You are in: eMedicine Specialties > Dermatology > FUNGAL INFECTIONS AspergillosisArticle Last Updated: Dec 17, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Annie Chiu, MD, Staff Physician, Department of Dermatology, Cedars-Sinai Medical Group Annie Chiu is a member of the following medical societies: American Academy of Dermatology and Women's Dermatologic Society Coauthor(s): Alexa F Boer Kimball, MD, MPH, Associate Professor of Dermatology, Harvard University School of Medicine; Director of Clinical Unit for Research Trials in Skin, Associate Dermatologist, Department of Dermatology, Massachusetts General and Brigham and Women's Hospitals Editors: Peter Fritsch, MD, Chair, Department of Dermatology and Venereology, University of Innsbruck, Austria; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center Author and Editor Disclosure Synonyms and related keywords: cutaneous aspergillosis, fungal infection, Aspergillus fumigatus, A fumigatus, Aspergillus flavus, A flavus, Aspergillus terreus, A terreus, Aspergillus chevalieri, A chevalieri, Aspergillus niger, A niger, Aspergillus ustus, A ustus INTRODUCTIONSection 2 of 12
  BackgroundCutaneous aspergillosis is most commonly a cutaneous manifestation of disseminated infection with the fungus Aspergillus, although primary cutaneous disease can rarely occur, especially in the setting of burns or trauma. Aspergillosis typically begins as a pulmonary infection subsequent to inhalation of fungal spores. In the immunocompromised host, hematogenous dissemination and invasion of other organ systems, including the skin, can then follow the initial pulmonary infection. Dermatologic manifestations of disseminated aspergillosis include single or multiple erythematous-to-violaceous plaques or papules, often characterized by a central necrotic ulcer or eschar. Skin lesions occur in 5-10% of patients with disseminated aspergillosis. Infrequently, they may be the presenting sign of systemic infection. Primary cutaneous aspergillosis occurs much less commonly in the absence of hematogenous disease. In these instances, the most typical presentation is implantation of the fungus following trauma, including infections at the site of intravenous cannulas, or venipuncture wounds, especially those that have been covered with occlusive dressings. Aspergillus is a frequent contaminant found in cultures of dystrophic nails, but it can occasionally cause a true onychomycosis. PathophysiologyCutaneous aspergillosis is caused by infection with ubiquitous soil- and water-dwelling saprophytes of the Aspergillus genus. Typically, infection of the pulmonary system occurs via inhalation of fungal spores, which then leads to disseminated hematogenous infection with the organism. Aspergillus fumigatus is the most common pathogen associated with disseminated disease with cutaneous involvement, whereas Aspergillus flavus1 or Aspergillus terreus most often causes the less frequent primary infections of the skin. Aspergillus FrequencyUnited StatesAspergillosis is the second most common opportunistic fungal infection in patients who are immunocompromised, accounting for as many as 20% of fungal infections in patients who have received bone marrow or solid organ transplants. Key risk factors include neutropenia from hematologic malignancy or chemotherapy, immunosuppressive therapy, AIDS, and cytomegalovirus infection. Mortality/MorbidityDisseminated aspergillosis is associated with a mortality rate of greater than 90%. In contrast, multiple case reports have documented resolution of primary cutaneous aspergillosis after surgical excision followed by, in some cases, systemic antifungal therapy. SexNo clear sexual predilection is reported. AgeNeonates occasionally develop disseminated disease, presumably because of their immature immune mechanisms. CLINICALSection 3 of 12
HistoryPatients with disseminated aspergillosis often present with febrile illness, pneumonia, or sinusitis unresponsive to antibiotics. Other possible presentations include the following:
PhysicalThe pertinent physical findings below are limited to the skin examination.
