Antifungal skin reactions David W. Denning University Hospital of South Manchester The University of...

Antifungal skin reactions

David W. DenningUniversity Hospital of South

ManchesterThe University of Manchester

Itraconazole and exanthematous pustulosis

Heymann J Am Acad Dermatol 1995;33:130; Min Park, JAAD 1997;36:754

Bx showed neutrophils in epidermis and neutrophils and eosinophils in the dermis

Itraconazole erythematous eruption (AIDS)

www.aspergillus.org.uk

Itraconazole and reported cutaneous reactions in the literature

Unpublished

Adverse events Number of patients

Total number patients 9065

Cutaneous side effects

Rash/pruritus 250

Alopecia 19

Site reaction / vasculitis 4

Steven-Johnson syndrome 2

Hirsuitism 1

Photosensitivity 1

Diaphoresis 1

Patient 1

Unpublished

•AW (♂, age 56) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and voriconazole

CPA had developed on a background of sarcoidosis. The only concurrent treatment was prednisolone 5mg.

Patient 1

Unpublished

July 2010

Aug 2009

Patient 1

Unpublished

•AW (♂, age 56) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and voriconazole

CPA had developed on a background of sarcoidosis. The only concurrent treatment was prednisolone 5mg.

Random therapeutic drug monitoring (TDM) revealed levels of 2.3mg/l (normal range > 0.5 mg/l).

Within one month of commencing posaconazole he developed a sparse papular rash on his face and forearms.

The rash did not progress and the patient continues on posaconazole.

Patient 2

Unpublished

• DC (♂, age 73) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and voriconazole.

CPA had developed on a background of asthma and ABPA. He also had severe aortic stenosis. Treatments included inhaled salmeterol/fluticasone 50/500mcg twice daily and prednisolone 5mg.

Patient 2

Unpublished

Jan 2010

Oct 2008

Patient 2

Unpublished

• DC (♂, age 73) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and voriconazole.

CPA had developed on a background of asthma and ABPA. He also had severe aortic stenosis. Treatments included inhaled salmeterol/fluticasone 50/500mcg twice daily and prednisolone 5mg.

Random TDM revealed levels of 2.8mg/l.

Within forty-eight hours of commencing posaconazole he developed a severe acneifrom rash, typical of folliculitis, across his face.

Patient 2

Unpublished

Patient 2

Unpublished

• Within one week the rash had progressed to cover his neck, ears, scalp and upper chest wall.

Posaconazole was discontinued due to the severe nature of the eruption.

Patient 3

Unpublished

• JB (♂, age 61) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and intolerance of voriconazole due to photosensitivity.

He had developed CPA following resection of lung cancer. Treatment included salmeterol/fluticasone 25/250mcg 2 puffs twice daily and tiotropium 18mcg daily.

Random TDM revealed levels of 2.6, mg/l.

Within two weeks of commencing posaconazole he developed a sparse acneifrom rash on his face. A similar eruption had occurred on itraconazole.

The rash did not progress and the patient continues on posaconazole.

Patient 3

Unpublished

• JB (♂, age 61) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and intolerance of voriconazole due to photosensitivity.

He had developed CPA following resection of lung cancer. Treatment included salmeterol/fluticasone 25/250mcg 2 puffs twice daily and tiotropium 18mcg daily.

Patient 3

Unpublished

Nov 2008

Sept 2008

Patient 3

Unpublished

Patient 3

Unpublished

• JB (♂, age 61) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and intolerance of voriconazole due to photosensitivity.

He had developed CPA following resection of lung cancer. Treatment included salmeterol/fluticasone 25/250mcg 2 puffs twice daily and tiotropium 18mcg daily.

Random TDM revealed levels of 2.6, mg/l.

Within two weeks of commencing posaconazole he developed a sparse acneifrom rash on his face. A similar eruption had occurred on itraconazole.

The rash did not progress and the patient continues on posaconazole.

Patient 4

Unpublished

• NC (♂, age 73) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole.

He had developed CPA following resection of lung cancer. He had had psoriasis for years, with little trouble and almost no treatment. Treatment included salmeterol/fluticasone 25/250mcg 2 puffs twice daily and tiotropium 18mcg daily.

