198
C H A P T E R 6 Fungal and Protozoal Diseases
• Fig. 6-15  Candidiasis. This medium-power photomicrograph
shows a characteristic pattern of parakeratosis, neutrophilic microab-
scesses, a thickened spinous layer, and chronic inflammation of the
underlying connective tissue associated with long-standing candidal
infection of the oral mucosa.
• Fig. 6-16  Candidiasis. This high-power photomicrograph shows
the tubular hyphae of Candida albicans embedded in the parakeratin
layer. (Periodic acid-Schiff [PAS] stain.)
on the surface of the lesion in conjunction with elongation
of the epithelial rete ridges (Fig. 6-15). Typically, a chronic
inflammatory cell infiltrate can be seen in the connective
tissue immediately subjacent to the infected epithelium,
and small collections of neutrophils (microabscesses) are
often identified in the parakeratin layer and the superficial
spinous cell layer near the organisms (Fig. 6-16). The can-
didal hyphae are embedded in the parakeratin layer and
rarely penetrate into the viable cell layers of the epithelium
unless the patient is extremely immunocompromised.
Diagnosis
The diagnosis of candidiasis is usually established by the
clinical signs in conjunction with exfoliative cytologic
examination. Although a culture can definitively identify
the organism as C. albicans, this process may not be practi-
cal in most office settings. The cytologic findings should
demonstrate the hyphal phase of the organism, and anti-
fungal therapy can then be instituted. If the lesion is
clinically suggestive of chronic hyperplastic candidiasis but
does not respond to antifungal therapy, then a biopsy should
be performed to rule out the possibility of C. albicans super-
imposed on epithelial dysplasia, squamous cell carcinoma,
or lichen planus.
The definitive identification of the organism can be made
by means of culture. A specimen for culture is obtained by
rubbing a sterile cotton swab over the lesion and then
streaking the swab on the surface of a Sabouraud agar slant.
C. albicans will grow as creamy, smooth-surfaced colonies
after 2 to 3 days of incubation at room temperature.
Treatment and Prognosis
Several antifungal medications have been developed for
managing oral candidiasis, each with its advantages and
disadvantages (Table 6-2).
Polyene Agents
Nystatin
In the 1950s, the polyene antibiotic nystatin was the first
effective treatment for oral candidiasis. Nystatin is formu-
lated for oral use as a suspension or pastille (lozenge). Many
patients report that nystatin has a very bitter taste, which
may reduce patient compliance; therefore, the taste has to be
disguised with sucrose and flavoring agents. If the candidia-
sis is due to xerostomia, the sucrose content of the nystatin
preparation may contribute to xerostomia-related caries in
these patients. The gastrointestinal tract poorly absorbs
nystatin and the other polyene antibiotic, amphotericin;
therefore, their effectiveness depends on direct contact with
the candidal organisms. This necessitates multiple daily
doses so that the yeasts are adequately exposed to the drug.
Nystatin combined with triamcinolone acetonide cream or
ointment can be applied topically and is effective for angular
cheilitis that does not have a bacterial component.
Amphotericin B
For many years in the United States, the use of amphoteri-
cin B was restricted to intravenous (IV) treatment of life-
threatening systemic fungal infections. This medication
subsequently became available as an oral suspension for the
management of oral candidiasis. Unfortunately, the interest
in this formulation of the drug was scant, and it is no longer
marketed in the United States.
Imidazole Agents
The imidazole-derived antifungal agents were developed
during the 1970s and represented a major step forward
in the management of candidiasis. The two drugs of this
group that are used most frequently are clotrimazole and
ketoconazole.
Clotrimazole
Like nystatin, clotrimazole is not well absorbed and must
be administered several times each day. It is formulated as
a pleasant-tasting troche (lozenge) and produces few side

