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

Itraconazole and exanthematous pustulosis Bx showed neutrophils in epidermis and neutrophils and eosinophils in the dermis Heymann J Am Acad Dermatol 1995;33:130; Min Park, JAAD 1997;36:754

Itraconazole erythematous eruption (AIDS) www.aspergillus.org.uk

Itraconazole and reported cutaneous reactions in the literature 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250 Alopecia 19 Site reaction / vasculitis 4 Steven-Johnson syndrome 2 Hirsuitism 1 Photosensitivity Diaphoresis Unpublished

Patient 1 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. Unpublished

Patient 1 Aug 2009 July 2010 Unpublished

Patient 1 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. Unpublished

Patient 2 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. Unpublished

Patient 2 Oct 2008 Jan 2010 Unpublished

Patient 2 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. Unpublished

Patient 2 Unpublished

Patient 2 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. Unpublished

Patient 3 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. Unpublished

Patient 3 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. Unpublished

Patient 3 Sept 2008 Nov 2008 Unpublished

Patient 3 Unpublished

Patient 3 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. Unpublished

Patient 4 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. Unpublished

Patient 4 Jan 2010 Unpublished

Patient 4 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. Unpublished

Patient 4 Unpublished

Patient 4 Unpublished

Patient 4 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. Unpublished

Posaconazole and rash 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. Unpublished

Voriconazole

Cheilitis, conjunctivitis and facial erythema with voriconazole

Voriconazole and photosensitivity (phototoxic reaction) 52 Denning & Griffiths J Exp Dermatol 2001;26:648

Voriconazole, photosensitivity and sunshine Denning & Griffiths J Exp Dermatol 2001;26:648

Photosensitivity and cutaneous blistering with voriconazole Voriconazole has ‘uncovered’ pophyria cutanea tarda, and may be mistaken for it (pseudoporphyria) WWW.aspergillus.org.uk

Voriconazole and pseudoporphyria Medscape

Patient 5 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. Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5 Swift & Denning J Otol Laryngol 1998;112:92

Patient 5 Right hypglossal nerve palsy Right lateral rectus palsy Swift & Denning J Otol Laryngol 1998;112:92

Patient 5 Swift & Denning J Otol Laryngol 1998;112:92

Patient 5 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. Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5 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. Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5 Patient AB. First patient (in the world) with aspergillosis treated with voriconazole. Enrolled 2 July 1993 Swift J Otol Laryngol 1998;112:92. Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5 July 1994 she developed slightly pruritic, non-tender, 1-2cm diameter red plaques on both sides of her neck. Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5 Denning & Griffiths J Exp Dermatol 2001;26:648

Patient 5 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. Denning & Griffiths J Exp Dermatol 2001;26:648

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 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. www.aspergillus.org.uk

Patient 6 www.aspergillus.org.uk

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

CGD and hyper IgE syndrome, aggressive multifocal SCCs, voriconazole for 4.5 yrs McCarthy Clin Infect Dis 2007;44:e55

CGD, multiple melanomas in situ, voriconazole for 4.5 yrs Miller Arch Dermatol 2010;146:300

HIV, SCC, on voriconazole for 15 months ALL, multiple SCCs in situ, voriconazole for 3 yrs Cowen, J Am Acad Dermatol 2010;62:31

Prior methotrexate, multiple SCCs on scalp, voriconazole for 2 yrs CF & Lung Tx, aggressive SCCs, on voriconazole for 3.5 yrs Epaulard, Clin Microbiol Infect 2010;16:1362

Multifocal Aggressive Squamous Cell Carcinomas Induced by Prolonged Voriconazole Therapy Pulmonary aspergillosis, skin carcinogenesis showed two variants of the MICR gene. Morice, Case Rep Med 2010

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?