# 111 - 218 Histoplasmosis

### 218 Histoplasmosis

to fluconazole or itraconazole. Posaconazole has been reported to be 
effective salvage therapy for aspergillosis, mucormycosis, fusariosis, 
cryptococcosis, histoplasmosis, and coccidioidomycosis, although 
controlled clinical trials are lacking. The tablet formulation is not ham­
pered by the suboptimal absorption that occurs with the suspension; 
the tablet also results in higher and more reliable blood levels of the 
drug. Posaconazole is less hepatotoxic than voriconazole and does not 
cause the skin, visual, or bone toxicity that occurs with voriconazole. 
However, the use of posaconazole is linked to significant P450-related 
drug interactions and can lead to pseudohyperaldosteronism, which 
may manifest with hypokalemia, edema, and/or hypertension.

Isavuconazole 
Isavuconazole is available in oral and IV formula­
tions and has broad antifungal activity similar to that of posaconazole. 
Isavuconazole is approved by the FDA for treatment of aspergillosis (on 
the basis of a randomized controlled trial that found it noninferior to 
voriconazole) and mucormycosis (on the basis of an open-label, non­
comparative trial of 37 patients). Isavuconazole appears to be less hepa­
totoxic than voriconazole; it does not cause skin, bone, or visual toxicity, 
and it causes fewer P450-associated drug interactions than voriconazole.
Oteseconazole 
The newest azole—a tetrazole—oteseconazole, is 
approved by the FDA for the treatment of recurrent vulvovaginal 
candidiasis. It has potent activity against Candida (including azoleresistant strains) species and endemic dimorphic fungi. Its long halflife allows for once-weekly dosing following induction. Oteseconazole 
does not appear to cause hepatotoxicity or P450-associated drug inter­
actions, but it is contraindicated in women of reproductive potential as 
it may cause fetal ocular toxicity.
PART 5
Infectious Diseases
■
■ECHINOCANDINS
The echinocandins include the FDA-approved drugs caspofungin, 
anidulafungin, micafungin, and rezafungin, which are available solely 
as an IV formulation and inhibit β-1,3-glucan synthase, an enzyme that 
is crucial for fungal cell-wall synthesis but is not a constituent of human 
cells. Rezafungin, a new generation echinocandin, has a prolonged 
half-life that allows for weekly dosing with front-loading. The different 
echinocandins have comparable efficacy, toxicity, and tissue penetration 
profiles; are fungicidal for Candida and fungistatic for Aspergillus; and 
have no activity against other molds, Cryptococcus, or endemic dimor­
phic fungi. Their most common use to date is in candidal infections. 
These drugs offer three major advantages: minimal toxicity, minimal 
drug interactions, and activity against all Candida species. The minimal 
inhibitory concentrations (MICs) of echinocandins are higher against 
Candida parapsilosis than against other Candida species, but the higher 
MICs do not translate into less clinical efficacy against this species.
In controlled trials, caspofungin was as efficacious as AmB against 
candidemia and invasive candidiasis and as efficacious as fluconazole 
against candidal esophagitis. Caspofungin has also been efficacious 
as salvage therapy for aspergillosis. Anidulafungin is approved by the 
FDA as therapy for candidemia in nonneutropenic patients and for 
Candida esophagitis, abdominal infection, and peritonitis. In con­
trolled trials, anidulafungin was noninferior and possibly superior to 
fluconazole against candidemia and invasive candidiasis and was as 
efficacious as fluconazole against candidal esophagitis. Micafungin is 
approved by the FDA for the treatment of candidal esophagitis and 
candidemia and for antifungal prophylaxis in hematopoietic stem cell 
transplantation. Moreover, micafungin yielded favorable results when 
used for the treatment of invasive aspergillosis and candidiasis in 
open-label trials. Rezafungin was recently approved by the FDA for the 
treatment of candidemia and invasive candidiasis.
■
■IBREXAFUNGERP
Ibrexafungerp is an oral antifungal agent that belongs to a new class of 
glucan synthase inhibitors called triterpenoids and has potent activity 
against Candida species. Ibrexafungerp has been approved by the FDA 
for the treatment of vulvovaginal candidiasis and recurrent vulvovaginal 
candidiasis as it maintains its antifungal efficacy at low pH that is often 
observed in the vaginal mucosa. Its use is contraindicated in pregnant 
and lactating women.

