Approach
The main goals of treatment of blastomycosis are resolution of the symptoms and signs of the disease and microbiologic eradication of the fungus. Eradication is sometimes not achievable, particularly in patients who are immunosuppressed, and can be difficult to prove. The treatment options are limited to a select few antifungal medications with activity against Blastomyces dermatitidis. These include amphotericin-B preparations and azole antifungals.[2] Of the available azoles that have been studied in small randomized trials, the most effective is itraconazole, followed by fluconazole and lastly ketoconazole.[2][41][42][43] Ketoconazole is not used routinely due to its associated toxicities; however, it may be all that is available in resource-limited settings. Echinocandins (e.g., caspofungin) do not have activity against this organism. Surgical therapy is rarely performed except occasionally in a solitary pulmonary nodule or skin lesion resected to rule out malignancy.
Treatment duration is generally at least 6 months in immunocompetent patients and can be longer in severe disease or in immunocompromised patients.[2] Clinical judgment is involved in treatment decisions, and infectious diseases consultation should be considered in the management of hospitalized or complicated cases. The most severe manifestation of the disease determines the treatment choice, and pregnancy supersedes other considerations.
Although the diagnosis of blastomycosis is sometimes made during an inpatient workup of an acutely ill patient, the decision on whether to hospitalize a patient with an outpatient diagnosis of blastomycosis must be individualized. There are no formal guidelines that outline criteria for hospitalization of patients. The treating clinician should take into account several factors, including the severity of the illness, the need for initiation of intravenous therapy, risk of potential complications, and availability of close outpatient follow-up.
Immunocompetent nonpregnant ambulatory adults
Outpatients with cutaneous, milder genitourinary (GU), or milder pulmonary disease are treated with full-dose itraconazole for 6 to 12 months.[2]
Choice of amphotericin-B preparation in hospitalized patients
A lipid formulation (liposomal or lipid complex) or the deoxycholate formulation can be used, depending on the particular patient group:
Most patients are treated with a lipid formulation.[2] In particular, it has good nervous system penetration for patients with central nervous system (CNS) disease, and it is amenable to dose escalation.
Children and infants are treated with the deoxycholate formulation, unless they have CNS disease. It is better tolerated in children than in adults, and is the least expensive formulation.
Hospitalized immunocompetent nonpregnant adults
CNS disease:
Treated with 4 to 6 weeks of intravenous amphotericin-B followed by 12 months of azole antifungal therapy, regardless of the immune status of the host or whether other sites are involved with infection.[2]
Azole therapy includes itraconazole, voriconazole, or high-dose fluconazole.[2] There are no head-to-head studies and no preferences. Itraconazole may have best overall effectiveness, but voriconazole has good blood-brain penetrability.
Pulmonary, osteoarticular, or GU disease:
Treated initially with 1 to 2 weeks of amphotericin-B until there is evidence of clinical improvement in symptoms or signs of the disease.[2]
This is then followed by itraconazole therapy. Pulmonary or GU disease requires 6 to 12 months of itraconazole; osteoarticular no less than 12 months.[2]
Corticosteroids are sometimes used for blastomycosis-associated acute respiratory distress syndrome in some centers. However, there is no evidence or expert consensus supporting this.[2]
Immunosuppressed nonpregnant adults
Immunosuppressed patients should be treated initially with 1 to 2 weeks of amphotericin-B.[2]
However, full-dose itraconazole therapy should be continued for 1 year, and consideration should be given to subsequent lifelong secondary prophylaxis with low-dose itraconazole therapy if the underlying immunosuppression cannot be reversed.
Pregnant patients
Pregnant patients should be treated with amphotericin-B. Azole antifungals are contraindicated in pregnancy due to teratogenicity.
Duration of treatment depends on the severity of the disease. Pregnancy always supersedes other treatment considerations.
Itraconazole is given postdelivery if not breastfeeding. There is not a recommended therapy for breastfeeding women, as there are insufficient data in this population. Risks of treatment should be reviewed with an infectious disease specialist in these circumstances.
Newborns and children
Ambulatory children can be treated with itraconazole with weight-based dosing for 6 to 12 months.
Children with more severe disease should receive amphotericin-B initially, followed by itraconazole for at least 12 months. All children with CNS involvement require amphotericin-B.
Neonates (<30 days old) should also be treated with amphotericin-B.
Antifungal therapy adverse effects
Amphotericin-B is associated with nephrotoxicity, hypokalemia, and hypomagnesemia. These are generally reversible and occur early in the course of therapy. Use of liposomal preparations when indicated decreases the risk of nephrotoxicity. If nephrotoxicity develops, and the patient is clinically improving, an early switch to oral antifungal therapy should be considered. If the patient's clinical condition warrants continued amphotericin-B therapy, aggressive pre-infusional hydration with normal saline and electrolyte replacement can be helpful.
Treatment with any azole antifungal is associated with a low risk of hepatotoxicity, usually manifested as asymptomatic elevated aminotransferase levels. Discontinuation of the medication should only be considered if aminotransferase levels are greater than 2.5 times the upper limit of normal. Serum itraconazole and voriconazole levels can be measured and dose adjusted accordingly. Otherwise, rechallenge with the same medication after liver enzymes return to normal is recommended to complete a treatment course.
Itraconazole has been associated with CNS depression, cardiovascular effects (e.g., new or worsening hypertension, new or worsening heart failure, prolonged QT interval [obtain a baseline ECG before starting treatment], torsades de pointes), transient or permanent hearing loss, pseudoaldosteronism, hypokalemia, and peripheral neuropathy. Discontinuation of the drug may be required in some circumstances.
Fluconazole has also been associated with cardiovascular effects such as prolonged QT interval and torsades de pointes. Serious dermatologic reactions have also been reported.
Azole antifungals undergo many significant drug-drug interactions.
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