.4-0.6mg/kg BID up to Day 14, then SID

0 1 2 7 14 28 56 840

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100Owner VAS Pruritus Score

Atopica Apoquel

Day of Study

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Extremely severe itch-ing

Severe itching

Moderate itching

Mild itching

Very mild itching

Normal dog

**

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*

Apoquel in Sydney

• Compassionate use – 5 dogs severe AD – 1-2 years

• Not readily controlled variety other tx

– 4 dogs x 2 years (JRT, Staffie, Sharpei X, Lab)• Owners extremely happy• Mild intermittent dermatitis – erythema, alopecia• Minimal pruritus• Worsening when daily dose due/if dose late (1 dog)• Weight gain (mild, 2 dogs)

– 1 dog (Lab) – moved to Canberra (AD signs resolved)

Apoquel in Sydney

• Compassionate use– 1 dog (choc lab)– severe AD

• Partially controlled - pred 0.5mg/kg EOD, azathioprine, shampoo– Couldn’t afford cyclosporin

• Responded brilliantly in trial on Apoquel (within one day)• Severe secondary infections – yeast, bacterial• Poor response 1yr later restarting under compassionate use

– severe infections, continued pruritus, ultimately euthenasia

When To Use Apoquel?• Indicated for Atopic dermatitis • Also FAD, Food allergy, Contact (?)

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1. Atopic DermatitisMulti-modal treatment plans1. Acute flare plan2. Long-term management plan

Strategies:1. Minimise allergen &/or irritant exposure2. Immunotherapy3. Symptomatic therapy

OLIVRY, DE BOER (2010). Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Veterinary Dermatology 21: 3; 233-248.

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1. Atopic DermatitisMultimodal Treatment• Allergen-specific Immunotherapy (“allergy vaccines”)

– May reduce need for life-long symptomatic therapy• Safe symptomatic options

– Antihistamines, Fatty acids– Topicals – cleansing, soothing, potent steroids– Manage secondary infections

• More potent options– Glucocorticoids– Cyclosporin– Oclacitinib

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1. Atopic DermatitisMultimodal Treatment• Allergen-specific Immunotherapy (“allergy vaccines”)• Safe symptomatic options• More potent options

– Glucocorticoids – flares & long-term (low regular dose e.g. 1-2X wkly)– Cyclosporin – slow onset: long-term (2-6wks; wean gradually)– Oclacitinib – quick onset: flares & long-term (daily for life)

• ADVANTAGES– small, easily divided tablets– rare, mild side effects – GIT– quick response– no interference with allergy testing

• DISADVANTAGES– Flare secondary infections/otitis?– Cost

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2. Food Allergy?

• Diagnosis– Elimination diet x 6-8 weeks

• Novel protein – fresh (ideal) or commercial• Hydrolysed commercial

– Rechallenge phase x 2wks (smorgasbord)• Role for Apoquel?

– During diagnostic trial - initial relief– Discontinue last week of diet

• Stabilise if flare before progress to rechallenge

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3. Flea Allergy?

• Diagnosis– Flea treatment trial x 4wks

• Adulticidal: quick flea kill• Consider environment: consider IGR

• Role for Apoquel?– During diagnostic trial - initial relief– Discontinue last week of trial

When Not To Use Apoquel• For pruritus due to infectious causes

– Bacterial pyoderma– Malassezia dermatitis– Bacterial &/or malassezia otitis– Sarcoptes, Demodicosis, Dermatophytosis etc.

When Not To Use Apoquel• For pruritus due to infectious causes• For AD with effective, safe, affordable control plans

– Allergen-specific immunotherapy– Safer symptomatic treatment plans– Cyclosporin (EOD or less)

• For FAD, Food allergy in long-term– Diagnose and avoid allergens

• In dogs under one year age• In dogs with history of demodicosis?

Using ApoquelDose:• 0.4-0.6mg/kg BID x 2wks, then SID long term

• Poor response – reconsider infections/diagnosis

Expectations:• Quick response• Pruritus flares common when reduce to SID

– Not severe– Usually settle over next ~2-4 weeks

• What if SID not sufficiently effective?– Consider timing of administration – AM vs PM– Can dose be raised?

– Remember the dose range– Consider off-label BID dosing (low dose)

Using Apoquel

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Vet Dermatol 2015; 26: 235–e52

5/12 Cats - AD

What’s new?