Patient 4

Unpublished

Jan 2010

Patient 4

Unpublished

• NC (♂, age 73) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole.

He had developed CPA following resection of lung cancer. He had had psoriasis for years, with little trouble and almost no treatment. Treatment included salmeterol/fluticasone 25/250mcg 2 puffs twice daily and tiotropium 18mcg daily.

Random TDM revealed levels of 2.6, mg/l.

After 3 weeks of posaconazole he had a remarkable exacerbation of psoriasis. He developed psoriatic plaques on his hands for the first time ever. The plaques on his lower legs became confluent. This occurred in association with worsening chest symptoms, notably increased coughing, more breathlessness and increasing oxygen requirement.

Patient 4

Unpublished

Patient 4

Unpublished

Patient 4

Unpublished

• Posaconazole was stopped after 3 weeks, and 2 weeks later he was still very symptomatic with his chest. This responded to a 2 week course of corticosteroids, and his psoriasis also improved.

Posaconazole and rash

Unpublished

• A search of Medline and Embase databases revealed no previous reports of adverse cutaneous reactions due to posaconazole.

The UK and US data sheets describe ‘rash’ (unspecified) as common, mouth ulceration and alopecia as uncommon and Stevens Johnson Syndrome and ‘vesicular rash’ as rare.

Voriconazole

Cheilitis, conjunctivitis and facial erythema with voriconazole

Voriconazole and photosensitivity (phototoxic

reaction)

Denning & Griffiths J Exp Dermatol 2001;26:648

52

Voriconazole, photosensitivity and sunshine

Denning & Griffiths J Exp Dermatol 2001;26:648

Photosensitivity and cutaneous blistering with voriconazole

WWW.aspergillus.org.uk

Voriconazole has ‘uncovered’ pophyria cutanea tarda, and may be mistaken for it (pseudoporphyria)

Voriconazole and pseudoporphyria

Medscape

Patient 5

Denning & Griffiths J Exp Dermatol 2001;26:648

• AB (♀, age 40) treated with voriconazole (Study 003) having failed itraconazole. She was the first patient in the world with aspergillosis to be treated with voriconazole.

Chronic invasive Aspergillus sinusitis and osteomyelitis of the base of the skull, with cranial neuropathies.

Patient 5

Swift & Denning J Otol Laryngol 1998;112:92

Patient 5

Swift & Denning J Otol Laryngol 1998;112:92

Right hypglossal nerve palsy

Right lateral rectus palsy

Patient 5

Swift & Denning J Otol Laryngol 1998;112:92

Patient 5

Denning & Griffiths J Exp Dermatol 2001;26:648

•AB (♀, age 40) treated with voriconazole having failed itraconazole

Chronic invasive Aspergillus sinusitis and osteomyelitis of the base of the skull.

Past history of acne rosacea (5 years of antibiotics), not present on starting voriconazole. She received voriconazole for 411 days, 200mg twice daily, starting on 12 July, 1993. After 4 weeks of therapy she developed cheilitis.

Patient 5

Denning & Griffiths J Exp Dermatol 2001;26:648

She then went on holiday in the UK (Lincolnshire) for 2 weeks.

At 8 weeks of therapy she reported erythema of her face, upper-chest and ears. Her legs and arms tanned normally.

Facial erythema and cheilitis apparent at each outpatient visit although less marked in February 1994.

Summer of 1994, the facial erythema was worse following a holiday at the Mediterranean during which she had used SPF-15 sunscreen.

Patient AB.First patient (in the world) with aspergillosis treated with voriconazole. Enrolled 2 July 1993

Patient 5

Swift J Otol Laryngol 1998;112:92. Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5

Denning & Griffiths J Exp Dermatol 2001;26:648

July 1994 she developed slightly pruritic, non-tender, 1-2cm diameter red plaques on both sides of her neck.

Patient 5

Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5

Denning & Griffiths J Exp Dermatol 2001;26:648

July 1994 she developed slightly pruritic, non-tender, 1-2cm diameter red plaques on both sides of her neck.

These plaques were clinically and histologically consistent with a diagnosis of discoid lupus erythematosus.

