F u n g a l In f e c t i o n s i n t h e

Hospitalized Patient
Devin C. Odom, MD*, Hilary E.L. Reno, MD, PhD

KEYWORDS
 Fungemia  Candidemia  Nosocomial infection  Candiduria  Histoplasmosis
 Blastomycosis  Coccidiomycosis  Cryptococcus

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Empiric fluconazole is appropriate in a stable fungemic patient before a species

is identified. However, an echinocandin is preferred in an unstable patient.
2. Candiduria does not always need antifungal treatment. Removal of an associ-
ated bladder catheter is often adequate.
3. Most endemic fungal infections are asymptomatic, and disseminated disease
may present as a chronic illness.
4. Mild pulmonary histoplasmosis in an immune-competent patient does not
require treatment.
5. All cases of cryptococcosis should be treated and continued on maintenance
treatment for up to 1 year.

FUNGEMIA

The general term fungemia describes the presence of a fungal species in the blood. A
positive culture may indicate a widespread infection or, commonly, the infection of an
intravenous catheter. Often the term fungemia is used synonymously with candidemia
because Candida species are more prevalent. This section primarily discusses
fungemia caused by Candida species.
Epidemiology

What are the risk factors for candidemia in a hospitalized patient?

The risk factors associated with fungemia are similar, but not identical, to those asso-
ciated with other nosocomial bloodstream infections.1 Colonization plays a larger role,
as the risk for nosocomial infection in patients colonized with Candida species is 38%

The authors have no disclosures.

Department of Medicine, Washington University in Saint Louis, 660 South Euclid Ave, Campus
Box 8058, St Louis, MO 63110, USA
* Corresponding author.
E-mail address: dodom@dom.wustl.edu

Hosp Med Clin 4 (2015) 313327

http://dx.doi.org/10.1016/j.ehmc.2015.03.005
2211-5943/15/$ see front matter 2015 Elsevier Inc. All rights reserved.
314 Odom & Reno

compared with only 25% of those colonized with vancomycin-resistant entero-

cocci.1,2 Risk factors for candidemia include known Candida colonization and use
of numerous broad-spectrum antibiotics.3 For additional risk factors, see Box 1.

Does a patients length of stay increase the risk for fungemia?

A longer hospitalization is a risk for fungemia according to research by Wisplinghoff
and colleagues.4 The average time interval between hospital admission and onset
of Candida bloodstream infection was nearly 22 days, which was similar to that for
Enterobacter and Klebsiella. Combined infections, candidemia with a bacterial infec-
tion, are also common, with a higher risk for septic shock and a trend toward higher
mortality.5 The presence of abdominal infection, hospitalization for more than 4 weeks,
and the prior presence of bacteremia appear to increase the risk for a combined infec-
tion and should increase clinical suspicion.5

How deadly is it?

The mortality rate of fungal infections ranges from 30% to 49% in all hospitalized
patients.6,7 Mortality from fungemia in nonintensive care unit (ICU) patients was
higher than all other nosocomial infections, at 29%,4 despite newer treatments, higher
clinical suspicion, and more rapid diagnosis.
Candida species are the most common cause of fungemia in hospitalized patients
and the fourth most common nosocomial bloodstream infection, representing 9% of
all hospital-acquired infections.4,8 Candida albicans is the predominant species, rep-
resenting 42% to 54% of all isolates.4,9,10 Studies have described a 200% increase in
the incidence of fungemia as a cause of sepsis over a 20-year period.11 Of the Candida
species, mortality appears to be highest with Candida krusei at 59%, but this species
represents only 2.4% of isolates reported at major medical centers in the United
States.4 C albicans, C krusei, and Candida tropicalis are isolated more in postsurgical,
oncologic, and transplant patients.1214 Candida parapsilosis bloodstream infection
originates more frequently in the urinary tract,15 but also is commonly seen in
catheter-associated candidemia.

Does a healthy immune system improve mortality in fungemic patients?

