1526 TABLE 209-1 Treatment of Blastomycosisa ACKNOWLEDGMENT

The authors thank Drs. Stanley W. Chapman and Donna C. Sullivan,

DISEASE PRIMARY THERAPY
Immunocompetent Patient/Life-Threatening Disease
Pulmonary Lipid AmB, 3–5 mg/kg qd,
or
AmB deoxycholate,
0.7–1.0 mg/kg qd (total
dose: 1.5–2.5 g)
Disseminated
CNS Lipid AmB, 3–5 mg/kg qd,
or
AmB deoxycholate,
0.7–1.0 mg/kg qd (total
ALTERNATIVE THERAPY
Itraconazole, 200–400
mg/d (once patient’s
condition has stabilized)
Fluconazole, 800 mg/d (if
patient is intolerant to full
course of AmB)
Professors Emeriti, University of Mississippi, for their continued help and
support and for their contributions to this chapter in an earlier edition.
■ FURTHER READING
Richer SM et al: Development of a highly sensitive and specific blas-
tomycosis antibody enzyme immunoassay using Blastomyces dermati-
tidis surface protein BAD-1. Clin Vaccine Immunol 21:143, 2014.
Thompson GR 3rd: Isavuconazole treatment of cryptococcosis and
dimorphic mycoses. Clin Infect Dis 63:356, 2016.

Non-CNS
dose: at least 2 g)
Lipid AmB, 3–5 mg/kg qd,
or
AmB deoxycholate,
0.7–1.0 mg/kg qd (total
dose: 1.5–2.5 g)
Immunocompetent Patient/Non-Life-Threatening Disease
Pulmonary or Itraconazole, 200–400 mg/d,
disseminated
or
(non-CNS)
Lipid AmB, 3–5 mg/kg qd,
or
AmB deoxycholate, 0.5–0.7
mg/kg qd (in patients
intolerant to itraconazole or
whose disease progresses
PART 5
Itraconazole, 200–400
mg/d (once patient’s
condition has stabilized)
210 Cryptococcosis
Arturo Casadevall
■ DEFINITION AND ETIOLOGY
Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of
Fluconazole, 400–800
mg/d,
cryptococcosis. Until recently, cryptococcal strains were separated
into two species, Cryptococcus neoformans and Cryptococcus gattii, both
or
of which can cause cryptococcosis in humans. The two varieties of
Ketoconazole,
400–800 mg/d
C. neoformans—grubii and neoformans—correlate with serotypes A and
D, respectively. C. gattii, although not divided into varieties, also is
antigenically diverse, encompassing serotypes B and C. However,
genome sequencing studies have now revealed tremendous diversity
among isolates previously assigned to each species, suggesting that

despite therapy)
some may be reclassified as new species. Most clinical microbiology
Immunocompromised Patientb
laboratories do not routinely distinguish between C. neoformans and
All infections Lipid AmB, 3–5 mg/kg qd, Itraconazole, 200–400 C. gattii or among varieties, but rather identify and report all isolates
or mg/d (non-CNS disease,
once clinically improved)
simply as C. neoformans.
Infectious Diseases

AmB deoxycholate, 0.7–1.0

mg/kg qd (total dose:
1.5–2.5 g)
a
Therapy is generally given for 6–12 months. For bone and joint disease, a
12-month course is usually necessary. bSuppressive therapy with itraconazole
may be considered for patients whose immunocompromised state continues.
Fluconazole (800 mg/d) may be useful for patients who have CNS disease or
cannot tolerate itraconazole.
Abbreviations: AmB, amphotericin B; CNS, central nervous system.
Approval of delayed-release tablets and intravenous formulations
may enhance the role of posazonazole in salvage therapy.
In a recent study including only three patients, isavuconazole,
the most recent addition to the azole antifungal class, showed vari-
able clinical efficacy (i.e., a 33% success rate) in the management
of pulmonary and non-CNS disseminated blastomycosis. Its role
in the management of blastomycosis is uncertain at this time, but
its consideration may be warranted for salvage therapy in milder
pulmonary disease.
