INTRODUCTION — Blastomycosis is a systemic pyogranulomatous infection, primarily involving the lungs, which arises after inhalation of the conidia of Blastomyces species, including B. dermatitidis, B. gilchristii, and B. helicus. The organism may then disseminate to other sites, especially the skin, but also bone, central nervous system, prostate, and essentially any organ. This topic will focus on B. dermatitidis, the organism for which we have the largest amount of information. The treatment principles for B. dermatitidis can also be applied to other Blastomyces species identified as causing disease in humans
Treatment approach depends on multiple factors, including severity of disease, site of infection, and degree of immunocompromise in the patient.
Treatment principles, selection of antifungal therapy, monitoring and duration of therapy, management of refractory disease, and prevention of disease will be reviewed here.
The mycology, pathogenesis, epidemiology, clinical manifestations, and diagnosis of blastomycosis are discussed separately. (See "Mycology, pathogenesis, and epidemiology of blastomycosis" and "Clinical manifestations and diagnosis of blastomycosis".)
GENERAL PRINCIPLES
Goals of therapy — The goals of treatment are to eradicate the infection and prevent progression of disease. We treat all patients diagnosed with blastomycosis, regardless of severity of disease, to prevent disease progression (table 1A) [1-3]. However, some experts may choose to defer therapy in select immunocompetent patients with mild pulmonary disease who are already improving when the diagnosis is established [4]. This approach should only be considered in a patient who has had complete resolution of pneumonia before a respiratory culture returns four to six weeks after initial presentation. In addition, this approach would only be an option if there are no remaining symptoms and after careful inspection looking for skin lesions or other physical examination abnormalities. Laboratory assessment for leukocytosis and abnormal inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) should prompt further investigation for disseminated infection. If therapy is deferred, the patients should be carefully monitored to ensure that the infection resolves.
Our recommendations for therapy are generally in keeping with the Infectious Diseases Society of America guidelines for the management of blastomycosis [1]. Guidelines for the management of fungal infections, including blastomycosis, have also been published by the American Thoracic Society [2] and the European Confederation of Medical Mycology and International Society for Human and Animal Mycology [3].
Defining severity of disease — Blastomycosis can range from asymptomatic pulmonary infection to severe, life-threatening disease with a high mortality rate. Hematogenous dissemination occurs frequently; extrapulmonary disease of the skin, bones, and genitourinary system is common, but almost any organ can be involved.
Choice of initial therapy is determined by the severity of disease (table 1A). Distinction of mild, moderate, and severe disease is based on clinical judgment. Generally, immunocompromised patients and those who have evidence of organ failure are classified as having severe disease while the rest are classified as mild to moderate disease. Patients are often already hospitalized for workup of the infection; however, if a patient presents to clinic, hospitalization is warranted for patients with evidence of organ failure, those with central nervous system involvement, and those requiring treatment with amphotericin B. (See 'Severe/life-threatening disease without CNS involvement' below and 'Mild to moderate disease without CNS involvement' below and 'Immunocompromised patients' below.)
Antifungal options — Amphotericin B and azoles are the mainstay of antifungal therapy for blastomycosis. Echinocandins (eg, micafungin, caspofungin, anidulafungin) should not be used for the treatment of blastomycosis due to limited data on efficacy and variable activity in vitro against B. dermatitidis [5,6]. No studies in animal models or human cases have been conducted.
CHOICE OF ANTIFUNGAL THERAPY — Treatment options for patients with blastomycosis include amphotericin B or one of the azole drugs (usually itraconazole) [1,7]. Several factors must be considered when deciding upon the appropriate regimen, such as the organs involved, severity of disease, and the patient’s immune status.
Severe/life-threatening disease without CNS involvement
Initial therapy with amphotericin B — For patients with life-threatening or severe blastomycosis without CNS involvement, we suggest initiating therapy with a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously [IV] once daily) (table 1A-B) [1]. If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate (0.7 to 1.0 mg/kg IV once daily) is an alternative option. We continue amphotericin B therapy until the patient shows signs of clinical improvement, typically after one or two weeks of therapy.