Although in isolation candidemia is a fatal disease, the susceptibility of a patient to
become fungemic is directly linked to the patients overall condition. Candidemia

Box 1
Risk factors for candidemia

 Known fungal colonization

 Current or recent use of multiple broad antibiotics
 Recent bowel surgery
 Dialysis
 Use or presence of central venous catheters
 Use of parenteral nutrition
 Prolonged stay in intensive care unit
 Severe illness
 Fungal Infections in the Hospitalized Patient 315

has also been viewed as a marker for illness severity and mortality risk. Table 1 lists
the predictors of survival in immune-competent individuals with candidemia.
Mortality from fungemia in immune-competent patients is comparable with that in
immune-compromised patients. In a study by Safdar and colleagues,16 the mortality
rate was identical (44%) in both groups.
Treatment

My patients blood culture found an unidentified yeast, what do I do? Is there a role for
empiric treatment?
Given the high mortality rate of fungemia, a positive blood culture for yeast should
prompt rapid initiation of an antifungal agent. Standard therapy includes treatment
with fluconazole with a loading dose (12 mg/kg or 800 mg, then 6 mg/kg or 400 mg
daily) in noncritically ill patients without fluconazole exposure.3,17
In critically ill patients, the empiric use of echinocandins when fungemia is discov-
ered, but before it has been speciated, has been associated with lower 30-day
mortality when compared with azoles in critically ill patients.10,18 Candida glabrata is
more resistant and should be considered in patients with prior exposure to flucona-
zole, the elderly, and patients with diabetes or cancer.3,10 Therefore, an echinocandin
(micafungin, caspofungin, or anidulafungin) is the recommended first-line agent in
patients who fall into one of these categories. Patients with confirmed or suspected
involvement of the central nervous system (CNS), heart valves, or other organs should
receive a fungicidal agent such as amphotericin B or an echinocandin.3 The increased
use of fluconazole as prophylaxis or empirically in critically ill patients has been
debated as a primary reason for the increased incidence of resistant C glabrata and
other non-albicans isolates.13,19

Is there a role for a broad-spectrum azole or other agent in empiric treatment?

Voriconazole does not have a role in empiric therapy because of its less predictable
pharmacokinetics, drug interactions, and lack of predictable activity against C glab-
rata.3,20 Posaconazole, an extended-spectrum azole, is only available in oral formula-
tion and also lacks a clear role in empiric therapy for immune-competent hosts. Lipid

Table 1
Candidemia mortality in immune-competent patients

Increased Mortality No Effect on Mortality Decreased Mortality

Advanced age
Malignancy (solid tumor)
High APACHE II score
Use of corticosteroids
Ischemic heart disease11
Persistent candidemia
Renal failure
Concurrent bacteremia11
Mechanical ventilation
Lung disease
Presence of central venous catheter Use of an echinocandin
Prior exposure to antifungals Candida parapsilosis
Presence or absence of fever or
leukocytosis
Diabetes, chronic renal disease
Malignancy (hematologic)
Total parenteral nutrition

Data from Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically
ill non-immunosuppressed patients. Lancet Infect Dis 2003;3:685702; and Martin GS, Mannino
DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N
Engl J Med 2003;348(16):154654.
316 Odom & Reno

based formulations of amphotericin B (3 to 5 mg/kg/d) are an appropriate first-line

therapy in patients with a history of resistant fungal infection, intolerance to first-line
therapy, or pregnancy, or when Cryptococcus species are suspected.3 Flucytosine
is typically not used as a single agent and should not be used for empiric therapy in
most patients.

I have a high suspicion for fungemia, but no proof; is empiric therapy recommended?
The presence of fungemia should be suspected in all critically ill patients admitted to
either an ICU or general ward setting. In the setting of risk factors for fungemia (see
earlier discussion) in a critically ill or decompensating patient with high clinical suspi-
cion for invasive fungemia, but without culture-proven disease, the aforestated recom-
mendations for empiric treatment should be followed after cultures are obtained.

Microbiology has identified the species, how should I tailor therapy?

