Clinics in Dermatology (2012) 30, 573–591

Coccidioidomycosis
Oliverio Welsh, MD a,⁎, Lucio Vera-Cabrera, PhD a , Adrian Rendon, MD b ,
Gloria Gonzalez, PhD c , Alexandro Bonifaz, BS, MS d
a
Department of Dermatology, “Dr. Jose E. Gonzalez” University Hospital, Universidad Autónoma de Nuevo León,
Ave Madero y Ave Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo Leon, 64460, México
b
Department of Pulmonology, Hospital Universitario “Dr. Jose E. Gonzalez,” Ave. Madero y Gonzalitos s/n,
Colonia Mitras Centro, Monterrey, N.L. 64460, México
c
Microbiology Department of the School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, N.L. 64460, México
d
Mycology Laboratory, Hospital General, México D.F. 04510, México

Abstract Coccidioidomycosis is a systemic disease caused by Coccidioides immitis and C posadasii

spp, which are predominant in arid zones of the American continent, mainly in the Southwestern United
States and the northern states of Mexico, as well as other regions with different environmental
conditions. Some countries of Central and South America are also endemic zones. Most infected
patients are asymptomatic. Disseminated disease develops in less than 5% of clinically affected
individuals. Culture, biopsy, and DNA probes are used for fungus identification. Prognosis is related to
low antibody detection and a positive intradermic skin reaction to coccidioidin. Immunodepressed
patients and pregnant women require special attention in diagnosis, therapy, and prognosis.
Amphotericin B in its different forms, itraconazole, and fluconazole, are the most frequently used
treatments. Posaconazole and voriconazole are prescribed in some unresponsive cases.
© 2012 Elsevier Inc. All rights reserved.

Introduction Nevada, Utah, and particularly, in the southwestern states of

Coccidioidomycosis is a systemic fungal infection that
is predominant in the Americas. It is caused by two
different species: Coccidioides immitis (California species)
and Coccidioides posadasii (non-California species). This
fungus grows in semiarid alkaline sandy clay areas with short
rainy seasons that aid the germination of the fungus. During
the hot season, it disappears from the surface of the ground
but can be found up to 20 cm below. Dust storms in dry
endemic areas can facilitate its inoculation, which is acquired
by inhalation of arthroconidia. The fungus is endemic in
⁎ Corresponding author. Tel.: +52 81 8348 0383; fax: +61 2 4968 6727.
E-mail address: owelsh@yahoo.com (O. Welsh).
the United States, with the highest incidence in Arizona,
New Mexico, Texas, and California. It is also found in the
northern states of Mexico, such as Baja California,
Chihuahua, Coahuila, Nuevo Leon, and Tamaulipas. These
areas in both countries are known as the lower Sonoran
life zone.1
The presence of different types of cactus (Figure 1) and
Larrea tridentata, known in Mexico as gobernadora and
in the United States as creosote bush, are common in the type
of soil where this fungus lives (Figure 2). Other states in the
central area of Mexico, such as San Luis Potosi, Durango,
and Colima,2 which have a different climate, have reported
sporadic autochthonous cases of coccidioidomycosis. Coun-
tries such as Guatemala, Nicaragua, Argentina (the Gran
Chaco zone), and the northeast zone of Brazil have endemic
areas with reports of infected patients.3-6

0738-081X/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clindermatol.2012.01.003
574
Fig. 1 Cactus frequently found in endemic sites of Coccidioides
immitis and C posadasii.
Alejandro Posadas first described coccidioidomycosis in
1888. He evaluated a 32-year-old soldier named Domingo
Ezcurra who lived in the Gran Chaco frontier of Argentina
(Figure 3). He consulted due to a papule on his right cheek
that was initially diagnosed as an insect bite. As this lesion
progressed, it became verrucous and was followed by the
appearance of multiple skin lesions and adenopathy. The
patient was referred to Rawson Military Hospital, where the
diagnosis of mycosis fungoides was made.
After unsuccessful treatment with potassium iodide and
mercury, the patient was referred to the university hospital
where Posadas took a specimen of the lesion and studied it in
the laboratory of his mentor, Dr Robert Wernicke, the
Hospital de Clinicas de Buenos Aires Pathology Department.
On microscopic examination, he observed spherical organ-
isms of different size with a double-refractile outer wall. He
believed that this was a new psorospermia and reported it as a
new case of mycosis fungoides with psorospermia. 7
Wernicke reported the same case in December of the same
year.8 Ezcurra's disease progressed, despite topical treat-
ments with carbolic acid, and he died in 1898.9
O. Welsh et al.
In the same period, two Portuguese patients from the
Azores were seen in California. The first, Joas Furtado-
Silveira, a farmer working in the San Joaquin Valley,
developed a dermatosis on his neck that later spread to the
forehead. The lesion had an erratic evolution. A specimen of
the lesion was sent to the pathologist, Dr Emmet Rixford, at
Cooper Medical College in California (later, Stanford
University School of Medicine) and to Dr T. Caspar
Gilchrist at Johns Hopkins. Both found the same structures
described by Alejandro Posadas and Robert Wernicke in the
pathology report of Domingo Ezcurra. They concluded that
Ezcurra did not have mycosis fungoides. Dr William H.
Welsh, a prominent pathologist and first dean of the Johns
Hopkins University School of Medicine, also reviewed the
specimen and did not believe that the organisms found were
protozoa. He provided other diagnoses such as cutaneous
tuberculosis, leprosy, and syphilis. The patient received
several topical and intralesional treatments, as well as
excision of the lesions, but the disease worsened, and he
died in 1895.9
The second patient was Jose Teixara, from the Azores,
who also worked in the same area. He was seen at St. Mary's
Hospital in San Francisco in 1894 due to acneiform lesions
on his forehead that later spread to other sites and were
accompanied by fever. Rixford and Gilchrist reviewed the
biopsy specimens from this second patient, agreeing that the
infection was similar to the Silveira case. They suggested
that the site of entry was through the skin, that it was not very
contagious, and that the etiologic agent was a protozoan of
the class Sporozoa. Owing to its resemblance to coccidia, it
was named coccidioides. They classified the organism
isolated from Silveira as Coccidiosis immitis (immitis
meaning severe, not mild), and the one isolated from Teixara
as Coccidiosis pyogens.10
Cultures from these patients grew fungal organisms that
were considered contaminants. Cultures from other farm
workers of the Azores who were working in the San Joaquin
Valley and died also grew a white mold. William Ophüls
(Figure 4), a pathology and bacteriology professor from
Cooper Medical College, and Herbert Moffitt, presented a
preliminary report on April 17, 1900, to the California
Medical Society that was published 74 days later. In it they
confirmed and defined the fungal etiology of C immitis,
described its life cycle, and corroborated Koch's postulates
by inoculating the agent in guinea pigs and reproducing the
disease.11,12
Ernest Dickson continued the work on coccidioidomycosis
of his professor, Dr Ophüls. In 1929, he acquired a medical
assistant, Dr Harold Chope, whose job was to continue
Dickson's research on coccidioidomycosis. Dr Chope
accidentally opened a petri dish containing an old colony of
C immitis, and 9 days later became quite ill with severe
pneumonia. The medical prognosis was that he would soon
die, because until that time, every case of severe coccidioi-
domycosis had had a fatal outcome. Chope recovered,
however, and remained several months in convalescence.
Coccidioidomycosis 575

Fig. 2 Larrea tridentata (creosote bush).