■
■FLUCYTOSINE (5-FLUOROCYTOSINE)
Flucytosine use has diminished as newer antifungal drugs have been 
developed. Its mechanism of action involves intrafungal conversion 
to 5-fluorouracil, which inhibits fungal DNA synthesis. The use of 
flucytosine in combination with AmB as induction therapy for cryp­
tococcal meningitis is based on the drugs’ synergistic interaction and 
favorable flucytosine CSF penetration that promotes a rapid decline 
of the cryptococcal burden in the CSF. Flucytosine is also used in 
combination with AmB for the treatment of candidal meningitis and 
endocarditis, although comparative trials with AmB monotherapy are 
lacking. Flucytosine monotherapy is not recommended as it is associ­
ated with the development of resistance. Flucytosine can cause bone 
marrow suppression and liver toxicity, which are intensified when the 
drug is used with AmB.
■
■TERBINAFINE
Terbinafine inhibits squalene epoxidase and ergosterol synthesis, is 
used for onychomycosis and ringworm infection, and is as effective as 
itraconazole in both conditions. Although active against other fungi, 
terbinafine penetrates poorly into tissues beyond the skin and nails 
and therefore is not preferred for systemic mycoses. Terbinafine carries 
a risk for hepatotoxicity.
■
■TOPICAL ANTIFUNGAL AGENTS
A detailed discussion of topical agents for mucocutaneous mycoses is 
beyond the scope of this chapter; the reader is referred to Chap. 225 
and the dermatology literature. Azoles such as clotrimazole, micon­
azole, and ketoconazole are often used topically to treat common 
cutaneous mycoses as well as oropharyngeal and vaginal candidiasis. 
In vaginal candidiasis, oral fluconazole given once has the advantage of 
not requiring repeated intravaginal application. The polyenes nystatin 
and AmB have also been used topically for oropharyngeal and vaginal 
candidiasis. Agents from other classes that are used to treat these con­
ditions include ciclopirox, haloprogin, terbinafine, naftifine, tolnaftate, 
and undecylenic acid.
■
■FURTHER READING
Bennett JE: Introduction to mycoses, in Mandell, Douglas, and Bennett’s 
Principles and Practice of Infectious Diseases, 9th ed, JE Bennett et al 
(eds). Philadelphia, Elsevier Saunders, 2020, pp 3082–3086.
Lionakis MS et al: Immune responses to fungal pathogens and thera­
peutic prospects. Nat Rev Immunol 23:433, 2023.
Pappas PG et al: Clinical mycology today: A synopsis of the mycoses 
study group education and research consortium (MSGERC) second 
biennial meeting, September 27–30, 2018, Big Sky, Montana, a pro­
posed global research agenda. Med Mycol 58:569, 2020.
Chadi A. Hage, L. Joseph Wheat

Histoplasmosis
■
■ETIOLOGY
Histoplasma capsulatum, a thermal dimorphic fungus, is the etiologic 
agent of histoplasmosis. In most endemic areas in North America, 
H. capsulatum var. capsulatum is the causative agent. In Central and 
South America, histoplasmosis is common and is caused by genetically 
different clades of H. capsulatum var. capsulatum. In Africa, H. capsulatum 
var. duboisii is also found. Yeasts of var. duboisii are larger than those 
of var. capsulatum.
Mycelia—the naturally infectious form of Histoplasma—have a 
characteristic appearance, with microconidial and macroconidial 
forms (Fig. 218-1). Microconidia are oval and are small enough