Once a particular species has been isolated, tailored antifungal therapy is recommen-
ded for all cases of fungemia. Potentially toxic or poorly tolerated antifungals such as
amphotericin B (nephrotoxicity in up to 50% or patients) or voriconazole (hepatotox-
icity and CNS side effects) should be switched to less toxic agents if possible.21 The
Infectious Disease Society of America guidelines recommend a short course of echi-
nocandin therapy for 3 to 5 days before switching to fluconazole if this agent was
selected for a stable patient.3
Most species of C albicans have good response to fluconazole, although resistant
strains have become more prevalent. Isolates of non-albicans species are demon-
strated to be more resistant to fluconazole and itraconazole.12 In general, all non-albi-
cans species except for C parapsilosis should be treated with an echinocandin (or
amphotericin B if not tolerated) until sensitivities can demonstrate good azole activity.
Echinocandins, however, have shown decreased in vitro activity against C parapsilo-
sis, so switching to azole therapy is preferred.22 Any patient who is critically ill or does
not appear to be responding to therapy should be considered for dual therapy or
adjustment of antifungal agents. A consultation from an infectious diseases specialist,
if available, is recommended.

Sensitivities confirm good activity with fluconazole or other azoles. Is oral therapy as
good as intravenous?
If sensitivities indicate good fluconazole activity in a stable patient, studies have shown
that oral formulations of fluconazole are as effective as intravenous formulations.23
Fluconazole should be used ahead of extended-spectrum azoles when possible because
they require frequent dosing, and exhibit a variable absorption rate and higher possibility
of intolerance.3 Some isolates of C krusei, Candida guilliermondii, and C glabrata are
resistant to fluconazole, but sensitive to voriconazole or itraconazole. In stable patients,
oral treatment of these isolates is appropriate once antifungal activity is confirmed.

How long do I treat a fungemic patient?

Antifungal treatment should continue for 2 weeks from the first negative blood culture
and the resolution of symptoms in uncomplicated fungemia without evidence of met-
astatic complications.3 Some agents require frequent laboratory monitoring (hepatic
function with azoles, renal function with amphotericin B), and close follow-up is
necessary.
 Fungal Infections in the Hospitalized Patient 317

Performance Improvement

Should I remove the central venous catheter?

In cases of proven intravenous catheter-related infections, catheters present at the
time of diagnosis or placed before blood cultures were cleared must be removed.3
Daily fungal cultures should be obtained from patients once an agent has been
initiated and catheters removed.

Are ophthalmologic examinations still recommended in all fungemic patients?

The gold standard for patients with confirmed fungemia includes an eye examination
performed by an ophthalmologic specialist. In a study of 238 patients with fungemia by
Ghodasra and colleagues,6 only 9.2% had ocular involvement and in only 3.7% did the dis-
covery of ocular involvement change management. Another study found an increased risk
for ocular involvement in patients with visual symptoms, patients unable to articulate
symptoms, and the identification of C albicans in culture isolates.24 Therefore, an ocular
examination is still recommended for all patients, with a follow-up examination recommen-
ded in the high-risk subset of patients or in any patient who reports new ocular symptoms.

Will I find the source?

Extensive investigation for an infectious source is recommended in a fashion similar to
that for all other bloodstream infections, with special consideration given to an
abdominal source and any foreign body. Fungal cultures should be sent from potential
infectious tissue or fluid that is clinically relevant. The most commonly identified sour-
ces are central venous catheters (19%) and the urinary tract with or without a stent,
catheter, or recent procedure (8%). In a recent review, a source could not be identified
in more than 60% of cases.15

FUNGURIA/CANDIDURIA

Urinary tract infections are a frequent cause of hospitalization, sepsis, and health care
associated infections.25 In ambulatory patients, fungal infections of the urinary tract,
most often Candida species, are less common than bacterial infections, although this is
not the case in hospitalized patients. Candida urinary tract infections are common in hos-
pitalized patients, especially those who are seriously ill.26 The decision to treat candiduria
is not a simple one, as fungal pathogens may be colonizers or represent contamination.

Epidemiology

Are Candida species a common cause of urinary tract infections?

Candida species can be common (third in rank to Escherichia coli and Pseudomonas)
in community-acquired urine cultures of hospitalized patients, and Candida species
can be the most common hospital-acquired organism in urine cultures.26 Funguria
in critically ill patients is usually C albicans or C glabrata.

