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

2. 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

3. Itraconazole erythematous eruption (AIDS)

4. 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Unpublished

5. 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Unpublished

6. Patient 1
Aug 2009
July 2010
Unpublished

7. 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Unpublished

8. 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Unpublished

9. Patient 2
Oct 2008
Jan 2010
Unpublished

10. 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Unpublished

11. Patient 2
Unpublished

12. 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

13. 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

14. 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

15. Patient 3
Sept 2008
Nov 2008
Unpublished

16. Patient 3
Unpublished

17. 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

18. 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

19. Patient 4
Jan 2010
Unpublished

20. 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

21. Patient 4
Unpublished

22. Patient 4
Unpublished

23. 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

24. 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

25. Voriconazole

26. Cheilitis, conjunctivitis and facial erythema with voriconazole

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

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

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

30. Voriconazole and pseudoporphyria
Medscape

31. 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

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

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

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

35. 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, After 4 weeks of therapy she developed cheilitis.
Denning & Griffiths J Exp Dermatol 2001;26:648

36. 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 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

37. 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

38. 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

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

40. 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

41. Pustular phototoxic reaction with voriconazole

42. Voriconazole adverse events in asthmatics
Chisimba, J Asthma In press

43. 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

44. Patient 6
LT (♀, age 49) lifelong asthma and atopy, with ABPA diagnosed in Recognised to have CPA complicating ABPA in 2001, but the CPA diagnosis was apparent but made in Recurrent infective exacerbations and colonisation by Aspergillus fumigatus and Pseudomonas aeruginosa. Treated with oral itraconazole.

45. Patient 6

46. 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”.

47. 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.

48. Patient 6

49. Patient 6

50. 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.

51. Patient 6
18 months later, new lesion on her forearm.

52. Patient 6
Biopsy showed squamous cell carcinoma in situ

53. Voriconazole and skin cancer

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

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

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

57. 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

58. 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

59. 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?