FIGURE 218-1  Spiked spherical conidia of H. capsulatum (lacto-phenol cotton blue 
stain) grown in the laboratory at room temperature.
(2–4 μm) to reach the terminal bronchioles and alveoli. Shortly after 
infecting the host, mycelia transform into the yeasts that are found 
inside macrophages and other phagocytes. The yeast forms are 
characteristically small (2–5 μm), with occasional narrow budding 
(Fig. 218-2). In the laboratory, mycelia are best grown at room tem­
perature, whereas yeasts are grown at 37°C on enriched media.
A
B
FIGURE 218-2  A. Small (2–5 μm) narrow budding yeasts of H. capsulatum from 
bronchoalveolar lavage fluid (Grocott’s methenamine silver stain). B. Intracellular 
yeasts of H. capsulatum within an alveolar macrophage from a patient with AIDS 
and disseminated histoplasmosis (Giemsa stain).

■
■EPIDEMIOLOGY
Histoplasmosis is the most prevalent endemic mycosis in North 
America. Although this fungal disease has been reported throughout 
the world, its endemicity is particularly notable in the Ohio and 
Mississippi river valleys of North America and in certain parts of 
Mexico, Central and South America (Brazil), Africa, and Asia. Histo­
plasmosis is increasingly reported outside of the traditionally known 
endemic areas. The geographic distribution of histoplasmosis is related 
to the humid and acidic nature of the soil in the endemic areas. Soil 
enriched with bird or bat droppings promotes the growth and sporula­
tion of Histoplasma. Disruption of soil containing the organism leads 
to aerosolization of the microconidia and exposure of humans nearby. 
Activities associated with high-level exposure and high infection attack 
rate include spelunking, excavation, cleaning of chicken coops, demoli­
tion and remodeling of old buildings, and cutting of dead trees. Most 
cases seen outside of highly endemic areas represent imported disease, 
e.g., in Europe, histoplasmosis is diagnosed fairly often, mostly in 
emigrants from or travelers to endemic areas on other continents. The 
epidemiology of histoplasmosis is changing as a result of global climate 
changes and with the continued expansion of at-risk populations and 
the acceleration of intercontinental and international travel that brings 
this infection to areas of the world that are not known to be endemic. 
The population at risk for histoplasmosis continues to grow as a result 
of increasing numbers of patients receiving immunosuppressive thera­
pies for autoimmune disorders, cancers, and organ transplants.

■
■PATHOGENESIS AND PATHOLOGY
Infection follows inhalation of microconidia (Fig. 218-1). Once they 
reach the alveolar spaces, microconidia are rapidly recognized and 
engulfed by alveolar macrophages, where they transform into yeasts 
(Fig. 218-2), a process that is integral to the pathogenesis of histo­
plasmosis and is dependent on the availability of calcium and iron 
inside the phagocytes. The yeasts are capable of evading the immune 
system and multiplying inside resting macrophages. Neutrophils and 
then lymphocytes are attracted to the site of infection. Before the 
development of cellular immunity, yeasts use the phagosomes as a 
vehicle for translocation to local draining lymph nodes, whence they 
spread hematogenously throughout the reticuloendothelial system. 
Effective cellular immunity develops ~2 weeks after infection. T cells 
produce interferon-γ to assist the macrophages in killing the organism 
and controlling the progression of disease. Interleukin 12 and tumor 
necrosis factor α (TNF-α) play an essential role in cellular immunity 
to H. capsulatum. In the immunocompetent host, macrophages, lym­
phocytes, and epithelial cells eventually organize and form granulomas 
that contain the organisms. These granulomas typically fibrose and calcify; 
calcified lung nodules, mediastinal lymph nodes, and hepatosplenic 
calcifications are frequently found in healthy individuals from endemic 
areas. In immunocompetent hosts, infection with H. capsulatum 
confers protective immunity to reinfection. In patients with impaired 
cellular immunity, the infection is not properly contained and can 
disseminate throughout the reticuloendothelial system. Progressive 
disseminated histoplasmosis (PDH) can involve multiple organs, most 
commonly the lungs, bone marrow, spleen, liver (Fig. 218-3), adrenal 
glands, and mucocutaneous membranes. Unlike latent tuberculosis, 
inactive histoplasmosis does not reactivate. In patients with mildly 
impaired immune systems, active infection may smolder and eventu­
ally worsen with further decline in immunity.
CHAPTER 218
Histoplasmosis
3 µm
Structural lung disease (e.g., emphysema) impairs the clearance 
of pulmonary histoplasmosis leading to the development of chronic 
pulmonary disease. This chronic process is characterized by progres­
sive inflammation, tissue necrosis, and fibrosis mimicking cavitary 
tuberculosis.
5 µm
■
■CLINICAL MANIFESTATIONS
The clinical spectrum of histoplasmosis ranges from asymptomatic 
infection to life-threatening illness. The attack rate and the extent and 
severity of the disease depend on the intensity of exposure, the immune 
status of the exposed individual, and the underlying lung architecture 
of the host.