What are risk factors for candiduria?

The presence of a bladder catheter and ICU level of care are risk factors for candidu-
ria2729 (see Box 2 for additional risk factors). Most studies of risk factors for
318 Odom & Reno

Box 2
Risk factors for candiduria

 Presence of a bladder catheter

 Intensive care unit level of care
 Bedridden
 Recent antibiotics
 Diabetes
 Malignancy
 Recent urologic procedures

Data from Refs.2729

candiduria have noted that Candida in the urine is more likely a marker of recent
invasive procedures and serious illness rather than a direct marker of mortality.30
Treatment

Is antifungal treatment required in candiduria?

Simpson and colleagues31 performed a retrospective study of patients with asymp-
tomatic funguria, in which about half of the patients were treated with antifungals
and half were managed with minimization of risk factors. There was no significant
difference in development of invasive fungal disease, hospital stay, or mortality be-
tween the two groups.

Are patients without symptoms managed differently than patients with symptoms?
Asymptomatic patients who have a positive urine culture for Candida should have a
repeat culture performed. The presence of pyuria may indicate infection in a patient
who is not able to provide a history of symptoms, but may also just be a marker of
a chronic bladder catheter. Similarly to asymptomatic bacteria recommendations,32
asymptomatic funguria does not require treatment. Elimination of the bladder catheter
may be adequate. Kauffman30 summarizes the risk factors that would lead to treat-
ment: asymptomatic patients undergoing urologic procedures and patients with
neutropenia.
Patients with planned urologic surgery may be treated with fluconazole, 200 to
400 mg per day or amphotericin B, 0.3 to 0.6 mg/kg per day in the perioperative
and postoperative periods.3 Patients with neutropenia and candiduria should be
managed as if they had candidemia.

What is the usual course of treatment in patients with symptoms?

Symptomatic patients with dysuria, lower abdominal pain, urgency, and/or frequency
should be treated by changing or removing the catheter and with appropriate anti-
fungal therapy. In general, fluconazole will be effective against most Candida urinary
tract infections (400 mg  1 dose then 200 mg per day  14 days). Culture and sen-
sitivities can guide therapy. Recurrent infection should lead to an investigation for se-
questrum using imaging and urologic evaluation. C glabrata requires a higher dose of
fluconazole (800 mg daily) for 14 days and microbiological sensitivities to determine
resistance. Other antifungals do not reach high concentrations in the urine, making
 Fungal Infections in the Hospitalized Patient 319

treatment of resistant fungal urinary tract infections difficult.33 Consultation with an in-
fectious disease specialist is recommended.

ENDEMIC FUNGI: HISTOPLASMOSIS, BLASTOMYCOSIS, COCCIDIOMYCOSIS

Endemic fungi are fungal organisms found in the environment, and include Histo-
plasma, Blastomyces, and Coccidioides. Infectious spores of these organisms are
found in soil or plant material. Most infections are asymptomatic or mild and self-
limited. Infections can be more severe in immune-compromised patients.
Epidemiology

What are risk factors for significant infections with endemic fungi?

Disease can occur in immune-competent patients, but patients who are immune
compromised are more at risk for symptomatic disease and disseminated fungal
infections. Patients with deficits in cellular immunity, particularly patients with human
immunodeficiency virus (HIV) infection and a low CD4 count, patients with a solid
organ or bone marrow transplant, or those receiving tumor necrosis factor inhibitors
are at highest risk.34 Other conditions may also contribute to infection with endemic
fungi, including diabetes, renal failure, chemotherapy, and steroid use.35

What endemic fungi are native to and most common in North America?