During this time, he asked his medical fraternity brother,

Charles Smith, to substitute for him in Dickson's laboratory.
Chope did not return after his recovery, and Smith remained
in the job with Dickson's condition of obtaining a doctorate
degree in public health; thereafter, he returned to Stanford
to work on the “fungus Coccidioidis.”
In the period 1934 to 1936, Smith also acquired the
fungal infection and recovered. He performed epidemio-
logic studies in endemic zones in Kern and Tulare counties
where he found and collected more than 400 patients with Fig. 4 Portrait of William Ophüls.
positive coccidioidin skin tests that had developed erythema
nodosum or erythema multiforme. During this time, he
established the incubation period of the disease and its Gifford (Figure 5), from the health department, had already
seasonal incidence. He also requested sputum from Kern begun studying benign coccidioidal pneumonia with
County cases of pneumonia and found that D. Myrnie erythema nodosum.

Fig. 3 The original anatomopathologic specimen investigated by Posadas and Wernicke.

576
Fig. 5 Portrait of Myrnie Gifford.
In his work, Smith accidently discovered precipitation
buttons in unwashed Wasserman tubes in which they had
incubated coccidioidin prepared from C immitis mycelia and
serum from guinea pigs infected with C immitis; the tubes
containing the control serum did not have precipitation. This
finding was useful for the development of serologic tests that
detect precipitin proteins against antigens from aerial
mycelia of C immitis in infected patients. Smith and
collaborators performed epidemiologic studies during the
1930s, establishing the parameters for performing further
research in endemic areas.
One of the highest incidences of cases was reported in
soldiers settled in the 1940s in Williams Field, Arizona,
where up to 50% of the recruits were infected in a period of
6 months.
Many other authors have had important participation in
the saga of coccidioidomycosis. Some of these are Hans
Einstein, William Winn, Antonino Catanzaro, Demosthenes
Pappagianis, David Stevens, David Drutz, Hillel Levine,
Antonio Gonzalez-Ochoa, John Galgiani, and Neil Ampel.10
In Mexico, González-Ochoa was the first to report the
endemic zones where the fungus grew and performed
coccidioidin studies for detecting positive individuals
among people that live in those areas.2
Currently, about 150,000 cases are reported yearly in the
United States. Filipinos, African Americans, and Hispanics
O. Welsh et al.
are among the most susceptible ethnic groups for acquiring
severe and disseminated infection.13,14
Microbiology
Taxonomy
Recent molecular procedures have made evident the
cryptic exchange of genetic information between the
two species of Coccidioides, C immitis and C posadasii.
Coccidioides is a dimorphic organism that is classified in
the fungus class Dikaryomycota, subclass Ascomycotina,
order Onygenales, family Onygenaceae, genera Coccidioides,
species immitis and posadasii (Table 1).15
In culture media, the fungus starts growing in 1 to 2 weeks
with abundant white aerial mycelia resembling angel hair
(Figure 6), which can turn tan as the culture ages.
Microscopically, it is characterized by septated hyphae
with barrel-shaped arthroconidia, 2 to 5 μm long (Figure 7).
These eventually easily separate and become airborne.
Occasionally, the hyphae are not septated (atypical strains).
Experimental coccidiomycosis has been induced with less
than 10 arthroconidia; exposure to high spore burdens
increases the likelihood of disease. There are two genetic
species,15 one resident in California (San Joaquin Valley)
named C immitis, and another, C posadasii, is prevalent in
other states of the United States as well as in Mexico and
other countries of the Americas, where it is the predominant
species.16 This classification was established by molecular
analysis of the strains detected; morphologically, both are
similar (Table 2).
Specimen collection
The collection, transport, and processing of clinical
samples for direct examination and culture must follow
specific guidelines that apply to specimens obtained for
isolation of dimorphic fungi. Specimens can include sputum,
bronchoalveolar lavage, transtracheal aspirates, pleural fluid,
Table 1 Taxonomy of Coccidioides immitis and Coccidioides
posadasii
Classification Name
Division Ascomycota
Class Dikaryomycota
Subclass Ascomycotina
Order Onygenales
Family Onygenaceae
Genera Coccidioides
Species immitis
posadasii
Adapted from Fisher et al.15
Coccidioidomycosis 577

Table 2 Comparative analysis of Coccidioides immitis and

Coccidioides posadasii
Characteristics Coccidioides Coccidioides
immitis posadasii
Ecologic niche Very similar Very similar
Geographic Limited Wide
distribution
Growth in NaCl Fast Slow
culture media
(0.034 or 0.136 M)
Arthroconidia (size) Large Small
Nucleotides Chitin synthase, dioxygenase, orotidine
decarboxylase, serine protease, chitinase,
and other 13 genes
Gene (–): Gene (+):
2/proline-rich 2/proline-rich
antigen (Ag2/PRA) antigen (Ag2/PRA)
Allelic distribution GAC2 621
Modified from Fisher et al.15

Fig. 6 Sabouraud colony of Coccidioides immitis and C posadasii.
and lung tissue, and in extrapulmonary sites, specimens from
skin and bone biopsy, pus from abscesses, joint fluid,
cerebrospinal fluid, and others. Universal precautions must
be observed when handling them. Processing should be
performed promptly. The laboratory must be alerted about
the possibility of isolating C immitis. Slides for direct
examination must be processed, stained, and reviewed right
away, and covered with a permanent mount.
When left unsealed for a few hours, formation of
hyphae from the spherule is observed (Figure 8). On
direct examination, thick-walled mature spherules of
different sizes, measuring up to 80 μm in diameter,
containing endospores, can be identified by hematoxylin
and eosin. Special stains (periodic acid-Schiff, Grocott;
Figure 9) can enhance, in doubtful cases, the sensibility
for fungus identification on direct slide examination.
Spherules do not take up Gram stain but may be
visualized with potassium hydroxide, Lugol, calcofluor
white, or Papanicolaou preparations.
Laboratory
Handling this fungus is dangerous, and laboratory
personnel require level II biosafety practices and a class II
biologic safety cabinet that has a vertical airflow and high-
efficiency particulate air–filtered supply and exhaust air for
working with the fungus. These protect the worker, the
processed material, and the environment.17 Because of the
capacity of the fungus to infect exposed individuals, a careful
protocol must be strictly enforced.

