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Fungi have emerged in the last two decades as major
causes of human disease, especially among those who
are immunocompromised or hospitalized with serious
underlying diseases (Horn et al. 2009; Kollef et al. 2008;
Lockhart et al. 2009; Neofytos et al. 2009a; Perlroth et al.
2007; Pfaller et al. 2006c; Richardson et al. 2008). High
risk groups include individuals undergoing hematopoe-
itic stem cell transplantation (HSCT), solid organ trans-
plantation (SOT), major surgery (especially gastrointes-
tinal [GI] surgery), those with AIDS, neoplastic disease,
immunosuppressive therapy, advanced age, and pre-
mature birth (Table 1) (Fishman et al. 2007; Fridkin et al.
2006; Mean et al. 2008; Morris et al. 2008; Neofytos et al.
2009a; Neofytos et al. 2009b; Perlroth et al. 2007; Procop
et al. 2004; Singh. 2003; Singh et al. 2008; Walzer et al.
2008; Zaoutis et al. 2005; Zaoutis et al. 2007).
Serious invasive fungal infections (IFI; those of blood,
normally sterile body uids, deep tissue and organs),
may be broken into two broad categories: (1) oppor-
tunistic and (2) endemic. e opportunistic mycoses
almost always represent health care-associated infec-
tions (HAI) and may be either nosocomial (occur after
~72 h hospitalization) or community onset in nature
(Kollef et al. 2008; Perlroth et al. 2007; Procop et al.
2004). Contributing factors include exposure to broad-
spectrum antibacterial agents, corticosteroids, cyto-
toxic chemotherapeutic agents, and prolonged use of
intravascular catheters (Table 1). e most important
agents of the opportunistic mycoses are Candida spp.,
Cryptococcus neoformans, Pneumocystis jirovecii, and
Aspergillus spp., although the list of potential pathogens
is ever expanding (Table 2).
e endemic mycoses are those in which susceptibil-
ity to the infection is acquired by living in a geographic
area constituting the natural habitat of the particular
fungus. e most commonly encountered endemic
mycoses in North America are due to Histoplasma capsu-
latum, Coccidioides immitis/posadasii, and Blastomyces
dermatitidis (Table 2) (Chiller et al. 2003; Chu et al. 2006;
Kauman 2001; Kauman 2007; Parish et al. 2008). e
organisms in this group are considered primary sys-
temic pathogens, owing to their ability to cause infec-
tion in both “normal” and immunocompromised hosts
and for their propensity to involve the deep viscera after
dissemination of the fungus from the lungs following its
inhalation from natural sources.
e prevention, diagnosis, and therapy of both
opportunistic and endemic mycoses remain extremely
Critical Reviews in Microbiology
Critical Reviews in Microbiology, 2010; 36(1): 1–53
2010
36
1
1
53
Address for Correspondence: Dr. Michael A. Pfaller, University of Iowa, 200 Hawkins Dr., Dept. of Pathology C606B GH, Iowa City, IA 52242. E-mail: michael-
pfaller@uiowa.edu
05 June 2009
00 00 0000
07 August 2009
1040-841X
1549-7828
© 2010 Informa UK Ltd
10.3109/10408410903241444
REVIEW ARTICLE
Epidemiology of Invasive Mycoses in North America
Michael A. Pfaller, and Daniel J. Diekema
Departments of Pathology and Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa
City, USA
Abstract
The incidence of invasive mycoses is increasing, especially among patients who are immunocompromised
or hospitalized with serious underlying diseases. Such infections may be broken into two broad categories:
opportunistic and endemic. The most important agents of the opportunistic mycoses are Candida spp.,
Cryptococcus neoformans, Pneumocystis jirovecii, and Aspergillus spp. (although the list of potential patho-
gens is ever expanding); while the most commonly encountered endemic mycoses are due to Histoplasma
capsulatum, Coccidioides immitis/posadasii, and Blastomyces dermatitidis. This review discusses the epide-
miologic proles of these invasive mycoses in North America, as well as risk factors for infection, and the
pathogens’ antifungal susceptibility.
Keywords:
MCB
424318
(Received 05 June 2009; accepted 07 August 2009)
ISSN 1040-841X print/ISSN 1549-7828 online © 2010 Informa UK Ltd
DOI: 10.3109/10408410903241444 http://www.informahealthcare.com/mby
2 M. A. Pfaller, and D. J. Diekema
dicult. Increased recognition of the importance of
these infections has spurred eorts to develop new diag-
nostic and therapeutic approaches, as well as to expand
our knowledge of the epidemiology and pathogenesis of
the mycoses.
is review discusses selected aspects of the epide-
miologic proles of the invasive mycoses that may be
encountered in North America as well as risk factors for
infection with various fungal pathogens. e susceptibil-
ity of pathogens to antifungal agents is also discussed.
Opportunistic mycoses
e frequency of IFI due to opportunistic fungal patho-
gens has clearly increased in recent years (Table 3)
(Pfaller et al. 2007a; Rees et al. 1998; Reingold et al.
1986; Wilson et al. 2002). A study of the epidemiology of
sepsis in the United States (U.S.) found that the annual
number of cases of sepsis caused by fungal organisms
increased by 207% between 1979 and 2000 (Martin et al.
2003). In the Surveillance and Control of Pathogens of
Epidemiological Importance (SCOPE) Study, a 49-center
study of 24,179 nosocomial bloodstream infections (BSI)
recorded between 1995 and 2002, 9.5% of the infections
were fungal in origin (Wisplingho et al. 2004). Candida
spp. were the fourth leading cause of nosocomial
BSI, surpassed only by staphylococci and enterococci
(Table 4) (Wisplingho et al. 2004). Notably, in a recent
population-based study of candidemia, Sofair et al.
(Sofair et al. 2006) determined that 31% of 1,143 cases of
candidemia were community onset infections, leading
participants in a recent HAI summit to conclude that cli-
nicians should be aware of the potential for candidemia
to be a cause of BSI in patients presenting to the emer-
gency department (Kollef et al. 2008). A majority of the
HAI summit panelists and Infectious Diseases Society of
America (IDSA) members responding to a Web-based
survey voiced support for the concept that “patients with
serious HAIs who have risk factors for fungal infections
require early empiric antifungal therapy to reduce mor-
tality,” further underscoring the recognized importance
of opportunistic mycoses occurring both inside and out
of the hospital setting (Kollef et al. 2008).
e most well-known causes of opportunistic
mycoses include Candida albicans, Cryptococcus neofor-
mans, Aspergillus fumigatus, and Pneumocystis jirovecii
(Fishman et al. 2008; Pfaller et al. 2006c; Pfaller et al.
2004a; Procop et al. 2004; Tellez et al. 2008; Zilberberg
et al. 2008). e estimated annual incidence of invasive
mycoses due to these pathogens is 72–290 infections
per million population for Candida, 30–66 infections
per million for C. neoformans, and 12–34 infections
per million population for Aspergillus species (Table 5)
Table 1. Predisposing factors for opportunistic and endemic mycoses.
Factor Possible role in infection Major fungal pathogens
Antimicrobial agents (no. and
duration)
Promote fungal colonization
Provide intravascular access
Candida spp., other yeast-like fungi
Adrenal corticosteroids Immunosuppression Candida spp., Cryptococcus neoformans, Aspergillus spp.,
Zygomycetes, other moulds, Pneumocystis, endemic fungi
Chemotherapy Immunosuppression Candida spp., Aspergillus spp., Pneumocystis
Hematologic/solid organ
malignancy
Immunosuppression Candida spp., Aspergillus spp., Zygomycetes, other moulds,
yeast-like fungi, Pneumocystis, endemic fungi
Previous colonization Translocation across mucosa Candida spp., Trichosporon spp.
Indwelling catheter (vascular) Direct vascular access,
contaminated product
Candida spp., other yeast-like fungi
Total parenteral nutrition Direct vascular access
Contamination of infusate
Candida spp., Malassezia spp., other yeast-like fungi
Neutropenia (<500 cells/μL) Immunosuppression Aspergillus spp., Candida spp., other moulds and yeast-like
fungi, Pneumocystis
Extensive surgery or burns Route of infection
Direct vascular access
Candida spp., Aspergillus spp., Fusarium spp., Zygomycetes
Assisted ventilation Route of infection Candida spp., Aspergillus spp.
Hospitalization or intensive care
unit stay
Exposure to pathogens
Exposure to additional risk factors
Candida spp., other yeast-like fungi, Aspergillus spp.,
Pneumocystis
Hemodialysis, peritoneal
dialysis
Route of infection
Immunosuppression
Candida spp., Rhodotorula spp., other yeast-like fungi
Malnutrition Immunosuppression Pneumocystis, Candida spp., C. neoformans, endemic fungi
HIV infection/AIDSaImmunosuppression (T-cell decit) C. neoformans, Pneumocystis, Candida spp., Histoplasma,
Coccidioides
Extremes of age Immunosuppression
Numerous co-morbidities
Candida spp., Histoplasma
aHIV, human immunodeciency virus; AIDS, acquired immunodeciency syndrome.
North American invasive mycoses 3
(Hajjeh et al. 2004; Pfaller et al. 2007a; Rees et al. 1998;
Reingold et al. 1986; Wilson et al. 2002; Zaoutis et al.
2005; Zilberberg et al. 2008). Although the incidence of
Pneumocystis pneumonia (PCP) has declined from a
high of approximately 90 infections per 1,000 person-
years in 1995, prior to the introduction of highly active
antiretroviral therapy (HAART), to approximately 30 per
1,000 person-years in 2001 (HAART introduced in 1996),
PCP remains the most common AIDS-dening oppor-
tunistic infection in the U.S. (Morris et al. 2004; Tellez
et al. 2008).
In addition to these agents, the growing list of “other”
opportunistic fungi is of increasing importance (Table
2) (Perlroth et al. 2007; Pfaller et al. 2004a; Pfaller et al.
2006c; Pfaller et al. 2009a; Procop et al. 2004; Richardson
et al. 2008). New and emerging fungal pathogens include
species of Candida and Aspergillus other than C. albicans
and A. fumigatus, opportunistic yeast-like fungi such as
Trichosporon spp., Saccharomyces spp., Rhodotorula
spp., and Blastoschizomyces capitatus, the Zygomycetes,
hyaline moulds such as Fusarium, Acremonium,
Scedosporium, Scopulariopsis, Paecilomyces, and
Trichoderma species, and a wide variety of dematia-
ceous fungi (Table 2) (Castelle et al. 2008; Cortez et al.
2008; Nucci et al. 2007; Pfaller et al. 2007d; Pfaller et al.
2009a; Procop et al. 2004; Richardson et al. 2008; Roden
et al. 2005; Sutton. 2008). Infections caused by these
organisms range from localized infections involving
lung, skin, and paranasal sinuses, to catheter-related
fungemia or peritonitis, to widespread hematogenous
Table 2. Agents of opportunistic and endemic mycoses.a
Opportunistic pathogens
Candida spp. Zygomycetes
C. albicans Rhizopus spp.
C. glabrata Mucor spp.
C. parapsilosis Rhizomucor spp.
C. tropicalis Absidia spp.
C. krusei Cunninghamella sp.
C. lusitaniae
C. guilliermondii Other hyaline moulds
C. rugosa Fusarium spp.
Cryptococcus neoformans and other Scedosporium spp.
opportunistic yeast-like fungi Acremonium spp.
C. neoformans Paecilomyces spp.
Cryptococcus gattii Trichoderma spp.
Trichosporon spp. Dematiaceous moulds
Rhodoturula spp. Alternaria spp.
Saccharomyces cerevisiae Bipolaris spp.
Blastoschizomyces capitatus Cladophialophora spp.
Aspergillus spp. Curvularia spp.
A. fumigatus Exophiala spp.
A. avus Exserohilum spp.
A. niger
A. versicolor Wangiella spp.
A. terreus
A. lentulus Pneumocystis
A. ustus P. jirovecii
Endemic pathogens
Blastomyces dermatitidis Coccidioides posadasii
Coccidioides immitis Histoplasma capsulatum
var. capsulatum
aList not all inclusive.
Table 4. Nosocomial bloodstream infections : most frequent
associated pathogens— Surveillance and Control of Pathogens of
Epidemiological Importance (SCOPE) surveillance program.a
Rank Pathogen % of isolatesb
1 Coagulase-negative staphylococci 31.3
2Staphylococcus aureus 20.2
3Enterococcus spp. 9.4
4Candida spp. 9.0
5Escherichia coli 5.6
6Klebsiella spp. 4.8
7Pseudomonas aeruginosa 4.3
8Enterobacter spp. 3.9
9Serratia spp. 1.7
10 Acinetobacter baumannii 1.3
aData compiled from Wisplingho et al. (2004).
bPercentage of a total of 20,978 infections.
Table 5. Incidence and case-fatality ratios for selected invasive
fungal infections.a
Pathogen
Incidence: no. of
cases per million
per year
Case-fatality
ratio (%) for rst
episode
Candida spp. 72.8 33.9
Cryptococcus neoformans 65.5 12.7
Coccidioides immitis 15.3 11.1
Aspergillus spp. 12.4 23.3
Histoplasma capsulatum 7.1 21.4
Zygomycetes 1.7 30.0
Hyalohyphomycosis 1.2 14.3
Phaeohyphomycosis 1.0 0.0
Sporothrix schenckii <1 20.0
Malassezia furfur <1 0.0
Total 178.3 22.4
aData compiled from Rees et al. (1998).
Table 3. Cumulative incidences of selected invasive mycoses.
Incidence per million per year (period)
CPHAaCDCbNHDScCDCdNHDSe
Mycosis (1980–1982) (1992–1993) (1996) (2000) (2003)
Candidiasis 2.6 72.8 228.2 100.0 290.0
Histoplasmosis 13.9 7.1 13.6 NAfNA
Aspergillosis 8.4 12.4 34.3 NA 22.0
Cryptococcosis 4.0 65.5 29.6 13.0 NA
aCPHA, Commission on Hospital and Professional Activities
(Reingold et al. 1986).
bCDC, Centers for Disease Control and Prevention (Rees et al. 1998).
cNHDS, National Hospital Discharge Survey (Wilson et al. 2002).
dCDC (Hajjeh et al. 2004; Mirza et al. 2003)
eNHDS (Pfaller et al. 2007a).
fNA, data not available.
4 M. A. Pfaller, and D. J. Diekema
dissemination (Pfaller et al. 2004a; Procop et al. 2004;
Richardson et al. 2008). Many of these fungi were previ-
ously thought to be nonpathogenic and now are recog-
nized causes of IFI in compromised patients. Estimates
of the annual incidence of the less common mycoses
have been virtually non-existent; however, data from
a population-based survey conducted by the Centers
for Disease Control (CDC) indicate that zygomycosis
occurs at a rate of 1.7 infections per million per year,
hyalohyphomycosis (Fusarium, Acremonium etc) at 1.2
infections per million per year, and phaeohyphomyco-
sis (dematiaceous moulds) at 1.0 infection per million
per year (Table 5) (Rees et al. 1998). Recent data from a
multicenter, prospective fungal registry, the Prospective
Antifungal erapy (PATH) Alliance, conducted in
23 U.S. medical centers between 2004 and 2008, shows
that the distribution of both common and uncommon
opportunistic IFIs may vary greatly according to the
clinical service and underlying condition of the patient
(Table 6) (Fishman et al. 2008; Horn et al. 2007; Horn
et al. 2009; Lockhart et al. 2009; Neofytos et al. 2009a;
Neofytos et al. 2009b). Among patients at highest risk of
fungal infection are solid organ transplant (SOT) recipi-
ents and hematopoietic stem cell transplant (HSCT)
recipients (Tables 6 and 7). For SOT recipients, the type
of organ transplanted may predispose a patient to one
type of fungal infection over another (Table 7) (Fishman
2007; Fishman et al. 2008; Neofytos et al. 2009b; Procop
et al. 2004), while for HSCT recipients, risk for fungal
infection depends on the degree of immunosuppres-
sion (e.g., higher for allogeneic than for autologous
transplants) (Garcia-Vidal et al. 2008; Marr et al. 2000a;
Marr et al. 2002a; Martin et al. 2003; Morgan et al 2005b;
Neofytos et al. 2009a). Risk factors for fungal infections
in transplant recipients include the use of large doses
of corticosteroids, multiple or acute rejection episodes
(SOT), graft-versus-host disease (HSCT), hypergly-
cemia, poor transplant function, leukopenia, and
advanced age (Fishman. 2007; Garcia-Vidal et al. 2008;
Singh. 2003).
Candida Species Infection
Although the array of fungal pathogens known to cause
IFI is very diverse (Table 2), most of these infections are
due to Candida spp. (Perlroth et al. 2007). Candida spp.
accounted for 88% of all nosocomial fungal infections in
the U.S. between 1980 and 1990 (Jarvis. 1995; Jarvis et al.