Histoplasmosis
Histoplasma capsulatum is endemic to North and South America, Africa, and Asia.
Most cases of histoplasmosis in the United States occur near the Ohio and Mississippi
river valleys. Spread in bird and bat droppings, the fungus is found extensively in soil
and is spread easily by air for miles.36 In most patients, H capsulatum causes no symp-
toms or a mild illness. However, some cases of pulmonary, CNS, or disseminated dis-
ease have high morbidity and mortality, especially in immune-compromised patients.
Seitz and colleagues37 showed that more than 20% of patients hospitalized for histo-
plasmosis had another diagnosis associated with immune compromise.
High clinical suspicion is needed for rapid diagnosis. Unfortunately, most patients
do not present with classic exposure history: exposure to wild bird or bat excrement
or direct yard work/soil exposure. A recent outbreak in 2011 in Arkansas was caused
by burning bamboo that unknowingly contained a blackbird roost.38 Yet another
occurred at a high school in Indiana in 2001 as a result of tilling of a nearby courtyard.39
Nonhealing wounds, particularly of the oral or nasal mucous membranes, have been
seen in immune-competent patients.40 Most patients develop cell-mediated immunity
within a few weeks of exposure, preventing progressive disease. Patients who cannot
mount this immunity may develop progressive disseminated histoplasmosis, defined
as clinical symptoms that persist for 3 weeks with evidence of involvement in tissues
outside the lungs.
Blastomycosis
Blastomyces dermatitidis is largely found in the Ohio and Mississippi River areas and
the Great Lakes regions of the United States. As occurs for histoplasmosis, the spores
in soil can become airborne and infection occurs via inhalation. Almost half of infec-
tions are asymptomatic, but infection requiring hospitalization can occur. Pulmonary
disease in the form of pneumonia is the most common presentation, although skin
manifestations and bone disease are well described.34
320 Odom & Reno

Seitz and colleagues37 reviewed the records of more than 4000 hospitalized pa-
tients with blastomycosis and discovered a male predominance, but only 5% of
patients had another diagnosis that conferred immune deficiency.

Coccidiomycosis
Coccidiomycosis is caused by Coccidioides immitis and Coccidioides posadasii, which
are found largely in southern Arizona and California. Inhalation causes a self-limited
pneumonia, referred to as valley fever, but disseminated disease involving skin,
bone, or CNS infection occurs largely in immune-compromised patients.41 Identifica-
tion is usually made after failed antibiotic therapy for community-acquired pneumonia.
Fig. 1 is a map showing distribution of the 3 endemic fungi in North America.

Cryptococcosis
Cryptococcus neoformans and Cryptococcus gatti are the primary causes of crypto-
coccosis worldwide. Cases are mostly reported in patients with HIV/AIDS. However, C
gatti has been isolated in several immunocompetent individuals in the Pacific North-
west and is endemic in this area. Cases have been reported in nearly all global
climates in healthy hosts.42 Incidence declined in the United States throughout the
1990s according to research by Mirza and colleagues,43 mostly attributable to
improved HIV treatment. Today, new diagnoses are made in diverse situations
including new HIV diagnoses, patients receiving steroids or immune-modulating
agents, and otherwise healthy individuals.42 Most cases of Cryptococcus are menin-
geal at diagnosis.44

Diagnosis
Symptoms of disseminated infection for all endemic fungi can be mild, characterized
only by fatigue, weight loss, fever, and night sweats.45 Pancytopenia, elevated alkaline
phosphatase, and an elevated erythrocyte sedimentation rate are often noted on basic
laboratory tests. High clinical suspicion, especially in immune-compromised patients,
is required for rapid diagnosis.

Fig. 1. Endemic fungi in North America. (From Winthrop KL, Chiller T. Preventing and treat-
ing biologic-associated opportunistic infections. Nat Rev Rheum 2009;5(7):408; with
permission.)
 Fungal Infections in the Hospitalized Patient 321

What role do antigen tests play in the diagnosis of endemic fungi?

Culture growth of endemic fungi may take 4 to 6 weeks.45 Diagnosis of endemic fungi
can occur via serologic or antigen testing or evaluation of biopsy materials. Histo-
plasma antigen can be detected in disseminated disease, with more than 90% suc-
cess in urine and 80% in serum using the MVista enzyme immunoassay (EIA).46 An
antibody assay via complement fixation is available, but its use is not widespread,
and patients with severe immune suppression are unlikely to develop detectable an-
tibodies. A urine Histoplasma antigen test with cross-reactivity to blastomycosis is
also available. Blastomyces antigen is detectable via the MVista EIA in urine or serum
with sensitivity of 93% and specificity of 98%.47 For coccidiomycoses, serology of
serum or urine is most useful, but serology may be negative for months after initial
infection, and sensitivity is near 70%.47 Immunoglobulin M appears earlier, but is
less specific than immunoglobulin G antibodies to C immitis. False positives can occur
between coccidiomycosis, blastomycosis, and histoplasmosis. Antigen levels can be
useful in combination with other clinical data when gauging response to therapy. Diag-
nosis is often made on biopsied tissue, although culture is necessary for detailed iden-
tification of the fungal species because pathology is not definitive.