■ PROGNOSIS
Cure rates are 90–95% among compliant immunocompetent patients
given itraconazole for mild to moderate pulmonary and extrapulmo-
nary disease without CNS involvement. Bone and joint disease usually
requires 12 months of therapy. The fewer than 5% of infections that
relapse after an initial course of itraconazole usually respond well to a
second treatment course.
■ GLOBAL CONSIDERATIONS
Blastomyces remains a prominent cause of dimorphic fungal
infections worldwide. In the United States, changes in manda-
tory reporting requirements have probably blurred estimates
of the current incidence of blastomycosis. Diagnostic delays continue to
contribute to increased use of health care resources and administration
of unnecessary antibacterial courses and probably contribute to global
resistance as well.
■ EPIDEMIOLOGY
Cryptococcosis was first described in the 1890s but remained relatively
rare until the mid-twentieth century, when advances in diagnosis and
increases in the number of immunosuppressed individuals markedly
raised its reported prevalence. Although serologic evidence of cryp-
tococcal infection is common among immunocompetent individuals,
cryptococcal disease (cryptococcosis) is relatively rare in the absence
of impaired immunity. Individuals at high risk for disease due to
C. neoformans include patients with hematologic malignancies, recip-
ients of solid organ transplants who require ongoing immunosup-
pressive therapy, persons whose medical conditions necessitate
glucocorticoid therapy, and patients with advanced HIV infection and
CD4+ T lymphocyte counts of <200/μL. In contrast, C. gattii–related
disease is not associated with specific immune deficits and often occurs
in immunocompetent individuals.
Cryptococcal infection is acquired from the environment.
C. neoformans and C. gattii inhabit different ecologic niches. C.
neoformans is frequently found in soils contaminated with
avian excreta and can easily be recovered from shaded and humid soils
contaminated with pigeon droppings. In contrast, C. gattii is not found
in bird feces. Instead, it inhabits a variety of arboreal species, including
several types of eucalyptus tree. C. neoformans strains are found
throughout the world; however, var. grubii (serotype A) strains are far
more common than var. neoformans (serotype D) strains among both
clinical and environmental isolates. The geographic distribution of
C. gattii was thought to be largely limited to tropical regions until an
outbreak of cryptococcosis caused by a new serotype B strain began in
Vancouver in 1999. This outbreak has extended into the United States,
and C. gattii infections are being encountered increasingly in several
states in the Pacific Northwest.
The global burden of cryptococcosis was recently estimated at
~1 million cases, with >600,000 deaths annually. Thus cryptococci are
important human pathogens. Since the onset of the HIV pandemic in
the early 1980s, the overwhelming majority of cryptococcosis cases
have occurred in patients with AIDS (Chap. 197). To comprehend 1527
the impact of HIV infection on the epidemiology of cryptococcosis,
it is instructive to note that in the early 1990s there were >1000 cases
of cryptococcal meningitis each year in New York City—a figure far
exceeding that for all cases of bacterial meningitis. With the advent
of effective antiretroviral therapy, the incidence of AIDS-related cryp-
tococcosis has been sharply reduced among treated individuals.
Therefore, most cases of cryptococcosis now occur in resource-limited
regions of the world. The disease remains distressingly common in
regions where antiretroviral therapy is not readily available (e.g., parts
of Africa and Asia); in these regions, up to one-third of patients with
AIDS have cryptococcosis. Among HIV-infected persons, those with
a decreased percentage of memory B cells expressing IgM may be at
greater risk for cryptococcosis.
