INTRODUCTION — Blastomycosis is a systemic pyogranulomatous infection, primarily involving the lungs, which arises after inhalation of the conidia of Blastomyces dermatitidis. Blastomyces gilchristii is a more recently described species that causes similar illness. Blastomyces helicus, which has been moved into the genus Blastomyces, has been identified as a cause of disease in a very small number of humans and domestic animals. Other newer species that may or may not be human pathogens include Blastomyces parvus, Blastomyces percursus, and Blastomyces silverae. This topic will focus on B. dermatitidis, the organism on which we have the largest amount of information.

Blastomycosis of the lung can be asymptomatic or manifest as acute or chronic pneumonia. Hematogenous dissemination occurs frequently; extrapulmonary disease of the skin, bones, and genitourinary system is common, but almost any organ can be involved.

Most patients with blastomycosis require therapy (unlike acute histoplasmosis, for which treatment often is not necessary). The antifungal agents proven to be useful in the treatment of blastomycosis will be reviewed here. The approach is generally in keeping with the 2008 Infectious Diseases Society of America clinical practice guidelines for the treatment of blastomycosis (table 1) [1]. The mycology, pathogenesis, epidemiology, and clinical manifestations of blastomycosis are discussed separately. (See "Mycology, pathogenesis, and epidemiology of blastomycosis" and "Clinical manifestations and diagnosis of blastomycosis".)

GENERAL APPROACH — Treatment options for patients with blastomycosis include amphotericin B or one of the azole drugs (usually itraconazole) [1]. Several factors must be considered when deciding upon the appropriate regimen:

●The clinical form and severity of disease – All patients with extrapulmonary disease or progressive pulmonary disease require therapy:

•Either a lipid formulation amphotericin B or amphotericin B deoxycholate should be given to patients with moderately severe to severe pulmonary or disseminated infection.

•A lipid formulation of amphotericin B is preferred for patients with central nervous system (CNS) infection.

•An azole, usually itraconazole, is preferred for patients with mild to moderate disease not involving the CNS.

●The immune status of the patient – Some immunocompetent patients with acute infection confined to the lungs spontaneously clear the infection and may not need treatment. In contrast, all immunocompromised patients should be treated, most frequently with amphotericin B.

STUDIES OF ANTIFUNGALS

Amphotericin B — Amphotericin B has broad fungicidal activity against yeasts, molds, and dimorphic fungi, including B. dermatitidis. Amphotericin B deoxycholate is the agent that has been used most frequently for the treatment of blastomycosis [2]. Lipid formulations of amphotericin B are effective in animal models of blastomycosis [3] but have not been studied in clinical trials [1]. Despite this limitation, a lipid formulation is generally recommended for the treatment of blastomycosis when amphotericin B is indicated, since lipid formulations have been used extensively and are thought to be as effective as amphotericin B deoxycholate [4-7] while being less nephrotoxic and having fewer infusional toxicities [1].

When administered in cumulative doses greater than 1 g, intravenous amphotericin B deoxycholate has been reported to result in cure without relapse in 77 to 91 percent of patients with blastomycosis [8]. A review of 326 blastomycosis cases over a 10-year period noted a cure rate of 86 percent and a relapse rate of only 4 percent for amphotericin B deoxycholate-treated patients [9]. Relapse rates appear to be dose dependent [2,10]. In one series, for example, relapse occurred in 1 of 28 patients who received more than 1.5 g of amphotericin B deoxycholate compared with 6 of 21 patients who received less than 1.5 g [2].

Amphotericin B deoxycholate therapy is frequently complicated by significant toxicity. A decline in kidney function is the most common serious complication and the most common reason for interruption or premature termination of therapy. Because of reduced nephrotoxicity and better central nervous system (CNS) penetration of one of the lipid formulations in an animal model, lipid preparations of amphotericin B are generally preferred. These are liposomal amphotericin B (AmBisome) and amphotericin B lipid complex (Abelcet). Of the lipid formulations, liposomal amphotericin B had the best CNS penetration in a study in rabbits, but it is unknown whether this is associated with greater clinical efficacy in humans [11]. (See "Amphotericin B nephrotoxicity".)

Azoles — For patients with moderate or milder forms of blastomycosis, the azoles are safe and effective; itraconazole is the agent used most commonly. (See "Pharmacology of azoles".)