Table 6. Distribution of invasive fungal pathogens based on the clinical service or underlying condition of the patient.a,b
Pathogen group
% Infections by clinical service (N)
GMED HEME SCT HIV NICU SOT ST SURG Total
(3,640) (1,010) (377) (263) (54) (886) (863) (1,906) (6,031)
Candida spp. 81.7 42.6 31.6 32.7 96.3 57.2 89.2 91.2 75.0
Cryptococcus spp. 4.0 2.1 0.0 48.7 0.0 6.4 1.6 1.0 4.5
Other yeastsc1.2 3.3 2.7 3.4 0.0 1.0 1.2 0.8 1.4
Aspergillus spp. 8.3 33.8 50.7 4.9 1.9 26.0 4.9 3.4 12.3
Zygomycetes 1.1 5.2 6.4 1.1 1.9 1.7 0.0 0.6 1.4
Other mouldd1.6 7.6 6.4 1.5 0.0 4.7 1.3 1.5 2.7
Endemic fungi 1.9 1.2 0.5 7.6 0.0 2.6 0.8 0.7 1.6
aData compiled from Horn et al. (2007); Horn et al. (2009); Neofytos et al. (2009 a,b).
bGMED, general medicine; HEME, hematologic malignancy; SCT, stem cell transplant; HIV, human immunodeciency virus/acquired
immunodeciency syndrome (AIDS); NICU, neonatal intensive care unit; SOT, solid organ transplant; ST, solid tumor; SURG, surgical
(nontransplant).
cOther yeasts include 6 cases of Malassezia spp., 26 Pneumocystis, 12 Rhodotorula, 21 Saccharomyces, and 6 Trichosporon.
dOther moulds include 2 cases of Acremonium, 9 Alternaria, 3 Bipolaris, 53 Fusarium, 10 Paecilomyces, 13 Scedosporium apiospermum, 6 S.
prolicans, and 1 Sporothrix.
Table 7. Compiled incidence of invasive fungal infections (IFIs) in organ transplant recipientsa
Organ transplant Incidence of IFIs
% IFIsb
Aspergillus Candida Cryptococcus Otherc
Renal 0–20% 11.9 60.6 19.3 8.2
Heart 5–21% 25.0 65.0 2.5 7.5
Liver 5–42% 7.9 78.7 7.1 6.3
Lung and heart-lung 15–35% 63.0 23.9 2.2 14.2
Small bowel 40–59% 2.2% 80–100% NAd0–11%
Pancreas and pancreas-kidney 6–38% 10.5 76.3 0.0 13.2
aData compiled from Fishman et al. (2008); Neofytos et al. (2009a); Singh (2003).
bIFIs were not mutually exclusive (patients could have >1).
cOther, infections due to Zygomycetes (10 infections), endemic fungi (10 infections), other yeast (7 infections), and other moulds (20 infections).
dNA, data not available.
North American invasive mycoses 5
1992; Rees et al. 1998). A more recent multicenter survey
found that Candida spp. accounted for 75% of IFI in hos-
pitalized patients, although the frequency of Candida
associated IFIs varied according to the clinical service
and underlying condition of the patient (Table 6) (Horn
et al. 2007; Horn et al. 2009; Neofytos et al. 2009a; Neofytos
et al. 2009b). Between 1995 and 2002, the frequency of
nosocomial candidemia in U.S. hospitals rose signi-
cantly from 8% to 12% of all reported BSI (Wisplingho
et al. 2004). Wenzel and Gennings (Wenzel et al. 2005),
extrapolating from these data, estimate the annual bur-
den of candidemia to be 10,500 to 42,000 infections in
the U.S., associated with between 2,800-11,200 deaths
per year. Zilberberg et al (Zilberberg et al. 2008) used
billing codes to study the secular trends in candidemia-
related hospitalization in the U.S. and found that the
incidence of candidemia rose by 52% between 2000 and
2005. A similar increase in incidence was seen among all
age groups; however, there was approximately a ten fold
dierence in the candidemia-related hospitalization
incidence between the youngest group (1.53–2.26 cases
per 100,000 population among those aged 18–44 years)
and the oldest group (17.32–25.01 cases per 100,000
population among those aged at least 85 years) through-
out the study period (Table 8). ese data lend support
to the earlier ndings of Wilson et al (Wilson et al. 2002)
and of Pfaller and Diekema (Pfaller et al. 2007a), who
used National Hospital Discharge Survey (NHDS) data
to show that estimates of invasive candidiasis incidence
have been steady or increasing between 1996 and 2003 at
22–29 infections per 100,000 population (Table 3). ese
data include not only candidemia but also other forms
of invasive candidiasis that may not be associated with
positive blood cultures, which may explain why the esti-
mates are higher than several population-based studies,
of candidemia incidence (Table 8) (Perlroth et al. 2007).
is increasing incidence of invasive candidiasis over-
all combined with data from the National Nosocomial
Infection System (NNIS) survey, which show a decline in
the frequency of candidemia among intensive care unit
(ICU) patients in the U.S. (Trick et al. 2002), suggest that
the burden of invasive candidiasis is shifting from the
ICU to the general hospital (and even outpatient) setting
(Hajjeh et al. 2004; Kollef et al. 2008; Sofair et al. 2006).
e predominant source of infection due to Candida
spp., from supercial mucosal and cutaneous disease
to hematogenous dissemination, is the patient. at is,
most types of candidiasis represent endogenous infection
in which the normally commensal host ora take advan-
tage of the “opportunity” to cause infection (Pfaller. 1996).
In order to do so, there must be a lowering of the host’s
anti-Candida barrier. In cases of Candida BSI, transfer
of the organism from the GI mucosa to the bloodstream
requires prior overgrowth of the numbers of yeasts in
their commensal habitat coupled with a breach in the
integrity of the GI mucosa (Agvald-Ohman et al. 2008;
Eggimann et al. 2003; Marco et al. 1999; Pappas. 2006).
Exogenous transmission of Candida may also
account for a proportion of certain types of candidia-
sis (Asmundsdottir et al. 2008). Examples of vehicles
which may introduce Candida into the human host
include the use of contaminated irrigation solutions,
parenteral nutrition uids, vascular pressure trans-
ducers, cardiac valves, and corneas (Pappas 2006).
Transmission of Candida spp., from healthcare work-
ers to patients and from patient to patient has been
well documented, especially in the ICU environment
(Asmundsdottir et al. 2008; Bliss et al. 2008; Mean et al.
2008). e hands of healthcare workers serve as poten-
tial reservoirs of nosocomial transmission of Candida
spp. (Pfaller et al. 1998b; Strausbaugh et al. 1994; Van
Asbeck et al. 2007).
Although >100 species of Candida have been
described, only a few species have been implicated
in clinical infections (Hajjeh et al. 2001; Hazen 1995;
Horn et al. 2009; Pfaller et al. 2007a; Pfaller et al. 2007d).
Candida albicans is the species most commonly recov-
ered from clinical material and generally is responsible
for 90–100% of mucosal infections and for 40%-70% of
episodes of candidemia, although this may vary con-
siderably according to the clinical service on which the
patient is hospitalized (Table 9) (Hachem et al. 2008;
Hajjeh et al. 2004; Horn et al. 2009; Pappas et al. 2003;
Perlroth et al. 2007; Pfaller et al. 2007a; Trick et al. 2002;
Wisplingho et al. 2004).
Approximately 95–97% of all Candida-associated
IFIs are caused by ve species: C. albicans, Candida
glabrata, Candida parapsilosis, Candida tropicalis, and
Candida krusei (Table 9) (Hajjeh et al. 2004; Horn et al.
2009; Pappas et al. 2003; Pfaller et al. 2007a). Among
these common species, only C. glabrata and C. krusei
can be said to be truly “emerging” as causes of IFI, due in
part to their intrinsic and acquired resistance to azoles
and other commonly used antifungal agents (Hachem
et al. 2008; Hajjeh et al. 2004; Haulata et al. 2007; Pfaller
et al. 2003; Pfaller et al. 2007a; Pfaller et al. 2007b; Pfaller
et al. 2008b; Sobel. 2007; Vos et al. 2006). Specic aspects
of each of these species will be addressed below.
e remaining 3–5% of Candida-associated IFIs are
caused by 15–18 dierent species including Candida
guilliermondii, Candida lusitaniae, and Candida rugosa
(Hawkins et al. 2003; Pfaller et al. 2004a; Pfaller et al.
2004b; Pfaller et al. 2006d; Pfaller et al. 2006e; Pfaller
et al. 2007d). Although these species must be consid-
ered to be rare causes of candidiasis, several have been
observed to occur in nosocomial clusters or to exhibit
innate or acquired resistance to one or more established
antifungal agents (Colombo et al. 2003; Dick et al. 1985;
Dube et al. 1994; Hawkins et al. 2003; Kabbara et al. 2008;
Nucci et al. 2005; Sobel 2007).
6 M. A. Pfaller, and D. J. Diekema
Candida albicans
Among the various species of Candida capable of caus-
ing human infection, C. albicans predominates (Table
9). Supercial infections of genital, oral, and cutaneous
sites almost always (>90% of cases) involve C. albicans
(Pfaller et al. 2007d). A wider array of Candida species
causes BSI (Table 9), and although C. albicans predomi-
nates, the frequency with which this and other species
of Candida are recovered from blood samples varies
according to the age of the patient and the local, regional,
or global setting (Abi-Said et al. 1997; Antoniadou et al.
2003; Eggimann et al. 2003; Hachem et al. 2008; Horn
et al. 2009; Kao et al. 1999; Pfaller et al. 2002c; Pfaller
et al. 2004b; Pfaller et al. 2007a; Sofair et al. 2006; Trick
et al. 2002). Globally, a decreasing trend in the rate of
C. albicans isolation (7%-10% decrease) was noted over
an 8.5-year period (1997–2005) among 134 sentinel sur-
veillance sites in 40 countries (Pfaller et al. 2007d). C.
albicans accounted for only 45.6% of Candida BSI in a
recent U.S. multicenter survey, ranging from only 22.4%
of infections among stem cell transplant recipients to
69.2% of infections in the neonatal ICU (NICU) (Table
9) (Horn et al. 2009). BSI due to C. albicans have been
shown to occur less frequently with increasing patient
age (Diekema et al. 2002; Horn et al. 2009; Kao et al. 1999;
Pfaller et al. 2002a; Pfaller et al. 2002c; Pfaller et al. 2004a;
Pfaller et al. 2007a), after exposure to azole antifungals
(Abi-Said et al. 1997; Goldman et al. 2000; Hachem et al.
2008; Hope et al. 2002; Laverdiere et al. 2000; Marr et al.
2000a; Pelz et al. 2001), and in the ICU setting (Trick et al.
2002). Recently, Hachem et al (Hachem et al. 2008) found
that in the setting of a cancer center, factors that were
predictive of C. albicans candidemia were an absence of
neutropenia, the presence of an underlying solid tumor,
and no prior use of prophylactic uconazole (Table 10).
Whereas C. albicans accounted for 45% of Candida BSI in
patients with solid tumors, it was observed in only 14% of
patients with hematologic malignancies (Hachem et al.
2008). ese ndings are supported by those of Horn
et al (Horn et al. 2009) who found C. albicans in 47.6%
of Candida BSI in patients with solid tumors versus only
27.4% in those with hematologic malignancies (Table
9). Chow et al. (Chow et al. 2008) also found C. albicans
to be favored in ICU patients without prior uconazole
exposure; however, this was not supported by Schorr
et al (Schorr et al. 2007) who found that among patients
whose fungemia was diagnosed when they were in an
ICU, no variable dierentiated infection with C. albicans
from that with non-albicans species. ese ndings
emphasize the need to understand that experiences in
various hospital settings may dier greatly with regard to
the epidemiology of candidemia (Riddell et al. 2008). It
Table 10. Multiple logistic regression analysis of independent risk
factors predisposing patients to candidemia caused by dierent
species.a
Candida spp. Risk factor Odds ratio
95% Condence
interval
C. albicans No neutropenia 1.53 1.2–2.44
No uconazole
prophylaxis
3.33 2.04–5.56
Solid tumor 2.50 1.54–4.0
C. tropicalis Neutropenia 2.325 1.287–4.202
C. glabrata Fluconazole
prophylaxis
2.041 1.361–3.060
C. krusei Fluconazole
prophylaxis
5.26 2.922–9.468
Neutropenia 5.378 2.696–10.727
C. parapsilosis Catheter-related
candidemia
2.470 1.587–3.845
aData compiled from Hachem et al. (2008).
Table 9. Species distribution of Candida bloodstream infection isolates by clinical service.a
Candida spp.
% Isolates by species and clinical service (N)b
GMED HEME SCT HIV NICU SOT ST SURG Total
(1,339) (197) (58) (41) (26) (166) (351) (662) (2,019)
C. albicans 46.3 27.4 22.4 43.9 69.2 39.2 47.6 47.9 45.6
C. glabrata 26.6 25.9 32.8 29.3 0.0 38.6 26.8 24.0 26.0
C. parapsilosis 15.7 11.7 15.5 9.8 26.9 12.0 12.8 17.7 15.7
C. tropicalis 7.5 17.3 8.6 7.3 0.0 6.0 7.4 7.3 8.1
C. krusei 1.9 13.7 15.5 4.9 0.0 1.8 2.6 1.4 2.5
Otherc2.0 4.0 5.2 4.8 3.9 2.4 2.8 1.7 2.1
aData compiled from Horn et al. (2009).
bGMED, general medicine; HEME, hematologic malignancy; SCT, stem cell transplant; HIV, human immunodeciency virus/acquired
immunodeciency syndrome (AIDS); NICU, neonatal intensive care unit; SOT, solid organ transplant, ST, solid tumor; SURG; surgical
(nontransplant).
cOther: 17 cases of C. lusitaniae, 5 of C. guilliermondii, 7 of C. dubliniensis, 11 other, and 3 unknown Candida spp.
Table 8. Population incidence of candidemia in the United States by
age group: 2001–2005.a
Age group
(y)
Rate per 100,000 population by year
2001 2002 2003 2004 2005
18–44 1.53 1.80 2.20 2.26 2.01
45–64 5.06 5.97 6.16 6.66 6.81
65–84 14.16 15.51 16.84 16.49 18.64
≥85 17.32 19.46 21.48 21.86 25.01
aData compiled from Zilberberg et al. (2008).
North American invasive mycoses 7
is vital to have knowledge of local epidemiologic trends
in order to guide initial therapy for Candida BSI (Kollef
et al. 2008; Pappas et al. 2009; Riddell et al. 2008; Rijnders
et al. 2000). Although C. albicans is usually considered to
be an endogenous pathogen (i.e., infection arises from
the patient’s own ora), exogenous transmission from
patient to patient via the hands of healthcare personnel
is well documented (Asmundsdottir et al. 2008; Bliss
et al. 2008; Marco et al. 1999).
Candida glabrata
C. glabrata has emerged as an important and poten-
tially antifungal-resistant opportunistic fungal pathogen
(Abi-Said et al. 1997; Alexander et al. 2005; Antoniadou
et al. 2003; Diekema et al. 2002; Eggimann et al. 2003;
Hachem et al. 2008; Hajjeh et al. 2004; Horn et al. 2009;
Kao et al. 1999; Klevay et al. 2008; Magill et al. 2006;
Malani et al. 2005; Marr et al. 2000a; Nucci et al. 2005;
Panackal et al. 2006; Pfaller et al. 2004a; Pfaller et al.
2004b; Pfaller et al. 2007a; Trick et al. 2002). Trick et al
(Trick et al. 2002) have demonstrated that, among the
Candida species, C. glabrata alone has increased as a
cause of BSI in U.S. ICUs since 1993. On a global scale,
the frequency of C. glabrata as a cause of BSI varies from
22–26% in North America to 4%-6% in Latin America
(Diekema et al. 2009a; Pfaller et al. 2004b; Pfaller et al.
2004d; Pfaller et al. 2007d; Pfaller et al. 2009b). Within
the U.S., the proportion of fungemia due to C. glabrata
has been shown to vary from 11% to 37% across the 9 US
Bureau of the Census Regions (Pfaller et al. 2003; Pfaller
et al. 2004b) and from <10% to >30% within single insti-
tutions over the course of several years (Baddley et al.
2001a; Malani et al. 2005). e variation in frequency
of C. glabrata as a cause of BSI across clinical services
has clearly been shown by Horn et al (Horn et al. 2009)
(Table 9) and by Hachem et al (Hachem et al. 2008).
Horn et al (Horn et al. 2009) found that patients with C.
glabrata fungemia were more likely than other patients
with candidemia to be older and to receive a solid organ
transplant, whereas Hachem et al (Hachem et al. 2008)
found that antifungal prophylaxis with uconazole was
a predisposing risk factor for C. glabrata BSI among
cancer patients (Table 10). Review of fungal surveillance
programs conducted in North America from 1992 to the
present shows that the proportion of Candida BSIs due
to C. glabrata has increased signicantly from 8–12%
in 1992 to 24–26% in 2004–2008 (Table 11). Numerous
studies have shown that both colonization and infection
with C. glabrata are rare among infants and children
and increase signicantly with patient age (Diekema
et al. 2002; Hajjeh et al. 2004; Horn et al. 2009; Kao et al.
1999; Kauman. 2001; Laupland et al. 2005; Malani et al.
2005; Pfaller et al. 2002a; Pfaller et al. 2002c; Pfaller et al.
2003; Pfaller et al. 2007a; Rangel-Frausto et al. 1999;
Saiman et al. 2000). Importantly, more than one-third
of Candida-associated BSIs among patients >60 years of
age are due to C. glabrata (Diekema et al. 2002; Kao et al.