Fig. 7 Microculture showing arthroconidia. Fig. 8 Direct examination of spherules growing hyphae.
578
Fig. 9 Grocott stain of tissue specimen shows spherules in black
on a green background (original magnification ×10).
Culture
There are many different media for growing C immitis;
the most used are brain-heart infusion agar, potato-dextrose
agar or potato flakes agar, Sabouraud-dextrose agar (selective
and nonselective), and bacterial media, including blood agar
and chocolate agar. Other media for bacteria, such as buffered
charcoal-yeast extract and Bordet-Gengou and Regan-Lowe
(both, selective and nonselective) also facilitate the growth of
C immitis. After approximately 2 to 3 weeks of incubation at
room temperature (28°-30°C), a white, cottony mold grows
resembling angel hair; as the colony ages, it turns brown.
Microcultures reveal arthrospores and barrel-shaped hyphae.
Scanning electron microscopy shows hyphae and endospores
(Figure 10). In atypical colonies, molecular DNA testing is
needed for diagnosis and species identification.18,19
Serology
Exoantigens had been used for evaluation of the activity
of the disease and its response to treatment. Antibodies
Fig. 10 Scanning electron microscopy of hyphae (left) and spherules (right) of Coccidioides immitis (courtesy of Dr Hillel Levine).
O. Welsh et al.
against C immitis antigens are demonstrated by immunodif-
fusion that forms precipitin lines of identity with reference
antisera. This method has been replaced by AccuProbe
assays. This nucleic acid hybridization test uses a single-
stranded DNA probe with a chemiluminescent label that is
complementary to the ribosomal RNA of the target
organism. After the ribosomal RNA is released, the labeled
DNA probe combines with the target ribosomal RNA to
form a stable DNA–RNA hybrid. The labeled DNA–RNA
hybrids are measured in a Gen-Probe luminometer. A
positive result is considered if the luminometer reading is
equal to or greater than the cutoff. A negative result is
considered when the value is below this limit.20 This test
helps to differentiate other fungi that can be confused
with C immitis.
When the fungus is atypical, experimental inoculation in
laboratory animals is needed. The interval for this process is
approximately 3 weeks, and the spherules of the parasitic
stage of the fungus can be identified in the animal tissue.
Other methods used are molecular biologic techniques. DNA
from C posadasii was identified by conventional nested
polymerase chain reaction (PCR) in 120 clinical strains
isolated from 114 patients within a 10-year period in
Monterrey, Nuevo León, Mexico.19 The sequence was
identified by a conventional nested PCR and a real-time
PCR assay targeting the gene encoding the 2/proline-rich
antigen (Ag2/PRA), which specifically identified all 120
strains as C posadasii. The Ag2/PRA gene is conserved
among non-Californian strains, now called C posadasii
(Table 2).15 This PCR test was used for selecting the gene
sequence of this strain; however, it was not useful as a direct
diagnostic procedure because of cross-reaction with other
dimorphic fungi.
A real-time PCR technique has been reported for direct
detection of C posadasii DNA in sputum samples of the
highly specific Ag2/PRA antigen gene.18 These researchers
stated that detection of the Ag2/PRA sequence in sputum was
an excellent method for the rapid and specific diagnosis of
coccidioidomycosis. The real value of this procedure will
require more studies in different settings with more patients
for evaluating its sensitivity and specificity.18
Coccidioidomycosis
Other methods, such as proteomic techniques, are used
for the study of fungus proteins, which are essential to
evaluate their antigenic activity and development. The
information obtained can be useful for designing new
therapeutic targets that could inhibit fungus reproduction
and facilitate its destruction.21
Immune detection of coccidiomycosis
Cellular and antibody analysis
Exposure to this fungus can be detected for clinical and
epidemiologic purposes with the coccidioidin or spherulin
skin tests. In the former, antigens are prepared from
arthroconidia proteins; in the latter, the antigen is obtained
from proteins of the parasitic stage of the fungus. A positive
cutaneous intradermal (CID) reaction indicates the individual
has been exposed to a subclinical infection or active disease.
In cases of immunosuppression, an anergic response is
observed. This usually occurs in individuals who receive
systemic corticoids or chemotherapy, or in individuals after
organ transplant or with AIDS. The CID reaction is
considered positive when the erythema and induration
exceed 0.5 cm. In Mexico, the antigen available in
laboratories is coccidioidin. Coccidioidin and spherulin are
no longer available in the United States.22
Coccidioidin was prepared using tuberculin as a
model. The antigen was obtained from mycelia grown
in a liquid media for 8 weeks. Thimerosal was added to
maintain the filtrate free of bacterial contamination. The
antigen, which contains some proteins and is rich in
polysaccharides, was heat-stable. The ability of coccidioidin
to induce late-type hypersensitivity is lost when the protein
content is destroyed.
Coccidioidin was used in airmen working in the San
Joaquin Valley during the 1940s. Those with a positive skin
test or those whose tests converted to positive were asked to
answer a questionnaire. The data from the 1,351 participants
showed that 60% did not recall having any symptoms.23 In
coccidioidomycosis only 40% of infected individuals
develop some flulike symptoms. From this group, 5% also
have erythema nodosum or erythema multiforme, and less
than 1% develop extrathoracic dissemination.24
A positive CID reaction reveals activation of cellular
immunity against C immitis/posadasii antigens. This immu-
nity is long-lasting but can disappear in cases of reinfection
due to severe immune cellular depression, as reported in
patients receiving chemotherapy,25 anti–tumor necrosis
factor-α treatment,26 and untreated patients with AIDS.27
Serologic tests
Serologic studies in coccidioidomycosis detection tradi-
tionally include, in the early stage, immunoglobulin (Ig) M
579
tube precipitin antibodies. This test detects antibodies
between the first and third week of onset. IgG antibodies
against the fungus can be detected with the complement
fixation (CF) test between weeks 2 and 28. Their levels can
remain detectable for several months and are usually related
to infection activity and response to treatment.
Serologic studies have been recognized as being less
sensitive in self-limited clinical cases and in immunocom-
promised patients. Therefore, a negative serologic result
cannot rule out the diagnosis, especially in the early period
of infection.
Three laboratory techniques are available for detecting
serologic response: enzyme immunoassays, immunodiffu-
sion, and CF. The first detects IgM and IgG antibodies.
Immunodiffusion is useful in sera that have anticomple-
mentary activity. Traditionally, the CID reaction and CF
have been used as the most common immunologic tests
for epidemiologic diagnosis and therapeutic prognosis.
The CF and immunodiffusion titers generally decrease as
the disease improves.
Pathophysiology
Infection is transmitted by inhalation of arthroconidia.
Transmission by direct inoculation is rare, and person-to-
person transfer is almost nonexistent; when it happens, it is
usually through fomites in which the fungus has transformed
into the arthroconidia saprophytic stage.
As a dimorphic fungus, C immitis changes in tissue to
endosporulating spherules that are easily recognized with
hematoxylin and eosin, periodic acid-Schiff, and Gomori-
Grocott stains. These spherules grow and mature with time.
Their wall eventually breaks, and many small spherules are
released that reinitiate this cycle in vivo.
Pathology
The lungs are the most affected area, but infection can
spread and involve other organs. Among these are lymph
nodes, the skin, the spleen, the liver and kidneys, bone,
joints, the meninges, and the central nervous system. Tissue
reacts with different histologic patterns that are characterized
by a coccidioidal granuloma. The presence of necrosis with
abundant polymorphonuclear leukocytes and eosinophils is a
common feature in abscesses, but they can also be present in
other clinical forms. Lymphocytes, epithelioid cells, multi-
nucleated giant cells, areas of necrotic tissue, and fibrosis are
also seen.
A common finding is the presence of double-walled
spherules with endospores varying in size from 10 to
80 μm. The spherules are sometimes abundant and at
other times scanty. They can be detected with hematox-
ylin and eosin (Figure 11), and special stains, such as
580
Fig. 11 Granulomas show large spherules and a giant cell containing small spherules (hematoxylin and eosin stain; original magnification ×400).
periodic acid-Schiff, Gridley, and particularly, Grocott-
Gomori and methenamine-silver (Figure 12). The latter two
are used in doubtful cases or when the spherules are scarce.
These reveal the spherules in black in a green background.
When the spherules are young and small, the differential
diagnosis with other fungal organisms, such as C neofor-
mans and Blastomyces dermatitides must be made, and when
the spherules are very large with rhinosporidiosis. Real-time
PCR can be used for identification of the fungus and is
sensitive and useful for genetic and epidemiologic studies.28
Coccidioides immitis and C posadasii have several
antigens that can induce a cellular immune response. A
preparation made by the lysate of spherules stimulated
peritoneal mast cells formation in immune but not in
nonimmune donors.29
Another study detected that T27K, a coccidioidal
antigen made by mechanical disruption of spherules, was
Fig. 12 Spherule with a broken outer wall releasing endospores
(Grocott stain, original magnification ×400).
O. Welsh et al.
able to induce production of interferon-γ and interleukin
(IL)-2 by peripheral blood mononuclear cells (PBMCs) in
coccidioidal immune individuals but not in nonimmune
individuals. T27K is highly glycosylated, and among its
contents, has elevated amounts of mannose, glucose, and
galactose, and also discrete antigens such as Ag2/PRA and
aspartyl protease. The recombinant proteins of these
antigens have been used as vaccines in experimentally
induced coccidioides infections in mice, achieving protec-
tion from infection.
Besides activation of the proinflammatory cytokines of
the host in fungal infections, other adaptive host defense
mechanisms are triggered through a set of ligands called
pattern recognition receptors that are located in dendritic
cells. These pattern recognition receptors molecules are
C-lectin–type receptors with the characteristic of identifying
carbohydrate structures and are calcium-dependent.30
Mannose-binding lectin is a soluble molecule that
increases the risk of diverse infections when present in low
levels. Low levels of mannose-binding lectin were seen in
patients with active and disseminated coccidioidomycosis.31
Other molecules involved in innate defense mecha-
nisms are the Toll-like receptors (TLRs). Up to now, 13
of these have been identified. The TLRs recognize a
broad series of ligands; for example, the first described
ligand for TLR4 is a lipopolysaccharide. An experimental
analysis of the response of PBMCs to the coccidioidal
antigen T27K after blockage of the activity of TLR2 and
TLR4 in immune individuals resulted in a significant
reduction of tumor necrosis factor-α concentration. These
results appear to support the thesis that TLR2 and TLR4
are involved in an in vitro cellular immune response in
human coccidioidomycosis.
The role of dendritic cells in patients with coccidioido-
mycosis has not been completely elucidated. Dendritic cells
from patients with disseminated coccidioidomycosis main-
tain the ability to react to coccidioidal antigens (T27K) and
Coccidioidomycosis
induce lymphocyte transformations in vitro. The explanation
of the involvement of these cells remains unsolved.31,32
Classification and clinical picture
Coccidioidomycosis is divided into three categories:
primary pulmonary infection, chronic pulmonary infection,
and disseminated disease. About 60% of infected individuals
with C immitis are asymptomatic. In symptomatic coccid-
ioidomycosis (40% of infected patients), flulike syndrome
with mild to moderate cough, myalgias, and fatigue are
frequent. Most patients recover in 2 to 3 weeks. Because the
most frequent port of entry is the lungs, a spectrum of
pulmonary manifestations can appear in severe infections,
such as miliary lesions, pneumonia, hilar adenopathy, and
pleural effusion. Some of these lesions become chronic
and progressive.
Bacterial, viral, and other fungal infections are considered
in the differential diagnosis in this location. When lung
cavities or solitary nodules appear, tuberculosis infection and
lung cancer should be included in the front line of the
differential diagnosis. When the respiratory tract is involved,
direct examination and culture for fungi in sputum,
bronchoalveolar lavage, or tissue specimens are needed
for identification and isolation of C immitis or C posadasii.
In patients with chronic progressive pneumonia (lasting
more than 3 months), symptoms, such as cough, hemoptysis,
and weight loss, persist. The presence of unifocal or
multifocal consolidations is common on chest x-ray images
and tomography.33
Disseminated coccidiomycosis is a rare clinical entity.
Immunosuppression can be caused by different factors,
including administration of immunosuppressive drugs,
organ transplants, cancer, chemotherapy, glucocorticoid
administration, and AIDS. These factors increase the
Fig. 13 Thin-walled cavity with a regular shape in the left upper
lobe. This image is characteristic of coccidioidomycosis. Several
small nodules are observed surrounding the cavity.
581
Fig. 14 Thick-walled cavity with an irregular shape in the left
upper lobe. Fibrotic lines are observed heading to an enlarged hilum.
possibility of acquiring severe forms of infection. As
mentioned in the Pathology section, the fungus can spread
to different organs, of which meningeal and brain involve-
ment are the most life-threatening.
Pulmonary coccidioidomycosis
This is the most frequent site of entry for this infection.
Acute lesions involve the lung parenchyma with pneumonial
foci. Endoscopy can detect inflammation and granulomatous
tissue. The most frequent findings on x-ray images are
infiltrates with a lobar distribution that are hazy and
homogenous; hilar adenopathies are often present. Pleural
effusion with fever and chest pain can appear. In some cases,
miliary lesions are detected in both lungs. The pneumonia
sites can become chronic, and the formation of cavities can be
seen; fever, cough, and hemoptysis are symptoms that can be
present in lung involvement. Solitary pulmonary nodules can
be observed in immunocompetent patients (Figures 13-18).
Fig. 15 Very irregularly shaped cavity with a thin wall located in
the right upper lobe. Several small nodules and interstitial infiltrates
are observed around the cavity.
582 O. Welsh et al.