Ketoconazole — Ketoconazole was the first azole proven to be effective for the treatment of immunocompetent patients with nonmeningeal blastomycosis of mild to moderate severity. In a randomized trial conducted by the Mycoses Study Group that compared 400 mg with 800 mg of ketoconazole per day, documented cure rates were 79 and 100 percent in 65 patients treated with ketoconazole at the lower and higher dose, respectively [12]. The higher dose was associated with an increased incidence of adverse effects. In other uncontrolled series, ketoconazole, at a dose of 400 mg/day or more, produced a cure rate of 76 to 82 percent [9,13]. However, relapse of blastomycosis is common after ketoconazole (10 to 14 percent), and toxicity occurs frequently [9,12,13]. Itraconazole has replaced ketoconazole as the oral azole of choice, as discussed below.

Due to the risk of severe liver injury and adrenal insufficiency associated with ketoconazole, in 2013, the US Food and Drug Administration revised the box warning, stating that oral ketoconazole should not be used as first-line treatment for any fungal infection and that it should be used for the treatment of endemic mycoses, such as blastomycosis, only when alternative antifungal therapies are not available or tolerated [14].

Itraconazole — In comparison with ketoconazole, oral itraconazole has better absorption, enhanced antifungal activity, and fewer adverse effects. Thus, itraconazole has replaced ketoconazole as the oral azole of choice for the treatment of non-life-threatening, non-CNS blastomycosis. Itraconazole has poor cerebrospinal fluid penetration. (See "Pharmacology of azoles".)

The efficacy of itraconazole was illustrated in a Mycoses Study Group nonrandomized open-label study in which it was effective in 90 percent of 48 patients with blastomycosis treated with daily doses of 200 to 400 mg [15]. In a separate study, only 1 of 42 patients failed the initial course of therapy with 200 mg itraconazole [16]. Four patients later relapsed; two were cured with a second course of itraconazole, and two required treatment with amphotericin B. Thus, 39 of 42 patients (93 percent) were eventually cured with itraconazole therapy.

Itraconazole is generally well tolerated. In the Mycoses Study Group report cited above, treatment was discontinued in only 1 of 48 treated patients because of drug toxicity [15]. Side effects include hepatotoxicity, hypokalemia, pedal edema, and, rarely, heart failure. (See "Pharmacology of azoles", section on 'Adverse effects'.)

There are important pharmacokinetic differences between the capsule and liquid preparations of itraconazole. Absorption of the capsule formulation is highly variable, requires gastric acidity, and is enhanced when the agent is taken with food. Thus, in patients who receive concomitant medications that decrease gastric acidity, blood levels are reduced. In contrast, the liquid formulation has better bioavailability, does not require an acidic environment, and is taken on an empty stomach. (See "Pharmacology of azoles", section on 'Pharmacokinetics'.)

Whether the capsule or the liquid formulation is given, monitoring serum levels of itraconazole in patients after two weeks of treatment is recommended [1]. Serum concentrations predictive of failure or success of treatment have not been defined, but serum concentrations of itraconazole greater than 1 mcg/mL are recommended. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

Super-BioAvailable (SUBA) itraconazole is a formulation of itraconazole that has better absorption from the gastrointestinal tract with reportedly better serum levels than the capsule. In the United States, the US Food and Drug Administration has approved it for treatment of endemic mycoses, including blastomycosis, although there are minimal data published for use in this infection. A clinical trial comparing SUBA itraconazole with conventional itraconazole for endemic mycoses, including blastomycosis, is ongoing. The dose of SUBA itraconazole for blastomycosis is two 65 mg tablets (130 mg) twice daily [17].

Fluconazole — Only a limited number of patients with blastomycosis have been treated with fluconazole. The results of a small pilot study employing lower-dose fluconazole were disappointing, with a successful outcome noted in only 65 percent of the 23 patients treated with daily doses of 200 mg and 400 mg [18]. In a second study reporting treatment of 39 patients with daily doses of 400 mg and 800 mg, a successful outcome was noted in 87 percent [19].

Drug interactions are less pronounced than those reported for ketoconazole or itraconazole. In addition, fluconazole is well absorbed in achlorhydric patients and in those treated with H2 blockers.

The efficacy results suggest that fluconazole is not as effective as itraconazole. However, fluconazole has excellent penetration into the CNS and may therefore have some role in the treatment of blastomycotic meningitis and cerebral abscesses in patients who are intolerant of amphotericin B. However, only a few patients with CNS blastomycosis have been treated with fluconazole.