effects. The efficacy of this agent in treating oral candidiasis
can be seen in Fig. 6-12. Clotrimazole cream is also effective
treatment for angular cheilitis, because this drug has anti-
bacterial and antifungal properties.
Ketoconazole
Ketoconazole was the first antifungal drug that could be
absorbed across the gastrointestinal tract, thereby providing
systemic therapy by an oral route of administration. The
single daily dose was much easier for patients to use; however,
several disadvantages have been noted. Patients must not
take antacids or H2-blocking agents, because an acidic envi-
ronment is required for proper absorption. If a patient is to
take ketoconazole for more than 2 weeks, then liver function
studies are recommended because approximately 1 in 10,000
individuals experience idiosyncratic liver toxicity from the
agent. For this reason, the US Food and Drug Administra-
tion has stated that ketoconazole should not be used as
initial therapy for routine oral candidiasis. Furthermore,
ketoconazole has been implicated in drug interactions
with macrolide antibiotics (e.g., erythromycin), which may
produce potentially life-threatening cardiac arrhythmias.
Triazoles
The triazoles are among the more recently developed anti-
fungal drugs. Both fluconazole and itraconazole have been
approved for treating candidiasis in the United States.
Fluconazole
Fluconazole appears to be more effective than ketoconazole;
it is well absorbed systemically, and an acidic environment
is not required for absorption. A relatively long half-life
allows for once-daily dosing, and liver toxicity is rare at the
doses used to treat oral candidiasis. Some reports have sug-
gested that fluconazole may not be appropriate for long-
term preventive therapy because resistance to the drug
seems to develop in some instances. Known drug interac-
tions include a potentiation of the effects of phenytoin
(Dilantin), an antiseizure medication; warfarin compounds
(anticoagulants); and sulfonylureas (oral hypoglycemic
agents). Other drugs that may interact with fluconazole are
summarized in Table 6-2.
Itraconazole
Itraconazole has proven efficacy against a variety of fungal
diseases, including histoplasmosis, blastomycosis, and fungal
conditions of the nails. Recently, itraconazole solution was
approved for management of oropharyngeal candidiasis, and
this appears to have an efficacy equivalent to clotrimazole
and fluconazole. As with fluconazole, significant drug inter-
actions are possible, and itraconazole is contraindicated for
patients taking erythromycin, triazolam, and midazolam.
(See Table 6-2 for other potential drug interactions.)
Posaconazole
This relatively new triazole compound has been shown
to be effective in the management of oropharyngeal
CHAPTER 6  Fungal and Protozoal Diseases 199
candidiasis in patients with HIV infection. Given the cost
of this drug and the proven effectiveness of other, less
expensive, oral antifungal agents, the use of this medication
for treatment of routine oral candidiasis would be difficult
to justify.
Echinocandins
This new class of antifungal drugs acts by interfering with
candidal cell wall synthesis. The formation of β-1,3-glucan,
which is a principal component of the candidal cell wall, is
disrupted and results in permeability of the cell wall with
subsequent demise of the candidal organism. These medica-
tions are not well absorbed; consequently they must be
administered intravenously and are reserved for more life-
threatening candidal infections. Examples include caspo-
fungin, micafungin, and anidulafungin.
Other Antifungal Agents
Iodoquinol
Although not strictly an antifungal drug, iodoquinol has
antifungal and antibacterial properties. When compounded
in a cream base with a corticosteroid, this material is very
effective as topical therapy for angular cheilitis.
In most cases, oral candidiasis is an annoying superficial
infection that is easily resolved by antifungal therapy. If
infection should recur after treatment, then a thorough
investigation of potential factors that could predispose to
candidiasis, including immunosuppression, may be neces-
sary. In only the most severely compromised patient will
candidiasis cause deeply invasive disease (Fig. 6-17).
◆ HISTOPLASMOSIS
Histoplasmosis, the most common systemic fungal infec-
tion in the United States, is caused by the organism Histo-
plasma capsulatum. Like several other pathogenic fungi, H.
capsulatum is dimorphic, growing as a yeast at body tem-
perature in the human host and as a mold in its natural
• Fig. 6-17  Candidiasis. This necrotic lesion of the upper lip devel-
oped in a man with uncontrolled type I diabetes mellitus. Biopsy and
culture showed a rare example of invasive oral infection by Candida
albicans.
200 C H A P T E R 6 Fungal and Protozoal Diseases

TABLE
6-2 
Antifungal Medications

Generic Name Trade Name Indications Dosage

Nystatin Mycostatin Oral candidiasis One or two pastilles (200,000-400,000 units) dissolved slowly in
pastilles the mouth 4 to 5 times daily for 10 to 14 days
Mycostatin oral
suspension
Clotrimazole Mycelex oral Oral candidiasis Dissolve 1 troche (10 mg) slowly in the mouth, 5 times daily for
troches 10 to 14 days

Ketoconazole Nizoral tablets Oral candidiasis Not to be used as initial therapy for oral candidiasis
Blastomycosis One tablet (200 mg) daily for 1 to 2 weeks for candidiasis

Coccidioidomycosis Minimum treatment period for systemic mycoses is 6 months

Histoplasmosis
Paracoccidioidomycosis
Fluconazole Diflucan Oral candidiasis For oral candidiasis: two tablets (200 mg) on day 1 and then
tablets one tablet (100 mg) daily for 1 to 2 weeks
Cryptococcal meningitis