Fig. 16 Nodulelike consolidation in the right upper lobe Fig. 18 Loculated right pneumothorax. There is severe pleural
above the hilum. An interstitial infiltrate is observed in the thickening and lung entrapment.
neighboring segments.
lesions reveal coccidial granulomas containing typical
These often disappear with time. The differential diagnosis spherules of the fungus (see Pathology section).
should include other systemic mycosis, tuberculosis, and The spectrum of skin manifestations can be present as
lung cancer.34 lesions of erythema nodosum and erythema multiforme,
and rarely, Sweet syndrome. Erythema nodosum generally
Cutaneous coccidioidomycosis appears in the first month after infection. Biopsy
specimens show a septal granulomatous panniculitis;
When the disease spreads out of the lungs, the skin is one coccidioidin and spherulin CID are positive in these
of the most affected organs. The first patient Posadas saw
presented because of a cutaneous lesion on his cheek that
spread in the following years to different organs, causing his
death. The clinical spectrum of the cutaneous lesions varies
from papules, nodules, gummas, acneiform pustular lesions,
ulcerated and verrucous plaques, scarlike lesions, abscesses,
which should be debrided (Figures 19-24), and fistulae. The
differential diagnosis includes histoplasmosis, blastomyco-
sis, tuberculosis, chromoblastomycosis, sporotrichosis, my-
cetoma, nocardiosis, other bacterial and viral infections, and
cancer. When lymph nodes are involved, the possibility of
lymphoma should be ruled out. Biopsy specimens of the