■ PATHOGENESIS
Cryptococcal infection is acquired by inhalation of aerosolized infectious
particles. The exact nature of these particles is not known; the two lead-
ing candidate forms are small desiccated yeast cells and basidiospores. FIGURE 210-1 Cryptococcal antigen in human brain tissue, as revealed by
Little is known about the pathogenesis of initial infection. Serologic immunohistochemical staining. Brown areas show polysaccharide deposits in
studies have shown that cryptococcal infection is acquired in child- the midbrain of a patient who died of cryptococcal meningitis. (Reprinted with
hood, but it is not known whether the initial infection is symptomatic. permission from SC Lee et al: Am J Pathol 148; 1267, 1996.)
Given that cryptococcal infection is common while disease is rare, the
consensus is that pulmonary defense mechanisms in immunologically
■ CLINICAL MANIFESTATIONS
intact individuals are highly effective at containing this fungus. It is not
The clinical manifestations of cryptococcosis reflect the site of fungal
clear whether initial infection leads to a state of immunity or whether
infection. The spectrum of disease caused by Cryptococcus species
most individuals are subject throughout life to frequent and recurrent
consists predominantly of meningoencephalitis and pneumonia, but
infections that resolve without clinical disease. However, evidence indi-
skin and soft tissue infections also occur; in fact, cryptococcosis can
cates that some human cryptococcal infections lead to a state of latency

CHAPTER 210 Cryptococcosis

affect any tissue or organ. CNS involvement usually presents as signs
in which viable organisms are harbored for prolonged periods, possibly
and symptoms of chronic meningitis, such as headache, fever, lethargy,
in granulomas. Thus the inhalation of cryptococcal cells and/or spores
sensory deficits, memory deficits, cranial nerve paresis, vision deficits,
can be followed by either clearance or establishment of the latent state.
and meningismus. Cryptococcal meningitis differs from bacterial men-
The consequences of prolonged harboring of cryptococcal cells in the
ingitis in that many Cryptococcus-infected patients present with symp-
lung are not known, but evidence from animal studies indicates that the
toms of several weeks’ duration. In addition, classic characteristics of
organisms’ prolonged presence could alter the immunologic milieu in
meningeal irritation, such as meningismus, may be absent in crypto-
the lung and predispose to allergic airway disease.
coccal meningitis. Indolent cases can present as subacute dementia.
Cryptococcosis usually presents clinically as chronic meningoen-
Meningeal cryptococcosis can lead to sudden catastrophic vision loss.
cephalitis. The mechanisms by which the fungus undergoes extrapul-
Pulmonary cryptococcosis usually presents as cough, increased
monary dissemination and enters the central nervous system (CNS)
sputum production, and chest pain. Patients infected with C. gattii can
remain poorly understood. The mechanism by which cryptococcal cells
present with granulomatous pulmonary masses known as cryptococco-
cross the blood–brain barrier is a subject of intensive study. Current
mas. Fever develops in a minority of cases. Like CNS disease, pulmo-
evidence suggests that both direct fungal-cell migration across the
nary cryptococcosis can follow an indolent course, and the majority of
endothelium and fungal-cell carriage inside macrophages as “Trojan
cases probably do not come to clinical attention. In fact, many cases are
horse” invaders can occur. Cryptococcus species have well-defined
discovered incidentally during the workup of an abnormal chest radio-
virulence factors that include the expression of the polysaccharide cap-
graph obtained for other diagnostic purposes. Pulmonary cryptococ-
sule, the ability to make melanin, and the elaboration of enzymes (e.g.,
cosis can be associated with antecedent diseases such as malignancy,
phospholipase and urease) that enhance the survival of fungal cells in
diabetes, and tuberculosis.
tissue. Among these virulence factors, the capsule and melanin pro-
Skin lesions are common in patients with disseminated cryptococ-
duction have been most extensively studied. The cryptococcal capsule
cosis and can be highly variable, including papules, plaques, purpura,
is antiphagocytic, and the capsular polysaccharide has been associated
vesicles, tumor-like lesions, and rashes. The spectrum of cryptococcosis
with numerous deleterious effects on host immune function. Crypto-
in HIV-infected patients is so varied and has changed so much since the
coccal infections can elicit little or no tissue inflammatory response.
