Antifungal skin reactions

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 199533130 Min Park,
JAAD 199736754
3
Itraconazole erythematous eruption (AIDS)
www.aspergillus.org.uk
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 1
Diaphoresis 1
Unpublished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Unpublished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Unpublished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 gt 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Unpublished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Unpublished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Unpublished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Unpublished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 200126648
28
Voriconazole, photosensitivity and sunshine
Denning Griffiths J Exp Dermatol 200126648
29
Photosensitivity and cutaneous blistering with
voriconazole
Voriconazole has uncovered pophyria cutanea
tarda, and may be mistaken for it
(pseudoporphyria)
WWW.aspergillus.org.uk
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 200126648
32
Patient 5
Swift Denning J Otol Laryngol 199811292
33
Patient 5
Right hypglossal nerve palsyRight lateral
rectus palsy
Swift Denning J Otol Laryngol 199811292
34
Patient 5
Swift Denning J Otol Laryngol 199811292
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,
  1993. After 4 weeks of therapy she developed
  cheilitis.

Denning Griffiths J Exp Dermatol 200126648
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
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 200126648
37
Patient AB.First patient (in the world) with
aspergillosis treated with voriconazole.
Enrolled 2 July 1993
Patient 5
Swift J Otol Laryngol 199811292. Denning
Griffiths J Exp Dermatol 200126648
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 200126648
39
Patient 5
Denning Griffiths J Exp Dermatol 200126648
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 200126648
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 supplementationThe 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 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
45
Patient 6
www.aspergillus.org.uk
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.
www.aspergillus.org.uk
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.
www.aspergillus.org.uk
48
Patient 6
www.aspergillus.org.uk
49
Patient 6
www.aspergillus.org.uk
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 200744e55
55
CGD, multiple melanomas in situ, voriconazole for
4.5 yrs
Multiple melanomas in situ, voriconazole for 3 yrs
Miller Arch Dermatol 2010146300
56
HIV, SCC, on voriconazole for 15 months
ALL, multiple SCCs in situ, voriconazole for 3 yrs
Cowen, J Am Acad Dermatol 20106231
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CF Lung Tx, aggressive SCCs, on voriconazole
for 3.5 yrs
Prior methotrexate, multiple SCCs on scalp,
voriconazole for 2 yrs
Epaulard, Clin Microbiol Infect 2010161362
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, Bowens 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?