• New Meds– Apoquel® – when and why?, compared to Atopica®

– Bravecto® & Nexgard®- demodicosis

• Update on tricky infections– MRSP dermatitis/otitis – diagnosis & treatment options– Malassezia dermatitis/otitis – treatments

Squeeze Tape Impressionfor Demodicosis

30 dogs – demodicosis 21 generalised; 9 localised 27 positive deep scrape (single) 30 positive tape squeeze (one squeeze)

Advantages Simple, less invasive Sensitivity comparable

(greater?) than deep scraping

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40 dogs – demodicosis 23 generalised; 17 localised 40 positive deep scrape 30 positive tape squeeze (one

squeeze per site) 29 positive trichogram

Advantage Simple, less invasive first test

Disadvantage Deep skin scraping more sensitive

16 dogs Demodicosis15 dogs – normal skin15 dogs – inflamed skin- Multiple squeezes per site 100% specificity – no mites in normal/inflamed skin (120 samples)

100% sensitivity – mites in each lesional sample 16 dogs (16 samples)

Deep skin scraping – 90% sensitivityMites in 14/16 samples

Squeeze Tape Impression• Simple, minimally invasive test

– Less patient discomfort– No skin trauma– Readily sample multiple sites

• High specificity• Apparent high sensitivity

Isoxazolines• Bravecto® - fluralaner

– 8 dogs generalised demodicosis

– No mites Days 56, 84

Isoxazolines• Nexgard® - afoxolaner

– Twice monthly– 8 dogs generalised

demodicosis; no mites day 84– Anecdotal: monthly very

effective

Isoxazolines• Simparica® - sarolaner

– Zoetis– Monthly flea/tick control

What’s new?

• New Meds– Apoquel® – when and why?, compared to Atopica®– Bravecto® & Nexgard®- demodicosis

• Update on tricky infections– MRSP dermatitis/otitis – diagnosis & treatment options– Malassezia dermatitis/otitis – treatments

• Superficial - pyoderma, folliculitis, impetigo, mucocutaneous pyoderma

• Deep• 2° to

– 1° Skin disease/defects– Systemic immune suppression

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Bacterial Pyoderma

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Bacterial Pyoderma

• Causal Bacteria– Staphylococcus pseudintermedius

• Normal flora – esp. moist sites: nares, mouth, perianal• Virulence factors

– Staphylococcus aureus– Staphylococcus schleiferi schleiferi

• Other normal flora – many – Gram +ve - coagulase negative Staph, α-haem.

Streptococci, Propionibacterium acnes– Gram –ve - Clostridium spp., Acinetobacter spp.

• Transients – many– Proteus mirabilis, Pseudomonas spp., Corynebacterium

spp.

• Historically – predictable antibiotic sensitivity– ~98% isolates sensitive to β-lactams

• cephalexin, amoxyclav

• Methicillin-resistance (MRSP, MRSA)– Small mobile gene (mecA), transferred amongst Staph spp.;

alters PBP

– MRSP - first report France – mid 1980’s; first dz USA – 1999

– Alarming MRSP since 2006 – clonal spread of small number isolates

• ST71 (Europe, Japan), ST68 (USA)

• ST45 (Israel, Thailand) 36

Staphylococcus pseudintermedius

• Colonisation/transient carriage (dogs, cats)

– 0-10% worldwide; 30% in Japan (2006)

• Pyoderma (dogs)

– 15-17% (USA 2001-4); 0.8% (Germany 2007); 10% (Spain 2009)

– ~30% (USA 2008); 55-67% (Japan 2007-9)

– Australia – Sydney, Brisbane, Melbourne, Adelaide, Perth

• Perth - 12 isolates/19 dogs 2011/12: some potentially related ST45 (Thailand); some new lineage Canada

• Sydney – 1/29 dogs 2010/12

– 55 dogs 2013 - ~ 20% 37

MRSP

Siak M, Burrows AK, Coombs GW et al. Journal of Medical Microbiology 2014; 63 (9): 1228-1233

Ravens PA, Vogelnest LJ, Ewen E et al. AVJ 2014; 92(5): 149-155.

• Concurrent transfer of resistance to multiple antibiotics: MDR

• Resistance to– Β-lactams: cephalexin, amoxyclav, cefovecin– Macrolides: clindamycin– Fluoroquinolones: enro, marbo– Tetracyclines: doxy– TMS– Chloramphenicol (European isolates)

• Sensitive to– Rifampicin, amikacin– Topicals: fusicid acid, mupirocin– Restricted: vancomycin, linezolid, teicoplanin

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MRSP Challenges

• Dissemination– risk MRSP infections – hospitalisation, prior antibiotic

therapy

– Positive cultures hospital environment/staff

– Hospital outbreaks

• Zoonosis– Rare

– concern – hospital staff, pet owners

• Survival 6mnth (environ)