●Adverse effects − Amphotericin B therapy is frequently complicated by significant toxicity, including infusion reactions, nephrotoxicity, and electrolyte abnormalities. Lipid formulations of amphotericin B (liposomal amphotericin B [AmBisome] and amphotericin B lipid complex [Abelcet]) are generally better tolerated than amphotericin B deoxycholate, but toxicities can occur with any formulation. (See "Pharmacology of amphotericin B", section on 'Adverse effects'.)
Renal function and electrolyte levels (including magnesium) should be monitored closely during treatment; need for potassium and magnesium replenishment is common. A sharp, steady decline in kidney function while on therapy should prompt attention, as acute kidney injury is the most common reason for interruption or premature termination of therapy. The dose of amphotericin B may need to be reduced or held for a day or two. (See "Amphotericin B nephrotoxicity".)
For patients who develop nonanaphylactic, immediate infusion-related reactions (eg, fever, chills, rigors, nausea, or vomiting), premedication with a nonsteroidal anti-inflammatory agent, acetaminophen, antihistamines, and/or hydrocortisone can be administered to help reduce symptoms. (See "Pharmacology of amphotericin B", section on 'Adverse effects'.)
●Efficacy − The evidence regarding the use of amphotericin B [8-11] for the treatment of blastomycosis comes from small observational studies in which only a subset of patients had disseminated disease. When administered in cumulative doses greater than 1 g, IV amphotericin B deoxycholate has been reported to result in cure without relapse in 77 to 91 percent of patients with blastomycosis [9]. 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 [10]. Relapse rates appear to be dose dependent [8,11]. 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 [8].
Amphotericin B deoxycholate is the agent that has been used most frequently for the treatment of blastomycosis [8]. Lipid formulations of amphotericin B are effective in animal models of blastomycosis [12] 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, because lipid formulations have been used extensively and are generally considered to be as effective as amphotericin B deoxycholate [13-16] while being less nephrotoxic and having fewer infusional toxicities [1].
Step-down azole therapy — Once improvement is noted (usually after one to two weeks), we switch therapy to itraconazole (200 mg orally three times daily for three days, then 200 mg twice daily). Several formulations of itraconazole are available. We generally continue treatment for 6 to 12 months, depending on clinical response and other host factors (table 1A-B). (See 'Duration of therapy' below.)
Details on itraconazole administration (eg, dosing, formulations) and efficacy are discussed elsewhere. (See 'Itraconazole' below.)
If itraconazole cannot be used, other step-down azole alternatives include posaconazole, isavuconazole, voriconazole, or fluconazole. (See 'Alternatives to itraconazole' below.)
Adjunctive therapies — Rarely, patients can present with fulminant pneumonia and adult respiratory distress syndrome (ARDS) [17,18]. Such patients have a mortality rate as high as 50 to 89 percent, and death usually occurs within the first few days of hospitalization [17]. Treatment with glucocorticoids has been used adjunctively in some patients with ARDS due to blastomycosis [1,19,20]. There have not been, and likely will never be, clinical trials to assess whether glucocorticoids are beneficial in reducing the inflammatory response associated with blastomycosis. Thus, steroids should only be administered in patients who are intubated, have ARDS, and meet the ARDS criteria for glucocorticoid initiation. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Glucocorticoids'.)
Case reports have also described the use of extracorporeal membrane oxygenation as a supportive measure in this setting [21-23].
Mild to moderate disease without CNS involvement
Itraconazole — For patients with mild to moderate blastomycosis and no CNS involvement, we suggest treating with oral itraconazole for 6 to 12 months (table 1A-B) [1]. We prefer itraconazole over other azoles because there are more clinical data supporting its efficacy in treatment of blastomycosis compared with fluconazole, voriconazole, posaconazole, and isavuconazole.
●Dosing and choice of formulation − There are important pharmacokinetic differences between the capsules and liquid preparations of itraconazole. We prefer starting with itraconazole capsules (200 mg three times daily for three days, then 200 mg twice a day) because this formulation has the most robust efficacy data in treatment of blastomycosis. However, absorption can be problematic; if serum drug concentration levels (discussed in detail below) are not adequate, or if the patient requires a medication that blocks gastric acid secretion (eg, proton pump inhibitor), we typically use the liquid formulation (200 mg three times daily for three days, then once or twice daily) or the Super-BioAvailable (SUBA) itraconazole capsule (130 mg three times daily for three days, then 130 mg once daily) [24] because of their improved absorption compared with the original capsule formulation (table 1B).