FIGURE 218-3  Intracellular yeasts (arrows) of H. capsulatum in a liver biopsy 
specimen (hematoxylin and eosin stain) from a patient who developed progressive 
disseminated histoplasmosis while receiving anti–tumor necrosis factor therapy for 
rheumatoid arthritis.
PART 5
Infectious Diseases
In immunocompetent individuals with low-level exposure, most 
Histoplasma infections are either asymptomatic or mild and self-limited. 
Of adults residing in endemic areas, up to 75% have immunologic 
and/or radiographic evidence of previous infection without clinical 
manifestations. Asymptomatic lung nodules representing controlled 
histoplasmosis are frequently found on chest computed tomography 
(CT) scans obtained during screening for lung cancer in smokers from 
endemic areas. When symptoms of acute histoplasmosis develop, they 
usually appear 1–4 weeks after exposure. Heavy exposure leads to a 
flulike illness with fever, chills, sweats, headache, myalgia, anorexia, 
dry cough, dyspnea, and chest pain. Chest radiographs usually show 
signs of pneumonitis with prominent hilar or mediastinal adenopathy. 
Pulmonary infiltrates may be focal with light exposure or diffuse with 
heavy exposure. Rheumatologic symptoms of arthralgia or arthritis, 
often associated with erythema nodosum, occur in 5–10% of patients 
with acute histoplasmosis. Pericarditis may also develop. These mani­
festations represent inflammatory responses to the acute pulmonary 
infection rather than extrapulmonary spread. Affected hilar or medi­
astinal lymph nodes may undergo necrosis and coalesce to form 
large mediastinal masses that can cause compression of great vessels, 
proximal airways, and the esophagus. These necrotic lymph nodes may 
also rupture and create fistulas between mediastinal structures (e.g., 
bronchoesophageal fistulae).
PDH is typically seen in immunocompromised individuals, who 
account for ~70% of cases. Common risk factors include AIDS 
(CD4+ T-cell count, <200/μL), extremes of age, the administration 
of immunosuppressive medications to prevent or treat rejection fol­
lowing transplantation (e.g., prednisone, mycophenolate, calcineurin 
inhibitors), and the use of methotrexate, anti-TNF-α agents, and other 
biologic response modifiers for autoimmune disorders. PDH may also 
occur in healthy individuals, some of whom may have rare undiag­
nosed genetic immunodeficiencies of the relevant immune pathways 
(IFN-γ and TNF-α). Workup for these conditions should be considered 
in healthy subjects with PDH.
The clinical spectrum of PDH ranges from an acute, rapidly fatal 
course—with diffuse interstitial or reticulonodular lung infiltrates 