• Ready transmission household pets39

MRSP Challenges

• Dogs, Cats, (Horses)• Skin/ears

– Pyoderma – superficial, deep– Otitis– Surgical wound infections

• Urinary tract infections

• Septicaemia

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MRSP Infections

• Clinical clues?– None – looks like ‘normal’ pyoderma

• Historical clues?– Poorly responsive to antibiotics

• Inadequate antibiotics dose/duration/poor owner compliance

• Concurrent GC therapy

• Active underlying disease (rare)

• MRSP

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MRSP Pyoderma

• Diagnosis?– Cytology

• Neutrophils, i/c bacterial cocci

– Exclude other causes for poor response to empirical ab’s

– Bacterial C&S (cytologically confirmed pyoderma sites)• Pustule - puncture sterile 25g needle, culture swab

• Other lesions - dry swab rubbed vigorously 5 sec

• Avoid moist sites/cytology confirms mixed microbes

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MRSP Pyoderma

• Skin cytology– Adhesive tape impression (all lesions)

• Diff-Quik stain (no fixative)

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Diagnosis

• Skin cytology– Adhesive tape impression (all lesions)– Glass slide impression/FNA (moist/nodular

lesions)

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Diagnosis

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Tape Impression - Normal skin - 4X lens (40x magnification)Keratinocytes dominate; normal flora very sparse

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Tape Impression – Pyoderma 4X lens (40x magnification)Clumped keratinocytes; Neutrophil rims/clusters

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4X lens (40x magnification)

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Neutrophils with intracellular & colonising cocci

1000X (oil)

200X (20X lens)

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Degenerate neutrophils with intracellular cocci – oif (1000x)

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Neutrophils with intracellular & colonising cocci – oif (1000x)

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Neutrophils with intracellular & colonising cocci

1000X (oil)

40X (4X lens)

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Neutrophils, colonising bacterial rods – oif (1000x)

Yeast, and colonising cocci, rods – oif (1000x)

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Deep Pyoderma: neutrophils with intracellular cocci (often sparse)

1000X (oil)

1. Address 1° disease/cause – Reduce immunosuppression

– Atopic Dermatitis – cyclosporin

2. Antibiotic susceptibility unpredictable– Susceptibility testing important, in light of cytology

findings!– Methicillin (oxacillin) resistance = resistant to all β

lactams

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MRSP Pyoderma - Treatment

1. Systemic Options– Possibly doxycycline – 10mg/kg SID

– Possibly TMS – 30mg/kg BID

– Rifampicin – 5-10mg/kg SID• Hepatotoxicity (25% dogs)

• Drug interactions – many

• Orange discolouration body fluids

• Combine with 2nd antibiotic?

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MRSP Pyoderma - Treatment

1. Systemic Options – doxy?, enro?, TMS? – based on C/S2. Topical Options

– Antibiotics - resistance documented; colonisation MRSA (people)

• Mupirocin oint/cream (Bactroban®)• Fusidic acid oint (Conoptal®, Fucidin® - tablet also)

– Antiseptics - act rapidly at bacterial cell walls; less susceptible to resistance?

• Chlorhexidine (more effective; less irritating/staining vs iodine)– Effective as sole tx MRSP in dogs; daily chlorhex baths reduce MRSA

(people)– 3-4% faster antibacterial effect; leave-on solution/cream;

shampoos/scrubs– Resistance documented

• Other: acetic/boric acid; benzoyl peroxide• Low irritant: silver sulfadiazine (Flamazine®); medical honey• Sodium hypochlorite (household bleach) ~ 1ml per litre water

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MRSP Pyoderma - Treatment

• Aggressive individual patient treatment plan

1. Minimum 3-wk treatment course• Topicals - chlorhexidine; bleach +/- antibiotics

• Cleaning - frequent swimming (salt water), gentle shampooing

2. NO CONCURRENT GLUCOCORTICOIDS!• Incomplete/delayed resolution of infections

• Encourages antimicrobial resistance

• Pruritus markedly reduced in 24-48 hours without steroids in most cases

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MRSP Pyoderma – Tx Summary

• Aggressive individual patient treatment plan

1. Minimum 3-wk treatment course• Topicals - chlorhexidine; bleach +/- antibiotics

• Cleaning - frequent swimming (salt water), gentle shampooing

2. NO CONCURRENT GLUCOCORTICOIDS!

3. Address underlying disease• Atopic Dermatitis/On-going immunosuppression – active

prevention plan

1. Topical antiseptics/cleaning

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MRSP Pyoderma – Tx Summary

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Diagnosis uncertain?• Options

1. Antibiotic (or antifungal) treatment trial (3wks; no steroids) • Pruritic: pruritus & lesions should improve by 5-7d• Non-pruritic: lesions should resolve by 2-3wks

2. Steroid-treatment trial (2-7 days; no antibiotics/antifungals)• Pruritic: pruritus and lesions should improve notably by 7d• Non-pruritic: not indicated!