advent of antiretroviral therapy that a distinction between HIV-related
The immune dysfunction seen in cryptococcosis has been attributed to
and HIV-unrelated cryptococcosis is no longer pertinent. In patients
the release of copious amounts of capsular polysaccharide into tissues,
with AIDS and solid organ transplant recipients, the lesions of cuta-
where it probably interferes with local immune responses (Fig. 210-1).
neous cryptococcosis often resemble those of molluscum contagiosum
In clinical practice, the capsular polysaccharide is the antigen that is
(Fig. 210-2; Chap. 191).
measured as a diagnostic marker of cryptococcal infection.
■ DIAGNOSIS
APPROACH TO THE PATIENT A diagnosis of cryptococcosis requires the demonstration of yeast cells
in normally sterile tissues. Visualization of the capsule of fungal cells
Cryptococcosis in cerebrospinal fluid (CSF) mixed with India ink is a useful rapid
Cryptococcosis should be included in the differential diagnosis diagnostic technique. Cryptococcal cells in India ink have a distinctive
when any patient presents with findings suggestive of chronic men- appearance because their capsules exclude ink particles. However,
ingitis. Concern about cryptococcosis is heightened by a history of the CSF India ink examination may yield negative results in patients
headache and neurologic symptoms in a patient with an underlying with a low fungal burden. This examination should be performed
immunosuppressive disorder or state that is associated with an by a trained individual, since leukocytes and fat globules can some-
increased incidence of cryptococcosis, such as advanced HIV infec- times be mistaken for fungal cells. Cultures of CSF and blood that
tion or solid organ transplantation. are positive for cryptococcal cells are diagnostic for cryptococcosis. In
cryptococcal meningitis, CSF examination usually reveals evidence of
 1528
FIGURE 210-2 Disseminated fungal infection. A liver transplant recipient
developed six cutaneous lesions similar to the one shown. Biopsy and serum
antigen testing demonstrated Cryptococcus. Important features of the lesion
include a benign-appearing fleshy papule with central umbilication resembling
molluscum contagiosum. (Photo courtesy of Dr. Lindsey Baden; with permission.)
chronic meningitis with mononuclear cell pleocytosis and increased
protein levels. A particularly useful test is cryptococcal antigen (CRAg)
detection in CSF and blood. The assay is based on serologic detection
of cryptococcal polysaccharide and is both sensitive and specific. A
PART 5
positive CRAg test provides strong presumptive evidence for crypto-
coccosis; however, because the result is often negative in pulmonary
cryptococcosis, the test is less useful in the diagnosis of pulmonary
disease and is of only limited usefulness in monitoring the response
to therapy.
Infectious Diseases
In areas of Africa where there is a high prevalence of HIV
infection, routine screening of blood for CRAg in HIV-infected
patients with low CD4+ T lymphocyte counts may identify
individuals at high risk of cryptococcal disease who are candidates for
antifungal therapy. CRAg screening has shown that a significant pro-
portion of HIV-infected patients hospitalized with pneumonia in Thai-
land harbor cryptococcal infection. Inexpensive point-of-care CRAg
tests are under development and could be of great diagnostic benefit in
resource-limited regions.