Is latex agglutination still the best serologic tool for diagnosing cryptococcal disease?

Detection of cryptococcal capsular polysaccharide by enzyme-linked immunosorbent

assay (ELISA) and latex agglutination is still the gold standard for diagnosis in all body
fluids.48 Sensitivity and specificity for these 2 tests is near 100%. High titers are asso-
ciated with more severe disease and higher mortality rates.48 High-risk patients are
often routinely screened. A lateral flow assay has been developed for more rapid diag-
nosis, with similar results for use in low-resource environments.
Treatment and Monitoring

My patient is otherwise healthy with mild symptoms, should I treat him/her?

Mild pulmonary disease in immune-competent patients does not require treatment in

the case of histoplasmosis and blastomycosis,34 although follow-up is recommended.
The management of mild pneumonia from coccidiomycosis is less clear, and it is
generally recommended to treat symptomatic patients.41 All cases of Cryptococcus
should be treated.

My patient is critically ill; which agent is best?

Histoplasmosis, blastomycosis, and coccidiomycosis

Immune-compromised patients with evidence of infection should be treated. Treat-
ment choice and length depends on the location of infection and time to resolution
of symptoms (see Table 2 for detailed treatment recommendations).
Several antifungal agents have proven activity against the endemic fungi, and there
is much overlap. For pulmonary and disseminated histoplasmosis and blastomy-
cosis, active agents include formulations of amphotericin B and itraconazole.49 Echi-
nocandins do not have proven activity against H capsulatum or B dermatitidis.
Intravenous liposomal amphotericin B is preferred over amphotericin B deoxycholate,
in accord with studies that show better response and lower mortality with the
former.50
322 Odom & Reno

Table 2
Treatment of endemic fungi

Moderate to
Severe
Mild Pulmonary Pulmonary Extrapulmonary Alternative
Disease Disease Disease Agent
Histoplasmosis NSAIDs or Amphotericin B NSAIDs or High-dose
observation for 12 wk observation for fluconazole or
Itraconazole if followed by mild disease posaconazole
longer than itraconazole Itraconazole if
1 mo of longer than 1 mo
symptoms or severe disease
Amphotericin B if
disseminated or
CNS disease
Blastomycosis Itraconazole Amphotericin B Itraconazole for High-dose
for 2 wk mild disease fluconazole or
followed by Amphotericin B voriconazole
itraconazole then oral
itraconazole
(amphotericin B
for 4 wk for CNS
disease)
Coccidiomycosis Observation Fluconazole or Fluconazole or Dual amphotericin
Fluconazole if itraconazole itraconazole for B and azole
immune If respiratory mild to moderate
compromised failure, disease
amphotericin B Amphotericin B for
until improved severe disease

Abbreviations: CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs.

For histoplasmosis and blastomycosis, itraconazole (200 mg 3 times daily  3 days

then 200 mg twice daily for at least 12 weeks) is preferred as first-line therapy in mild or
moderate disease that persists for more than 1 month, but no treatment is usually
needed sooner. Nonsteroidal anti-inflammatory agents are the only treatment recom-
mended for mild disease in immunocompetent hosts.51 Itraconazole has at least an
80% response rate for pulmonary histoplasmosis.49 Itraconazole is available in an
intravenous formulation but not in the United States. Liquid oral formulations are
preferred to tablets, and absorption is poor when taken with H2 blockers or proton-
pump inhibitors. Itraconazole levels should be obtained at 2 weeks to maintain levels
between 1 and 10 mg/mL. For intolerant patients, high-dose fluconazole has shown
some, but reduced, efficacy.36
Although amphotericin is preferred in patients without renal dysfunction and who
have severe disease with acute illness, it is often replaced with an azole once a
response is documented to reduce the incidence of toxicity.36 Liposomal amphoteri-
cin B dosed intravenously at 5 mg/kg daily for 1 to 2 weeks followed by itraconazole is
recommended for severe disease. Any patient receiving amphotericin B should
receive frequent laboratory panels (electrolytes, renal function, and blood counts)
for evidence of toxicity.
The treatment of coccidiomycosis is slightly different. Mild disease can be treated
similarly to histoplasmosis and blastomycosis, with close monitoring and anti-
inflammatory agents. Patients of African or Filipino decent, and patients with diabetes
 Fungal Infections in the Hospitalized Patient 323