Sunscreen of SPF-30 was recommended and some improvement was noted a month later. Her neck lesions and general erythema improved further over the following six weeks. Treatment with voriconazole was then stopped (completion of therapy).

All her cutaneous abnormalities resolved over the following four months and she is free of aspergillosis three years later.

Pustular phototoxic reaction with voriconazole

Voriconazole adverse events in asthmatics

Chisimba, J Asthma In press

Voriconazole photosensitivity – cause?

Inhibition of all-trans retinol (vitamin A)?

5/6 CF children developed photosensitivity, all on vitamin A supplementation

The imidazole liarazole blocks retinoic acid 4-hydroxylase, raising all-trans retinoic acid

Patient 6

www.aspergillus.org.uk

LT (♀, age 49) lifelong asthma and atopy, with ABPA diagnosed in 1993. Recognised to have CPA complicating ABPA in 2001, but the CPA diagnosis was apparent but made in 1993.

Recurrent infective exacerbations and colonisation by Aspergillus fumigatus and Pseudomonas aeruginosa. Treated with oral itraconazole.

Patient 6

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Patient 6

Better pulmonary status on voriconazole initially, but then slow deterioration,

On 4l/min oxygen dependent 24 hours a day.

Mild photosensitivity on voriconazole, even with little sun exposure. As wheelchair bound very little outside time, so mostly indoor light.

She developed rough scaly patches over her face, neck and lower arms. Dermatological review indicated “multiple solar keratoses”.

www.aspergillus.org.uk

Patient 6

Skin biopsy from the right forearm confirmed this clinical diagnosis – “skin showing hyperkeratosis with a little parakeratosis and acanthosis. The keratinocytes have a glassy appearance but show nuclear atypia with dyskeratotic cells, and occasional suprabasal mitoses. The intraepidermal sweat ducts are spared. Appearances suggest an actinic keratosis with moderate to severe dysplasia.” These features are characteristic of a low grade premalignant change.

She was treated with local 5-fluorouracil cream (Efudix) (3 cycles) to the affected lesions.

www.aspergillus.org.uk

Patient 6

www.aspergillus.org.uk

Patient 6

www.aspergillus.org.uk

Patient 6

These photos were taken at the apogee of inflammation. The inflammation resolved after discontinuing the cream. This reaction is expected with application of this mild chemotherapy agent.

Following treatment her skin was much softer and considerably improved. Voriconazole has been stopped, and posaconazole substituted.

Patient 6

18 months later, new lesion on her forearm.

Patient 6

Biopsy showed squamous cell carcinoma in situ

Voriconazole and skin cancer

McCarthy Clin Infect Dis 2007;44:e55

CGD and hyper IgE syndrome, aggressive multifocal SCCs, voriconazole for 4.5 yrs

Miller Arch Dermatol 2010;146:300

Multiple melanomas in situ, voriconazole for 3 yrs

CGD, multiple melanomas in situ, voriconazole for 4.5 yrs

Cowen, J Am Acad Dermatol 2010;62:31

ALL, multiple SCCs in situ, voriconazole for 3 yrs

HIV, SCC, on voriconazole for 15 months

Epaulard, Clin Microbiol Infect 2010;16:1362

Prior methotrexate, multiple SCCs on scalp, voriconazole for 2 yrs

CF & Lung Tx, aggressive SCCs, on voriconazole for 3.5 yrs

Morice, Case Rep Med 2010

Multifocal Aggressive Squamous Cell Carcinomas Induced by Prolonged Voriconazole

Therapy

Pulmonary aspergillosis, skin carcinogenesis showed two variants of the MICR gene.

Summary and questions

• Cutaneous adverse effects uncommon with itraconazole and posaconazole

• Acneiform eruption a new adverse event with posaconazole

• Photosensitivity, cheilitis and conjunctivitis common with voriconazole

• Photosensitivity may develop into carcinoma in situ, Bowen’s dieases, squamous cell carcinoma or melanoma.

• Photoaging not properly described separately• Mechanism of photosensitivity could involve elevated

retinol levels locally, but not understood• Is there a limit to the duration of treatment of caucasians

with voriconazole? • How should these patients be best monitored?