TREATMENT
Cryptococcosis
Both the site of infection and the immune status of the host must
be considered in the selection of therapy for cryptococcosis. The
disease has two general patterns of manifestation: (1) pulmonary
cryptococcosis, with no evidence of extrapulmonary dissemination;
and (2) extrapulmonary (systemic) cryptococcosis, with or without
meningoencephalitis. Pulmonary cryptococcosis in an immuno-
competent host sometimes resolves without therapy. However,
given the propensity of Cryptococcus species to disseminate from the
lung, the inability to gauge the host’s immune status precisely, and
the availability of low-toxicity therapy in the form of fluconazole,
the current recommendation is for pulmonary cryptococcosis in
an immunocompetent individual to be treated with fluconazole
(200–400 mg/d for 3–6 months). Extrapulmonary cryptococcosis
without CNS involvement in an immunocompetent host can be
treated with the same regimen, although amphotericin B (AmB;
0.5–1 mg/kg daily for 4–6 weeks) may be required for more severe
cases. In general, extrapulmonary cryptococcosis without CNS
involvement requires less intensive therapy, with the caveat that
morbidity and death in cryptococcosis are associated with menin-
geal involvement. Thus the decision to categorize cryptococcosis
as “extrapulmonary without CNS involvement” should be made
only after careful evaluation of the CSF reveals no evidence of cryp-
tococcal infection. For CNS involvement in a host without AIDS or
obvious immune impairment, most authorities recommend initial
therapy with AmB (0.5–1 mg/kg daily) during an induction phase,
which is followed by prolonged therapy with fluconazole (400 mg/d)
during a consolidation phase. For cryptococcal meningoencephalitis
without a concomitant immunosuppressive condition, the recom-
mended regimen is AmB (0.5–1 mg/kg) plus flucytosine (100 mg/
kg) daily for 6–10 weeks. Alternatively, patients can be treated with
AmB (0.5–1 mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks
and then with fluconazole (400 mg/d) for at least 10 weeks. Patients
with immunosuppression are treated with the same initial regimens
except that consolidation therapy with fluconazole is given for a
prolonged period to prevent relapse.
Cryptococcosis in patients with HIV infection always requires
aggressive therapy and is considered incurable unless immune func-
tion improves. Consequently, therapy for cryptococcosis in the setting
of AIDS has two phases: induction therapy (intended to reduce the
fungal burden and alleviate symptoms) and lifelong maintenance
therapy (to prevent a symptomatic clinical relapse). Pulmonary and
extrapulmonary cryptococcosis without evidence of CNS involvement
can be treated with fluconazole (200–400 mg/d). In patients who
have more extensive disease, flucytosine (100 mg/kg per day) may
be added to the fluconazole regimen for 10 weeks, with lifelong flu-
conazole maintenance therapy thereafter. For HIV-infected patients
with evidence of CNS involvement, most authorities recommend
induction therapy with AmB. An acceptable regimen is AmB (0.7–1
mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks followed by
fluconazole (400 mg/d) for at least 10 weeks and then by lifelong
maintenance therapy with fluconazole (200 mg/d). Fluconazole
(400–800 mg/d) plus flucytosine (100 mg/kg per day) for 6–10 weeks
followed by fluconazole (200 mg/d) as maintenance therapy is an
alternative. Newer triazoles like voriconazole and posaconazole are
highly active against cryptococcal strains and appear to be clinically
effective, but clinical experience with these agents in the treatment
of cryptococcosis is limited. Lipid formulations of AmB can be sub-
stituted for AmB deoxycholate in patients with renal impairment.
Neither caspofungin nor micafungin is effective against Cryptococcus
species; consequently, neither drug has a role in the treatment of
cryptococcosis. Cryptococcal meningoencephalitis is often associ-
ated with increased intracranial pressure, which is believed to be
responsible for damage to the brain and cranial nerves. Appropriate
management of CNS cryptococcosis requires careful attention to
the management of intracranial pressure, including the reduction
of pressure by repeated therapeutic lumbar puncture and the place-
ment of shunts. Studies suggest that the addition of a short course
of interferon γ to antifungal therapy in patients with HIV infection
increases clearance of cryptococci from the CSF.
In HIV-infected patients with previously treated cryptococcosis
who are receiving fluconazole maintenance therapy, it may be possi-
ble to discontinue antifungal drug treatment if antiretroviral therapy
results in immunologic improvement.
