Patients with a subclinical disease (presence of serologic or other markers without symptoms) can be observed and do not require antifungal treatment. Mild to moderate disease should be treated in all patients. All immunocompromised patients and patients with progressive pulmonary disease or extrapulmonary disease require treatment.
Therapeutic approaches have evolved in recent years with the advent of oral azoles, primarily itraconazole, which has replaced amphotericin B for mild-to-moderate pulmonary blastomycosis in adult patients, and is used for completion of therapy after initial amphotericin treatment in more severe cases. [3, 33, 34, 35] Voriconazole may have a role in the treatment of CNS blastomycosis. [36, 37]
The need for inpatient and intensive care unit (ICU) care is based on the acuity and pace of the disease progression as well as the immune status of the patient. Admit severely and progressively ill patients to the ICU, including those with acute respiratory distress syndrome (ARDS).
Inpatient care often is needed for workup and treatment of blastomycosis presenting as an undiagnosed pneumonia, for pleural effusion, and for extrapulmonary manifestations such as meningitis. In addition, initiation of amphotericin B treatment is preferably performed in an inpatient setting (ie, with infusion through an indwelling central venous line in an observation room with a trained staff).
Amphotericin B and itraconazole continue to be the main drugs used in blastomycosis. Clinical data on using newer drugs (ie, posaconazole, caspofungin, micafungin) for the treatment of blastomycosis are insufficient.
Itraconazole is the drug of choice in mild-to-moderate pulmonary blastomycosis. It offers the ease of oral administration, low toxicity, and high efficacy. The appropriate dose is 600 mg per day for 3 days then 200-400 mg per day for 6-12 months. Gastric acidity is required for absorption of itraconazole. Ketoconazole is an effective alternative to itraconazole in mild to moderate disease in open-label trials.  However, it has a worse safety profile than itraconazole and higher relapse rates.
Patients with mild-to-moderate disseminated blastomycosis without CNS involvement should be treated with itraconazole 200-400 mg per day for 6-12 months. The treatment period should be 12 months in patients with osteoarticular disease.
Other azoles (eg, ketoconazole, fluconazole) are less desirable alternatives. Itraconazole is absorbed better, has less toxicity, and has a stronger antifungal effect than ketoconazole.  A high incidence of serious adverse effects has been reported with ketoconazole, along with relapse rates of 10-14%.  If ketoconazole is used, close follow-up monitoring for 1-2 years is warranted.
Fluconazole has only a limited role in therapy for blastomycosis. Although this agent demonstrates excellent CNS penetration, only anecdotal evidence supports its use in the treatment of blastomycotic meningitis and cerebral abscesses. 
If disease progresses while the patient is on any azole, therapy should be changed to amphotericin B. Azoles are contraindicated in pregnancy.
Patients with life-threatening disease, pulmonary (eg, ARDS) or extrapulmonary, should be treated with amphotericin B at a high dose of 0.7-1 mg/kg/d to a total dose of 1.5-2 g. Amphotericin B is also the recommended drug for patients with moderately severe to severe pulmonary disease or disseminated disease, and in most cases the dosage recommended is the same as in life-threatening disease.  Liposomal amphotericin B can also be used for severe disease at a dose of 3-5 mg/kg per day.
Cure without relapse has been reported in 77-91% of patients who receive total amphotericin doses of greater than 1 g. Cure rates of 97% have been reported with total doses greater than 2 g. 
Amphotericin is associated with several toxic effects, most notably renal impairment. Other effects include thrombophlebitis at the injection site, chills, fever, nausea, hypokalemia, and anemia. Toxicity often necessitates interruption of therapy. The lipid formulation of amphotericin (daily intravenous at 3-5 mg) is less likely to cause renal impairment and may be a better alternative in patients with CNS infection.
Once patients receiving amphotericin demonstrate clinical improvement, switching to an oral azole is the standard of care.  Current expert opinion is to treat with itraconazole 200 mg 3 times daily for 3 days, then twice daily for 6 months. It is recommended to check the serum itraconazole level 2 weeks into treatment to ensure the level is appropriate.
Patients with CNS blastomycosis should be treated with amphotericin B, using the same dose schedule as in life-threatening disease. However, liposomal amphotericin B is preferred because of its better CNS penetration at a dose of 5 mg/kg per day for 4-6 weeks followed by an oral azole for at least one year. Voriconazole, a newer antifungal agent, has good cerebrospinal fluid penetration. [38, 39]
Immunocompromised patients should be treated early and aggressively with amphotericin B as in life-threatening disease. After the amphotericin B course, chronic suppressive therapy with itraconazole may be needed in most cases. Most experts recommend treating blastomycosis in children with AIDS with 30 mg/kg of amphotericin B over 4-6 weeks, followed by itraconazole for at least 6 months in those who have responded to a primary course of amphotericin B.
Blastomycosis should be treated in pregnant women. Liposomal amphotericin B, 3-5 mg/kg per day, is recommended. Azoles are contraindicated because of possible teratogenicity embryotoxicity.
Since blastomycosis is rarely encountered, it is advisable for primary care physicians to seek consultation with a physician more experienced with this disease. In cases with extrapulmonary involvement, consult a specialist (pulmonologist or infectious disease specialist) for diagnosis and treatment recommendations. Consult a pulmonologist or an intensivist for patients who present with or develop ARDS.
Surgical consultation may be needed for a tissue biopsy, but only rarely for adjunctive surgical treatment (eg, evacuation of a joint abscess, pleural empyema). Alert the microbiologist to the possibility of blastomycosis before sending any specimen to the laboratory, because of the risk of cutaneous infection from accidental autoinoculation. Consultation with a dermatologist may facilitate making the diagnosis by recognition of typical skin lesions, aspiration, or expression of microbiologically diagnostic pus, or skin biopsy.
In Arkansas, Louisiana, Michigan, Minnesota, Mississippi, and Wisconsin, blastomycosis is a reportable disease, and the treating physician needs to contact the state department of health.
Ongoing studies of cell wall properties of Blastomyces dermatitidis are promising for the development of a preventive vaccine. Such a vaccine could be targeted to patients at high risk of exposure and immunocompromised patients. 
Although immunocompromised patients (including those with HIV/AIDS) living in or visiting blastomycosis-endemic areas cannot completely avoid exposure to B dermatitidis, they should be counseled about reducing the risk of acquiring blastomycosis by avoidance of occupational and recreational activities known to be associated with increased risk (eg, wooded areas along waterways).
No specific data are available regarding blastomycosis in children with HIV. Nevertheless, administering lifelong suppressive therapy with itraconazole after an acute episode of the disease is reasonable.
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