Voriconazole — B. dermatitidis is susceptible to voriconazole, and this agent has proven effective in murine models of blastomycosis [20,21]. Clinical experience is limited.

There have been reports of the successful use of voriconazole for treatment of refractory blastomycosis and for treatment in immunosuppressed patients [22]. Voriconazole has also been used as an alternative therapeutic agent in patients who have CNS blastomycosis [6,23,24] based on its ability to achieve therapeutic concentrations in the brain and cerebrospinal fluid [25]. In a multicenter review of 22 CNS cases, an amphotericin B formulation was followed by voriconazole in eight patients; all but one patient who received voriconazole had a favorable outcome [26].

Other azoles — B. dermatitidis is susceptible to posaconazole, and this agent has proven effective in murine models of blastomycosis [27]. B. dermatitidis is also susceptible to isavuconazole. The use of posaconazole or isavuconazole has been reported in only a few cases of blastomycosis in humans [28-30]. Isavuconazole may be preferred in certain settings (eg, concerns regarding QTc prolongation, drug interactions with warfarin), since this is the only azole that does not prolong the QTc interval, and it has a reduced risk of drug-drug interactions.

Echinocandins — Caspofungin has shown variable activity in vitro against B. dermatitidis [31,32]. Micafungin is active against the mycelial form but not the yeast form of B. dermatitidis [33].

The echinocandins have not been studied in animal models or human cases of blastomycosis and should not be used for the treatment of blastomycosis.

CHOICE OF THERAPY — Unlike acute histoplasmosis, for which treatment may not be necessary, most patients with blastomycosis require therapy. (See "Diagnosis and treatment of pulmonary histoplasmosis".)

Treatment options for patients with blastomycosis include amphotericin B or one of the azole drugs (usually itraconazole) [1,34]. Several factors must be considered when deciding upon the appropriate regimen, such as the clinical form and severity of disease and the immune status of the patient. (See 'General approach' above.)

The following recommendations reflect the 2008 Infectious Diseases Society of America guidelines for the management of blastomycosis [1]. Guidelines for the management of fungal infections, including blastomycosis, in adult pulmonary and critical care patients have also been published by the American Thoracic Society (ATS) [35]. These can be accessed at the ATS website.

Pulmonary blastomycosis — The evidence regarding the use of amphotericin B [2,8-10] and itraconazole [15,16] for the treatment of pulmonary blastomycosis comes from small observational studies. Lipid formulations of amphotericin B are effective in animal models of blastomycosis [3] but have not been studied in clinical trials [1].

Moderately severe to severe — A lipid formulation of amphotericin B (3 to 5 mg/kg intravenously [IV] once daily) or amphotericin B deoxycholate (0.7 to 1.0 mg/kg intravenously once daily) is the treatment of choice for initial therapy in patients with moderately severe to severe pulmonary blastomycosis (table 1) [1]. We prefer a lipid formulation of amphotericin B to avoid the nephrotoxicity of amphotericin B deoxycholate. Once improvement is noted (usually after one to two weeks), therapy can be switched to itraconazole (200 mg orally three times daily for three days, followed by twice daily for 6 to 12 months). The serum itraconazole concentration should be measured after at least two weeks of therapy to ensure adequate levels.

Rare patients present with fulminant pneumonia and adult respiratory distress syndrome (ARDS) [36,37]. Such patients have a mortality rate as high as 50 to 89 percent, and death usually occurs within the first few days of hospitalization [36]. Treatment with glucocorticoids has been used adjunctively in some patients with ARDS due to blastomycosis [1,38]. Case reports have also described the use of extracorporeal membrane oxygenation as supportive treatment in this setting [39]. However, there have been no clinical trials to assess whether these adjunctive treatments are beneficial, and further data are needed before they can be routinely recommended for patients with fulminant pneumonia and ARDS due to Blastomyces spp.

Mild to moderate — We suggest treating patients with mild to moderate pulmonary blastomycosis with oral itraconazole (200 mg three times daily for three days, then once or twice daily) for 6 to 12 months (table 1) [1]. The serum itraconazole concentration should be measured after at least two weeks of therapy to ensure adequate levels.