■ PROGNOSIS AND COMPLICATIONS
Even with antifungal therapy, cryptococcosis is associated with high
rates of morbidity and death. For the majority of patients with cryp-
tococcosis, the most important prognostic factors are the extent and
the duration of the underlying immunologic deficits that predisposed
them to develop the disease. Therefore, cryptococcosis is often curable
with antifungal therapy in individuals with no apparent immunologic
dysfunction, but, in patients with severe immunosuppression (e.g.,
those with AIDS), the best that can be hoped for is that antifungal ther-
apy will induce remission, which can then be maintained with lifelong
suppressive therapy. Before the advent of antiretroviral therapy, the
median overall survival period for AIDS patients with cryptococcosis
was <1 year. Cryptococcosis in patients with underlying neoplastic
disease has a particularly poor prognosis. For CNS cryptococcosis,
poor prognostic markers are a CSF assay positive for yeast cells on
initial India ink examination (evidence of a heavy fungal burden), high
CSF pressure, low CSF glucose levels, low CSF pleocytosis (<2/μL),
recovery of yeast cells from extraneural sites, absence of antibody to
capsular polysaccharide, a CSF or serum cryptococcal antigen level of
≥1:32, and concomitant glucocorticoid therapy or hematologic malig-
nancy. A response to treatment does not guarantee cure since relapse of
cryptococcosis is common even among patients with relatively intact
immune systems. Complications of CNS cryptococcosis include cranial
nerve deficits, vision loss, and cognitive impairment.
■ IMMUNE RECONSTITUTION INFLAMMATORY
SYNDROME
The frequent chronicity of cryptococcal infections and their common
occurrence in settings of changing immunity can result in new clinical
syndromes, such as the immune reconstitution inflammatory syn-
drome (IRIS). IRIS occurs when immunity rebounds in the setting of
treated cryptococcosis (or an undiagnosed asymptomatic infection)
and the immune response to cryptococcal antigens in tissue triggers
an inflammatory response that can be difficult to distinguish from
a relapsing infection. IRIS can occur when patients with AIDS and
treated cryptococcosis are given antiretroviral therapy that results
in improved immunity. Apart from the difficulties in distinguishing
IRIS from cryptococcal relapse, the management of this syndrome is
complex because it is caused by the desirable outcome of improving
immunity, which is important in controlling cryptococcal infection
and preventing relapses. The approach to the patient with IRIS must
attempt to balance resurgent immunity against immune-mediated
damage. Currently, management of IRIS is individualized and can
involve the use of glucocorticoids to reduce inflammation.
■ PREVENTION
No vaccine is available for cryptococcosis. In patients at high risk (e.g.,
those with advanced HIV infection and CD4+ T lymphocyte counts of
<200/μL), primary prophylaxis with fluconazole (200 mg/d) is effec-
tive in reducing the prevalence of disease. Since antiretroviral therapy
raises the CD4+ T lymphocyte count, it constitutes an immunologic
form of prophylaxis.
■ FURTHER READING
Kwon-Chung KJ et al: The case for adopting the “species complex”
nomenclature for the etiologic agents of cryptococcosis. mSphere
2 pii:e00357, 2017.
Maziarz EK, Perfect JR: Cryptococcosis. Infect Dis Clin North Am
30:179, 2016.
Robertson EJ et al: Cryptococcus neoformans ex vivo capsule size is
associated with intracranial pressure and host immune response in
HIV-associated cryptococcal meningitis. J Infect Dis 209:74, 2014.
Saag MS et al: Practice guidelines for the management of cryptococcal
disease. Infectious Diseases Society of America. Clin Infect Dis 30:710,
2000.
Srichatrapimuk S, Sungkanuparph S: Integrated therapy for HIV
and cryptococcosis. AIDS Res Ther 13:42, 2016.
211 Candidiasis
John E. Edwards, Jr.
