Published online June 30, 2006
PEDIATRICS Vol. 118 No. 2 August 2006, pp. e506-e508 (doi:10.1542/10.1542/peds.2005-2213)
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EXPERIENCE AND REASON

Topical Voriconazole Solution for Cutaneous Aspergillosis in a Pediatric Patient After Bone Marrow Transplant

Kristin C. Klein, PharmDa and R. Alexander Blackwood, MD, PhDb

a Clinical Sciences Division, University of Michigan College of Pharmacy and Health System, Ann Arbor, Michigan
b Division of Infectious Diseases, University of Michigan Medical School and Health System, Ann Arbor, Michigan


   ABSTRACT
TOP
 ABSTRACT
CASE REPORT
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Invasive aspergillosis seems to be on the rise, especially in immunocompromised children. Historically, only systemic amphotericin B has been effective against Aspergillus. Development of newer antifungal agents, such as voriconazole and caspofungin, has improved the treatment options available for aspergillosis, although no definitive management strategy has been established. Here we describe the use of topical voriconazole combined with systemic antifungal agents for cutaneous aspergillosis in a pediatric patient after bone marrow transplant.

Key Words: topical voriconazole • cutaneous aspergillosis • pediatric bone marrow transplant

Abbreviations: BMT, bone marrow transplant • GVHD, graft-versus-host disease

Little exists in the medical literature regarding the incidence of Aspergillus infections in pediatric patients, although they seem to be on the rise, especially in immunocompromised children.1 Cutaneous Aspergillus infections have been described in immunocompromised children, in neonates, and after traumatic injuries with varying treatment options and degrees of successful recovery.1–4 Here we describe a case of cutaneous aspergillosis in a pediatric patient after bone marrow transplant (BMT) who was successfully treated with topical voriconazole in combination with systemic antifungal agents.


   CASE REPORT
TOP
 ABSTRACT
 CASE REPORT
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A 19-year-old female, 224 days status–post matched, unrelated donor BMT secondary to aplastic anemia, was admitted to the pediatric bone marrow service at our institution with severe graft-versus-host disease (GVHD). Eight days into her hospitalization, she was noted to have a 5 x 5-cm nodule on her midthigh at the site of a previous insulin injection. The lesion was surgically resected with a 0.5-cm margin, leaving the remaining skin, fat, and muscle appearing viable, with adequate bleeding and no evidence of necrotic tissue (Fig 1). Subsequently, cultures grew Aspergillus flavus, and because she had been on voriconazole prophylaxis, therapy was initiated with amphotericin B. No definitive evidence of fungal dissemination was noted on computed tomography scans of the abdomen, chest, or pelvis; however, persistent pericardial and pleural effusions were noted on chest computed tomography (possibly secondary to GVHD), and bilateral transient wedge-shaped defects were noted in the kidneys. Cultures from the wound remained persistently positive despite daily dressing changes, the addition of caspofungin, and 2 additional surgical debridements for an additional 3 weeks; therefore, the addition of a topical voriconazole solution was instituted. A 1% solution was prepared by diluting 400 mg of the lyophilized intravenous preparation of voriconazole with 40 mL of normal saline for irrigation, and a 24-hour expiration date was assigned to the preparation. The solution was used in conjunction with wet-to-dry dressing changes twice a day.


Figure 1
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  		FIGURE 1 Photograph taken before initiation of topical voriconazole 1% solution.

 
After ~5 weeks of topical voriconazole and continued systemic antifungal therapy, the lesion diminished to 2.5 x 3 cm (Fig 2). At that time, the topical voriconazole solution was discontinued in favor of topical nystatin powder in preparation for discharge from the hospital. The patient received systemic antifungal agents and topical nystatin for 30 additional days, at which point she resumed voriconazole prophylaxis. No adverse reactions were reported by the patient. At 4 month's follow-up, the wound demonstrated continued healing with no evidence of recurrence.


Figure 2
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  		FIGURE 2 Photograph taken 10 days before discontinuation of topical voriconazole 1% solution.