Voriconazole, posaconazole, or fluconazole can be used as alternatives to itraconazole in patients who are unable to take itraconazole [1]. However, there is less clinical experience with these agents compared with itraconazole. Ketoconazole was previously recommended but is no longer because it has greater toxicity than either itraconazole or fluconazole. If a patient has progressive pulmonary symptoms on an azole, therapy should be changed to an amphotericin B, preferably a lipid formulation.

Selected immunocompetent patients with mild disease confined to the lungs who are already improving when the diagnosis is established may not require therapy but must be carefully monitored to ensure that the infection resolves [40]. However, we suggest treating such patients with itraconazole in an attempt to prevent extrapulmonary disease (table 1) [1].

Disseminated blastomycosis — The evidence regarding the use of amphotericin B [2,8-10] and itraconazole [15,16] for the treatment of disseminated blastomycosis comes from small observational studies; in these studies, only a small subset of patients had disseminated disease. Lipid formulations of amphotericin B are effective in animal models of blastomycosis [3] but have not been studied in clinical trials [1].

All patients with disseminated (extrapulmonary) blastomycosis should be treated. The presence or absence of central nervous system (CNS) infection is the major determinant of the treatment regimen.

Moderately severe to severe disseminated — Moderately severe to severe disseminated infection (excluding CNS involvement) should be treated initially with a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously once daily) or amphotericin B deoxycholate (0.7 to 1.0 mg/kg intravenously once daily) for one to two weeks or until improvement is observed (table 1) [1]. We prefer a lipid formulation of amphotericin B to avoid the nephrotoxicity of amphotericin B deoxycholate. This should be followed by oral itraconazole (200 mg three times daily for three days, then 200 mg twice daily) for a total of at least 12 months. The serum itraconazole concentration should be measured after at least two weeks of therapy to ensure adequate levels.

Mild to moderate disseminated — Patients with mild to moderate disseminated disease (excluding CNS involvement) should be treated with oral itraconazole (200 mg three times daily for three days, then once or twice daily) for 6 to 12 months (table 1) [1].

Bone disease is more difficult to treat and more likely to relapse than other forms of blastomycosis [1,41]. Thus, patients with osteoarticular blastomycosis should continue therapy for at least one year [1]. The serum itraconazole concentration should be measured after at least two weeks of therapy to ensure adequate levels.

Central nervous system — The recommendations for treatment of CNS blastomycosis are based upon case reports and small case series [6,7,26]. Patients with CNS infection should be treated with a lipid formulation of amphotericin B (5 mg/kg per day) for 4 to 6 weeks followed by an oral azole for at least 12 months (table 1) [1]. Of the lipid formulations, liposomal amphotericin B had the best CNS penetration in an animal model, but it is unknown whether this is associated with greater clinical efficacy [11].

It is not clear which azole is optimal for step-down therapy for CNS blastomycosis. Based upon the limited data available, we suggest voriconazole (200 to 400 mg twice daily) [26]. If voriconazole cannot be used, we favor itraconazole (200 mg two to three times daily after a loading regimen of 200 mg three times daily for three days). High-dose fluconazole (800 mg/day) is also an option, but in our experience we have seen more failures with fluconazole compared with itraconazole [1].

Voriconazole has good CNS and cerebrospinal fluid (CSF) penetration and excellent activity against B. dermatitidis and has been an effective treatment for CNS blastomycosis in case reports and small case series [6,23,24,42]. No clinical trials have been performed comparing oral azole regimens for step-down therapy of CNS blastomycosis. Because voriconazole exhibits nonlinear pharmacokinetics resulting in inter- and intra-patient variability in serum concentrations, monitoring trough concentrations should be considered in patients receiving voriconazole for CNS blastomycosis. This is discussed in detail separately. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

Fluconazole has excellent CNS and CSF penetration but has less activity against B. dermatitidis than the other azoles [43]. There are anecdotal reports of success with fluconazole for the treatment of CNS blastomycosis [42,44,45]. Itraconazole has poor CSF penetration but has greater activity against B. dermatitidis than fluconazole [1]. There are a few case reports of success with itraconazole for the therapy of CNS blastomycosis [46,47].

Immunocompromised hosts — The recommendations for treatment of blastomycosis in immunocompromised hosts are based upon case reports and small case series [5,48-53]. Blastomycosis has been reported in patients with advanced HIV infection and in solid organ transplant recipients [48,49]. Immunocompromised patients with blastomycosis are more likely to present with severe pulmonary or disseminated infection, especially to the central nervous system, and to have a fatal outcome [1,48,49].