Itraconazole Sporanox Blastomycosis For blastomycosis and histoplasmosis: two capsules (200 mg)
capsules Histoplasmosis daily, increasing by 100-mg increments up to 400 mg daily in
divided doses if no clinical response is noted
Aspergillosis refractory to For aspergillosis: 200 to 400 mg daily
amphotericin B therapy
For life-threatening situations: loading dose of 200 mg t.i.d. for
first 3 days, then dose can be reduced
Treatment should continue for at least 3 months for all of the
above

Itraconazole Sporanox oral Oral candidiasis 10 mL (100 mg) vigorously swished in the mouth and
solution swallowed, twice daily for 1 to 2 weeks

Amphotericin B Fungizone oral Oral candidiasis 1 mL (100 mg) rinse and hold in the mouth for as long as
suspension possible, q.i.d., p.c., and h.s. for 2 weeks

h.s., Hora somni (at bedtime); p.c., post cibum (after meals); q.i.d., quarter in die (four times a day); t.i.d., ter in die (three times a day).

environment. Humid areas with soil enriched by bird or bat
excrement are especially suited to the growth of this organ-
ism. This habitat preference explains why histoplasmosis is
seen endemically in fertile river valleys, such as the region
drained by the Ohio and Mississippi Rivers in the United
States. Airborne spores of the organism are inhaled, pass
into the terminal passages of the lungs, and germinate.
Approximately 500,000 new cases of histoplasmosis are
thought to develop annually in the United States. Other
parts of the world, such as Central and South America,
Europe, and Asia, also report numerous cases. Epidemio-
logic studies in endemic areas of the United States suggest
that 80% to 90% of the population in these regions has
been infected.
Clinical and Radiographic Features
Most cases of histoplasmosis produce either no symptoms
or such mild symptoms that the patient does not seek
medical treatment. The expression of disease depends on the
quantity of spores inhaled, the immune status of the host,
and perhaps the strain of H. capsulatum. Most individuals
who become exposed to the organism are relatively healthy
and do not inhale a large number of spores; therefore, they

Side Effects/Adverse Reactions
Nausea, diarrhea, vomiting with large doses
Mild elevations of liver enzymes in 15% of patients
Periodic assessment of liver function in patients with hepatic
impairment
Nausea, vomiting
Serious hepatotoxicity in 1 : 10,000 patients
Monitoring of liver function is indicated for patients with
preexisting hepatic problems, patients who develop symptoms
of hepatic failure, or patients treated for more than 28 days
Serum testosterone is lowered
Nausea, vomiting
Anaphylaxis
Rare cases of hepatotoxicity, ranging from mild transient
elevation of liver enzymes to hepatic failure
Headache, nausea, vomiting, abdominal pain, diarrhea
Rare cases of hepatoxicity
Liver function should be monitored in patients with preexisting
hepatic problems on therapy for more than 1 month
Nausea, diarrhea, vomiting
Rare cases of hepatotoxicity
Liver function should be monitored in patients with preexisting
hepatic problems on therapy for more than 1 month
Nausea, diarrhea, vomiting
Rash, gastrointestinal symptoms
have either no symptoms or they have a mild, flulike illness
for 1 to 2 weeks. The inhaled spores are ingested by mac-
rophages within 24 to 48 hours, and specific T-lymphocyte
immunity develops in 2 to 3 weeks. Antibodies directed
against the organism usually appear several weeks later. With
these defense mechanisms, the host is usually able to destroy
the invading organism, although sometimes the macro-
phages simply surround and confine the fungus so that
viable organisms can be recovered years later. Thus patients
who formerly lived in an endemic area may have acquired
the organism and later express the disease at some other
geographic site if they become immunocompromised.
CHAPTER 6  Fungal and Protozoal Diseases 201
Drug Interactions
None known
No significant drug interactions
Serious and/or life-threatening interactions with erythromycin
Metabolism of cyclosporine, tacrolimus, methylprednisolone,
midazolam, triazolam, coumarin-like drugs, phenytoin, and
rifampin may be altered
Clinically or potentially significant side effects have been
noted with the following medications: oral hypoglycemic
agents, coumarin-like drugs, phenytoin, cyclosporine,
rifampin, theophylline, rifabutin, and tacrolimus
Serious and/or life-threatening interactions with erythromycin,
pimozide, quinidine, oral triazolam, and oral midazolam
Lovastatin and simvastatin should be discontinued
Increased plasma concentrations may be seen with warfarin,
ritonavir, indinavir, vinca alkaloid agents, diazepam,
cyclosporine, dihydropyridine medications, tacrolimus,
digoxin, and methylprednisolone
Serious and/or life-threatening interactions with erythromycin,
oral triazolam, and oral midazolam,
Lovastatin and simvastatin should be discontinued
No significant drug interactions
Acute histoplasmosis is a self-limited pulmonary infec-
tion that probably develops in only about 1% of people who
are exposed to a low number of spores. With a high con-
centration of spores, as many as 50% to 100% of individu-
als may experience acute symptoms. These symptoms (e.g.,
fever, headache, myalgia, nonproductive cough, and
anorexia) result in a clinical picture similar to that of influ-
enza. Patients are usually ill for 2 weeks, although calcifica-
tion of the hilar lymph nodes may be detected as an
incidental finding on chest radiographs years later.
Chronic histoplasmosis also primarily affects the lungs,
although it is much less common than acute histoplasmosis.
202 C H A P T E R 6 Fungal and Protozoal Diseases