causing respiratory failure, shock, coagulopathy, and multiorgan 
failure—to a subacute or chronic course with a focal organ distribution. 
Common manifestations include fever, weight loss, hepatospleno­
megaly, and thrombocytopenia. Other findings may include meningitis 
or focal brain lesions, ulcerations of the oral mucosa, gastrointestinal 
ulcerations and bleeding, and adrenal insufficiency. Prompt recogni­
tion of this devastating illness is of paramount importance in patients 
with severe manifestations or with underlying immunosuppression, 
especially those due to AIDS (Chap. 208) or anti-TNF therapy.
Chronic cavitary histoplasmosis is seen in smokers who have 
structural lung disease (e.g., bullous emphysema). This chronic ill­
ness is characterized by productive cough, dyspnea, low-grade fever, 
night sweats, and weight loss. Chest radiographs usually show upperlobe infiltrates, cavitation, and pleural thickening—findings resem­
bling those of tuberculosis. Without treatment, the course is slowly 
progressive.
Fibrosing mediastinitis is an uncommon but serious complication 
of histoplasmosis. In certain patients, acute infection is followed for 
unknown reasons by progressive fibrosis around the hilar and medi­
astinal lymph nodes, encasing mediastinal structures with potentially 
devastating consequences. Major manifestations include superior vena 
cava syndrome, obstruction of pulmonary vessels, and airway obstruc­
tion. Patients may experience recurrent pneumonia, hemoptysis, or 
respiratory failure. Fibrosing mediastinitis is fatal in up to one-third 
of cases.
In healed histoplasmosis, calcified mediastinal nodes or lung paren­
chymal nodules may erode through the walls of the airways and cause 
hemoptysis and expectoration of calcified material. This condition is 
called broncholithiasis.
The clinical features and management of histoplasmosis caused 
by the genetically different clades in Central and South America are 
similar to those of the disease in North America. African histoplasmo­
sis caused by var. duboisii is clinically distinct and is characterized by 
frequent skin and bone involvement.
■
■DIAGNOSIS
Recommendations for the diagnosis and treatment of histoplasmosis 
are summarized in Table 218-1. Once suspected, the diagnosis of 
histoplasmosis is usually straightforward as many diagnostic tools are 
now available in the United States. This is not the case in resourcelimited endemic regions of Central America, South America, and 
Africa, where the diagnosis is often delayed, with consequently poor 
outcomes.
Fungal culture remains the gold standard diagnostic test for his­
toplasmosis. However, culture results may not be known for up to 1 
month, and cultures are often negative in less severe cases. Cultures are 
positive in ~75% of patients with PDH and chronic pulmonary histo­
plasmosis. Cultures of bronchoalveolar lavage (BAL) fluid are positive 
in about half of patients with acute pulmonary histoplasmosis causing 
diffuse infiltrates and hypoxemia. In PDH, the culture yield is highest 
for BAL fluid, bone marrow aspirate, and blood. Cultures of sputum 
or bronchial washings are usually positive in chronic pulmonary his­
toplasmosis. Cultures are typically negative, however, in other forms of 
histoplasmosis.
Fungal stains of cytopathology or biopsy materials showing struc­
tures resembling Histoplasma yeasts are helpful in the diagnosis of 
PDH, yielding positive results in about half of cases. Yeasts can be 
seen in BAL fluid (Fig. 218-2) from patients with diffuse pulmonary 
infiltrates, in bone marrow biopsy samples, and in biopsy specimens 
of other involved organs (e.g., liver, adrenal glands). Occasionally, 
yeasts are seen within circulating phagocytes on blood smears from 
patients with severe PDH. However, staining artifacts and other fungal 
elements sometimes stain positively and may be misidentified as Histo­
plasma yeasts. Culture and pathology are no longer performed in most 
patients because diagnosis is more often established by antigen detec­
tion and/or serology, more rapidly and without subjecting the patient 
to invasive procedures.
The detection of Histoplasma antigen in body fluids is extremely use­
ful in the diagnosis of PDH and acute diffuse pulmonary histoplasmosis.