Fig. 17 Nodule with cavitation in the right upper lobe. This

lesion could have started as in Figure 4 and progressed to any of Fig. 19 Patient with coccidioidomycosis seen in Monterrey,
those pictured in Figures 1, 2, or 3. Mexico that resembles Posadas' patient.
Coccidioidomycosis 583

Fig. 20 Ulcerated nodule of coccidioidomycosis.

Fig. 22 Sporotrichoid plaque and nodules of coccidioidomycosis.

patients. This cutaneous manifestation is usually associated

with a better disease outcome.35 cosis and the treatment of Sweet syndrome is based on
Different authors have associated erythema multiforme systemic steroids, exclusion of C immitis infection before
with C immitis infection, but whether C immitis is truly starting treatment is necessary.37
erythema multiforme or resembles erythema multiforme is
debatable. A generalized exanthema can be present in the Primary chancriform cutaneous coccidioidomycosis
first days of symptoms. The lesions can be papular, macular,
urticarial, target-type, or morbilliform. The dermatosis can This is a very rare clinical form of primary cutaneous
last for several weeks, and the lesions in some patients are coccidioidomycosis caused by direct inoculation through
accompanied by moderate to severe pruritus. The biopsy
specimen shows a reactional dermatitis with spongiosis and
mixed inflammatory cells (neutrophils, eosinophils, and
lymphocytes) with perivascular distribution that can mislead
the clinician on the diagnosis.36,37
Sweet syndrome, also known as acute febrile neutro-
philic dermatosis, is characterized by fever and painful
vesicular, pustular lesions that appear mainly on the arms,
face, and neck. Seven cases have been reported associated
with coccidioidal pulmonary infection. Clinicians should
eliminate the possibility of coccidioidomycosis in patients
who live in or have been in endemic zones where C immitis
or C posadasii is present. Because systemic corticoid
administration could aggravate nontreated coccidioidomy-