The chronic form usually affects older, emphysematous, lections of macrophages organized into granulomas
white men or immunosuppressed patients. Clinically, it (Fig. 6-20). Multinucleated giant cells are usually seen in
appears similar to tuberculosis. Patients typically exhibit association with the granulomatous inflammation. The
cough, weight loss, fever, dyspnea, chest pain, hemoptysis, causative organism can be identified with some difficulty in
weakness, and fatigue. Chest roentgenograms show upper- the routine hematoxylin and eosin (H&E)-stained section;
lobe infiltrates and cavitation. however, special stains, such as the PAS and Grocott-
Disseminated histoplasmosis is even less common than Gomori methenamine silver methods, readily demonstrate
the acute and chronic types. It occurs in 1 of 2000 to 5000 the characteristic 1- to 3-µm yeasts of H. capsulatum
patients who have acute symptoms. This condition is char- (Fig. 6-21).
acterized by the progressive spread of the infection to extra-
pulmonary sites. It usually occurs in either older, debilitated, Diagnosis
or immunosuppressed patients. In some areas of the United
States, 2% to 10% of patients with acquired immunode- The diagnosis of histoplasmosis can be made by histopatho-
ficiency syndrome (AIDS) (see page 251) develop dissemi- logic identification of the organism in tissue sections or by
nated histoplasmosis. Patients who are being treated with a culture. Other helpful diagnostic studies include serologic
tumor necrosis factor-alpha (TNF-α) inhibitor (such as, testing in which antibodies directed against H. capsulatum
infliximab, etanercept, or adalimumab) and who live in are demonstrated and antigen produced by the yeast is
endemic geographic regions also are at risk for disseminated identified.
disease, probably due to reactivation of the organism.
Tissues that may be affected include the spleen, adrenal
glands, liver, lymph nodes, gastrointestinal tract, central
nervous system (CNS), kidneys, and oral mucosa. Adrenal
involvement may produce hypoadrenocorticism (Addison
disease) (see page 784).
Most oral lesions of histoplasmosis occur with the dis-
seminated form of the disease. The most commonly affected
sites are the tongue, palate, and buccal mucosa. The condi-
tion usually appears as a solitary, variably painful ulceration
of several weeks’ duration; however, some lesions may
appear erythematous or white with an irregular surface (Fig.
6-18). The ulcerated lesions have firm, rolled margins, and
they may be indistinguishable clinically from a malignancy
(Fig. 6-19).

Histopathologic Features
Microscopic examination of lesional tissue shows either a
diffuse infiltrate of macrophages or, more commonly, col-
• Fig. 6-19  Histoplasmosis. This chronic ulceration of the ventral
and lateral tongue represents an oral lesion of histoplasmosis that had
disseminated from the lungs. The lesion clinically resembles carci-
noma; because of this high-risk site, biopsy is mandatory.

• Fig. 6-18  Histoplasmosis. This ulcerated granular lesion involves • Fig. 6-20  Histoplasmosis. This medium-power photomicrograph
the mandibular labial vestibule and is easily mistaken clinically for shows scattered epithelioid macrophages admixed with lymphocytes
carcinoma. Biopsy established the diagnosis. (Courtesy of Dr. John and plasma cells. Some macrophages contain organisms of Histo-
Werther.) plasma capsulatum (arrows).