Immunocompromised patients with blastomycosis should be treated with a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously once daily) or amphotericin B deoxycholate (0.7 to 1.0 mg/kg intravenously once daily) for one to two weeks or until improvement is observed (table 1) [1]. We prefer a lipid formulation of amphotericin B to avoid the nephrotoxicity of amphotericin B deoxycholate.

Immunocompromised patients without CNS disease can then be switched to itraconazole therapy (200 mg three times per day for three days, followed by 200 mg twice per day for 12 months) as step-down therapy. The serum itraconazole concentration should be measured after at least two weeks of therapy to ensure adequate levels.

Relapses are common in patients in whom the immunosuppression cannot be reversed [48,49,54]. As a result, long-term suppressive therapy with itraconazole is recommended [1]. Patients with AIDS receiving antiretroviral therapy who have had a CD4 cell count of >150 cells/microL for at least six months can discontinue itraconazole therapy for blastomycosis after a minimum of one year [1]. This recommendation is derived from data demonstrating that it is safe to discontinue itraconazole under these circumstances in AIDS patients with histoplasmosis [55].

Pregnancy — The treatment of blastomycosis in pregnancy has not been studied. Pregnant women with blastomycosis should be treated with a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously once daily) (table 1) [1]. The azoles have embryotoxic and teratogenic properties and are therefore contraindicated in pregnancy.

Children — The treatment of blastomycosis is based upon case reports and small case series [6,53,56,57]. Blastomycosis occurs less commonly in children; however, the clinical spectrum of disease and therapeutic considerations are similar to adults [56]. Children tolerate the deoxycholate formulation of amphotericin B better than adults.

Treatment varies with age and the site of infection (table 1):

●Neonates with blastomycosis should be treated with amphotericin B deoxycholate (1 mg/kg IV once daily) [1].

●Children with life-threatening disease should be treated initially with amphotericin B deoxycholate (0.7 mg/kg IV once daily) or a lipid formulation of amphotericin B (3 to 5 mg/kg IV once daily) [1]. This should be followed by oral itraconazole (10 mg/kg per day, up to 400 mg per day) for a total of 12 months. If CNS involvement is present, liposomal amphotericin B (5 mg/kg IV once daily) should be used for the first four to six weeks, followed by step-down therapy with voriconazole. (See 'Central nervous system' above.)

●Children with mild-to-moderate infection without CNS involvement should be treated with oral itraconazole (10 mg/kg per day up to 400 mg per day) for 6 to 12 months [1].

SUMMARY AND RECOMMENDATIONS

●Blastomycosis is a systemic pyogranulomatous infection, primarily involving the lungs, that arises after inhalation of the conidia of Blastomyces dermatitidis. Unlike acute histoplasmosis, for which treatment often is not necessary, most patients with blastomycosis require therapy. (See 'Introduction' above.)

●For patients with mild to moderate disease (pulmonary or extrapulmonary, but excluding central nervous system [CNS] disease), we suggest treatment with itraconazole rather than another oral antifungal agent or amphotericin B (Grade 2C). (See 'Mild to moderate' above and 'Mild to moderate disseminated' above.)

●For patients with moderately severe to severe disease (pulmonary or extrapulmonary), we recommend initial therapy with amphotericin B (Grade 1C). We prefer a lipid formulation of amphotericin B in all patients except children, who tolerate the deoxycholate formulation better than adults do; in patients with CNS disease (including children), we recommend using a lipid formulation (Grade 1C).

After an initial induction phase, we recommend that patients moderately severe to severe disease (except for those with CNS disease) be switched to itraconazole for step-down therapy rather than being continued on amphotericin B (Grade 1C). Other oral antifungals may also be effective, but the greatest clinical experience is with itraconazole. (See 'Moderately severe to severe' above and 'Moderately severe to severe disseminated' above.)

For patients with CNS blastomycosis, we suggest voriconazole for step-down therapy (Grade 2C). (See 'Central nervous system' above.)

●Appropriate dosing regimens and duration of therapy for amphotericin B and itraconazole are discussed above and in the Table (table 1). Serum levels of itraconazole should be checked after two weeks of therapy. (See appropriate sections above.)