The oral capsules should be taken with a fatty meal and many clinicians also suggest a carbonated beverage (eg, Coca-Cola) be added. The liquid formulation should be taken on an empty stomach. When using itraconazole, serum concentration levels should be obtained after two weeks of therapy to ensure adequate blood levels. (See 'Therapeutic drug monitoring' below.)
The absorption of the original itraconazole capsule formulation is highly variable and requires gastric acidity. In patients who must continue to receive concomitant medications that decrease gastric acidity (eg, proton pump inhibitors), drug concentration levels in the blood are reduced and may not reach therapeutic levels. In contrast, the liquid formulation has better bioavailability, does not require an acidic environment, and is taken on an empty stomach.
SUBA itraconazole is a capsule formulation that has better absorption from the gastrointestinal tract with reportedly better blood levels than the original 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 regarding its use in this infection. A clinical trial comparing SUBA itraconazole with conventional itraconazole for endemic mycoses, including blastomycosis, is ongoing. (See "Pharmacology of azoles", section on 'Pharmacokinetics'.)
●Adverse effects − Itraconazole is generally well tolerated. In a nonrandomized open-label study of 48 patients with blastomycosis, treatment was discontinued in only 1 of 48 treated patients because of drug toxicity [25].
Patients taking itraconazole may experience gastrointestinal symptoms, such as nausea, vomiting, and abdominal pain. This can often lead to poor adherence. Other side effects include the triad of hypokalemia, peripheral edema, and hypertension, as well as hepatotoxicity, which can occur with all azoles. Heart failure has been reported, and there is a boxed warning that itraconazole should not be used in patients who are known to have congestive heart failure. Very rarely, itraconazole (and posaconazole) can cause pseudohyperaldosteronism with severe hypokalemia, hypertension, and metabolic alkalosis. Itraconazole solution is reported to have a bad taste and can cause diarrhea. We generally check aminotransferases at the initiation of itraconazole, one month into therapy, and, if normal, then every two months thereafter. (See "Pharmacology of azoles", section on 'Itraconazole'.)
If hypertension, heart failure, or pretibial edema is discovered, serum concentrations should be obtained and dose lowered if levels are elevated above 5 mcg/mL. If these adverse effects are seen in patients with serum concentrations within the preferred range, the drug must be stopped.
●Efficacy − The evidence regarding the use of itraconazole [25-27] for the treatment of blastomycosis comes from small observational studies. As an example, in a nonrandomized open-label study of 48 patients with blastomycosis, a daily dose of 200 to 400 mg itraconazole was 90 percent effective [25]. In a separate study, 39 of 42 were cured with itraconazole therapy, although two required a second course of itraconazole due to relapse [27]. Of the three who failed itraconazole therapy, 1 failed initial therapy and two had relapses that required amphotericin B therapy.
Alternatives to itraconazole — Posaconazole, isavuconazole, voriconazole, or fluconazole can be used as alternatives in patients who are unable to take itraconazole [1]. When itraconazole cannot be used, we prefer using oral posaconazole delayed-release capsules as an alternative option due to its tolerability and similar molecular structure to itraconazole.
The use of posaconazole or isavuconazole has been reported in only a few cases of blastomycosis in humans [28-31]. B. dermatitidis is susceptible to posaconazole, and this agent has proven effective in murine models of blastomycosis [32]. B. dermatitidis is also susceptible to isavuconazole. Isavuconazole may be preferred in certain settings (eg, organ transplant recipients) because it is the only azole that does not prolong the QTc interval and it has a reduced risk of drug-drug interactions [31].
Voriconazole and fluconazole are discussed in detail elsewhere. (See 'Voriconazole as preferred agent' below and 'Alternatives to voriconazole' below.)
Ketoconazole is not recommended any longer for blastomycosis because of serious adverse effects and a higher relapse rate than itraconazole [33-35].