• Fig. 6-21  Histoplasmosis. This high-power photomicrograph of a
tissue section readily demonstrates the small yeasts of Histoplasma
capsulatum. (Grocott-Gomori methenamine silver stain.)
Treatment and Prognosis
Acute histoplasmosis, because it is a self-limited process,
generally warrants no specific treatment other than sup-
portive care with analgesic and antipyretic agents. Often the
disease is not treated because the symptoms are so nonspe-
cific and the diagnosis is not readily evident.
Patients with chronic histoplasmosis require treatment,
despite the fact that up to half of them may recover spon-
taneously. Often the pulmonary damage is progressive if it
remains untreated, and death may result in up to 20% of
these cases. For severe cases of chronic histoplasmosis, the
treatment of choice is IV administration of one of the lipid
preparations of amphotericin B, which are significantly less
toxic than standard formulations of amphotericin B deoxy-
cholate. Itraconazole may be used in nonimmunosuppressed
patients because it is associated with even fewer side effects
and is less expensive, but this medication requires daily
dosing for at least 3 months. Although fluconazole has been
used for treatment of histoplasmosis, this agent appears to
be less effective than itraconazole and less likely to produce
a desired therapeutic response.
Disseminated histoplasmosis occurring in an immune-
suppressed individual is a very serious condition that results
in death in 80% to 90% of patients if they remain untreated.
One of the lipid preparations of amphotericin B is indicated
for such patients; once the life-threatening phase of the
disease is under control, daily itraconazole is necessary for
6 to 18 months. Despite therapy, however, a mortality rate
of 7% to 23% is observed. Itraconazole alone may be used
if the patient is nonimmunocompromised and has relatively
mild to moderate disease; however, the response rate is
slower than for patients receiving amphotericin B, and the
relapse rate may be higher.
◆ BLASTOMYCOSIS
Blastomycosis is a relatively uncommon disease caused by
the dimorphic fungus known as Blastomyces dermatitidis.
CHAPTER 6  Fungal and Protozoal Diseases 203
Although the organism is rarely isolated from its natural
habitat, it seems to prefer rich, moist soil, where it grows as
a mold. Much of the region in which it grows overlaps the
territory associated with H. capsulatum (affecting the eastern
half of the United States). The range of blastomycosis
extends farther north, however, including Wisconsin, Min-
nesota, and the Canadian provinces surrounding the Great
Lakes. Sporadic cases have also been reported in Africa,
India, Europe, and South America. By way of comparison,
histoplasmosis appears to be at least ten times more common
than blastomycosis. In some series of cases, a prominent
adult male predilection has been noted, often with a male-
to-female ratio as high as 9 : 1. Although some researchers
have attributed this to the greater degree of outdoor activity
(e.g., hunting, fishing) by men in areas where the organism
grows, others have noted that these series were typically
reported from VA hospital data, which has an inherent male
bias. The occurrence of blastomycosis in immunocompro-
mised patients is relatively rare.
Clinical and Radiographic Features
Blastomycosis is almost always acquired by inhalation of
spores, particularly after a rain. The spores reach the alveoli
of the lungs, where they begin to grow as yeasts at body
temperature. In most patients, the infection is probably
halted and contained in the lungs, but it may become
hematogenously disseminated in a few instances. In order
of decreasing frequency, the sites of dissemination include
skin, bone, prostate, meninges, oropharyngeal mucosa, and
abdominal organs.
Although most cases of blastomycosis are either asymp-
tomatic or produce only very mild symptoms, patients who
do experience symptoms usually have pulmonary com-
plaints. Acute blastomycosis resembles pneumonia, char-
acterized by high fever, chest pain, malaise, night sweats,
and productive cough with mucopurulent sputum. Rarely,
the infection may precipitate life-threatening adult respira-
tory distress syndrome.
Chronic blastomycosis is more common than the acute
form, and it may mimic tuberculosis; both conditions are
often characterized by low-grade fever, night sweats, weight
loss, and productive cough. Chest radiographs may appear
normal, or they may demonstrate diffuse infiltrates or one
or more pulmonary or hilar masses. Unlike the situation
with tuberculosis and histoplasmosis, calcification is not
typically present. Cutaneous lesions usually represent the
spread of infection from the lungs, although occasionally
they are the only sign of disease. Such lesions begin as ery-
thematous nodules that enlarge, becoming verrucous or
ulcerated (Figs. 6-22 and 6-23).
Oral lesions of blastomycosis may result from either
extrapulmonary dissemination or local inoculation with the
organism. These lesions may have an irregular, erythema-
tous or white intact surface, or they may appear as ulcer-
ations with irregular rolled borders and varying degrees of
pain (Figs. 6-24 and 6-25). Clinically, because the lesions