CausesAspergillosis is an uncommon disease in patients who are not immunocompromised because normal neutrophilic and macrophagic functions prevent infection; however, any deficiency in these immunologic parameters increases the risk of aspergillosis. For example, systemic corticosteroid therapy is a known risk factor for cutaneous aspergillosis. Some environmental risk factors have also been implicated; these factors include construction sites and contaminated ventilation systems, presumably caused by effects on spore distribution. DIFFERENTIALSSection 4 of 12
Cellulitis Ecthyma Ecthyma Gangrenosum
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| Drug Name | Amphotericin B (Amphocin, Fungizone) |
|---|---|
| Description | Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. |
| Adult Dose | 3-5 mg/kg/d IV of liposomal amphotericin B over 120 min; increase as tolerated |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine, aminoglycosides, tacrolimus, cisplatin, and acetazolamide; in vitro and animal studies have suggested the development of fungal resistance to amphotericin B concurrently administered with imidazoles; when administered with amphotericin B, zidovudine leads to an increased risk of nephrotoxicity and hematologic toxicity via an unknown mechanism |
| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals |
| Precautions | Monitor renal function, serum electrolyte levels (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for >7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock |
| Drug Name | Itraconazole (Sporanox) |
|---|---|
| Description | Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. |
| Adult Dose | 200 mg PO qd; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses) 200 mg IV bid for 4 doses, followed by 200 mg/d |
| Pediatric Dose | Not established; suggested dose 100 mg/d for systemic fungal infections |
| Contraindications | Documented hypersensitivity; breastfeeding |
| Interactions | Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered) |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Caution in hepatic insufficiencies |
| Drug Name | Voriconazole (VFEND) |
|---|---|
| Description | Used for primary treatment of invasive aspergillosis and salvage treatment for infection with Fusarium species or Scedosporium apiospermum. A triazole antifungal that inhibits fungal CYP450–mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. |
| Adult Dose | Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses Maintenance: 4 mg/kg IV q12h infused over 2 h; when able to tolerate PO, may switch to 200 mg PO q12h (administer PO 1 h ac or pc) Note: For inadequate response, may increase to 300 mg PO q12h; <40 kg administer oral maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h) |
| Pediatric Dose | <12 years: Not established >12 years: Data limited; administer as in adults |
| Contraindications | Documented hypersensitivity; do not administer IV form with CrCl <50 mL/min (decreased excretion of IV vehicle); coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, or ergot alkaloids |
| Interactions | CYP450 2C19 (highest affinity), CYP2C9, and CYP3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady state peak plasma levels by as much as 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or CYP2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids), others may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG-CoA inhibitors, benzodiazepines, calcium channel blockers) |
| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus |
| Precautions | Decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, rash (including Stevens-Johnson syndrome and phototoxicity), vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder; rare cases of severe hepatotoxicity have been reported |
| Drug Name | Caspofungin (Cancidas) |
|---|---|
| Description | Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall. |
| Adult Dose | 70 mg IV over 1 h on day 1; 50 mg IV qd thereafter |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels; may decrease levels of tacrolimus; rifampin decreases caspofungin levels by 30% (ie, adjust dose to 70 mg/d) |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Caution in moderate hepatic dysfunction (ie, decrease dose to 35 mg/d); may exacerbate preexisting renal dysfunction or myelosuppression |
| Drug Name | Micafungin (Mycamine) |
|---|---|
| Description | Member of new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells. |
| Adult Dose | Dosages vary |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Increases sirolimus and nifedipine AUC approximately 20% |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Common adverse effects may include headache, nausea, vomiting, and abdominal pain; other adverse effects include rash, delirium, phlebitis, shock, leukopenia, and hyperbilirubinemia; rare cases of elevated hepatic enzyme, BUN, and creatine levels have been reported; transient acute intravascular hemolysis and hemoglobinuria may occur; do not mix or infuse in same IV line with other medications because precipitate forms with other commonly used medications (flush existing IV line with 0.9% sodium chloride solution before and after infusion); protect from light following dilution |
| Drug Name | Posaconazole (Noxafil) |
|---|---|
| Description | Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus infections in patients at high risk because of severe immunosuppression. |
| Adult Dose | 200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption |
| Pediatric Dose | <13 years: Not established >13 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine) |
| Interactions | Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk) Inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine) |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding |
Laminar airflow protection and high-efficiency particulate air filters have been reported as effective ways to prevent nosocomial pulmonary infection in patients who are immunocompromised. To prevent primary cutaneous disease, use sterile dressings at catheter sites or other susceptible areas.
When cutaneous involvement occurs in the setting of systemic aspergillosis, the prognosis is poor.
Because of the potentially serious nature of these infections, prompt medical diagnosis is important.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous Editor-in-Chief, William James, MD, to the development and writing of this article.
| Media file 1: Primary cutaneous aspergillosis at a site of an intravenous catheter in a boy with leukemia. | |
 | View Full Size Image | Media type: Photo |
Article Last Updated: Dec 17, 2007