Central nervous system disease
Initial therapy with amphotericin B — For patients with CNS involvement, we suggest a lipid formulation of amphotericin B (5 mg/kg per day) for four to six weeks followed by an oral azole for at least 12 months (table 1A-B) [1]. If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate (1.0 mg/kg IV once daily) is an alternative option. We prefer the lipid formulations of amphotericin B over the conventional formulation because they are less toxic and liposomal amphotericin has better CNS penetration. The recommendations for treatment of CNS blastomycosis are based upon case series and small observational studies [15,16,36,37].
Step-down therapy — It is not clear which azole is optimal for step-down therapy for CNS blastomycosis. Based upon the limited data available, our choice of azole in order of preference is voriconazole, itraconazole, and fluconazole.
Voriconazole as preferred agent — For patients with CNS blastomycosis, we suggest voriconazole (200 to 400 mg twice daily) as the preferred azole agent (table 1A-B) [36]. Voriconazole has good CNS and cerebrospinal fluid (CSF) penetration [38] and excellent activity against B. dermatitidis [39,40]. Although no clinical trials have been performed comparing oral azole regimens for step-down therapy of CNS blastomycosis, voriconazole has been demonstrated to be an effective treatment for CNS blastomycosis in case reports and small retrospective studies [15,36,41,42]. In a multicenter review of 22 CNS blastomycosis cases, eight patients received an amphotericin B formulation followed by voriconazole; all but one patient had a favorable outcome [36].
In addition to hepatotoxicity, which is a known adverse effect of all azoles, voriconazole is also associated with other adverse effects, such as vision changes, visual and/or auditory hallucinations, myoclonic movements, confusion, agitation, alopecia, nail changes, bone pain due to periostitis, rashes, and QTc prolongation. Patients taking voriconazole should be counseled on the possibility of these adverse effects and asked at each visit about any vision abnormalities, any hallucinatory or other neurologic symptoms, and skin and soft tissue symptoms. We generally check aminotransferases at the initiation of therapy and monthly thereafter. We obtain an electrocardiogram (EKG) to evaluate baseline QTc prior to treatment initiation and do not repeat an EKG unless the patient initiates other QTc-prolonging drugs.
Many of these adverse effects are dose-dependent and increase with higher trough levels. Because voriconazole exhibits nonlinear pharmacokinetics resulting in inter- and intrapatient variability in serum concentrations, monitoring trough concentrations should be performed in patients receiving voriconazole. This is discussed in detail separately. (See 'Therapeutic drug monitoring' below and "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
Alternatives to voriconazole — For patients with CNS blastomycosis in whom voriconazole cannot be used, we favor itraconazole above other azole agents. High-dose fluconazole is also an option, but in our experience, we have seen more failures with fluconazole compared with itraconazole.
●Itraconazole − For patients with CNS blastomycosis in whom voriconazole cannot be used, we use itraconazole (200 mg three times daily for three days followed by 200 mg two to three times daily) (table 1B). 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 [43,44]. Details of administration of itraconazole are discussed elsewhere. (See 'Itraconazole' above.)
●Fluconazole − For patients with CNS blastomycosis in whom neither voriconazole nor itraconazole can be used, high-dose fluconazole (800 mg once daily) is an option due to its excellent CNS and CSF penetration. Drug interactions are less pronounced than those reported for itraconazole, and fluconazole is well absorbed in achlorhydric patients and in those treated with H2 blockers. However, it has less activity against B. dermatitidis than the other azoles [45].
Only a few patients with CNS blastomycosis have been treated with fluconazole. Although there are anecdotal reports of successful treatment of CNS blastomycosis with fluconazole [36,46,47], the data in patients without CNS involvement suggest that fluconazole is not as effective as itraconazole in the treatment of blastomycosis. The results of a small pilot study in patients who did not have CNS blastomycosis 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 [48]. 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 [49].
Special populations
Immunocompromised patients — For immunocompromised patients (eg, advanced human immunodeficiency virus [HIV], solid organ transplant recipients) with blastomycosis, we start treatment with a lipid formulation of amphotericin B regardless of severity of disease (table 1A-B), because of the higher morbidity and mortality and higher relapse rates in this patient population [50-52]. If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate is an alternative. We prefer a lipid formulation of amphotericin B to avoid the nephrotoxicity of amphotericin B deoxycholate. Details of administration of amphotericin B are discussed elsewhere. (See 'Initial therapy with amphotericin B' above.)