1999; Malani et al. 2005). is dramatic variation in the
incidence of C. glabrata fungemia appears to be multi-
factorial (Malani et al. 2005; Pfaller et al. 2004d; Riddell
et al. 2008). It has been shown that the prevalence of this
species is potentially related to disparate factors, includ-
ing geographic characteristics (Pfaller et al. 2004b; Pfaller
et al. 2004d; Pfaller et al. 2007c), age (Diekema et al.
2002; Malani et al. 2005; Pfaller et al. 2003; Pfaller et al.
2007a), and characteristics of the patient population
studied (Abi-Said et al. 1997; Hachem et al. 2008; Marr
et al. 2000a; Marr et al. 2000b; Pasqualotto et al. 2008).
Because C. glabrata is relatively resistant to uconazole,
the frequency with which it causes BSI has important
implications for therapy (Collins et al. 2007; Hachem
et al. 2008; Klevay et al. 2008; Pappas et al. 2009; Parkins
et al. 2007; Riddell et al. 2008; Rijnders et al. 2000).
Candida parapsilosis
C. parapsilosis is the third most common species
of Candida recovered from blood cultures in North
America, accounting for 10%-20% of Candida B S I ( Tables
9 and 11) (Clark et al. 2004; Diekema et al. 2009a; Hajjeh
et al. 2004; Horn et al. 2009; Kao et al. 1999; Laupland
Table 11. Temporal variation in species distribution among bloodstream infection (BSI) isolates of Candida in North America.
Location Study period Reference
No. of
isolates
% Total by Candida spp.a
CA CG CP CT CK
United States 1992–1993 Kao et al. (1999) 837 52 12 21 10 4
United States 1993–1995 Pfaller et al. (2002a) 79 56 15 15 10
United States 1995–1997 Pappas et al. (2003) 1,593 46 20 14 12 2
United States 1995–1998 Pfaller et al. (2002a) 934 53 20 10 12 3
United States 1998–2000 Hajjeh et al (2004) 935 45 24 13 12 2
Canada 1999–2004 Laupland et al. (2005) 209 51 22 6 6 5
North America 2001–2004 Pfaller et al (2007a) 2,773 51 22 14 7 2
North America 2001–2006 Pfaller et al (2008a) 1,489 50 24 14 8 2
North America 2001–2007 Pfaller et al. (2009b) 11,682 49 21 14 7 3
North America 2004–2006 Diekema et al (2009a) 1,657 52 23 14 7 1
North America 2004–2008 Horn et al. (2009) 2,019 46 26 16 8 3
aCA, C. albicans; CG, C. glabrata; CP, C. parapsilosis; CT, C. tropicalis; CK, C. krusei.
8 M. A. Pfaller, and D. J. Diekema
et al. 2005; Pappas et al. 2003; Pfaller et al. 2002a; Pfaller
et al. 2006c; Pfaller et al. 2008a; Pfaller et al. 2008d;
Pfaller et al. 2009b; Safdar et al. 2002; Trofa et al. 2008).
C. parapsilosis is an exogenous pathogen that may be
found on skin rather than mucosal surfaces (Almirante
et al. 2006; Bonassoli et al. 2005; Clark et al. 2004; Kuhn
et al. 2004; Strausbaugh et al. 1994; Trofa et al. 2008; Van
Asbeck et al. 2007). C. parapsilosis is known for the abil-
ity to form biolms on catheters and other implanted
devices (Clark et al. 2004; Kuhn et al. 2004; Levy et al.
1998; Trofa et al. 2008), for nosocomial spread by hand
carriage, and for persistence in the hospital environ-
ment (Almirante et al. 2006; Fridkin. 2005; Kwon-Chung
et al. 2002; Perlroth et al. 2007; Reiss et al. 2008; Safdar
et al. 2002; San Miguel et al. 2005; Sarvikivi et al. 2005;
Trofa et al. 2008; Van Asbeck et al. 2007). It is also well
known for causing infections in infants and neonates
(Table 9) (Fridkin et al. 2006; Kuhn et al. 2004; Levy et al.
1998; Lupetti et al. 2002; Pfaller et al. 2008d; Reiss et al.
2008; Saiman et al. 2000; Sarvikivi et al. 2005; Saxen et al.
1995; Trofa et al. 2008; Van Asbeck et al. 2007; Zaoutis
et al. 2005; Zaoutis et al. 2007). C. parapsilosis aects
critically ill neonates and ICU patients likely because
of its association with parenteral nutrition and central
venous catheters (Clark et al. 2004; Hachem et al. 2008;
Horn et al. 2009; Kuhn et al. 2004; Sarvikivi et al. 2005).
Horn et al. (Horn et al. 2009) found that patients with C.
parapsilosis BSI were more likely than other candidemic
patients to have undergone recent surgery and to have a
peripherally inserted central venous catheter, whereas
Hachem et al (Hachem et al. 2008) reported that C. par-
apsilosis was the most common non-albicans species of
Candida among solid tumor patients and that catheter-
related infection was an independent risk factor for C.
parapsilosis BSI (Table 10). Notably, a recent report by
Kabbara et al (Kabbara et al. 2008) describes break-
through C. parapsilosis BSI in HSCT patients receiv-
ing long-term caspofungin therapy and Forrest et al
(Forrest et al. 2008) found a strong correlation between
caspofungin usage and a 400% increase in cases of C.
parapsilosis BSI. e close MIC-to-therapeutic eect of
the echinocandins towards C. parapsilosis may account
for the presumed selection pressure for this organism
(Forrest et al. 2008; Kabbara et al. 2008; Pfaller et al.
2008a; Pfaller et al. 2008e). Fortunately, BSI due to this
species is associated with a signicantly lower mortality
rate than are infections due to other common species
of Candida (Abi-Said et al. 1997; Almirante et al. 2006;
Hajjeh et al. 2004; Horn et al. 2009; Nguyen et al. 1996a;
Pappas et al. 2003; San Miguel et al. 2005; Trofa et al.
2008).
C. parapsilosis isolates can be divided into three
groups on the basis of molecular studies (Lockhart et al.
2008; Tavanti et al. 2005). e C. parapsilosis complex is
now known to be comprised of three separate species,
C. parapsilosis (formerly C. parapsilosis group I), C.
orthopsilosis (formerly C. parapsilosis group II), and C.
metapsilosis (formerly C. parapsilosis group III) (Tavanti
et al. 2005). Lockhart et al (Lockhart et al. 2008) recently
demonstrated that among 1,929 isolates of presumed C.
parapsilosis, 91.3% were C. parapsilosis, 6.1% were C.
orthopsilosis, and 1.8% were C. metapsilosis. Notably,
the percentage of C. parapsilosis isolates that were C.
orthopsilosis increased from 4.5% in the years 2001–2004
to 8.3% in the years 2005–2006 (Lockhart et al. 2008). C.
orthopsilosis accounted for only 5% of C. parapsilosis
complex isolates from North America, 59% of which
were isolated from patients in the ≥60-year-old age
group (versus only 38% of C. parapsilosis isolates). None
of the C. orthopsilosis or C. metapsilosis isolates were
resistant to uconazole, and all were susceptible to the
echinocandins (Lockhart et al. 2008).
Candida tropicalis
C. tropicalis has long been considered to be an impor-
tant cause of IFI in patients with cancer, especially
leukemia, and in HSCT patients (Abi-Said et al. 1997;
Baran et al. 2001; Hachem et al. 2008; Horn et al. 2009;
Kontoyiannis et al. 2001; Marr et al. 2000a; Wingard.
1995). Horn et al. (Horn et al. 2009) found C. tropicalis
to be especially prominent among patients with hema-
tologic malignancies (17.3% of Candida BSI) versus
patients on other clinical services (0–8.6%) (Table 9) and
Hachem et al. (Hachem et al. 2008) reported that the
presence of neutropenia was an independent risk factor
for C. tropicalis candidemia in cancer patients (Table
10). Among patients with neutropenia who are found
to be colonized with C. tropicalis, as many as 60–80%
eventually develop invasive infection with this species
(Pfaller et al. 1987; Sanford et al. 1980, Wingard. 1995).
As such, C. tropicalis has been considered to exhibit
increased virulence, especially in those individuals
with disrupted mucosal integrity (Kontoyiannis et al.
2001; Walsh et al. 1986; Wingard. 1995). Given these
considerations, prophylaxis treatment with uconazole
for patients with neutropenia has been used in an eort
to decrease infections due to C. tropicalis, as well as C.
albicans (Abi-Said et al. 1997; Antoniadou et al. 2003;
Marr et al. 2000a). Indeed, Hachem et al. (Hachem et al.
2008) has shown a signicant decrease in the frequency
of C. tropicalis BSI associated with the widespread use
of uconazole prophylaxis in patients with leukemia,
lymphoma, and HSCT during the 1990s and 2000s. C.
tropicalis accounted for 23% of Candida BSIs (2nd in
rank order) in the pre-uconazole era (1988–1992) ver-
sus only 9.6% (5th in rank order) in the years following
the introduction of uconazole (1993–2003) (Hachem
et al. 2008). Overall, C. tropicalis accounted for 10–12%
of Candida BSI in North America during the 1990s and
7–8% in the 2000s (Table 11).
North American invasive mycoses 9
Candida krusei
C. krusei accounts for 1–5% of all Candida-associated
BSIs (Table 11) and is best known for its propensity
to emerge in settings where uconazole is used for
prophylaxis (Abi-Said et al. 1997; Antoniadou et al. 2003;
Hachem et al. 2008; Hope et al. 2002; Horn et al. 2009;
Marr et al. 2000a; Pfaller et al. 2008b). Similar to C. tropi-
calis infections, C. krusei infections occur most often in
patients with neutropenia, and colonization of patients
is often predictive of BSI with this species (Abi-Said et al.
1997; Antoniadou et al. 2003; Hachem et al. 2008; Hope
et al. 2002; Horn et al. 2009; Pfaller et al. 1987; Sanford
et al. 1980, Wingard. 1995). Both neutropenia and proph-
ylaxis with uconazole were independent risk factors
for C. krusei BSI at M.D. Anderson Cancer Center (Table
10) where C. krusei increased as a cause of Candida BSI
from 7.4% of infections (5th in rank order) in the pre-
uconazole era (1988–1992) to 24.2% of infections (2nd
in rank order) following the introduction of uconazole
(1993–2003) (Hachem et al. 2008). Likewise, Horn et al
(Horn et al. 2009) found C. krusei BSI to be associated
most commonly with prior use of antifungal agents,
hematologic malignancy, neutropenia and receipt of
HSCT (Table 9). Although C. krusei is best known for
resistance to uconazole, it may also exhibit decreased
susceptibility to amphotericin B and ucytosine, further
complicating therapy (Pappas et al. 2009; Pfaller et al.
2007a; Pfaller et al. 2008b; Spellberg et al. 2006). BSI due
to C. krusei is associated with a high mortality rate (80%
crude mortality and 40% attributable mortality), pos-
sibly related to its poor response to antifungal therapy
(Antoniadou et al. 2003; Horn et al. 2009; Viudes et al.
2002). It should be noted that colonization and infection
with C. krusei were apparent in certain medical centers
well in advance of the use of uconazole (Baran et al.
2001; Iwen et al. 1995; Merz et al. 1986; Wingard. 1995).
Other Candida species
Among the remaining 15–18 species of Candida known
to cause invasive candidiasis (Pfaller et al. 2007d), there
are several that merit discussion either because they
have been shown to cause clusters of infection in the
hospital setting, because they appear to be increasing
in frequency, or because they exhibit decreased suscep-
tibility to one or more antifungal agents and therefore
pose a threat of emergence in certain settings (Atkinson
et al. 2008; Barchiesi et al. 2006; Diekema et al. 2009b;
Kabbara et al. 2008; Nucci et al. 2005; Perlroth et al. 2002;
Pfaller et al. 2004a; Pfaller et al. 2006d; Pfaller et al. 2006e;
Pfaller et al. 2007a; Richardson et al. 2008; Spellberg et al.
2006). ose species addressed in this review include C.
lusitaniae, C. guilliermondii, and C. rugosa.
C. lusitaniae most often causes fungemia in patients
with malignancies or other serious comorbid conditions
(Atkinson et al. 2008; Hawkins et al. 2003). Atkinson and
colleagues (Atkinson et al. 2008) recently compared 13
episodes of C. lusitaniae-related fungemia with 41 epi-
sodes of C. albicans fungemia and found that patients
having C. lusitaniae fungemia were more likely to have
neutropenia, stem cell transplantation, and to have
received prior antifungals. C. lusitaniae is often men-
tioned in the literature as being capable of developing
resistance to amphotericin B during the course of therapy
and may present as breakthrough fungemia in immuno-
compromised patients (Blinkhorn et al. 1989; Hawkins
et al. 2003; Holzshu et al. 1979; McClenny et al. 2002;
Merz 1984; Miller et al. 2006; Minari et al. 2001; Nguyen
et al. 1996b; Pappagianis et al. 1979; Sanchez et al. 1992;
Yoon et al. 1999). Indeed, Atkinson et al (Atkinson et al.
2008) found that in contrast with patients with C. albi-
cans BSI, patients with candidemia due to C. lusitaniae
had an increased treatment failure rate when they were
treated with an amphotericin B-based regimen (10%
vs. 38%, respectively; p = 0.028), and a greater need for
subsequent ICU admission (22% vs. 54%, respectively;
p = 0.04). C. lusitaniae appears to be unique among
Candida species due to an acquired or inducible abil-
ity to exhibit high-frequency phenotypic switching from
amphotericin B susceptibility to resistance upon expo-
sure to the drug (Atkinson et al. 2008; McClenny et al.
2002; Miller et al. 2006; Yoon et al. 1999). Atkinson et al
(Atkinson et al. 2008) demonstrated that amphotericin
B resistance may be readily selected out from originally
amphotericin B-susceptible strains in vitro and that
amphotericin B is considerably less fungicidal against
C. lusitaniae when compared with C. albicans (eec-
tive concentration 50% [EC50] of 4 μg/ml vs 0.5 μg/ml,
respectively). ese ndings indicate that C. lusitaniae,
even originally susceptible to amphotericin B, may be
less amenable to therapy with this agent.
C. guilliermondii and C. rugosa are uncommon spe-
cies of Candida that appear to be increasing in frequency
as causes of invasive candidiasis (Pfaller et al. 2006d;
Pfaller et al. 2006e). Both species have been responsible
for clusters of infection in the hospital setting, and both
demonstrate decreased susceptibility to amphotericin
B, uconazole, and the echinocandins (Colombo et al.
1999; Colombo et al. 2003; Dick et al. 1985; Diekema
et al. 2009b; Dube et al. 1994; Masala et al. 2003; Pfaller
et al. 2004a; Pfaller et al. 2006d; Pfaller et al. 2006e).
C. guilliermondii is best known as a cause of ony-
chomycosis and supercial cutaneous infections
(Dignani et al. 2003; Hay 2003); however, Kao et al (Kao
et al. 1999) found candidemia due to this species to be
common among patients with prior cardiovascular or
abdominal surgery. Likewise, Masala et al. (Masala et al.
2003) reported a nosocomial cluster of catheter-related
infections due to C. guilliermondii among surgical
patients. e infections were successfully managed with
catheter removal and administration of uconazole.
10 M. A. Pfaller, and D. J. Diekema
One of the initial descriptions of invasive candidiasis
due to C. guilliermondii was that of a fatal case of dis-
seminated infection in which the patient succumbed
despite amphotericin B therapy (Dick et al. 1985). e
isolate was subsequently shown by in vitro testing to
be resistant to amphotericin B. More recently Kabbara
et al. (Kabbara et al. 2008) reported a breakthrough C.
guilliermondii BSI in a HSCT recipient receiving caspo-
fungin prophylaxis. As with C. parapsilosis (Pfaller et al.
2008d), C. guilliermondii is known to show reduced
susceptibility to the echinocandin class of antifungal
agents (Pfaller et al. 2006d; Pfaller et al. 2008a; Pfaller
et al. 2008e). is reduced susceptibility may come into
play when infections with C. guilliermondii involve
anatomical sites where adequate free drug levels can-
not be readily obtained (Pfaller et al. 2008a; Pfaller
et al. 2008e).
C. rugosa is a rare cause of fungemia (Reinhardt et al.
1985); however, it has been implicated in clusters of
nosocomial fungemia in burn patients in the U.S. (Dube
et al. 1994). C. rugosa is reported to exhibit decreased
susceptibility to polyenes, azoles, and echinocandins
and may cause catheter-related fungemia in seriously ill
patients (Diekema et al. 2009b; Dube et al. 1994; Nucci
et al. 2005; Pfaller et al. 2006e; Reinhardt et al. 1985).
In a multicenter survey of invasive candidiasis (Pfaller
et al. 2006e), we have found that C. rugosa was recovered
most often in cultures of blood and urine obtained from
patients hospitalized on medical and surgical in-patient
services.
Risk factors
e burden of invasive candidiasis is tremendous in
terms of morbidity, mortality, and cost, and it is clear
that we must do more than simply seek better therapeu-
tic agents if we are to impact this burden (Diekema et al.
2004; Fridkin 2005; Garey et al. 2006; Garey et al. 2007;
Morgan et al 2005a; Morrell et al. 2005; Parkins et al. 2007;
Wenzel et al. 2005). Fungal BSIs have been shown to have
some of the highest rates of inappropriate therapy and
hospital mortality among all etiologic agents examined
(Harbarth et al. 2002; Ibrahim et al. 2000; Klevay et al.