The genus Candida encompasses >150 species, only a few of which
cause disease in humans. With rare exceptions (although the excep-
tions are increasing in number), the human pathogens are C. albicans,
C. guilliermondii, C. krusei, C. parapsilosis, C. tropicalis, C. kefyr, C. lusitaniae,
C. dubliniensis, C. glabrata, and C. auris. Ubiquitous in nature, they
inhabit the gastrointestinal tract (including the mouth and orophar-
ynx), the female genital tract, and the skin. Although cases of candid-
iasis have been described since antiquity in debilitated patients, the
advent of Candida species as common human pathogens dates to the 1529
introduction of modern therapeutic approaches that suppress normal
host-defense mechanisms. Of these relatively recent advances, the most
important is the use of antibacterial agents that alter the normal human
microbiota and allow nonbacterial species to become more prevalent
in the commensal flora. With the introduction of antifungal agents,
the causes of Candida infections shifted from an almost complete dom-
inance of C. albicans to the common involvement of C. glabrata and the
other species listed above. The non-albicans species now account for
approximately half of all cases of candidemia and hematogenously
disseminated candidiasis. Recognition of this change is clinically
important, since the various species differ in susceptibility to the newer
antifungal agents.
Candida is a small, thin-walled, ovoid yeast that measures 4–6 μm in
diameter and reproduces by budding. Organisms of this genus occur in
three forms in tissue: blastospores, pseudohyphae, and hyphae. Candida
grows readily on simple medium; lysis centrifugation enhances its
recovery from blood. Species are identified by biochemical testing (cur-
rently with automated devices) or on special agar (e.g., CHROMagar).
■ EPIDEMIOLOGY
Candida are present in humans as commensals, in animals, in
foods, and on inanimate objects. In developed countries, where
contemporary medical therapeutics are commonly used, Candida
species are now among the most common nosocomial pathogens. In the
United States, these species are the fourth most common isolates from
the blood of hospitalized patients. In a recent point-prevalence study,
Candida species were the most common organisms infecting the blood-
CHAPTER 211 Candidiasis
stream of hospitalized patients. In regions where advanced medical care
is rarely available, mucocutaneous Candida infections, such as thrush,
are more common than deep-organ infections, which rarely occur.
However, the incidence of deep-organ candidiasis increases steadily as
advances in health care—such as therapy with broad-spectrum antibi-
otics, more aggressive treatment of cancer, and the use of immunosup-
pression for sustaining organ transplants—are implemented. In
aggregate, the global incidence of infections due to Candida species has
risen steadily over the past few decades. Of great recent concern has
been the global emergence of C. auris; certain strains of this organism
are resistant to all classes of antifungal agents, and mortality rates from
infection have been very high.
■ PATHOGENESIS
In the most serious form of Candida infection, the organisms dissem-
inate hematogenously and form microabscesses and small macroab-
scesses in major organs. Although the exact mechanism is not known,
Candida probably enters the bloodstream from mucosal surfaces after
growing to large numbers as a consequence of bacterial suppression
by antibacterial drugs; alternatively, in some instances, the organism
may enter from the skin. A change from the blastospore stage to the
pseudohyphal and hyphal stages is generally considered integral to
Candida’s penetration into tissue. However, C. glabrata can cause exten-
sive infection even though it does not transform into pseudohyphae or
hyphae. Adherence to both epithelial and endothelial cells is thought to
be the first step in invasion and infection; several adhesins have been
identified as well as a mucosal toxin, candidalysin. Biofilm formation
also is considered important in pathogenesis. Numerous reviews of
cases of hematogenously disseminated candidiasis have identified
the predisposing factors or conditions associated with disseminated
disease (Table 211-1). Women who receive antibacterial agents may
develop vaginal candidiasis.
Innate immunity is the most important defense mechanism against
hematogenously disseminated candidiasis, and the neutrophil is the
most important component of this defense. Macrophages also play an
important defensive role. STAT1, Dectin-1, CARD9, and TH1 and TH17
lymphocytes contribute significantly to innate defense (see “Clinical Man-
ifestations,” below). Although many immunocompetent individuals have
antibodies to Candida, the role of these antibodies in defense against the
organism is not clear. Multiple genetic polymorphisms that predispose to
disseminated candidiasis will most likely be identified in future studies.