Fig. 21 Ulcerated scarlike lesion of coccidioidomycosis. Fig. 23 Abscess caused by coccidioidomycosis infection.
584
Fig. 24 Verrucose lesion and edema caused by coccidioides.
the skin by an external source containing the infectious
arthroconidia of C immitis/posadasii. The rarity of reports
is due to the difficult substantiation of the history of a skin
abrasion after trauma (simple bumps or bruises may
represent a site of less resistance for a disseminated
lesion). Other facts required to identify this form of
infection are a shorter incubation period (1 month or less),
the subsequent development of a relatively painless
indurated nodule, or nodular plaque with ulceration
(chancroid-lesion), a doubtful positive CID reaction, a
negative CF test (that later may become weakly positive),
lymphangitis, and sporotrichoid lymphadenopathy.
In the mid-1980s, we had the opportunity of seeing the 9-
year-old son of a physician. The boy had accidentally
abraded the dorsum of his foot with a log, and a chancriform
lesion, 2.5 to 3 cm in diameter, developed 10 days later,
accompanied by inguinal lymph node enlargement. The
patient did not develop fever. He was treated with antibiotics
for a bacterial infection, and a culture was taken to discard
the possibility of sporotrichosis.
We were surprised when the laboratory chemist reported
that a mycology culture grew a colony of C immitis. We
reviewed the microculture, finding typical C immitis
arthroconidia hyphae. A biopsy specimen showed typical
fungal spherules. Results of x-ray imaging, laboratory
examination, and cellular and humoral-immunity studies
O. Welsh et al.
were all reported within normal limits. The CID (1:100)
was negative.
The patient was prescribed ketoconazole (200 mg daily),
which he took for approximately 6 months with no adverse
effects. Precipitins and CF were and remained negative. He is
currently a 28-year-old healthy individual, and his CID has
remained negative. After seeing a fair number of coccidioi-
domycosis patients in the last 42 years, this is the only patient
we can claim presented with a primary chancriform
cutaneous coccidioidomycosis (unpublished data).
Bones and joints
Infection of bones, joints, and tendons is also a frequent
manifestation of disseminated coccidioidomycosis. This can
adopt the form of osteomyelitis affecting several bones. The
spine is commonly affected (thoracic and lumbar regions).
Other common sites include the tibia, the skull, metatarsals,
metacarpals, the femur, and ribs. Bone lesions of the vertebrae
and skull can extend to the central nervous system, causing
meningitis. Computed tomography scans can show lytic bone
lesions, and occasionally, cysts. Soft tissue abscesses are
initially accompanied by the classic signs of inflammation,
which can later become cold abscesses and form fistulae. The
differential diagnosis in this clinical form includes osteomy-
elitis caused by different bacteria and tuberculosis or other
fungal infections, multiple myeloma, sarcoidosis, histiocyto-
sis, and metastatic carcinoma.38-40 Tuberculosis and coccid-
ioidomycosis can coexist. The diagnosis of the fungal
infection is made by identification of spherules by direct
examination, culture, and biopsy.
Central nervous system and ocular coccidioidomycosis
Approximately 200 to 300 individuals with coccidioidal
meningitis have been reported annually in endemic areas in
the United States. The main clinical manifestations are those
of basilar meningitis. Symptoms include headache, fever,
meningeal irritation (in 50% of the cases), cognitive
impairment and personality changes, nausea and vomiting,
and general malaise. Seizures and an altered mental state can
be present. Tumorlike lesions, abscesses, and aneurysms
infrequently occur. Subarachnoid hemorrhage usually has a
fatal outcome. Differential diagnoses must include benign
and malignant tumors, parasitic diseases, and viral, bacterial,
and other fungal infections.41,42
If cerebrospinal fluid culture is positive, the diagnosis is
certain; however, it can be negative and cerebrospinal fluid
serology identifying IgM precipitins or IgG antibodies can
help to establish the diagnosis. White blood cell count and
protein elevation also contribute to the diagnosis. If
cerebrospinal fluid pressure exceeds 200 mm H2O, the
possibility of hydrocephalus must be considered. If cocci-
dioidal meningitis remains untreated, the patient can die
within 2 years.
Coccidioidomycosis
Opthalmic involvement is very infrequent. The only
patient we have seen in Monterrey was a 40-year-old woman
with a history of an erythematous plaque in the left
supraciliary region, with the diagnosis of coccidioidomyco-
sis made by biopsy. When we examined the patient, the skin
lesion had disappeared, but the eye examination detected a
whitish retinal streak in her left eye. The patient was treated
with itraconazole (400 mg) for 16 months, showing
improvement of the retinal lesion. After treatment was
discontinued, the disease returned, and amphotericin B had
to be administered (unreported case).43
Genitourinary involvement
Genitourinary coccidioidomycosis can affect patients
with severe disseminated disease. The localization and
severity of the infection will determine the symptoms.
Coccidiodouria culture isolation, and identification of the
fungus by biopsy specimen establish the diagnosis.44
Coccidioidomycosis in children
The infection is more frequent in infants than in adults. It
predominates among dark-skinned individuals. Most primary
coccidioidomycosis in children is controlled by the host
immune response and resolves without treatment.45 Only 1 in
every 500 infections will progress to a disseminated form, and
there are no differences in sex before puberty. In these cases,
survival is less frequent at age younger than 5 years. There are
three clinical presentations in children: primary coccidioido-
mycosis, primary coccidioidal granuloma, and disseminated
disease. All three can lead to a chronic or systemic illness.
Although several authors have stated that infection is milder
in children than in adults, children with disseminated disease
and bone and meningeal involvement have a high mortality
rate. The diagnosis of coccidioidomycosis may be difficult to
achieve in young children.46
Pregnancy
Coccidioidomycosis in pregnancy has a wide range of
clinical manifestations that can vary from mild symptoms
resembling influenza (90%) to disseminated disease (10%).
Pregnant patients with disseminated disease can present
central nervous system manifestations and skin involve-
ment. When erythema nodosum appears, the prognosis is
relatively benign. Most patients present with clinical
manifestations that include pulmonary signs and symp-
toms, as previously described. The mortality rate increases
when the diagnosis is delayed (third trimester). Because
azoles are contraindicated in pregnancy, amphotericin B is
the drug of choice, especially in the early stages of
pregnancy. This antifungal has been used in pregnant
patients for 50 years without significant adverse effects to
the mother or fetus. Caspofungin is a category C drug in
585
pregnancy and can only be used if the potential benefit
justifies the potential risk to the fetus.47
Differential diagnosis
We have included the differential diagnosis of this
infection under each clinical form. We want to emphasize
that in our state (Nuevo León), which is part of the
northeastern endemic zone of Mexico for coccidioidomyco-
sis, each time we think of coccidioidomycosis, our first
differential diagnosis is tuberculosis and vice versa. Other
fungal (histoplasmosis, South American blastomycosis),
viral, and bacterial infections, such as tularemia, actinomy-
cetoma, pyogenic bacterial infections, viral warts, and
cancer, are often considered in the differential diagnosis.
Vaccines
Vaccines for coccidioidomycosis are needed for patients
who could be at risk for acquiring the disease by living in
endemic zones, particularly transplant recipients, pregnant
women, and individuals receiving chemotherapy or immu-
nosuppressive doses of corticosteroids. Coccidioides is a
highly immunogenic organism that induces a good immu-
nologic response in most individuals. That 60% of infected
individuals did not notice any symptoms of infection and all
had a positive CID reaction (also present in most individuals
with clinical disease) is indicative of a good native and
specific cellular immune response. Coccidioidal antigens
with a proven antigenic response in vitro have been
successfully used in protecting against lethal inoculation of
the fungus in experimental animals. Up to now, a successful
vaccine for use in humans remains elusive.48-50
Prevention
Public health measures that can be used to lower the