TABLE 218-1  Recommendations for the Diagnosis and Treatment of Histoplasmosis
TYPE OF 
HISTOPLASMOSIS
DIAGNOSTIC TESTS
TREATMENT RECOMMENDATIONS
COMMENTS
Acute pulmonary, 
mild to moderate with 
no improvement by 
the time of diagnosis
Histoplasma antigen (BAL fluid, serum, urine)
Cytopathology and fungal culture of BAL fluid
Histoplasma serology (ID and CF), (EIA): 
IgG and IgM
Acute pulmonary, 
severe illness, 
respiratory failure 
(ARDS)
Histoplasma antigen (BAL fluid, serum, urine)
Cytopathology and fungal culture of BAL fluid
Histoplasma serology (ID and CF), (EIA): 
IgG and IgM
Chronic/cavitary 
pulmonary
Histoplasma serology (ID and CF), (EIA): 
IgG and IgM
Fungal culture of sputum or BAL fluid
Progressive 
disseminated
Histoplasma antigen (BAL fluid, serum, urine)
Histoplasma serology (ID and CF), (EIA): 
IgG and IgM
Fungal culture of blood or bone marrow aspirate
Cytopathology on biopsy of affected organ
Central nervous 
system
Histoplasma antigen CSF
Histoplasma serology (ID and CF), (EIA): 
IgG and IgM
Fungal culture of CSF
Abbreviations: AmB, amphotericin B; BAL, bronchoalveolar lavage; CF, complement fixation; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; ID, immunodiffusion; MRI, 
magnetic resonance imaging.
The sensitivity of this method is >95% in patients with PDH and >80% 
in patients with severe acute pulmonary histoplasmosis resulting from 
heavy exposure, if both urine and serum are tested. Antigen levels 
correlate with severity of illness in PDH and can be used to follow dis­
ease progression, as levels predictably decrease with effective therapy. 
Increasing antigen levels also predict relapse. Histoplasma antigen can 
be detected in cerebrospinal fluid from patients with Histoplasma men­
ingitis and in BAL fluid from those with pulmonary histoplasmosis. 
Lateral flow antigen detection allows the diagnosis of histoplasmosis at 
the bedside as a point-of-care testing method, which might offer access 
to rapid testing in resource-limited areas of the world where traditional 
antigen testing might not be available. Cross-reactivity occurs with 
African histoplasmosis, blastomycosis, coccidioidomycosis, paracoc­
cidioidomycosis, talaromycosis, and rarely aspergillosis.
Serologic tests, including immunodiffusion (ID), complement fixa­
tion (CF), and IgG and IgM enzyme immunoassay (EIA), are useful 
for the diagnosis of histoplasmosis, especially in immunocompetent 
patients. One month may be required for the detection of antibodies 
after the onset of infection by ID or CF, but antibodies may be detected 
earlier by more sensitive methods (EIA). IgM appears first then 
declines, and IgG appears later and increases during the infection. EIA 
for IgG and IgM antibodies provides a more accurate method for moni­
toring changes and antibody levels. Serologic tests are especially useful 
for the diagnosis of chronic pulmonary histoplasmosis. Limitations of 
ID and CF, however, include insensitivity early in the course of infec­
tion and reduced sensitivity in immunosuppressed patients, especially 
those receiving immunosuppression for organ transplantation. Also, 
antibodies may persist for several years after infection. Positive results 
from past infection may lead to a misdiagnosis of active histoplasmosis 
in a patient with another disease process.
TREATMENT
Histoplasmosis
Treatment is indicated for all patients with PDH or chronic pulmo­
nary histoplasmosis as well as for most symptomatic patients with 
acute pulmonary histoplasmosis who have not improved by the 
time the diagnosis is established, especially in those with diffuse 