Once clinical improvement in observed (generally after one to two weeks of amphotericin B therapy), we transition immunocompromised patients without CNS disease to itraconazole therapy. In patients with CNS disease, we continue liposomal amphotericin B for four to six weeks and then transition to voriconazole. Patients not tolerant to the initial azole agent can be switched to another azole for the remainder of treatment duration but should be monitored closely for symptom worsening or relapse (table 1A-B). Details of administration of these azole agents are discussed elsewhere. (See 'Itraconazole' above and 'Voriconazole as preferred agent' above and 'Alternatives to itraconazole' above.)
Immunocompromised patients with blastomycosis are more likely to present with severe pulmonary or disseminated infection, especially to the CNS, and to have a fatal outcome [1,50,51]. The recommendations for treatment of blastomycosis in immunocompromised hosts are based upon case reports and small case series [14,50,51,53-57].
Pregnant females — In pregnant females with blastomycosis, we administer a lipid formulation of amphotericin B (3 to 5 mg/kg IV once daily) (table 1A-B) [1] for the duration of treatment while pregnant, regardless of disease severity. Azoles have embryotoxic and teratogenic properties and are therefore contraindicated in pregnancy.
Children — We approach the choice of antifungal therapy in children similar to that in adults, with the exception of neonates who should receive amphotericin B deoxycholate (1 mg/kg IV once daily) for the duration of therapy, regardless of disease severity (table 1A-B) [1]. In general, children tolerate the deoxycholate formulation of amphotericin B better than adults, and we do not have a preference between the different formulations of amphotericin B in the treatment of blastomycosis in children. The approach to treatment in immunocompromised children is similar to that of immunocompromised adults.
The treatment of blastomycosis in children is based upon case reports and small case series [15,56,58,59]. Blastomycosis occurs less commonly in children; however, the clinical spectrum of disease and therapeutic considerations are similar to adults [58].
MONITORING AND TREATMENT DURATION
Monitoring — Patients with blastomycosis should be monitored closely, especially in the first few months of therapy. For azole antifungals, therapeutic drug monitoring is recommended. Monitoring for medication adherence, adverse effects, and clinical response is necessary to ensure treatment response and to detect treatment failure and relapses early.
Therapeutic drug monitoring — We suggest therapeutic drug monitoring for itraconazole, voriconazole, and posaconazole at the beginning of therapy, when there is a concern for inadequate serum drug concentrations (eg, lack of clinical improvement), or when other drugs that could have drug-drug interactions have been added to the patient’s therapeutic regimen (see 'Approach to patients with treatment failure' below). This is discussed further elsewhere. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
●Itraconazole − The serum itraconazole concentration should be measured after at least two weeks of therapy to ensure adequate levels [1]. Serum concentrations can be measured at any time since steady state has already been achieved. Serum concentrations depend on the type of assay used. High-performance liquid chromatography (HPLC) assays report the hydroxyitraconazole and itraconazole concentrations and these two should be added together to obtain the final serum concentration. Thus, when using an HPLC assay, serum concentrations (itraconazole plus the hydroxyitraconazole metabolite) greater than 1 to 2 mcg/mL and less than 5 mcg/mL are preferred [60]. In contrast, when using a bioassay, which does not separate out the two forms of itraconazole, a serum level greater than 3 mcg/mL is preferred. (See "Pharmacology of azoles", section on 'Itraconazole'.)
●Voriconazole – The serum trough voriconazole concentration should be measured four to seven days into therapy. Trough levels should be obtained within an hour of the next scheduled voriconazole dose. A target goal is a trough concentration between 1 mcg/mL and 5.5 mcg/mL, although some experts prefer a minimum serum concentration of 2 mcg/mL. Trough concentrations below 1 mcg/mL and above 5.5 mcg/mL warrant an increase and decrease, respectively, in voriconazole dose to optimize therapeutic effect and minimize adverse effects. (See "Pharmacology of azoles", section on 'Voriconazole'.)