2008; Morgan et al 2005a; Morrell et al. 2005; Parkins
et al. 2007). e most common causes of inappropriate
therapy for fungal BSIs are omission of initial empirical
therapy (Garey et al. 2006; Klevay et al. 2008; Morrell
et al. 2005; Parkins et al. 2007) followed by incorrect dos-
ing of uconazole (Armstrong-James. 2007; Garey et al.
2007; Horn et al. 2009; Parkins et al. 2007; Patel et al.
2005). Such inadequate therapy has been linked directly
to mortality (Garey et al. 2006; Klevay et al. 2008; Morrell
et al. 2005; Parkins et al. 2007). us, despite an unprec-
edented array of new, potent, and non-toxic antifungal
agents, we are failing in the management of these infec-
tions (Diekema et al. 2004; Garey et al. 2006; Garey et al.
2007; Morrell et al. 2005; Parkins et al. 2007; Pfaller et al.
2007a; Puzniak et al. 2006).
Lack of specic clinical ndings and slow, insensitive
diagnostic testing complicate the early recognition and
treatment of invasive candidiasis (Alexander et al. 2006;
Morrell et al. 2005; Munoz et al. 2000; Ostrosky-Zeichner
et al. 2006; Parkins et al. 2007; Schorr et al. 2007). Most
authors recommend the use of clinical risk factors to
identify patients who may benet from prophylactic or
empirical antifungal therapy in the proper clinical set-
ting (Charles 2006; Kollef et al. 2008; Munoz et al. 2000;
Ostrosky-Zeichner 2004; Paphitou et al. 2005; Procop
et al. 2004; Rex. 2006; Sobel et al. 2001; Wenzel et al. 2005).
Unfortunately, the predominant risk factors for invasive
candidiasis are common iatrogenic and/or nosocomial
conditions (Table 1) (Perlroth et al. 2007). Additional
meaningful stratication of identied risk factors will be
required to identify those select high-risk patients who
would derive maximal benet from early therapeutic
interventions (Sobel et al. 2001; Wenzel et al. 2005).
It is important to realize that the risk for invasive can-
didiasis is a continuum (Diekema et al. 2004; Lockhart
et al. 2009; Pfaller et al. 2006c; Sobel et al. 2001; Wenzel
et al. 2005). Certain hospitalized individuals are clearly
at increased risk of acquiring candidemia during hos-
pitalization as a result of their underlying medical
condition: patients with hematologic malignancy and/
or neutropenia, those undergoing GI surgery, prema-
ture infants, and patients greater than 70 years of age
(Table 1). Among patients with candidemia in the U.S.,
the mean time to onset of candidemia was 22 days of
hospitalization (Pappas et al. 2003; Wisplingho et al.
2004). us, it must be emphasized rst and foremost
that invasive candidiasis typically aects individuals
with severe illness who have prolonged hospitalizations
(Perlroth et al. 2007).
Within the high-risk groups, specic additional expo-
sures have been recognized to further increase the risk
of invasive candidiasis: the presence of vascular cath-
eters, exposure to broad-spectrum antimicrobial agents,
renal failure, mucosal colonization with Candida spp.,
prolonged ICU stay, and receipt of total parenteral nutri-
tion (TPN) (Table 12) (Blumberg et al. 2001; Ostrosky-
Zeichner et al. 2007; Wenzel et al. 2005; Wey et al. 1989).
Compared to controls without the specic risk factors
or exposures, the likelihood of these already high-risk
patients contracting candidemia in hospital is approxi-
mately 2 times greater for each class of antibiotics they
receive, 7 times greater if they have a central venous
catheter, 10 times greater if Candida has been found to
be colonizing other anatomic sites, and 18 times greater
if the patient has undergone hemodialysis (Table 12)
(Wenzel et al. 2005; Wey et al. 1989). Hospitalization in
the ICU provides the opportunity for transmission of
Candida among patients (Asmundsdottir et al. 2008;
North American invasive mycoses 11
Mean et al. 2008) and has been shown to be an addi-
tional independent risk factor (Blumberg et al. 2001;
Eggimann et al. 2003; Ostrosky-Zeichner. 2004; Saiman
et al. 2000; Wenzel et al. 2005). Notably, the single most
important risk factor for candidemia among patients
hospitalized in the surgical ICU is prolonged (>7 days)
stay in the ICU (Ostrosky-Zeichner et al. 2007; Pelz et al.
2001). Several investigators have now used these risk
factors to develop clinical risk assessment strategies that
could be used in the ICU to (1) predict certain rates of
invasive candidiasis, (2) capture a substantial propor-
tion of patients who actually go on to develop invasive
candidiasis, and (3) be practical for use as selection
tools for risk-targeted prevention (prophylaxis) or treat-
ment (preemptive or empirical) strategies (Leon et al.
2006; Ostrosky-Zeichner et al. 2007; Wenzel et al. 2005).
Preliminary application of these strategies show that risk
stratication is possible and practical; however, their
clinical utility remains to be established in prospective
studies (Mean et al. 2008).
Mortality, length of stay, and cost
e consequences of candidemia in hospitalized
patients are severe. Patients with candidemia have
been shown to be at a 2-fold greater risk of death during
hospitalization than are patients with noncandidal BSI
(Pittet et al. 1997). Among all patients with nosocomial
BSI, candidemia was found to be an independent pre-
dictor of death during hospitalization (Miller et al. 1987;
Pittet et al. 1997). In a multicenter U.S. study of candi-
demia, risk factors for mortality included an APACHE II
score >18 (P < .001), cancer (P = .002), the presence of a
urinary catheter (P = .004), male sex (P = .004), the use of
corticosteroids (P < .001) and the presence of an arterial
catheter (P < .001) (Pappas et al. 2003).
Estimates of the mortality attributable to candidemia
and other forms of invasive candidiasis have been
reported from retrospective matched-cohort studies
conducted in single institutions (Gudlaugsson et al.
2003; Pelz et al. 2000; Puzniak et al. 2006; Wey et al. 1988)
and in the context of population surveillance studies
(Table 13) (Morgan et al. 2005a; Zaoutis et al. 2005). e
weight of the evidence provided by these studies sug-
gests that candidemia or invasive candidiasis is associ-
ated with an important attributable mortality ranging
from 10% to 49% (Pfaller et al. 2007a; Wenzel et al. 2005).
Furthermore, these data demonstrate that candidemia
carries no less risk of death during hospitalization today
than it did 20 years ago (Diekema et al. 2004), despite the
introduction of new antifungal agents with good activ-
ity against most species of Candida (Perlroth et al. 2007;
Spellberg et al. 2006).
Treatment of candidemia is often found to be inad-
equate due to delay in administration of therapy, treat-
ment with an agent to which the organism is resistant,
inadequate dose or duration of treatment, or no treat-
ment at all (Armstrong-James 2007; Atkinson et al. 2008;
Garey et al. 2006; Garey et al. 2007; Klevay et al. 2008;
Morgan et al. 2005a; Morrell et al. 2005; Parkins et al.
2007). Several studies have now shown that delays in
the initiation of adequate antifungal therapy of >12 h
(Morrell et al. 2005), >24 h (Garey et al. 2006; Garrouste-
Orgeas et al. 2006; Parkins et al. 2007), and >48 h (Blot
et al. 2002) were independently associated with mortal-
ity in candidemia patients. A population-based study of
candidemia found that removal of vascular catheters, in
addition to receipt of at least 5 days of antifungal treat-
ment, was independently associated with a decreased
risk for both early and late mortality (Almirante et al.
2006). Likewise, Morgan et al (Morgan et al. 2005a)
demonstrated that the attributable mortality rate was
lower among patients who received adequate (>7 days)
treatment for candidemia (11% in Connecticut and
Table 12. Factors for increased risk of high-risk patients contracting
candidemia in the hospital setting compared with control subjects
without specic risk factors or exposures.a,b
Risk factors Fold increased risk
Each class of antimicrobial received 2
Patient has a central venous catheter 7
Candida colonization 10
Patient has undergone acute hemodialysis 18
aData compiled from Wenzel et al. (2005) and Wey et al. (1989).
bHospitalization in an intensive care unit is an independent risk
factor.
Table 13. Incidence, mortality rates, and costs attributable to candidemia in the United States.a
Period
Location/patient
population
No. cases per
100,000/yr Mortality (%) LOS (days) Cost ($) Reference
1983–1986 Iowa NA 38.0 30.0 NA Wey et al. (1988)
1996 Baltimore, MD/SICU NA 19.0 17.0 21,590 Pelz et al. (2000)
1997–2001 Iowa 6.0 49.0 10.5 NA Gudlaugsson et al. (2003)
1998–1999 Connecticut 7.1 19.0 3.4 6,214 Morgan et al (2005a)
1998–2000 Baltimore, MD 24.0 24.0 12.9 29,094 Morgan et al (2005a)
2000 U.S./pediatrics 43.0 10.0 21.1 92,266 Zaoutis et al. (2005)
2000 U.S./adults 30.0 14.5 10.1 39,331 Zaoutis et al. (2005)
2000 St. Louis, MO NA 35.7 NA 44,051 Puzniak et al. (2004)
aSICU, surgical intensive care unit; NA, data not available; LOS, length of stay in hospital.
12 M. A. Pfaller, and D. J. Diekema
16% in the Baltimore metropolitan area) than among
patients who did not receive adequate treatment (31% in
Connecticut and 41% in Baltimore). Finally, Parkins et al
(Parkins et al. 2007) found that empirical therapy with
an antifungal agent to which the organism was suscep-
tible in vitro was associated with a signicant reduction
in all-cause mortality from 46% to 27% (P = .02). Notably,
empirical uconazole therapy was more likely to be
deemed inadequate (due to both inadequate dosing as
well as in vitro resistance) and inadequate therapy was
an independent predictor of death in hospital (Parkins
et al. 2007). us, reduction of the mortality due to
candidemia and invasive candidiasis is dependent on
administration of appropriate antifungal therapy (right
drug and dose) early in the course of infection and for
an adequate duration.
Several studies have examined the excess length of
stay (LOS) and hospital costs attributable to IFI due to
Candida (Table 13). Candidemia patients have been
shown to have between 3 and 30 more hospital days than
uninfected patients with the same underlying disease
and disease severity (Table 13). Given the prevalence
of Candida infections and their attributable impact
on mortality and LOS, it is not surprising that these
infections are associated with substantial health care
costs (Fridkin 2005; Miller et al. 2001a; Pelz et al. 2000;
Perlroth et al. 2007; Rentz et al. 1998; Wilson et al. 2002).
e excess costs attributable to candidemia range from
$6,214 to $92,266 per episode depending on geographic
location and patient type (Table 13). It is estimated
that 85% of the increase in cost of care for patients with
candidemia is due to the excess LOS (Rentz et al. 1998).
Because each case of candidemia adds tens of thousands
of dollars to hospitalization costs, the estimated health
care cost associated with hematogenously disseminated
candidiasis is $2–4 billion/year in the U.S. alone (Miller
et al. 2001a; Perlroth et al. 2007; Rentz et al. 1998; Wilson
et al. 2002; Zaoutis et al. 2005).
Antifungal susceptibility
Among the eight species of Candida discussed in this
review, C. albicans, C. parapsilosis, C. tropicalis, C.
lusitaniae, and C. guilliermondii remain reliably sus-
ceptible to ucytosine, the azoles (except for itracona-
zole), and the echinocandin antifungal agents (Table
14) (Diekema et al. 2009a; Diekema et al. 2009b; Pfaller
et al. 2002b; Pfaller et al. 2002d; Pfaller et al. 2004e;
Pfaller et al. 2005a; Pfaller et al. 2005c; Pfaller et al.
2007b; Pfaller et al. 2008a; Pfaller et al. 2008e). Both C.
parapsilosis and C. guilliermondii are known to exhibit
higher MICs than other species of Candida for the echi-
nocandins (modal MIC, 0.25–2 μg/ml vs. 0.06-0.12μg/
ml, respectively); however, 92–100% of all clinical BSI
isolates of these species are susceptible to echinocan-
dins at the Clinical and Laboratory Standards Institute
(CLSI) breakpoint of ≤2 μg/ml (Pfaller et al. 2008a;
Pfaller et al. 2008e).
Although 94% of C. guilliermondii isolates are sus-
ceptible to uconazole, the MIC90 value of 8μg/ml is
considerably higher than that determined for other
uconazole-susceptible species (e.g., 0.5–2 μg/ml for
C. albicans, C. parapsilosis, C. tropicalis, C. lusitaniae).
Likewise, C. glabrata, C. krusei, and C. rugosa are all
inherently less susceptible to uconazole (Table 14).
Although both voriconazole and posaconazole are
active against the majority of these isolates, cross-
resistance within the azole class is well documented
for C. glabrata and C. rugosa (Ostrosky-Zeichner et al.
2003; Pfaller et al. 2006a; Pfaller et al. 2006b; Pfaller et al.
2006e; Pfaller et al. 2007a; Pfaller et al. 2007c; Pfaller
et al. 2008c). Both C. glabrata and C. krusei are very
susceptible to the echinocandins (Pfaller et al. 2008a;
Pfaller et al. 2008e), whereas these agents are consider-
able less potent against C. rugosa (Table 14) (Diekema
et al. 2009b). In addition to its intrinsic resistance to u-
conazole, C. krusei also shows decreased susceptibility
to ucytosine (Table 14) (Pfaller et al. 2002b).
Agar-based susceptibility testing methods such as
Etest (AB BIODISK Solna, Sweden) have proven to be
the most sensitive and reliable means by which to detect
resistance to amphotericin B among Candida species
(Clancy et al. 1999; Krogh-Madsen et al. 2006; McClenny
et al. 2002; Park et al. 2006; Pfaller et al. 1998a; Pfaller
et al. 2004c; Wanger et al. 1995). Although interpretive
breakpoints for amphotericin B have not been estab-
lished, isolates of Candida for which MICs are >1μg/ml
are unusual and possibly “resistant” or, at the very least,
may require high doses of amphotericin B for optimal
treatment (Pappas et al. 2009; Rex et al. 2002; Spellberg
et al. 2006). Given these considerations, it is now evi-
dent that C. glabrata, C. krusei, and C. rugosa exhibit
decreased susceptibility to amphotericin B compared
with C. albicans (Table 15) (Diekema et al. 2009b; Pfaller
2005; Pfaller et al. 2004c; Pfaller et al. 2007a). Whereas
C. guilliermondii and C. lusitaniae have been described
as amphotericin B-resistant Candida species (Atkinson
et al. 2008; Dick et al. 1985; Pfaller et al. 2006d), both of
these species appear to be susceptible to amphotericin
B upon initial isolation from blood (Table 15). us,
resistance to amphotericin B may develop secondarily
during treatment and repeat amphotericin B suscepti-
bility testing is recommended for patients with persist-
ent infection with either species while on amphotericin
B therapy (Atkinson et al. 2008; McClenny et al. 2002;
Pfaller et al. 2006d).