 

   DISCUSSION
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Similar to the adult population, A fumigatus and A flavus seem to be the most common Aspergillus species to cause infections in children.1 In pediatric oncology or patients after BMT, the infecting species seems to be location dependent, with A flavus associated with cutaneous disease and A fumigatus associated with pulmonary aspergillosis.1 As one might expect, transplant patients with severe GVHD have a higher risk of developing invasive aspergillosis.1

Mortality rates from invasive aspergillosis are high and in pediatric patients have ranged from 68.2% to 76.9% in the literature and seem to be higher than those of adult patients with invasive aspergillosis.1 Not surprisingly, patients with pulmonary aspergillosis have worse outcomes than those with isolated cutaneous aspergillosis.1

Cutaneous aspergillus infections, particularly in immunocompromised patients, are frequently the result of hematogenous seeding from a primary source, usually the lungs. They frequently begin as erythematous, indurated papules and progress to necrotic or ulcerative lesions,5–8 as in our patient's case. Primary invasive disease has also been associated with intravenous access devices and adhesive dressings.6,8 In the case of our patient, the cutaneous lesion was at a previous insulin-injection site, suggesting primary invasive disease; however, subsequent investigation for pulmonary or disseminated disease was inconclusive, partially because of the severity of her underlying GVHD. Because of the high mortality rates associated with invasive aspergillosis in pediatric patients, aggressive treatment in our patient was warranted.

Voriconazole is one of the newer azole antifungal agents, all of which act by inhibiting the production of ergosterol in the plasma membrane of the fungus, and exhibits activity against many pathogenic molds such as Aspergillus.9 Although the systemic use of voriconazole is known to be effective clinically, limited data exist regarding topical antifungal therapy for molds or fungi that historically have been resistant to azole antifungal agents, such as Aspergillus or Scedosporium. Conventional antifungal therapy failed in our patient, as evidenced by repeated positive wound cultures; therefore, adjunctive measures were sought. Prats et al10 described a case of Scedosporium apiospermum keratitis after a traumatic eye injury in a 19-year-old male who was successfully treated in 3 months with topical voriconazole 1% solution in combination with systemic voriconazole. The only adverse effect reported by the authors was an episode of blurred vision that occurred with the first dose of intravenous voriconazole.10

The use of topical (or intracavitary) antifungal therapy has been reported sporadically in the literature. Barret et al11 published a case series describing 4 patients with full-thickness burns to a mean of 72% of their total body surface area who also developed invasive fungal wound infections. Topical nystatin combined with wet-to-dry dressings was added to each patient's regimen when the infections progressed despite surgical debridement and systemic antifungal agents. After 2 weeks of topical nystatin and continued systemic itraconazole, improvement in each of the wounds was noted, and evidence of fungal invasion was no longer apparent on pathology review.11 None of the patients complained of pain after application of nystatin powder.

The use of topical antifungal agents has been described in many other patient care settings, as well. Inhaled amphotericin B has been used in conjunction with systemic antifungal agents for the treatment of fungal sinusitis12 and tracheobronchial aspergillosis.13 A variety of topical antifungal agents have been used in the treatment of chronic otitis, including amphotericin B 3% topical solution, 5-flucytosine ointment, clotrimazole, and ketoconazole.14 Topical antifungal agents are frequently used in the management of scleral abscesses and keratitis, whereas collagen shields impregnated with amphotericin B have also been used for corneal infections.15–18 Intraperitoneal and systemic amphotericin B have been used for Aspergillus peritonitis,14,19 and Baquero-Artigao20 reported the use of systemic and intrapleural amphotericin B for treatment of a pulmonary empyema.


   CONCLUSIONS
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Topical voriconazole solution combined with systemic antifungal therapy was effective in inhibiting further invasion of cutaneous aspergillosis and, thereby, promoting better wound healing in our patient post-BMT. No adverse effects were reported by the patient after administration. Although we do not advocate using topical voriconazole as monotherapy for cutaneous aspergillomas, the administration of topical voriconazole solution seems to be a viable adjunctive therapy when combined with systemic antifungal agents for the treatment of cutaneous aspergillosis.


   FOOTNOTES
 
Accepted Feb 28, 2006.

Address correspondence to Kristin C. Klein, PharmD, MCHC F2758, Box 0221, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0221. E-mail: kriklein{at}umich.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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