●Posaconazole – The serum posaconazole concentration should be measured four to seven days into therapy. Trough levels should be obtained within an hour of the next scheduled posaconazole dose. A trough concentration ≥1 mcg/mL is preferred. (See "Pharmacology of azoles", section on 'Posaconazole'.)
Monitoring for clinical response — After initiation of therapy, patients should be followed closely for clinical improvement (eg, symptoms, radiographic features). In general, patients show signs of clinical improvement within the first two weeks of therapy. Lack of any clinical improvement after two weeks of therapy is concerning for treatment failure. In patients with central nervous system (CNS) involvement, lack of clinical improvement after four to six weeks should prompt goals of care discussion given the poor prognosis. (See 'Approach to patients with treatment failure' below.)
Monitoring generally entails repeated assessments of the patient’s clinical signs and symptoms and radiographic findings. In some situations (eg, pulmonary blastomycosis), repeating cultures may be reasonable. Although urine antigen levels for blastomycosis appear to decline with successful treatment and increase with recurrence of illness, data are limited to guide use of antigen testing in monitoring of patients on treatment [61,62].
Duration of therapy — We treat most patients with blastomycosis for 6 to 12 months (table 1A); treatment should generally extend several months beyond the time of resolution of clinical symptoms and radiographic findings [1]. For example, for patients presenting with skin lesions, we typically treat for six additional months after the skin lesions have resolved. For patients with bone or CNS disease or who are immunocompromised, we continue therapy for at least 12 months because of the higher risk of relapse in these cases [1,63]. Children with severe or life-threatening blastomycosis also warrant at least 12 months of therapy.
APPROACH TO PATIENTS WITH TREATMENT FAILURE — Treatment failure should be suspected when there is minimal to no improvement in symptoms after two to three weeks of therapy or initial improvement has stalled and symptoms persist after three to six months of therapy.
Reasons for treatment failure include subtherapeutic serum drug levels, poor adherence to medications (often due to drug intolerance), or poor host immune response. Relapse of infection after a patient has completed treatment is more common in immunocompromised patients [50-52] and in those who received alternative antifungal options during their treatment course (eg, fluconazole) [10,34,35].
In patients with suspected treatment failure, every effort should be made to establish evidence of ongoing infection, either by a positive culture or histopathology. In cases of suspected treatment failure where obtaining repeat culture or tissue specimen is not feasible, urinary antigen testing may be helpful. Urinary antigen testing has suboptimal specificity, but high sensitivity, for detection of blastomycosis. We assess whether the patient is receiving therapeutic drug doses by evaluating for nonadherence and checking drug levels. If drug levels are subtherapeutic, we adjust the dose to target therapeutic levels and re-evaluate several days to a week later. Immune status should be optimized in immunosuppressed patients by making sure patients with HIV are on effective antiretroviral therapy and stopping or reducing doses of immunosuppressive agents when possible.
Patients who experience treatment failure or relapse should be managed in consultation with an infectious diseases provider experienced in the treatment of blastomycosis.
PREVENTION — Prevention of blastomycosis primarily consists of secondary prevention, as avoiding exposure in endemic areas is difficult and there are no data to suggest benefit of primary prophylaxis.
Avoiding exposure — Avoidance of exposure is difficult as the fungus is ubiquitous in the environment in endemic areas. Waterways, animal waste substrates, and wood byproducts have all been associated with Blastomyces spp or blastomycosis outbreaks. For patients at increased risk of blastomycosis (eg, severely immunocompromised individuals such as transplant patients or those with acquired immunodeficiency syndrome [AIDS]) living in areas endemic for blastomycosis, we educate them on avoiding activities involving disruption of soil and vegetation (eg, forestry work, hunting, camping) but also acknowledge that it is very difficult to eradicate risk completely.