Cryptococcus Infection
Cryptococcosis is a systemic mycosis caused by the
encapsulated, basidiomycetous, yeast-like fungi
North American invasive mycoses 13
Cryptococcus neoformans and Cryptococcus gattii.
ese species were previously classied on the basis
of antigenic dierences in the capsular polysaccharide
into ve serotypes of C. neoformans (A, B, C, D, and AD)
which were grouped into two varieties: var neoformans
(serotypes A,D, and AD) and var gattii (serotypes B and
C) (Kwon-Chung 1975; Kwon-Chung 1976). Given their
signicant divergence at the molecular level, the two
Table 14. Comparative in vitro susceptibility of clinical isolates of Candida spp. to ucytosine, azoles, and echinocandins determined by Clinical
and Laboratory Standards Institute broth microdilution methods.a
Candida spp. Antifungal agent No. tested
Minimum inhibitory concentration (MIC) (µg/ml)b%c
Range 50% 90% S R/NS
C. albicans Flucytosine 5,208 0.12–>128 0.25 1 97.0 3.0
Fluconazole 5,827 0.007–>128 0.25 0.5 99.3 0.1
Itraconazole 7,647 0.007–>8 0.06 0.12 96.1 0.7
Posaconazole 5,827 0.007–2 0.015 0.06 99.9 0.0
Voriconazole 5,826 0.007–4 0.007 0.015 99.9 <0.1
Anidulafungin 2,869 0.007–2 0.03 0.06 100.0 0.0
Caspofungin 2,869 0.007–0.5 0.03 0.06 100.0 0.0
Micafungin 2,869 0.007–1 0.015 0.03 100.0 0.0
C. glabrata Flucytosine 1,267 0.12–>128 0.12 0.12 99.0 1.0
Fluconazole 1,517 0.25–>128 8 32 53.1 9.6
Itraconazole 1,929 0.03–>8 1 2 2.3 59.9
Posaconazole 1,517 0.03–>8 1 2 79.6 8.3
Voriconazole 1,516 0.007–8 0.25 1 91.1 5.7
Anidulafungin 747 0.015–4 0.06 0.12 99.9 0.1
Caspofungin 747 0.015–>8 0.03 0.06 99.9 0.1
Micafungin 747 0.007–1 0.015 0.015 100.0 0.0
C. parapsilosis Flucytosine 1,047 0.12–>128 0.12 0.25 99.0 1.0
Fluconazole 1,542 0.12–>128 0.5 2 96.2 0.6
Itraconazole 1,508 0.15–2 0.25 0.5 47.8 3.1
Posaconazole 1,542 0.007–1 0.06 0.12 100.0 0.0
Voriconazole 1,541 0.007–8 0.015 0.06 99.6 0.1
Anidulafungin 759 0.03–4 2 2 92.5 7.5
Caspofungin 759 0.015–4 0.25 1 99.9 0.1
Micafungin 759 0.015–2 1 2 100.0 0.0
C. tropicalis Flucytosine 759 0.12–>128 0.25 1 92.0 7.0
Fluconazole 1,198 0.12–128 0.5 2 99.2 0.2
Itraconazole 1,207 0.015–>8 0.12 0.5 53.0 3.1
Posaconazole 1,198 0.015–2 0.06 0.12 99.9 0.0
Voriconazole 1,197 0.007–8 0.03 0.06 99.8 <0.1
Anidulafungin 625 0.007–2 0.03 0.06 100.0 0.0
Caspofungin 625 0.007–>8 0.03 0.06 99.8 0.2
Micafungin 625 0.007–1 0.03 0.06 100.0 0.0
C. krusei Flucytosine 184 0.12–>128 16 32 5.0 28.0
Fluconazole 305 8–>128 32 64 1.3 34.1
Itraconazole 306 0.12–4 1 1 1.0 56.2
Posaconazole 305 0.03–4 0.25 1 99.0 0.3
Voriconazole 305 0.007–4 0.25 0.5 99.7 0.3
Anidulafungin 136 0.015–0.5 0.06 0.06 100.0 0.0
Caspofungin 136 0.015–1 0.12 0.25 100.0 0.0
Micafungin 136 0.015–0.25 0.06 0.12 100.0 0.0
C. lusitaniae Flucytosine 82 0.12–>128 0.12 0.5 93.0 5.0
Fluconazole 171 0.12–64 0.5 1 97.0 1.0
Itraconazole 129 0.03–2 0.25 0.25 48.8 2.3
Posaconazole 171 0.06–1 0.06 0.12 100.0 0.0
Voriconazole 171 0.06–1 0.06 0.06 100.0 0.0
Anidulafungin 171 0.06–1 0.25 0.5 100.0 0.0
Caspofungin 171 0.06–4 0.25 0.5 99.0 1.0
Micafungin 171 0.06–1 0.12 0.25 100.0 0.0
Table 14. continued on next page
14 M. A. Pfaller, and D. J. Diekema
varieties of C. neoformans have recently been awarded
separate species status, as C. neoformans and C. gattii.
In addition, dierentiation of C. neoformans into two
varieties, var grubii (serotype A) and var neoformans
(serotype D) has been proposed (Boekhout et al. 2001;
Kwon-Chung et al. 2002). For purposes of this review we
will refer to C. neoformans (serotypes A, D, and AD) and
C. gattii (serotypes B and C).
C. neoformans is found worldwide, invariably isolated
from pigeon droppings and soil (Emmons.1955). More
recently, the environmental habitat of C. neoformans
appears to be related to trees and plant material, speci-
cally a specialized niche resulting from the natural bio-
degradation of wood (Lazera et al. 1996). Pigeons only
contribute to the propagation and spread of the fungus
by providing an enriched medium for fungal growth and
by dispersing the fungus via their contaminated beaks
and feet (Littman et al. 1968).
C. gattii is usually found in tropical and subtropical
regions in association with Eucalyptus trees. Recently,
however, C. gattii has been isolated from several envi-
ronmental samples (e.g. r and oak trees) in Vancouver
Island, British Columbia mainland, as well as in the states
of Oregon and Washington associated with human and
animal infections (Bartlett et al. 2007; Kidd et al. 2007;
McDougal et al. 2007).
Mode of acquisition
Cryptococcosis is usually acquired by inhaling aero-
solized cells of C. neoformans or C. gattii from the envi-
ronment. Subsequent dissemination from the lungs,
usually to the central nervous system (CNS), produces
clinical disease in susceptible individuals. Primary
cutaneous cryptococcosis may occur rarely following
transcutaneous inoculation (Naka et al. 1995); however,
the majority of cases of cutaneous cryptococcosis reect
hematogenous dissemination (Hay 1985; Sarosi et al.
1971).
Incidence
Prior to the AIDS epidemic, cryptococcal infection was
diagnosed in less than 1,000 patients per year in the U.S.
(Graybill et al. 2000; Hajjeh et al. 1999). Indeed, among
persons without AIDS the incidence of cryptococcosis
in the U.S. has been shown to be 0.2 to 0.8 per 100,000
population per year and has remained unchanged
for more than a decade (Hajjeh et al. 1999; Mirza
et al. 2003).
Candida spp. Antifungal agent No. tested
Minimum inhibitory concentration (MIC) (µg/ml)b%c
Range 50% 90% S R/NS
C. guilliermondii Flucytosine 100 0.12–4 0.12 0.5 100.0 0.0
Fluconazole 162 0.5–64 4 8 94.0 0.0
Itraconazole 90 0.06–4 0.5 1 4.0 27.0
Posaconazole 162 0.06–2 0.25 0.5 98.0 0.0
Voriconazole 162 0.06–2 0.06 0.12 99.0 0.0
Anidulafungin 162 0.06–4 1 2 93.0 7.0
Caspofungin 162 0.06–8 0.5 1 96.0 4.0
Micafungin 162 0.06–8 0.5 1 99.0 1.0
C. rugosa Fluconazole 16 0.5–16 2 16 69.0 0.0
Itraconazole 15 0.03–0.5 0.12 0.5 60.0 0.0
Posaconazole 16 0.06–0.25 0.06 0.25 100.0 0.0
Voriconazole 16 0.06–0.25 0.06 0.25 100.0 0.0
Anidulafungin 16 0.06–8 1 8 80.0 20.0
Caspofungin 16 0.06–4 0.5 2 91.0 9.0
Micafungin 16 0.06–0.25 0.06 0.25 100.0 0.0
aData compiled from Diekema et al. (2009b); Pfaller et al. (2002b; 2005a; 2006a; 2006b; 2007b; 2008a).
b50% and 90%, MIC encompassing 50% and 90% of all isolates tested, respectively.
cS, susceptible at MIC breakpoint for itraconazole (≤0.12 µg/ml); ucytosine (≤4 µg/ml) uconazole (≤8 µg/ml); posaconazole and voriconazole
(≤1 µg/ml); anidulafungin, caspofungin, micafungin (≤2 µg/ml); R, resistant at MIC breakpoint for itraconazole (≥1 µg/ml); ucytosine (≥32 µg/
ml); uconazole (≥64 µg/ml); posaconazole and voriconazole (≥4 µg/ml); NS, nonsusceptible at MIC breakpoint ≥ 4 µg/ml for anidulafungin,
caspofungin, and micafungin.
Table 14. Continued.
Table 15. Is amphotericin B uniformly active against Candida spp.?a
Candida spp.
No isolates
tested
Minimum inhibitory
concentration (MIC) (µg/ml)b
50% 90%
C. albicans 4,195 0.5 1
C. glabrata 949 2 4
C. krusei 234 4 8
C. lusitaniae 171 0.25 0.5
C. dubliniensis 101 0.25 0.5
C. guilliermondii 162 0.25 0.5
C. rugosa 16 2 4
aData compiled from Diekema et al. (2009b); Pfaller (2005); Pfaller
et al. (2004c; 2004d).
bAmphotericin B MICs were determined by using Etest (Pfaller et al.
[2004c]). 50% and 90%, MICs for 50% and 90% of isolates tested,
respectively.
North American invasive mycoses 15
A dramatic increase in the incidence of cryptococco-
sis was observed with the advent of the AIDS pandemic
(Table 3), and subsequently HIV infection has been
associated with more than 80% of cryptococcosis cases
worldwide (Dromer et al. 1996; Hajjeh et al. 1999; Mirza
et al. 2003). During the 1990s, the prevalence of crypto-
coccosis progressively declined in developed countries,
rst as a result of the widespread use of uconazole and
later due to successful treatment of HIV infection with
the use of highly active antiretroviral therapy (HAART)
(Tables 3 and 16) (Mirza et al. 2003). A population-based
surveillance study conducted by the CDC during 1992
through 2000 in Atlanta, GA and Houston, TX showed
that the overall mean annual incidence of cryptococ-
cosis decreased from 4–5 cases per 100,000 population
in 1992/1993 to 0.4–1.3 cases per 100,000 population in
2000 (Table 16) (Mirza et al. 2003). e majority of cases
(89%) occurred in persons known to be HIV infected. e
annual incidence of cryptococcosis in the Atlanta area
among persons with HIV infection ranged from 66 cases
per 1,000 persons in 1992 to 7 cases per 1,000 in 2000
and in the Houston area the incidence ranged from 23.6
cases per 1,000 persons in 1993 to 1.6 cases per 1,000 per-
sons in 2000 (Table 16) (Mirza et al. 2003). Despite this
progress, cryptococcosis continues to carry a signicant
morbidity and mortality: the annual case fatality ratio in
Atlanta and Houston was 11% among HIV-infected per-
sons and 21% among HIV-uninfected individuals and
did not change signicantly over the 8-year study period
(Mirza et al. 2003). In industrialized countries crypto-
coccosis continues to occur in those with undiagnosed
HIV infection and in socio-economically disadvantaged
HIV-infected people without access to HAART or other
HIV-supportive care (Mirza et al. 2003). In Atlanta and
Houston fewer than one-third of patients infected with
HIV who had cryptococcosis had received HAART
before being diagnosed with cryptococcosis (Mirza et al.
2003). Lack of access to HAART and antifungal therapy
is a major problem in resource-limited regions such as
Africa and Southeast Asia where both AIDS and crypto-
coccosis are rampant (Viviani et al. 2009).
e incidence of cryptococcosis among HIV-
uninfected persons remains low. It varied from 0.4 cases
per million population in 1992 in the Atlanta area to 5
cases per million population in 1994 in the Houston
area, with no signicant changes noted during the study
period (Mirza et al. 2003). Compared with HIV-infected
persons with cryptococcosis, HIV-uninfected persons
with cryptococcosis tended to be older (median age, 36
years vs. 56 years, respectively) and most cases occurred
in white persons (40% vs. 66% of cases, respectively).
At least one underlying condition (diabetes, cancer,
lung disease) was reported in 82% of cases (Mirza et al.
2003).
Cryptococcus neoformans is the most common spe-
cies aecting patients with AIDS and other immuno-
compromising conditions (Chayakulkeeree et al. 2006;
Mirza et al. 2003; Viviani et al. 2009), whereas C. gattii
infections occur mainly in immunocompetent hosts
in endemic regions throughout the world (Speed et al.
1995). e emergence of C. gattii infections in immu-
nocompetent human and animal populations in the
Pacic Northwest region of North America is nothing
short of remarkable (Bartlett et al. 2007). Prior to 1999
no evidence of C. gattii infections existed on Vancouver
Island, but their sudden emergence since this time is
well documented (Bartlett et al. 2007; Kidd et al. 2005).
Study of the environment in this and other areas of the
Pacic Northwest showed a striking change in the envi-
ronmental niches for this species to a variety of trees in
a temperate climate (Bartlett et al. 2007). e incidence
in this new endemic area has reached 35 cases per mil-
lion population per year, markedly higher than rates
reported in other endemic areas such as Australia (1.2
cases per million per year) (McDougal et al. 2007; Sorrell
2001). Molecular studies have shown the potential
direct link between the environmental and clinical iso-
lates from the Vancouver Island outbreak (Bartlett et al.
2007). Furthermore, the major genotype was found to
be more virulent in an animal model than the parental
strain (Fraser et al. 2005). Compared with C. neoformans
infections, cryptococcosis caused by C. gattii is associ-
ated with a lower mortality rate, but is characterized by
more severe neurologic sequelae due to the formation of
granulomas that require surgery and prolonged therapy
(Speed et al. 1995). Although C. gattii clearly is a patho-
gen of immunocompetent hosts, a recent epidemiologi-
cal survey in Southern California showed that C. gattii
produced disease in a substantial number of persons
infected with HIV (Chaturvedi et al. 2005).
Risk factors
Cryptococcosis, particularly meningitis, commonly
occurs in patients with underlying immunodeciency
Table 16. Incidence of cryptococcosis in two U.S. cities before
and after the introduction of highly active antiretroviral therapy
(HAART).a
Location Period (y)
Annual incidence
%
Decrease
Cases/100,000
population
Cases/1,000
HIV-infectedb
Atlanta, GA Pre-HAART
(1992)
5 66
Post-HAART
(2000)
1.3 7 89
Houston, TX Pre-HAART
(1993)
4 23.6
Post-HAART
(2000)
0.4 1.6 92
aData compiled from Mirza et al. (2003).
bHIV, human immunodeciency virus.
16 M. A. Pfaller, and D. J. Diekema
(Table 1) (Chayakulkeeree et al. 2006); however, both
local and disseminated infections are observed in
patients with no known immunologic defect (Mirza
et al. 2003; Mitchell et al. 1995; Pappas et al. 2001).
Characteristically, normal or immunocompetent indi-
viduals may develop cryptococcosis due to C. gattii in
those regions where this species is endemic; however, C.
gattii is now being found in AIDS patients (Chaturvedi
et al. 2005); suggesting that the reduced frequency of
C. gattii infections in immunosuppressed patients may
be partly caused by a limited environmental exposure
as opposed to a specic tropism for those individu-
als who are immunocompetent (Bartlett et al. 2007).
Cryptococcosis is uncommon in children, with a preva-
lence of approximately 1% among children with AIDS.
Immunosuppressed patients at particular risk for
cryptococcal infection include those with malignancies
or sarcoid and those receiving corticosteroid therapy,
organ transplants, or immunosuppressive therapy.
Among neoplastic disorders lymphoproliferative malig-
nancies, mainly Hodgkin’s lymphoma, are known to be
the major predisposing diseases (Viviani et al. 2009).
e AIDS epidemic has clearly demonstrated the
importance of a defect in cell-mediated immunity as the
major immunologic risk factor for cryptococcosis. ose
individuals with CD4+ lymphocyte counts of less than
100 per cubic mm are at high risk for CNS and dissemi-
nated cryptococcosis (Mirza et al. 2003). Despite the
favorable impact of HAART on the incidence of crypto-
coccosis in AIDS patients, the number of patients with
cryptococcosis in medically developed countries has
not approached zero as risk groups broaden in concert
with new developments in transplantation medicine
and the creation of new therapies to manipulate immu-
nity (Fishman 2007; Fishman et al. 2008). e increased
number of patients undergoing SOT and the use of cor-
ticosteroids and other immunosuppressive agents, such
as alemtuzumab and iniximab, can produce a pro-
foundly immunosuppressive state and allow reactivation
of a cryptococcal infection (Hage et al. 2003; Nath et al.
2005). e type of immunosuppression after SOT may
also inuence the predominant clinical manifestation
of cryptococcosis: patients receiving tacrolimus have
been shown to be less likely to have CNS involvement
and more likely to have skin, soft tissue, or osteoarticular
involvement than patients who received other forms of
immunosuppression (Husain et al. 2001).
Cryptococcosis is the third most common IFI after
candidiasis and aspergillosis in patients who undergo
SOT (Tables 6 and 7) (Fishman et al. 2008; Neofytos et al.
2009b; Singh et al. 2008). In the PATH Alliance Fungal
Registry (Fishman et al. 2008; Horn et al. 2007; Neofytos
et al. 2009b), cryptococcal disease was predominantly
observed in kidney and liver transplant recipients (Table
7). Published data suggest that cryptococcal disease in
SOT recipients is more likely to occur late post-trans-
plant at a mean of 1.6 years and it presents later in kid-
ney (median 35 months) than after liver transplantation
(median 8.8 months) (Singh 2003). In the PATH Alliance
series, cryptococcosis was observed at a median of
26.8 and 16.7 months for kidney and liver transplants,
respectively (Neofytos et al. 2009b).
In addition to HIV infection and SOT, risk factors for
acquiring cryptococcal infections include other medical
conditions producing an immunocompromised state
and associated with treatment with corticosteroids,
such as systemic lupus erythematosis, diabetes mellitus,
and hematologic malignancies (Kiertiburanakul et al.
2006; Mirza et al. 2003). e most common underlying
conditions among HIV-uninfected persons with cryp-
tococcosis in Atlanta and Houston were diabetes (23%),
cancer (20%), lung disease (14%), and rheumatologic or
immunologic disease (13%) (Mirza et al. 2003). Notably,
approximately one-fth of all cases in this group
occurred in persons with no known underlying medical
conditions (Mirza et al. 2003).
Mortality
Untreated, cryptococcal meningitis carries a 100% mor-
tality rate (Corbett et al. 2002; Mwaba et al. 2001). e
introduction of amphotericin B deoxycholate in the 1950s
improved the prognosis of this disease, and cure rates
for cryptococcal meningitis rose to over 50%. With the
currently recommended antifungal treatment regimens
(amphotericin B ± ucytosine followed by uconazole
maintenance therapy) coupled with HAART, the prog-
nosis for patients diagnosed with AIDS-associated CNS
cryptococcosis has improved dramatically (Lortholary
et al. 2006). However, the acute mortality remains in the
range of 6–15% (Brouwer et al. 2004; Lortholary et al.