incidence of coccidioidomycosis are detection of endemic
zones with a higher incidence and increased awareness
among health professionals. Modification of the habitat
where the fungus grows can be achieved by advising
construction companies to reduce dust by wetting the soil
before digging and by paving roads. Planting trees and lawns
around residences and industrial plants can reduce the rate of
infection by about half.51,52
Treatment and brief description of current
antifungal therapy
The first effective treatment for coccidioidomycosis was
amphotericin B, reported in 1959.53 This drug is a polyene
586
isolated from Streptomyces nodosus, a strain obtained from
the soil on the riversides of the Orinoco River in
Venezuela.54 The amphotericin molecule has a hydrophilic
and a hydrophobic region; therefore, it has very little
solubility in aqueous solutions and for this reason addition
of another agent (deoxycholate containing sodium phos-
phate as buffers) is required for clinical administration. The
addition of amphotericin B to a solution containing salt
will cause precipitation of the drug. Prepared amphotericin
B is compatible with dextrose solutions for intravenous
(IV) and intrathecal administration and with sterile water
for local application. Its mechanism of action is due to
binding of the hydrophobic moiety to the spherule's cell
membrane ergosterol moiety, producing cell membrane
damage leading to fungal cell death. Amphotericin B also
binds to the cholesterol of mammalian cell membranes,
which causes some of its toxic potential.55 The differential
rate binding of ergosterol (much higher) and of cholesterol
allows its therapeutic use in patients. This antifungal agent
promotes inflammatory cytokine release by TLR and
CD14-dependent mechanisms.56
Amphotericin B deoxycholate can be given in an IV
dose range of 0.3 to 1.5 mg/kg (average of approximately
1 mg/kg). It is often associated with fever, chills, headache,
nausea, vomiting, hypotension, and bronchospasm. These
symptoms can be reduced with the administration of
diphenhydramine, acetaminophen, and meperidine. Potas-
sium and magnesium levels should be evaluated periodi-
cally to detect low levels of these electrolytes. The main
adverse effect of amphotericin B is renal toxicity; therefore,
renal function should be closely monitored. A basal and
follow-up electrocardiogram is indicated for detection of
cardiac abnormalities.
Other compounds containing amphotericin B are ampho-
tericin B colloidal dispersion, amphotericin B lipid complex,
and amphotericin B liposomal. These lipid formulations have
less renal toxicity than amphotericin B deoxycholate,
without changes in their therapeutic efficacy.57-59 Doses
fluctuate between 2 and 5 mg/kg (or more) daily,
administered IV.60 In developing countries, a limiting factor
for indicating these amphotericin B compounds is their price
and availability.
Daily doses are indicated for severe forms of coccidioi-
domycosis; in mild forms, the regimen can be three times per
week. The duration of treatment with amphotericin B
deoxycholate or lipid medications of amphotericin B is
similar, lasting about 1 to 4 months.
Current treatment of coccidioidomycosis with amphoter-
icin B is indicated for severely affected individuals, pregnant
women, in patients in whom azoles cannot be administrated,
in osteoarticular involvement, mainly in patients with rapid
progression, and particularly, in patients in whom treatment
with azoles is unable to solve the infection.
Many patients with coccidioidomycosis develop mild
symptoms that resolve spontaneously in 2 to 4 months.
When infection persists, progresses, or disseminates in
O. Welsh et al.
individuals with immunosuppression (AIDS, chemotherapy,
high-dose steroids, anti–tumor necrosis factor-α), treatment
is always indicated.
Azoles have been the milestones for oral treatment of
coccidioidomycosis. Clinical trials started at the end of the
1970s and the beginning of the 1980s. These fungistatic drugs
exert their therapeutic action by binding to fungal cytochrome
P-450 isozymes (lanosterol 14-alpha-demethylase), causing
inhibition of ergosterol synthesis that alters membrane-bound
enzyme function and fungal membrane permeability and
causes blunted cell growth and cell death.
The first studies with miconazole showed an in vitro
inhibitory concentration of C immitis. A limiting factor was
that the drug had to be given IV for a long time, and clinical
relapse was often seen.61
The first azole used for oral treatment of coccidioidomy-
cosis was ketoconazole. We performed one of the first trials
with this antifungal. The drug was given orally, once daily
after meals, avoiding milk and antacids. The dose fluctuated
between 200 and 400 mg daily. In 7 of 11 patients included,
we observed clinical improvement. The general symptoms
disappeared, and there was clinical amelioration of lesions
during treatment. The best results were found in patients
with a chronic pulmonary lesion. Another study stated
that ketoconazole seemed to suppress but not eradicate
C immitis. 62-64 Itraconazole and fluconazole have
become the main drugs for treatment of uncomplicated
primary and disseminated coccidioidomycosis.65
Fluconazole is a bis-triazole antifungal drug with
metabolic stability and relatively high water solubility,
which contribute to its therapeutic activity. Its relatively
high polarity results in low protein binding and uniform
tissue distribution. Its penetration to cerebrospinal fluid is
approximately 80% of serum levels, which offers a good
therapeutic option in fungal meningitis. Accessibility of oral
and IV formulations permits, depending on the patient's
condition, the administration of either formulation. Absolute
bioavailability facilitates administration of fluconazole and
results in predictable tissue levels. Fluconazole has been one
of the most commonly administered antifungals for treatment
of coccidioidomycosis. In a study of 75 patients who
received 200 to 400 mg of fluconazole daily, a satisfactory
response was observed in 12 of 14 patients (86%) with
skeletal involvement, in 22 of 40 patients (55%) with chronic
pulmonary disease, and in 16 of 21 patients (76%) with soft
tissue involvement. Treatment was modified in five patients
(7%) because of adverse effects. Forty-one patients who
responded were monitored off drug, and 15 (37%)
experienced reactivation of the infection.66
Itraconazole is a common triazole used for treatment of
coccidioidomycosis. It is more effective and has fewer side
effects than ketoconazole. Itraconazole seems to have a
better effect in skin, subcutaneous tissue, and skeletal
lesions. Its bioavailability after oral solution administration
during fasting conditions is 60% greater compared with
capsules taken after meals. Hydroxyitraconazole is an active
Coccidioidomycosis
antifungal metabolite of this drug that accumulates at twice
the rate of the parent drug, increasing the absolute
bioavailability of itraconazole to at least 80%.67
There is a long list of drugs that interact with azoles,
which can affect the concentration of the administered
antifungal or of the drugs. This list increases with time;
therefore, it is essential for clinicians to consult up-to-date
sources. A representative list of these drugs includes
rifampin, statins, warfarin, digoxin, H+ blockers, and
cyclosporine A. The most commonly described adverse
effects include gastrointestinal disturbances, dizziness, and
headache. Liver toxicity has been rarely described. Blood
pressure should be monitored periodically.65
Itraconazole (400 mg daily) is frequently administered for
coccidioidomycosis; however, higher doses have been used
without complications. Total duration of therapy with
fluconazole or itraconazole is variable and will depend on
the location, extension, severity of the disease, and the
patient's comorbidities that induce immunosuppression. In
limited and uncomplicated cases, 4 to 6 weeks of treatment,
after active infection has resolved, can achieve cure of the
disease. Therapy for extrapulmonary disease may be
extended, depending on clinical and paraclinical results.
Treatment lasts 6 months to 1 year after the disease has
become inactive. In some patients, this may be lengthened
to years.14
For the purpose of defining whether fluconazole or
itraconazole is superior for treatment of nonmeningeal
progressive coccidioidal infections, a multicenter, random-
ized, double-blind, placebo-controlled trial was conducted in
centers in California, Arizona, and Texas. Included were 198
patients with chronic pulmonary, soft tissue, or skeletal
coccidioidal infections. The antifungal doses given were
fluconazole (400 mg once daily) or itraconazole (200 mg