or heart disease, widespread pulmonary infiltrates, weight loss, pregnancy, or a high

antibody titer may be considered for early treatment owing to their increased risk for
morbidity.41 High-dose fluconazole is appropriate for moderate disease (400 mg daily
for 3 to 6 months). Itraconazole can also be used. For significant hypoxia or severe
extrapulmonary disease, amphotericin B is recommended.
For pulmonary disease, treatment should continue until infiltrates are resolved on
chest radiographs (Fig. 2).
In patients who have failed treatment with itraconazole or amphotericin B, posaco-
nazole and voriconazole can be used as salvage agents.40,52 For patients with rheu-
matologic manifestations from histoplasmosis or blastomycosis, mediastinal
disease, or chronic pulmonary nodules, no treatment at all or anti-inflammatory agents
are generally sufficient. CNS disease should be treated with liposomal amphotericin B
for 1 month followed by itraconazole for at least 1 year.36,53 Azoles should be avoided
in pregnancy. Immune-compromised patients should be considered for earlier treat-
ment, especially HIV patients with a CD4 count of less than 250 cells/mL and transplant
recipients. Prophylaxis is often ineffective.
Cryptococcosis

My patient has pulmonary cryptococcal infection. What other tests need to be

performed?

Immune-competent patients with mild isolated pulmonary cryptococcosis without

CNS symptoms do not require a lumbar puncture; however, immune-compromised
patients or any patient with CNS symptoms should receive one.42 In addition, all
patients should receive an HIV test.

Fig. 2. Pulmonary histoplasmosis. (From Weinberg M, Weeks J, Lance-Parker S, et al. Severe

histoplasmosis in travelers to Nicaragua. Emerg Infect Dis 2003;9(10):1323.)
324 Odom & Reno

What is the treatment and management of cryptococcal infection?

Mild to moderate pulmonary disease without evidence of dissemination can be treated

with fluconazole (6 mg/kg/d) for 6 to 12 months. Severe pulmonary disease is treated
similarly to CNS disease.42 Consultation from an infectious diseases specialist is
recommended.
All patients with immune compromise should be screened for CNS involvement with
a lumbar puncture. Cryptococcal meningoencephalitis and disseminated cryptococ-
cemia are treated in similar fashion with amphotericin B (0.71.0 mg/kg/d) intrave-
nously plus flucytosine (100 mg/kg/d) orally or intravenously in 4 divided doses as
an induction for at least 2 weeks (4 weeks if immune competent) followed by flucon-
azole (6 mg/kg/d) for at least 8 weeks.42,48 Patients with severe CNS disease may be
treated for 6 to 8 weeks. If amphotericin B cannot be tolerated, fluconazole at high
doses (8001200 mg/d) plus flucytosine for 6 weeks is a less effective alternative.42
Suppressive or maintenance therapy with fluconazole 200 mg/d should be considered
for all patients for up to 1 year.
In addition, measurement and management of cerebrospinal fluid (CSF) pressure in
patients with CNS cryptococcal infection is essential. Patients with extremely high
CSF opening pressures are at increased risk of death.54 Management of elevated
CSF pressures is via repeat lumbar punctures, even performed daily if necessary, to
remove CSF and lower pressures.42

Performance Improvement
Detailed guidelines for these fungal infections and others not mentioned here are
detailed in a variety of articles included on the Infectious Disease Society of Americas
Web site (idsociety.org).

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