2006; Mirza et al. 2003; Robinson et al. 1999; Saag et al.
1992). Several clinical and laboratory parameters have
been shown to be predictors of mortality during initial
therapy including abnormal mental status, a CSF cryp-
tococcal antigen titer greater than 1:1024, and a CSF
white blood count of less than 20 per microliter (Saag
et al. 1992; Saag et al. 2000). Diastolic hypertension,
probably reective of increased intracranial pressure,
has also been associated with earlier death among those
with AIDS-associated cryptococcosis (Fan-Havard et al.
1992). Aggressive management of elevated intracranial
pressure is one of the most important factors in reduc-
ing mortality and minimizing morbidity in patients with
cryptococcal meningitis (Pappas 2005; Saag et al. 2000).
Among HIV-uninfected individuals with cryptococ-
cosis, Mirza et al. (Mirza et al. 2003) reported a case-
fatality ratio of 21%, which did not change signicantly
over the surveillance period from 1992 through 2000.
Notably, SOT recipients were underrepresented in the
study of Mirza et al (only 5 out of 124 HIV-uninfected
North American invasive mycoses 17
patients with cryptococcosis) (Mirza et al. 2003). Others
have reported that mortality rates in SOT recipients have
ranged from 33% to 42% and may be as high as 49% in
those with CNS disease (Husain et al. 2001); however,
the overall mortality rate in SOT recipients with crypto-
coccosis is approximately 15% in the current era (Singh
et al. 2007; Singh et al. 2008). Whereas the mortality rate
among SOT recipients with CNS cryptococcosis is higher
among patients with abnormal mental status, lack of
headache, renal failure and liver failure, and receipt of
calcineurin inhibitor agents has been associated with a
lower mortality rate (Singh et al. 2007; Wu et al. 2004).
Improved outcomes with the use of calcineurin inhibi-
tor agents may be attributable in part to their synergistic
interactions with antifungal agents (Kontoyiannis et al.
2008; Singh et al. 2008).
Antifungal susceptibility
Pharmacologic management of cryptococcal infections
usually consists of primary therapy with amphotericin
B, with or without ucytosine, followed by maintenance
therapy, or in some instances lifelong suppressive ther-
apy, with uconazole (Saag et al. 2000). Prior to HAART,
high rates of fungal persistence and frequent disease
relapse contributed to a growing concern among clini-
cians regarding the potential for the emergence of anti-
fungal resistance among C. neoformans (Berg et al. 1998;
Brandt et al. 2001; Pfaller et al. 2005b). ere are now
several published reports of the emergence of resistance
to amphotericin B, uconazole, ucytosine, or itraco-
nazole in C. neoformans during treatment (Armengou
et al. 1996; Bicanic et al. 2006; Birley et al. 1995; Brandt
et al. 1996; Brandt et al. 2001; Cuenca-Estrella et al. 2001;
Currie et al. 1995; Davey et al. 1998; Paugam et al. 1994;
Powderly et al. 1992). Most of these reports involve resist-
ance to uconazole emerging in the setting of meningi-
tis in AIDS patients after long treatment or prophylaxis
with uconazole (Armengou et al. 1996; Berg et al. 1998;
Bicanic et al. 2006; Paugam et al. 1994).
Studies of clinical isolates of C. neoformans by Brandt
et al. (Brandt et al. 2001), Davey et al (Davey et al. 1998),
Klepser and Pfaller (Klepser et al. 1998), Pfaller et al.
(Pfaller et al. 2005b), and Yildiran et al. (Yildiran et al.
2002) provide antifungal susceptibility data generated
by CLSI reference MIC methods (M27-A3), indicating
that in vitro resistance to commonly used antifungal
agents (i.e., amphotericin B, ucytosine, uconazole,
and itraconazole) remains uncommon among C. neo-
formans and has not increased with time over more than
a decade in the U.S. and the United Kingdom (Table 17).
Analysis of trends in susceptibility of U.S. isolates of C.
neoformans to uconazole from 1992 to 2004 shows that
the susceptibility prole has actually improved or at
least remained stable since the introduction of HAART
(Brandt et al. 2001; Pfaller et al. 2005b; Pfaller et al. 2009a).
Comparing the percentage of U.S. isolates susceptible
(S, MIC ≤8 μg/ml) to uconazole from the time periods
1992 to 1994, 1996 to 1998, and 2000 to 2004 shows a
steady improvement in the %S from 71% to 89% to 96%,
respectively (Brandt et al. 2001; Pfaller et al. 2005b). is
improvement in susceptibility of C. neoformans over
time may reect in part a decrease in the overall drug
pressure concomitant with a decrease in cryptococcosis
among HIV-infected persons receiving HAART. In con-
trast, reports from Cambodia (Chandenier et al. 2004)
Africa (Bicanic et al. 2005; Bicanic et al. 2006; Bicanic
et al. 2007; Bii et al. 2006) and Spain (Perkins et al. 2005)
indicate that recent isolates from those areas exhibit
decreased susceptibility to uconazole and other azoles.
In one report from Africa (Bicanic et al. 2006), 75% of iso-
lates from patients with a clinical relapse following treat-
ment with uconazole as rst-line therapy had reduced
susceptibility (MIC ≥ 32μg/ml) to uconazole. Factors
underlying this emerging resistance include increased
use of uconazole in low doses as primary therapy or
prophylaxis and the lack of access to amphotericin B,
ucytosine and HAART in some areas (Berg et al. 1998;
Bicanic et al. 2005; Bicanic et al. 2006; Bicanic et al. 2007;
Lortholary. 2007). In a recent global survey covering the
years 2001 through 2007, we found that resistance to
uconazole among C. neoformans was less prominent
in Europe and North America compared to that seen in
the Asia-Pacic, Africa/Middle East and Latin American
regions (Pfaller et al. 2009a). Furthermore, the rates of
resistance in those latter regions increased steadily from
2001 through 2007.
Amphotericin B, as well as the newer triazoles (posa-
conazole, ravuconazole, and voriconazole), has potent
activity against C. neoformans with more than 99% of
isolates tested showing MICs of ≤1μg/ml (Table 17).
Some cross-resistance between uconazole and the
newer triazoles exists as only 80% of uconazole-resist-
ant strains remain susceptible to voriconazole (Pfaller
et al. 2009a).
Flucytosine exhibits modest activity against C.
neoformans (Table 17) and continues to have a role in
combination with amphotericin B in the treatment of
cryptococcosis. Notably none of the echinocandins are
active against this organism. Limited in vitro data sug-
gests that C. gattii is less susceptible to uconazole than
C. neoformans, although it is similarly susceptible to
the other antifungal agents (Gomez-Lopez et al. 2008;
Pfaller et al. 2009a).
Infections Due to Other Opportunistic Yeast-like Fungi
Aside from Candida and Cryptococcus, there are other
genera of yeast-like fungi that have emerged as patho-
gens paralleling the increases in immunocompro-
mised populations (Table 2). e genera most likely to
18 M. A. Pfaller, and D. J. Diekema
Table 17. In vitro susceptibility of noncandidal yeasts to systemically active antifungal agents determined by using Clinical and Laboratory
Standards Institute (CLSI) M27-A3 broth microdilution methods.a
Organism Antifungal agent No. tested
Minimum inhibitory concentration (MIC) (µg/ml)b
Range 50% 90%
Cryptococcus
neoformans
Amphotericin Bc661 0.03–32 0.5 1
Flucytosine 1,614 0.06–128 4 8
Fluconazole 1,615 0.007–64 4 8
Itraconazole 1,615 0.007–64 0.25 4
Posaconazole 1,437 0.007–2 0.12 0.25
Ravuconazole 1,205 0.007–4 0.06 0.25
Voriconazole 1,608 0.007–2 0.06 0.12
Cryptococcus gattii Amphotericin Bc18 0.002–0.38 0.25 0.38
Flucytosinec18 0.004–>32 0.016 0.19
Fluconazolec18 0.75–48 4 16
Itraconazolec18 0.002–0.5 0.1 0.38
Posaconazoled23 0.03–0.5 0.25 0.5
Ravuconazoled23 0.03–2 0.5 2
Voriconazoled23 0.03–1 0.5 1
Trichosporon asahii Amphotericin B 43 1–8 4 4
Fluconazole 43 0.25–16 2 8
Itraconazole 43 0.06–4 0.5 1
Posaconazole 24 0.06–>16 0.12 NA
Ravuconazole 10 0.25–0.5 0.25 0.5
Voriconazole 10 0.25–2 0.5 2
Micafungin 10 >64 >64 >64
Non-T. asahii Amphotericin B 15 0.06–1 0.25 NA
Fluconazole 15 0.5–4 2 NA
Itraconazole 15 0.03–0.5 0.12 NA
Posaconazole 15 0.03–0.5 0.12 NA
Ravuconazole 15 0.03–>16 0.5 NA
Voriconazole 15 0.03–0.25 0.06 NA
Rhodotorula spp. Amphotericin B 64 0.5-2 1 1
Flucytosine 64 ≤0.06–0.5 0.12 0.25
Fluconazole 64 32–≥64 ≥64 ≥64
Itraconazole 64 0.5–16 2 16
Posaconazole 64 0.5–16 2 4
Ravuconazole 64 ≤0.06–2 0.25 1
Voriconazole 64 0.25–16 2 4
Caspofungin 64 8–16 16 16
Micafungin 10 >64 >64 >64
Saccharomyces
cerevisiae
Amphotericin B 74 0.12–2 1 1
Flucytosine 74 0.25–32 0.25 0.25
Fluconazole 74 0.12–16 2 8
Itraconazole 74 0.015–1 0.5 1
Posaconazole 22 0.12–1 0.5 0.5
Voriconazole 17 ≤0.008–0.5 0.06 0.12
Caspofungin 15 NA 0.5 1
Blastoschizomyces
capitatus
Amphotericin B 23 0.06–0.25 0.12 0.12
Flucytosine 23 0.12–16 0.12 4
Fluconazole 23 1–32 8 8
Itraconazole 23 0.03–0.5 0.12 0.25
Posaconazole 25 NA 0.12 0.25
Voriconazole 23 0.03–0.5 0.25 0.25
Caspofungin 25 NA 16 >16
aData compiled from Arikan et al. (2002); Asada et al. (2006); Diekema et al (2005); Paphitou et al (2002); Pfaller (2005); Pfaller et al. (2004a;
2005b); Serena et al (2004); Serena et al. (2005); Swinne et al (2005); Tay et al (2006).
b50% and 90%; MIC encompassing 50% and 90% of isolates tested, respectively.
cMICs determined by using Etest (Tay et al. 2006).
dMICs determined by using EUCAST broth microdilution (Gomez-Lopez et al [2008]).
North American invasive mycoses 19
cause infections include Trichosporon, Rhodotorula,
Saccharomyces, and Blastoschizomyces (Pfaller et al.
2004a; Pfaller et al. 2009a). Although in many instances
these organisms may be considered colonizers or
supercial pathogens (skin or mucosal infections), all
may cause fungemia with or without organ invasion in
compromised patients, often are resistant to antifungals,
and are a challenge to diagnose and treat (Flemming
et al.2002; Nucci et al. 2005; Pfaller et al. 2004a; Pfaller
et al. 2006c; Pfaller et al. 2009a; Spanankis et al. 2006;
Walsh et al. 1999; Walsh et al. 2004).
ese genera are a very heterogeneous group of
fungi, some of which have undergone revisions in clas-
sication and nomenclature (Guarro et al. 1999; Masala
et al. 2003). Trichosporon and Rhodotorula are basidi-
omycetous yeasts characterized by their urease activity,
diazonium blue B (DBB) staining reactions, guanine/
cytosine (G/C) content, DNA association rates, and RNA
sequencing (Guarro et al. 1999). Saccharomyces and
Blastoschizomyces are ascomycetous yeasts character-
ized by a lack of urease production and the formation of
ascoconidia.
Trichosporon
Trichosporon spp. are among the most common of the
non-Candida, non-Cryptococcus yeasts isolated from
clinical specimens throughout the world (Pfaller et al.
2009a). Prior to 1992, Trichosporon beigelii was the pre-
dominant cause of human disease. Partial sequencing
of the small and large subunits, as well as the intergenic
spacer 1 (IGS1) region, of rRNA have clearly delineated
numerous species (Guarro et al. 1999; Hazen et al. 2007;
Rodriguez-Tudela et al. 2005; Rodriguez-Tudela et al.
2006). ese species have dierent habitats and usually
occupy narrow ecologic niches (Guarro et al. 1999). Some
are soil borne and others are associated with humans
and animals. Six species are of clinical signicance: T.
asahii, T. inkin, T. mucoides, T. cutaneum, T. ovoides,
and T. asteroides (Guarro et al. 1999; Hazen et al. 2007;
Rodriguez-Tudela et al. 2005; Rodriguez-Tudela et al.
2006). e rst three are regularly isolated from clinical
specimens (Kontoyiannis et al. 2004; Nettles et al. 2003;
Ramos et al. 2004; Roden et al. 2005; Wolf et al. 2001),
whereas the others are uncommon. Recently, T. lou-
beri and T. mycotoxinivorans have been described and
reported as causes of disseminated disease (Hazen et al.
2007; Marty et al. 2003).
Trichosporon spp. have long been recognized as
causing invasive disease in patients who are immuno-
suppressed in the setting of hematologic or solid tumor
malignancies or SOT (Abliz et al. 2002; Antachopoulos
et al. 2005; Erer et al. 2000; Goodman et al. 2002;
Kontoyiannis et al. 2004; Marty et al. 2003; Matsue et al.
2006; Nettles et al. 2003; Ramos et al. 2004; Watson et al.
1970). Although T. beigelii was reported as the cause
of invasive infections in the older literature (Erer et al.
2000; Hoy et al. 1986; Walsh et al. 1990), T. asahii and
less frequently T. mucoides, T. inkin, T. louberi, and T.
mycotoxinivorans are now recognized as the species
causing invasive trichosporinosis (Rodriguez-Tudela
et al. 2006).
Trichosporon infections in immunocompromised
patients are usually disseminated, involve major
organs, and most have been fatal (Erer et al. 2000; Hoy
et al. 1986; Kontoyiannis et al. 2004; Walsh et al. 1990).
Investigations in a U.S. cancer center have noted a
change from disseminated disease to a predominance
of catheter-related infection without evidence of tissue
invasion (Hoy et al. 1986; Kontoyiannis et al. 2004). e
authors speculated that this may be due to the increased
utilization of central venous catheters in a susceptible
population or that extensive use of uconazole prophy-
laxis has been eective in preventing tissue invasion
(Kontoyiannis et al. 2004).
In addition to neutropenic cancer patients, other
patients at risk for trichosporonosis include those with
AIDS, extensive burns, intravascular catheters, those
receiving corticosteroids or undergoing heart valve
surgeries (Abliz et al. 2002; Antachopoulos et al. 2005;
Cawley et al. 2000; Erer et al. 2000; Goodman et al. 2002;
Nettles et al. 2003; Ramos et al. 2004; Wolf et al. 2001).
A report of an outbreak involving three dierent ICUs
found T. asahii causing supercial and invasive disease
in six non-granulocytopenic patients (Wolf et al. 2001).
e authors suggested that the pathogenesis of trichos-
poronosis in the ICU may be similar to that of candidia-
sis with mucosal colonization and subsequent invasion
via breaks in mucosal or cutaneous surfaces (Wolf et al.
2001). Notably, the isolates of T. asahii in this report
were found to be multi-drug-resistant (amphotericin
B, ucytosine, azoles, and echinocandins) and shared a
common genotype, suggesting a common origin. us,
a colonized gastrointestinal tract and central venous
catheters are considered portals of entry for the estab-
lishment of trichosporonosis. e ability of T. asahii to
form a biolm on catheters or other biomaterials may
be a major factor in the persistence of the infection by
enhancing resistance to antifungal agents and protec-
tion from host defenses (Di Bonaventura et al. 2006).
Susceptibility of Trichosporon spp. to amphotericin B
is variable and this agent lacks fungicidal activity against
this organism (Table 17) (Puzniak et al. 2006; Raad et al.
2006). Clinical failures with amphotericin B, ucona-
zole, and combinations of the two have been reported,
and the outcome is generally dismal in the absence of
neutrophil recovery (Erer et al. 2000; Kontoyiannis et al.
2004; Raad et al. 2006). Kontoyiannis et al. (Kontoyiannis
et al. 2004) have noted that breakthrough trichosporo-
nosis may occur during systemic therapy with most anti-
fungal agents, regardless of the dosage or duration. e
20 M. A. Pfaller, and D. J. Diekema
intrinsic resistance of this organism to the echinocandin
antifungal agents is underscored by reports of break-
through infections in bone marrow transplant recipients
(Goodman et al. 2002) and in patients with hematologic
malignancies (Matsue et al. 2006) receiving caspofungin
and micafungin, respectively. Notably, the new triazoles,
voriconazole, posaconazole, and ravuconazole, appear
to be more active that uconazole against Trichosporon
(Table 17) (Arikan et al. 2002; Falk et al. 2003; Paphitou
et al. 2002; Pfaller et al. 2009a; Ramos et al. 2004;
Rodriguez-Tudela et al. 2005; Serena et al. 2004; Serena
et al. 2005), and voriconazole has been used successfully
to treat disseminated T. asahii infection in three patients
with acute leukemia (Antachopoulos et al. 2005; Asada
et al. 2006; Fournier et al. 2002). In general, non-T. asahii
isolates appear to be more susceptible than T. asahii iso-
lates to amphotericin B, uconazole, and itraconazole,
while the new triazoles are active against both T. asahii
and non-T. asahii isolates (Table 17) (Rodriguez-Tudela
et al. 2005). Given the diculty in accurately identify-
ing the various species of Trichosporon, it may be more
practical to perform antifungal susceptibility testing on
clinical isolates, as opposed to species identication, as
an aid in selecting an antifungal agents which exhibits
activity against the infecting strain (Rodriguez-Tudela
et al. 2005).