twice daily). A predefined scoring system was used at 4, 8,
and 12 months to assess changes in severity of infection.
The findings were compared with baseline data, and 50%
of patients (47 of 94) in the fluconazole group and 63%
(61 of 97) in the itraconazole group responded to 8 months
of treatment (P=.08). Patients with skeletal infections
responded twice as frequently to itraconazole as to
fluconazole. By 12 months, 57% of patients had responded
to fluconazole and 72% had responded to itraconazole
(P=.05). An increased likelihood of response was associated
with soft tissue involvement. Serum drug concentrations for
both azoles were not helpful in predicting therapeutic
outcome. Neither group showed a difference in relapse rate
after stopping antifungals (28% after fluconazole treatment
and 18% after itraconazole treatment). Both drugs were well
tolerated. The authors concluded that neither fluconazole
nor itraconazole showed statistically superior efficacy in
nonmeningeal coccidioidomycosis, although there was a
slight trend toward greater efficacy with itraconazole at the
doses studied.68
The infection caused by Coccidioides spp has an ample
variety of clinical presentations, ranging from a mild
587
respiratory illness, which can spontaneously resolve, to
progressive pulmonary involvement with dissemination to
other organs, including the central nervous system, which
could require life-long treatment,69 as well as in some
chronically immunosuppressed patients, such as those with
AIDS or after organ transplantation. Treatment strategies can
vary depending on the background and clinical picture of
each patient. Immunocompetent individuals with early
infections and minimal pulmonary lesions often resolve
without antifungal treatment. Patients should be monitored to
detect recurrence, progression to chronic stages, and
development of extrapulmonary disease.
The antifungal drugs currently indicated for chronic and
extrapulmonary disease include amphotericin B deoxycolate,
lipid formulations of amphotericin B, fluconazole, and
itraconazole. Recommendations for treatment are reviewed
in depth in the Infectious Diseases Society of America
guidelines14 and more recently in the American Thoracic
Society statement70 (see treatment algorithm, Figure 25).
Posaconazole and voriconazole are the latest commer-
cially available triazoles for treatment of coccidiodomyosis.
Posaconazole (Noxafil, Schering Corporation, Kenilworth,
NJ) was approved by the Food and Drug Administration for
use as prophylaxis against invasive Aspergillus and Candida
infections in immunocompromised patients. This triazole is
structurally similar to itraconazole and has a wide spectrum
of activity against human fungal infection and emerging
fungi that require systemic treatment.71
Unlike newer azoles, posaconazole is not extensively
metabolized by cytochrome P450 enzymes and is primarily
excreted as a parent compound in the feces. Posaconazole is
a cytochrome P3A4 inhibitor but does not inhibit the activity
of other cytochrome P enzymes. Posaconazole therefore
have may have potentially fewer drug interactions compared
with other azoles.72,73
In a report of posaconazole treatment (800 mg daily in
divided doses given for 1 to 2 years) in six patients with
chronic coccidioidomycosis unresponsive to previous
treatments, success was reported in five of six patients.
Two patients continued treatment after the trial was
ended.74 Efficacy of posaconazole was 85% in patients
with chronic pulmonary or nonmeningeal disseminated
coccidioidomycosis.75 Another multicenter clinical trial
evaluated the therapeutic effect of posaconazole treatment
for chronic refractory coccidioidomycosis in 15 patients, 7
with pulmonary disease, and 8 with a disseminated form.
The response to treatment was prompt in most patients (1 to
3 months), with a final overall response of 73%. The
authors suggest that this antifungal can be used for treating
patients with coccidioidomycosis when standard therapy is
not successful.76
The dose of posaconazole prescribed for coccidioido-
mycosis has been 400 mg twice daily in the form of an
oral suspension (40 mg/mL). Administration with meals
ensures maximal absorption levels of the antifungal.77
Coadministration of an antacid with posaconazole had no
588
††
Fig. 25 Treatment algorithm for coccidioidomycosis. DM, diabetes mellitus; TNF, tumor necrosis factor.
significant effects on its bioavailability under fasting or
nonfasting conditions.78
The most commonly reported adverse events with this
triazole were fever, diarrhea, nausea, vomiting, and head-
ache. Other less frequent manifestations included hypokale-
mia, rash, thrombocytopenia, and abdominal pain. Elevated
liver enzyme levels, hyperbilirubinemia, and hepatocellular
damage have been reported. These enzyme elevations were
generally mild and resolved upon discontinuation of therapy.
Liver function tests should be monitored at baseline and
throughout posaconazole therapy. Treatment should be
discontinued if serious hepatic abnormalities occur. Posaco-
nazole administration is contraindicated if the patient is
taking terfenadine, astemizole, pimozide, cisapride, quini-
dine, or ergot alkaloids due to potential QT prolongation.
When other drugs are concomitantly administered, the
clinician must consult the latest list of drug interactions of
this triazole.
Voriconazole (Vfend), a second-generation triazole, is
fungistatic against yeasts and fungicidal against susceptible
filamentous molds. It is a synthetic derivant of fluconazole
that exerts improved antifungal action that include some
O. Welsh et al.
•
•
•
•
•
fungi that are resistant to fluconazole. It is formulated for
oral (oral suspension and 50- and 200-mg tablets) and IV
administration. The dose varies from 3 to 4 mg/kg IV or
200 to 300 mg orally daily. Drug interactions are the same
as with other triazoles. When administered 1 hour before or
1 hour after a meal, the bioavailability of the oral
formulation exceeds 90%. Gastric acid is not needed for
absorption; fatty foods decrease bioavailability to less than
80%. In adults, after oral administration of 200 mg twice
daily, steady-state plasma concentrations of 2 to 3 mg/mL
are obtained. Adverse effects such as gastrointestinal
disturbances, rash and photosensitivity, transient visual
disturbances (nonsight threatening), as well as hepatitis,
have been reported.79,80
In coccidioidomycosis (coccidioidal meningitis), there
have been isolated reports of successful treatment with
voriconazole. Up to now, there is no further informa-
tion about clinical trials evaluating its efficacy for this
fungal infection.81-83
Caspofungin belongs to a recently developed class of
antifungal agents, the echinocandins, which targets the fungal
cell wall itself via interruption of b-1,3 glucan synthesis.84
Coccidioidomycosis
There is a report of a patient with meningeal coccidioi-
domycosis who was treated with caspofungin, 70 mg IV and
50 mg daily thereafter for 22 days, without changes in the
clinical course. Afterward, fluconazole and amphotericin B
were restarted, with no therapeutic response, and ending in a
fatal outcome.85 Another patient, who had received a renal
allograft from a cadaver, developed flulike symptoms and
multiple nodules that were detected by chest x-ray imaging.
Bronchoscopy and analysis of a nodular lesion specimen
substantiated the diagnosis of coccidioidomycosis. He was
initially treated with fluconazole for 3 days, but after
detection of an increase in creatinine levels (3.2 mg/dL),
the treatment was changed to amphotericin B liposomal
given for 7 days, which caused a further increase in
creatinine levels (4.2 mg/dL). Thereafter, treatment was
changed to caspofungin (50 mg/d IV) for 4 weeks. General
symptoms and renal and liver function tests improved.
Maintenance with fluconazole (200 mg daily) was then given
for 6 months.86
Combination therapy with caspofungin (initially 70 mg
and then 50 mg daily IV) and oral fluconazole (400 mg daily)
was reported to be successful in the treatment of a patient
with pulmonary and cutaneous coccidioidomycosis.87 Fur-
ther evaluation of the therapeutic efficacy of caspofungin is
needed for defining the usefulness of this drug in the
treatment of coccidioidomycosis.
Conclusions
Coccidioidomycosis remains a challenging disease in its
diagnosis and treatment. We have to keep in mind the
possibility of this diagnosis in patients with the signs and
symptoms described in this contribution. Despite treatment
guidelines, therapy should be customized according to the
severity and dissemination of the infection as well as the
patient's comorbidities, immune status, and response to
initial treatment.
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