Secondary prophylaxis — Relapses are common in patients in whom immunosuppression cannot be reversed [50-52]. As a result, we suggest long-term suppressive therapy with itraconazole for immunocompromised patients while they remain immunocompromised and for patients with HIV and a CD4 count of ≤150 cells/microL [1]. We generally check an itraconazole level after two to three months of therapy. Further levels can be considered if there are concerns for toxicity or lack of adherence. Patients with HIV 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 in patients with HIV and histoplasmosis demonstrating that it is safe to discontinue itraconazole under these circumstances [64]. No data are available for the discontinuation of secondary prophylaxis in other immunocompromised states (eg, transplant recipients).
SUMMARY AND RECOMMENDATIONS
●Overall approach to treatment
•Blastomycosis is a systemic pyogranulomatous illness, infecting the lungs, which arises after inhalation of the conidia of Blastomyces species. The infection has the potential to disseminate to skin, bone, prostate, and other organs. (See 'Introduction' above.)
•The goals of treatment are to eradicate the infection and prevent progression of disease. We treat all patients diagnosed with blastomycosis, regardless of severity of disease, to prevent disease progression. (See 'Goals of therapy' above.)
•Patients with severe disease include immunocompromised patients, those with organ failure, and are usually hospitalized. Patients with mild to moderate symptoms generally can be managed as outpatients. (See 'Defining severity of disease' above.)
●Choice of antifungal therapy
•Severe/life-threatening disease without CNS involvement − For immunocompetent patients with life-threatening or severe blastomycosis (eg, hospitalized patients) and no central nervous system (CNS) involvement, we suggest initiating therapy with a lipid formulation of amphotericin B rather than oral antifungal therapy (table 1A-B) (Grade 2C). Once the patient clinically improves, we suggest switching to itraconazole rather than another oral antifungal agent or continuing therapy with amphotericin B (Grade 2C). (See 'Severe/life-threatening disease without CNS involvement' above.)
•Mild and moderate disease without CNS involvement – For immunocompetent patients with mild or moderate blastomycosis who do not warrant hospitalization and have no CNS involvement, we suggest initiating treatment with itraconazole rather than another oral antifungal agent or amphotericin B (table 1A-B) (Grade 2C). (See 'Mild to moderate disease without CNS involvement' above.)
•CNS disease − For patients with CNS involvement, we suggest initiating treatment with a lipid formulation of amphotericin B rather than an oral antifungal agent (Grade 2C). Following initial amphotericin B therapy, we suggest transitioning to voriconazole (Grade 2C) rather than another oral antifungal agent or amphotericin B (table 1A-B). If there is no clinical improvement after four to six weeks, prognosis is poor and goals of care should be discussed. (See 'Central nervous system disease' above.)
•Special populations
-For immunocompromised patients, regardless of disease severity, we suggest initiating therapy with amphotericin B rather than an oral azole agent (table 1A-B) (Grade 2C). We transition to azole therapy once they are clinically improving. (See 'Immunocompromised patients' above.)
-Pregnant females with blastomycosis should remain on amphotericin B for the duration of treatment while pregnant due to azole agents’ embryogenic and teratogenic effects (table 1A-B). (See 'Pregnant females' above.)
●Therapeutic drug monitoring – Serum trough levels of voriconazole or posaconazole should be checked after four to seven days of therapy (goal trough level: 1 to 5.5 mcg/mL and >1 mcg/mL, respectively). Serum levels of itraconazole should be checked after two weeks of therapy (goal level: 1 to 2 mcg/mL). (See 'Therapeutic drug monitoring' above.)
●Duration of therapy – For patients with severe or life-threatening blastomycosis or with immunocompromising conditions, we generally administer amphotericin B for one to two weeks or until there is clinical improvement. For patients with CNS disease, we generally administer amphotericin B for four to six weeks. Duration of oral azole therapy is typically 6 to 12 months (table 1A). Details on duration of oral azole therapy for specific patient populations and disease severity are discussed in detail above. (See 'Duration of therapy' above and 'Special populations' above.)
●Secondary prophylaxis – For immunocompromised patients, such as patients with HIV and CD4 count ≤150 cells/microL, we suggest long-term suppressive therapy with itraconazole (Grade 2C). Patients with HIV receiving antiretroviral therapy who have had a CD4 cell count of >150 cells/microL for at least six months can discontinue itraconazole therapy after a minimum of one year of treatment. (See 'Prevention' above.)
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