Itraconazole (200 mg bid) for 
6–12 weeks.
Monitor renal and hepatic function.
Patients with mild cases usually recover without 
therapy, but itraconazole should be considered if the 
patient’s condition is not already improving by the 
time the diagnosis is established.
Lipid AmB (3–5 mg/kg per day) ± 

glucocorticoids for 1–2 weeks; 
then itraconazole (200 mg bid) for 
6–12 weeks. Monitor renal and 
hepatic function.
Adjust itraconazole dose to achieve blood levels of 
2–5 μg/mL.
Itraconazole (200 mg bid) Adjust dose 
to achieve blood levels of 2–5 μg/mL 
for at least 12 months. Monitor hepatic 
function.
Continue treatment until radiographic findings show 
no further improvement. Monitor for relapse after 
treatment is stopped.
Lipid AmB (3–5 mg/kg per day) for 
1–2 weeks; then itraconazole (200 mg 
bid); adjust dose to achieve blood levels 
of 2–5 μg/mL for at least 12 months. 
Monitor renal and hepatic function.
Liposomal AmB is preferred, but the AmB lipid complex 
may be used because of cost. Chronic antifungal 
maintenance therapy may be necessary if the degree 
of immunosuppression cannot be substantially 
reduced. Monitor antigen levels in urine and serum 
during treatment to ensure proper response.
Liposomal AmB (5 mg/kg per day) for 
4–6 weeks; then itraconazole (200 mg 
bid) Adjust dose to achieve blood levels 
of 2–5 μg/mL for at least 12 months. 
Monitor renal and hepatic function.
A longer course of lipid AmB is recommended 
because of the high risk of relapse. Itraconazole 
should be continued until CSF or MRI abnormalities 
clear.
CHAPTER 218
infiltrates and difficulty breathing. In most other cases of pulmo­
nary histoplasmosis, treatment is not recommended, especially if 
the immune system of the host is intact and the degree of exposure 
is not heavy. The symptoms usually are mild, subacute, and not pro­
gressive, and the illness resolves without therapy. Treatment should 
be considered if the symptoms are not improving within a month.
Histoplasmosis
The preferred treatments for histoplasmosis (Table 218-1) 
include the lipid formulations of amphotericin B in severe cases 
and itraconazole in others. Liposomal amphotericin B is more effec­
tive and better tolerated than the deoxycholate formulation and is 
more effective in patients with AIDS and PDH. The deoxycholate 
formulation of amphotericin B is an alternative to a lipid formula­
tion for patients at low risk for nephrotoxicity and if liposomal 
amphotericin B is not available. Posaconazole and isavuconazole are 
alternatives for patients who cannot take itraconazole. Histoplasma 
may develop resistance to fluconazole and voriconazole, and they 
are not the preferred alternative to itraconazole, especially in immu­
nocompromised patients.
In severe cases requiring hospitalization, a lipid formulation of 
amphotericin B is used first for 2 weeks, followed by itraconazole. 
In patients with meningitis, a lipid formulation of amphotericin 
B should be given for 4–6 weeks before switching to itraconazole. 
In immunosuppressed patients, the degree of immunosuppression 
should be reduced if possible, although immune reconstitution 
inflammatory syndrome (IRIS) may ensue. Antiretroviral treat­
ment improves the outcome of PDH in patients with AIDS and is 
recommended; however, whether antiretroviral treatment should 
be delayed to avoid IRIS is unknown.
Blood levels of itraconazole should be monitored to ensure ade­
quate drug exposure, with target concentrations of the parent drug 
and its hydroxy metabolites measuring 2–5 μg/mL. Drug interac­
tions should be carefully assessed; itraconazole not only is cleared 
by cytochrome P450 metabolism but also inhibits cytochrome 
P450. This profile causes interactions with many other medications 
used routinely in organ transplant recipients.
The duration of treatment for acute pulmonary histoplasmosis 
is 6–12 weeks, while that for PDH and chronic pulmonary his­
toplasmosis is at least 1 year. Antigen levels in urine and serum 
should be monitored during and for at least 1 year after therapy