Rhodotorula
Rhodotorula is a basidiomycetous yeast that produces
carotenoid pigments ranging from pink to red that
can be visualized with individual colonies. is genus
shares physiologic and morphologic properties with
Cryptococcus spp. Species of Rhodotorula recovered
from clinical specimens include R. mucilaginosa (syn.
R. rubra), R. glutinis, and R. minuta. Rhodotorula spp.
can also be recovered from environmental sources and
are transient colonizers of moist skin (Hazen et al. 2007;
Pfaller et al. 2007d; Pfaller et al. 2009a).
Rhodotorula spp. have been increasingly recognized
as important human pathogens. Immunocompromised
patients, particularly those with central venous catheters
(CVC) or other indwelling devices, are at highest risk
for infection due to Rhodotorula spp., most commonly
presenting as fungemia (Anatoliotake et al. 2003; Chung
et al. 2002; Hseuh et al. 2003; Kiehn et al. 1992; Kiraz
et al. 2000; Lo et al. 2003; Lundardi et al. 2006; Perniola
et al. 2006; Petrocheilou-Paschou et al. 2001; Pfaller
et al. 2009a; Zaas et al. 2003). In addition to fungemia,
other sites of infection include endocarditis (Naveh et al.
1975), meningitis (Pore et al. 1976), peritonitis (Wong
et al. 1998), and ocular infections (Gregory et al. 1992;
Guerra et al. 1992; Muralidhar et al. 1995).
Risk factors for fungemia due to Rhodotorula spp.
are similar to those described for other opportunistic
fungal BSIs (Table 1) (Chung et al. 2002; Kiehn et al.
1992; Lundardi et al. 2006; Perniola et al. 2006; Zaas
et al. 2003): CVC, hyperalimentation, broad-spectrum
antibacterials, immunosuppression, neutropenia, and
surgery. More recently, prophylaxis or treatment with
uconazole has also been found to be a risk factor for
Rhodotorula fungemia (Goldani et al. 1995; Lundardi
et al. 2006; Perniola et al. 2006; Petrocheilou-Paschou
et al. 2001). e importance of CVCs and uconazole
prophylaxis as risk factors was highlighted in a report of
a nosocomial outbreak of R. mucilaginosa fungemia in
a neonatal ICU (Perniola et al. 2006). Rhodotorula fun-
gemia has been associated with a crude mortality of 20%
(Lundardi et al. 2006) and can cause sepsis syndrome
and other life-threatening complications (Kiehn et al.
1992; Pien et al. 1980).
ere are few studies in the literature dealing with
the in vitro susceptibility of Rhodotorula to systemically
active antifungal agents (Table 17) (Diekema et al. 2005;
Galen-Sanchez et al. 1999; Gomez-Lopez et al. 2005;
Pfaller et al. 2009a; Serena et al. 2004; Serena et al. 2005;
Zaas et al. 2003). When isolates are tested by CLSI meth-
ods they are most susceptible to amphotericin B and
ucytosine (Table 17). e MICs of uconazole and the
echinocandins are all high, representing resistance to
these agents. Among the extended-spectrum triazoles,
only ravuconazole appears to have promising activity
(Diekema et al. 2005; Serena et al. 2004; Zaas et al. 2003).
Due to the intrinsic resistance of Rhodotorula spp. to
triazoles and echinocandins, patients receiving these
agents are susceptible to develop Rhodotorula fungemia
(Lundardi et al. 2006; Zaas et al. 2003). Amphotericin B,
coupled with catheter removal, is an optimal therapeutic
approach to infections with Rhodotorula spp. (Lundardi
et al. 2006; Zaas et al. 2003).
Saccharomyces
Saccharomyces cerevisiae is widespread in nature and
can be found on plants and fruit and in soil (Kwon-
Chung et al. 1992). is yeast is now included in some
diet or health foods and S. cerevisiae subtype boulardii
is also used in probiotic preparations for the prevention
and treatment of various diarrheal disorders, such as
those associated with enteral nutrition and Clostridium
dicile infection (Herbrecht et al. 2005; Marteau et al.
2001).
S. cerevisiae is a common colonizer of mucosal sur-
faces and part of the normal ora of the GI tract, the
respiratory tract, and the vagina (Salonen et al. 2000).
It accounts for 27% of clinical isolates of non-Candida,
non-Cryptococcus yeasts in North America (Pfaller et al.
2007d; Pfaller et al. 2009a).
Since the 1980s, S. cerevisiae has also been isolated
from persons with pathologic conditions and has been
considered to be a cause of IFIs (Enache-Angoulvant
et al. 2005; Munoz et al. 2005; Olver et al. 2002; Rijnders
North American invasive mycoses 21
et al. 2000; Viggiano et al. 1995; Zerva et al. 1996). S. cer-
evisiae can cause a wide variety of clinical syndromes
such as pneumonia, empyema, liver abscess, peritonitis,
vaginitis, esophagitis, urinary tract infection, cellulitis,
unexplained fever, or septic shock (Herbrecht et al. 2005;
Munoz et al. 2005; Salonen et al. 2000). Its presence in
normally sterile sites has been attributed to rupture of
local barriers or secondary to high fungal loads. Portals
of entry include translocation of ingested organisms
from the enteral or oral mucosa and contamination of
intravenous catheter sites (Enache-Angoulvant et al.
2005; Hennequin et al. 2000; Munoz et al. 2005; Olver
et al. 2002; Salonen et al. 2000).
Saccharomyces infection is clinically indistinguish-
able from invasive candidiasis. Fever is common and
chorioretinitis may be seen in both conditions. e most
important clinical syndrome caused by S. cerevisiae is
fungemia. S. cerevisiae fungemia has been described in
immunosuppressed patients and critically ill patients
but also in relatively healthy hosts (Enache-Angoulvant
et al. 2005; Munoz et al. 2005). Population-based studies
indicate that S. cerevisiae accounts for 0.1% to 3.6% of
all episodes of fungemia, and the crude mortality is 28%
(Lherm et al. 2002; Munoz et al. 2005; Rees et al. 1998).
More than 80% of reports of S. cerevisiae as the etio-
logic agent of serious IFI have been published since
1990, and 40% of those infections have implicated S.
cerevisiae subtype boulardii (Enache-Angoulvant et al.
2005; Munoz et al. 2005). Risk factors associated with
Saccharomyces fungemia are similar to those reported for
invasive candidiasis (Table 1), except for treatment with
a probiotic containing S. cerevisiae subtype boulardii
(Enache-Angoulvant et al. 2005). Several recent reviews
of the literature concerning fungemia and IFI due to S.
cerevisiae have concluded the following (Cassone et al.
2003; Enache-Angoulvant et al. 2005; Herbrecht et al.
2005; Munoz et al. 2005): (1) fungemias can occur in
immunocompetent persons and may contribute to mor-
bidity and mortality in immunocompromised patients,
(2) enteral translocation of ingested organisms and CVC
hub or insertion site contamination are the main portals
into the bloodstream, (3) prevention of CVC-related fun-
gemias can be achieved by attention to catheter care and
other simple prophylactic measures, and (4) uconazole
and amphotericin B are eective therapeutic options:
removal of CVCs and withdrawal of the probiotic regi-
men, if it was being given, are also advised.
S. cerevisiae has been consistently susceptible to both
amphotericin B and ucytosine (Table 17) (Cuenca-
Estrella et al. 2006; Swinne et al. 2005; Zerva et al. 1996).
Most isolates are moderately susceptible to ucona-
zole and itraconazole (Table 17); however, high-level
resistance to uconazole has been described (Salonen
et al. 2000) as has therapeutic failure with this agent
(Burkhardt et al. 2005). Although data remain scarce,
voriconazole and posaconazole, as well as caspofun-
gin, have demonstrated good activity against a limited
number of strains (Table 17). Voriconazole has been
used successfully to treat sepsis due to S. cerevisiae sub-
type boulardii following initial failure with uconazole
(Burkhardt et al. 2005).
Blastoschizomyces
Blastoschizomyces is a genus with many similarities to
Trichosporon. ere is only one species, B. capitatus
(teleomorph Dipodascus capitatus) (Salkin et al. 1985).
B. capitatus may be dierentiated from Trichosporon
by specic assimilation patterns, a negative urease test,
and by the ability to grow on Sabouraud glucose agar
at 42°C and on cycloheximide-containing agar at room
temperature (Hazen et al. 2007). B. capitatus is com-
monly found in the environment and may be recovered
from the skin, GI tract, and respiratory tract of healthy
humans. Invasive disease has been documented in
immunocompromised patients (Girmenia et al. 2005;
Martino et al. 2004).
Although opportunistic infections with B. capitatus
can occur in various types of immunocompromised
hosts, those with hematologic malignancies are by far
the most common victims of this infection (Girmenia
et al. 2005; Martino et al. 2004). Among the 88 cases of B.
capitatus infection reported in the world’s literature, 92%
had hematologic disease (Girmenia et al. 2005). Most of
the infected patients had acute leukemia and had been
treated with conventional cytotoxic chemotherapy. Very
few had received a hematopoietic stem cell transplant
and the infections usually occurred during a period of
profound neutropenia (<100 cells/mm3).
Infection with B. capitatus presents similarly to that of
invasive candidiasis in neutropenic patients (Girmenia
et al. 2005; Martino et al. 2004). us, most (>70%)
patients have fungemia, but 60% to 80% of patients with
IFI due to B. capitatus develop deep organ involvement,
compared with only 10% to 20% of patients with candi-
demia (Martino et al. 2004). e 30-day mortality asso-
ciated with B. capitatus infection ranges from 60% to
80% (Girmenia et al. 2005; Martino et al. 2004). As with
Trichosporon, a chronic disseminated form of B. capita-
tus infection, similar to chronic disseminated candidia-
sis, may be seen upon resolution of neutropenia.
In vitro antifungal susceptibilities of B. capitatus
determined by CLSI methods indicate high levels of
susceptibility to amphotericin B, itraconazole, posaco-
nazole, and voriconazole (Table 17) (Cuenca-Estrella
et al. 2006; Girmenia et al. 2003; Pfaller et al. 2009a).
Most isolates are susceptible to ucytosine and uco-
nazole, although isolates with decreased susceptibility
to both of these agents, as well as amphotericin B, have
been observed (Bouza et al. 2004; Buchta et al. 2001;
Girmenia et al. 2003; Girmenia et al. 2005; Martino et al.
22 M. A. Pfaller, and D. J. Diekema
2004; Plum et al. 1996). Indeed, up to 36% of infections
present as breakthrough infections during treatment
or prophylaxis with amphotericin B or uconazole
(Bouza et al. 2004; Girmenia et al. 2005; Plum et al.
1996). Caspofungin, and the other echinocandins, lack
any meaningful activity against this organism (Table 17)
(Cuenca-Estrella et al. 2001).
Pneumocystis Infections
e organism Pneumocystis jirovecii (formerly P. carinii
f. sp. hominis) is an ascomycetous fungus that causes
life-threatening pulmonary infection in debilitated
and immunocompromised individuals (Cushion.
2007; Morris et al. 2004; Morris et al. 2008; Tellez et al.
2008; Walzer et al. 2008). Despite prophylaxis and the
immunomodulating eects of HAART, Pneumocystis
pneumonia (PCP) remains among the most important
opportunistic infections in HIV-infected persons (Bin
et al. 2006; Dei-Cas. 2000; Morris et al. 2002; Morris et al.
2004, Morris et al. 2008; Patel et al. 2004; Tellez et al.
2008; omas et al. 2004; Wakeeld. 2002; Walzer et al.
2008; Wazir et al. 2004). In the U.S. and other industri-
alized countries, PCP in HIV-infected persons is seen
largely in those unaware of their HIV serostatus or in
those non-compliant with or intolerant of prophylaxis
and antiretroviral therapies (Bin et al. 2006; Mikaelsson
et al. 2006; Morris et al. 2004; Patel et al. 2004; Tellez
et al. 2008; Teshale et al. 2007; omas et al. 2004; Walzer
et al. 2008). In non-HIV associated immunosuppressed
patients (transplantation, malignancy, connective tis-
sue disease), Pneumocystis infection remains a signi-
cant cause of morbidity and mortality (Bin et al. 2006; de
Boer et al. 2007; De Castro et al. 2005; Hocker et al. 2005;
Manolo et al. 2003; Morris et al. 2004; Rabodonirina
et al. 2004, Roblot et al. 2004).
Pneumocystis is ubiquitous throughout nature,
infecting a variety of warm-blooded animals. Despite
a potential reservoir of this fungus in rodents (Stringer.
1996), it is now understood that human pneumocys-
tosis is not a zoonotic disease (Dei-Cas. 2000; Miller
et al. 2004; Redhead et al. 2006; Stringer et al. 2002;
Wakeeld. 2002). Molecular evidence conrms the host
species-specic nature of each species of Pneumocystis
and the genetic diversity within each species has been
utilized to trace the spread of P. jirovecii throughout
the human population (Beard et al. 2000; Beard et al.
2004; Larsen et al. 2007; Medrano et al. 2005; Peterson
et al. 2005; Redhead et al. 2006; Totet et al. 2003; Totet
et al. 2004; Wakeeld et al. 2003). Using PCR-based
methods of detection and strain typing, it appears that
the most important potential reservoirs of P. jirovecii
are children and both symptomatic and asymptomatic
immunocompromised individuals (Beard et al. 2004;
Larsen et al. 2007; Medrano et al. 2005; Morris et al.
2002; Morris et al. 2004; Morris et al. 2008; Peterson
et al. 2005; Wakeeld et al. 2003).
Reports of the detection of P. jirovecii in both infant
and adult populations, ranging from those without
immunosuppression to those with chronic underlying
diseases that have not been historically associated with
its presence suggest colonization, or expansion of its
host range (Larsen et al. 2007; Morris et al. 2008; Totet
et al. 2004; Vargas et al. 2001). It has been shown that P.
jirovecii is carried in the respiratory tracts of infants with
mild respiratory infections, in asymptomatic adults with
mild immunosuppression induced by HIV or malig-
nancy, in patients receiving long-term corticosteroid
therapy for malignancy or connective tissue disease, and
in pregnant women (Morris et al. 2008). e detection of
P. jirovecii DNA in respiratory samples of these asymp-
tomatic patient groups has been variously described
as colonization, carriage, asymptomatic infection, and
subclinical infection (Morris et al. 2008). ese groups
of patients may be important in the human-to-human
transmission of P. jirovecii and they may be a reservoir
for future Pneumocystis infection in other susceptible
(immunosuppressed) individuals (Morris et al. 2008;
Peterson et al. 2005; Wakeeld 2002).
PCP has been diagnosed in patients worldwide.
Studies in humans and animals clearly favor airborne
transmission and there is now compelling evidence for
both human and environmental sources of infection
(Beard et al. 2000; Dei-Cas. 2000; Kovacs et al. 2001;
Larsen et al. 2007; Manolo et al. 2003; Medrano et al.
2005; Morris et al. 2002; Morris et al. 2004; Morris et al.
2008; Peterson et al. 2005; Rabodonirina et al. 2004; Totet
et al. 2003; Totet et al. 2004). Traditionally it was thought
that pneumocystosis resulted from reactivation of latent
infection that was acquired during childhood (Cushion
2007; Totet et al. 2003; Wakeeld 2002). Although pri-
mary infection clearly does occur early in life (Morris
et al. 2002; Morris et al. 2004; Morris et al. 2008), there
is now evidence that Pneumocystis organisms are fre-
quently acquired and cleared by the immune system of
immune competent humans, that patients with recur-
rent episodes of PCP are often reinfected with a dierent
genotype of P. jirovecii associated with each new episode
of infection, and that allelic variation patterns in isolates
of P. jirovecii are correlated with the patients’ place of
diagnosis and not their place of birth (Beard et al. 2000;
Kovacs et al. 2001; Medrano et al. 2005; Morris et al. 2002;
Morris et al. 2004; Morris et al. 2008; Peterson et al. 2005;
Totet et al. 2003). us, reactivation may certainly occur,
but the bulk of the evidence supports the acquisition
of new infections via environmental exposure, or more
likely person-to-person transmission (Beard et al. 2000;
Beard et al. 2004; Peterson et al. 2005; Wakeeld 2002).
Clusters of PCP in oncology and transplant centers
suggest the possibility that P. jirovecii can be transmitted
North American invasive mycoses 23
from person to person (de Boer et al. 2007; Hocker et al.