3. Referral?DON’T use pred & 5-10 days antibiotics !!

Pyoderma (& MD) - Treatment

1. Prudent Antibiotic Use1. Pruritic presentations

1. DO NOT USE pred/dex + 5-10d course cephalexin/cefovecin inj

2. Identify pyoderma (cytology or tx trial)– 3wk cephalexin/amoxyclav AND NO concurrent GC

– Only use 2nd line drugs e.g. fluoroquinolones, clindamycin, cefovecin IF supported by C&S

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MRSP – Limiting Spread

1. Sensitivity testing SP isolates Sydney

– 27 dogs; 227 isolates - dry swab, saline-moistened swab, skin scraping

– Cephalexin, amoxyclav, TMS (96%)

– Enrofloxacin, chloramphenicol (96%)

– Less to cefovecin (90%) , clindamycin (88%), doxycycline (78%)

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Staph Pseudintermedius - Sydney

Ravens PA, Vogelnest LJ, Ewen E et al. Canine superficial bacterial pyoderma: evaluation of skin surface sampling methods and antimicrobial susceptibility of casual Staphylococcus isolates. AVJ 2014; 92(5): 149-155.

1. Prudent Antibiotic Use– When clearly indicated, wise choices, complete courses (3wks), no

GC2. Adequate staff and patient hygiene

– Strict hand hygiene• Remove gross contamination – soap/water• Alcohol hand gel

– Patient barrier nursing – if MRSP infection confirmed3. Hospital disinfection/maintenance

– Regular decontamination – two-step process• Remove organic debris• Disinfection

– Alcohol (70-90% ethanol, isopropanol) – fastest action– Bleach 0.5% (1:10 dilution) – 10-min contact time– Chlorhexidine 0.15% - 10-min contact time– Quarternary ammonium compounds e.g. Trigene® – less

effective62

MRSP – Limiting Spread

1. Treat the infection first Topicals essential

Fusidic Acid - Canaural®

Miconazole/Polymixin B - Surolan®/Dermotic®

2. Reduce any chronic inflammatory changes

3. Treat the underlying disease

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Treatment – MRSP Otitis

What’s new?

• New Meds– Apoquel® – when and why?, compared to Atopica®– Bravecto® & Nexgard®- demodicosis

• Update on tricky infections– MRSP dermatitis/otitis – diagnosis & treatment options– Malassezia dermatitis/otitis – treatments

• 2° to– Allergies – AD (can markedly pruritus)– Systemic immune suppression

• Immuno-suppressive therapies (e.g. pred)• Disease (e.g. neoplasia, FIV)

– Hormonal – hypoT, hyperA (can cause pruritus)– Keratinisation defects - primary seborrhoea, sebaceous

adenitis

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Malassezia dermatitis

• Skin cytology– Adhesive tape impression (all lesions)

• Diff-Quik stain (no fixative)

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Diagnosis

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MD – oil lens (1000X)Dx = >1 yeast per oif

• Surface cytology– Most important– Not 100% sensitive (esp. pyoderma)

• Clinical appearance– Rarely reliable– Odour – variable

• Consider treatment trial– Antifungals alone (3wks min - superficial)

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Diagnosis

1. Treat the infection first (underlying dz 2nd) Systemic most reliable (min. 3wk course)

Itraconazole 5-10mg/kg SID

Pulse tx: 2 consecutive days/wk?

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Treatment – Malassezia Dermatitis

1. Treat the infection first (underlying dz 2nd) Systemic most reliable (min. 3wk course)

Topicals can be useful

Enilconazole rinse (twice wkly), miconazole cream (BID)

Chlorhexidine solution (2-3%) sid-bid

Shampoos – adjunctive only (limited residual effect)

Chlorhexidine, miconazole

Piroctone olamine, econazole

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Treatment – Malassezia Dermatitis

1. Treat the infection first (underlying dz 2nd) Topicals essential

‘azoles’ - BID seems most effective

Miconazole - Surolan®/Dermotic®

Clotrimazone - Otomax®

Nystatin – BID

Canaural®, Topigen®

Systemics – may be helpful, especially if otitis media?

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Treatment - Otitis

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Questions?