2005; Manolo et al. 2003; Rabodonirina et al. 2004;
Roblot et al. 2004). Epidemiologic investigations of such
clusters have demonstrated that many of the infected
patients had contact with each other (de Boer et al. 2007;
Hocker et al. 2005; Manolo et al. 2003; Rabodonirina
et al. 2004). Whereas this may be construed as evidence
for patient-to-patient transmission, it could also repre-
sent a common environmental exposure (Morris et al.
2002). Notably, it has been shown that some asympto-
matic healthcare workers (HCW) may be Pneumocystis
carriers (Durand-Joly et al. 2003; Miller et al. 2001b;
Nevez et al. 2003; Peterson et al. 2005). HCW who were in
contact with HIV patients were shown to be at increased
risk for carriage of Pneumocystis (24%) compared with
non-exposed workers (11%), suggesting patient-to-
HCW transmission (Miller et al. 2001b; Peterson et al.
2005). Although this and other studies suggest that
transmission from PCP patients to others can occur,
other sources of exposure must exist (Morris et al. 2008;
Peterson et al. 2005).
e rst cases of PCP were reported in malnourished
children in Europe during World War II (106). In the
late 1960s and early 1970s, there were fewer than 100
cases per year of PCP in the U.S. (Walzer et al. 1974). e
disease was recognized in patients who were immuno-
compromised because of malignancies, immunosup-
pressive therapy, or congenital immunodeciencies.
SOT increased the number of patients at risk for PCP
although rates decreased after the introduction of che-
moprophylaxis. Without chemoprophylaxis, rates of
PCP are 5–25% in transplant recipients, 2–6% in patients
with collagen vascular disease, and 1–25% in patients
with cancer (Kovacs et al. 2001). Defects in CD4+ T lym-
phocytes are a primary risk factor for development of
PCP, but defects in B cells and antibody production may
also predispose to PCP (Bin et al. 2006; Cushion 2007;
De Castro et al. 2005; Roblot et al. 2004). Among patients
with malignancies and transplantation, additional risk
factors include prolonged corticosteroid administra-
tion, other immunosuppressive regimens, chronic graft-
versus-host disease (GVHD), and relapse of hematologic
malignancy (De Castro et al. 2005; Kovacs et al. 2001;
Morris et al. 2004; Roblot et al. 2004).
In the early stages of the AIDS epidemic, PCP rates
were as high as 20 per 100 person-years for those with
CD4+ counts <200 cells/μl (Morris et al. 2004; Phair
et al. 1990). In the early 1990s, there was a decline in the
incidence that was largely due to the widespread use of
PCP prophylaxis (Morris et al. 2004). Although the abso-
lute number of cases remained stable from 1989 to 1992
due to the increasing incidence of AIDS, the percentage
of AIDS cases with PCP declined from 53% in 1989 to
49%, 46%, and 42% in 1990, 1991, and 1992, respectively
(Morris et al. 2004).
Data from the Adult and Adolescent Spectrum of
HIV Disease (ASD) Project indicated a marked reduc-
tion in the incidence of PCP, and other opportunistic
infections, in 1996 and 1997, when HAART rst became
widely available (Cushion 2007; Kaplan et al. 2000;
Kovacs et al. 2001; Morris et al. 2004). PCP cases declined
by 3.4% per year from 1992 through 1995, whereas the
rate of decline increased to 21.57% per year from 1996
through 1998 (Kaplan et al. 2000; Morris et al. 2004;
Tellez et al. 2008). Despite these substantial advances,
P. jirovecii remains a major pathogen in HIV-infected
persons who: (1) are unaware of their HIV-positive
serostatus; (2) have inadequate access to medical care;
(3) do not adhere to chemoprophylaxis or HAART
(Masur et al. 2002; Morris et al. 2002; Tellez et al. 2008;
Teshale et al. 2007). Although HAART has decreased
the mortality of PCP among HIV-infected individuals,
it remains extremely high. Tellez et al (Tellez et al. 2008)
studied PCP-related mortality among a population of
medically underserved HIV-infected inner city persons
living in Atlanta, GA during the pre-HAART period
(1990 to 1995) and in the HAART period (1996 to 2001).
e overall mortality rate was 47% during the pre-
HAART era compared with 37% during the HAART era
(p = 0.02). However, among those patients that required
ICU admission and mechanical ventilation, the mortal-
ity rate was over 80% during both periods. When both
periods were combined the overall risk of death was
higher for those patients who did not take PCP prophy-
laxis, those who smoked tobacco, and those who were
admitted to the ICU and required mechanical ventila-
tor support (Tellez et al. 2008).
e broad use of sulfa agents for prophylaxis and
treatment of PCP has placed extraordinary selective
pressure on this organism. Recent reports have suggested
the emergence of P. jirovecii resistant to sulfonamides
(Huang et al. 2004; Stein et al. 2004). Mutations found
in the P. jirovecii dihydropteroate synthase (DHPS) gene,
which are homologous to mutations causing sulfa resist-
ance in other pathogens (e.g., Plasmodium falciparum,
Streptococcus pneumoniae, Neisseria meningitidis), are
associated with previous exposure to sulfa drugs and
with an increased risk of death from PCP (Dei-Cas 2000;
Helweg-Larsen et al. 1999; Huang et al. 2004; Kovacs
et al. 2001; Stein et al. 2004; Wakeeld 2002). e pres-
ence of multiple mutations in a gene locus that otherwise
lacks variability is indicative of pronounced selective
pressure (Huang et al. 2004; Stein et al. 2004). Although
such a degree of selection is not itself an indication of
resistance, it does suggest that resistance may be emerg-
ing. Potential drug-resistant strains of P. jirovecii could
present more of a problem for HIV-negative immuno-
suppressed persons than HIV-infected persons who
may recover immune function thanks to HAART (Huang
et al. 2004; Kovacs et al. 2001; Stein et al. 2004). e
24 M. A. Pfaller, and D. J. Diekema
development of new anti-Pneumocystis treatment and
prevention strategies remains a priority.
Aspergillus Infections
Aspergillus species are ubiquitous fungi that may be iso-
lated from a variety of environmental sources, includ-
ing soil, grain, leaves, grass, and air (Barnes et al. 2006;
Patterson et al. 2000). Reservoirs in hospitals from which
aspergilli have been cultured include unltered air, ven-
tilation systems, dust dislodged during construction,
carpeting, food, ornamental plants, and water systems
(Anaissie et al. 2002; Barnes et al. 2006; Lass-Florl et al.
2000; Patterson et al. 2000; Vonberg et al. 2006). Although
several hundred species of Aspergillus have been
described, relatively few are known to cause disease in
humans. A. fumigatus remains the most common cause
of invasive aspergillosis (IA), although the proportion of
IA cases caused by A. fumigatus has fallen from approxi-
mately 90% of cases in the 1980s to 50% to 60% of cases
in the 1990s into the 2000s (Table 18) (Marr et al. 2002b;
Neofytos et al. 2009a; Neofytos et al. 2009b). e other
species of Aspergillus commonly causing IA include A.
avus, A. niger, A. terreus, A. versicolor, and A. nidu-
lans (Baddley et al. 2001b; Baddley et al. 2003; Perfect
et al. 2001; Sutton. 2008). e application of molecular
techniques to the genus Aspergillus has revealed several
uncommon but potentially important species includ-
ing A. lentulus and A. ustus (Alcazar-Fuoli et al. 2008;
Balajee et al. 2005; Balajee et al. 2007; Panackal et al.
2006; Sutton. 2008).
Exposure to Aspergillus conidia in the environment
may cause allergic reactions in hypersensitized hosts or
destructive invasive pulmonary and disseminated dis-
ease in highly immunosuppressed individuals (Baddley
et al. 2001b; Garcia-Vidal et al. 2008; Marr et al. 2002b;
Neofytos et al. 2009a; Neofytos et al. 2009b; Patterson
et al. 2000). Aspergillus infections occur worldwide
and appear to be increasing in prevalence (Barnes
et al. 2006; Garcia-Vidal et al. 2008; Morgan et al 2005b;
Patterson et al. 2000). National Hospital Discharge
data from the 1990s through 2003 reveal that there are
approximately 10,000 aspergillosis-related hospitaliza-
tions annually in the U.S. (Dasbach et al. 2000; Pfaller
et al. 2007a). Although the total number of infections
due to Aspergillus spp. is small compared with those
caused by Candida spp. (Table 3), Aspergillus spp. are
particularly important causes of infections in patients
who are immunocompromised as a result of burn
injury, malignancy, leukemia, HSCT, and SOT (Tables
6 and 7) (Barnes et al. 2006; Garcia-Vidal et al. 2008;
Neofytos et al. 2009a; Neofytos et al. 2009b; Patterson
et al. 2000).
Although IA is a devastating complication for SOT
recipients (Barnes et al. 2006; Morgan et al 2005b; Neofytos
et al. 2009b), the incidence of IA in these patients has
been lower than in HSCT recipients (Table 6), probably
because of the greater degree of granulocytopenia among
HSCT recipients (Morgan et al. 2005b). Most studies
place the cumulative incidence of IA among allogeneic
HSCT recipients at between 3% and 15% (Chamilos et al.
2006; Morgan et al. 2005b; Siwek et al. 2006). e fre-
quency of IA varies according to the type of HSCT donor
and the organ transplanted (Table 7) (Garcia-Vidal et al.
2008; Morgan et al. 2005b; Neofytos et al. 2009a). e rate
of IA is highest among recipients of HSCT from an HLA-
mismatched or unrelated donor, whereas among SOT
recipients IA most often aects those undergoing lung
transplantation (Table 7) (Fishman et al. 2007; Garcia-
Vidal et al. 2008; Morgan et al. 2005b; Neofytos et al.
2009a; Neofytos et al. 2009b).
A shift from early (0 to 40 days post transplant) to
late (>40 days post transplant) IA after HSCT was noted
in the early 1990s (Grow et al. 2002; Marr et al. 2002a).
Similarly, a shift towards a later occurrence of IA in SOT
recipients (liver) was noted at about the same period
with more than 50% of cases occurring >90 days post-
transplant (Collins et al. 1994; Gavalda et al. 2005; Patel
et al. 1996; Singh et al. 2003). In a recent assessment
of invasive mould infection (IMI) in HSCT recipients,
Garcia-Vidal et al. (Garcia-Vidal et al. 2008) found that
among 142 cases of IA 25% occurred within the rst 40
days post-transplant (early IA), 42% occurred between
day 41 and day 100 (late IA), and 33% occurred after day
100 (very late IA). Neofytos et al (Neofytos et al. 2009a)
found that almost two-thirds of IA cases in allogeneic
HSCT recipients in the PATH Alliance Fungal Registry
were observed more than 40 days post-transplant; how-
ever, a number of IA cases in allogeneic (37.1%) and
autologous (48.9%) HSCT recipients were diagnosed
within 40 days after transplant. Among SOT recipients
in the PATH Alliance registry, IA occurred earlier post-
transplant in liver (median 99.5 days) compared to lung
(median 504 days) and heart (median 382 days) trans-
plant recipients (Neofytos et al. 2009b). Notably, 75% of
liver transplant recipients with IA were diagnosed after
Table 18. Species distribution of Aspergillus isolates from
hematopoietic stem cell transplant (HSCT) and solid organ transplant
(SOT) recipients.a
Aspergillus spp.
HSCT SOT
(N = 149) (N = 128)
A. fumigatus 36.9 61.7
A. avus 3.4 10.2
A. niger 3.4 10.2
A. terreus 0.6 3.1
Other spp. 3.4 7.8
Unknown spp.b52.3 7.0
aData compiled from Neofytos et al. (2009a; 2009b).
bDiagnosis made by means of either histopathology or galactomannan
detection.
North American invasive mycoses 25
100 days, whereas 61.8% of lung transplant recipients
with IA developed disease greater than 1 year post-
transplant (Neofytos et al. 2009b). ese changes are
likely attributable to changing HSCT practices (e.g., use
of peripheral blood as a stem cell source, nonmyeloab-
lative conditioning), routine antifungal prophylaxis, and
improvement in SOT surgical technique and immuno-
suppressive regimens that result in attenuated cytope-
nias and that allow patients to survive for much longer
than previously (Garcia-Vidal et al. 2008; Neofytos et al.
2009a; Neofytos et al. 2009b).
Risk factors
IA aects a more narrow range of patients than invasive
Candida infection (Table 6). Nearly two-thirds (61%) of
patients with IA have underlying hematological diseases
(including hematological malignancies) or have under-
gone HSCT (Morgan et al. 2005b; Patterson et al. 2000).
Major risk factors for IA include prolonged or repeated
episodes of neutropenia, age greater than 40 years,
broad-spectrum antibacterial therapy, administration
of corticosteroids, grade III-IV graft-versus-host disease
(GVHD), receipt of HSCT from an HLA-mismatched or
unrelated donor, and the use of iniximab or other TNF
inhibitors (Kontoyiannis et al. 2005; Lin et al. 2001; Marr
et al. 2002b; Patterson et al. 2000; Perfect. 2004). Garcia-
Vidal et al (Garcia-Vidal et al. 2008) recently examined
IMI risk factors according to time after transplantation
in allogeneic HSCT recipients, 86% of which were IA.
Risk factors associated with early IA included receipt of
antithymocyte globulin, poor-risk underlying disease,
and receipt of an unrelated-donor or HLA-mismatched
HSCT. Additional biological risk factors for early IA
included hyperglycemia, iron overload (elevated ferritin
level, receipt of transfusions), and lymphopenia (Garcia-
Vidal et al. 2008). Risk factors associated with late IA
included advanced age and female sex. No transplant-
related factors were independently associated with late
IA, whereas a number of transplant complications posed
signicant risks, including acute GVHD (grade ≥3), CMV
disease, high corticosteroid dose, and high frequency of
blood transfusions (Garcia-Vidal et al. 2008).
Baddley et al (Baddley et al. 2001b) found that more
than half of the allogeneic HSCT recipients who devel-
oped invasive mycoses due to pathogens other than
A. fumigatus had received antifungal prophylaxis with
amphotericin B. e causes of breakthrough aspergil-
losis in these patients included species such as A. ter-
reus and A. ustus with demonstrated in vitro resistance
to amphotericin B. e authors suggested that ampho-
tericin B prophylaxis may have led to the emergence of
resistant organisms (Baddley et al. 2001b).
e most important extrinsic risk factor for IA is the
presence of Aspergillus spp. in the hospital environment.
Transmission of Aspergillus to high-risk patients occurs
primarily by the airborne route, but contact transmis-
sion (e.g. direct inoculation from occlusive materi-
als) has also been implicated (Vonberg et al. 2006).
Outbreaks of nosocomial aspergillosis occur most com-
monly among granulocytopenic patients (<1000 cells/
mm3) and have been described in association with
exposure to Aspergillus conidia aerosolized by hospital
construction, contaminated air-handling systems, and
insulation or reproong materials within walls or ceil-
ings of hospital units (Barnes et al. 2006; Patterson et al.
2000; Vonberg et al. 2006). Hospital water, which may
become aerosolized during such activities as patient
showering, is an additional potential source (Anaissie
et al. 2002).
In high-risk patients, a respiratory tract specimen
(e.g., sputum or bronchoalveolar lavage) that is culture-
positive for Aspergillus spp. is predictive of invasive dis-
ease. A positive respiratory tract culture was associated
with IA in nearly two-thirds of allogeneic HSCT recipi-
ents (64%) and patients with neutropenia (64%) and
in half the patients with hematological malignancies
(Perfect et al. 2001).
Mortality
e crude mortality associated with IA is high, but the
attributable mortality has been dicult to determine
given the high mortality rate in susceptible patients. A
review of cases of IA in the U.S. between 1995 and 2000
placed the attributable mortality rate at approximately
58% (Lin et al. 2001). e highest attributable mortality
rates have been observed among patients with aplastic
anemia and after HSCT (Cordonnier et al. 2006; Marr
et al. 2002a; Marr et al. 2002b). e survival rate of
patients with IA has been steadily improving, especially
in HSCT patients. e mortality rate in 1990 was >95%
but by the end of that decade the mortality rate had
decreased to between 55% and 80% (Barnes et al. 2006).
Analysis of the PATH Alliance database for the years
2004 through 2007 revealed 6- and 12-week mortality
rates of 21.5% and 35.5%, respectively, among 148 HSCT
recipients with IA (Neofytos et al. 2009a). Host variables
associated with improved survival at 6 weeks after the
diagnosis of IA were non-myeloablative conditioning
(P = 0.01) and absence of mechanical ventilation and/or
hemodialysis (P = 0.01) (Neofytos et al. 2009a). Among
SOT recipients in the PATH Alliance Registry, non-signif-
icant dierences in 12-week mortality were observed for
patients with IA between liver (50.0%), kidney (25.0%),
lung (21.3%), and heart (0.0%) (Neofytos et al. 2009b).
Improved survival in lung transplant recipients with IA
may reect increased clinical suspicion and the avail-
ability of new diagnostic surrogate markers (i.e., com-
puterized tomography [CT], galactomannan assay) that
lead to more timely diagnoses and initiation of eective
therapies, especially the use of voriconazole.
26 M. A. Pfaller, and D. J. Diekema
Prevention
Prevention of IA is a dicult issue and requires active
surveillance for cases of aspergillosis in the hospital set-
ting, minimization of host risk factors, and maintenance
of an environment as free as possible of Aspergillus
spores for patients with severe granulocytopenia (Tablan
et al. 2004). For those at highest risk of IA, provision of
high-eciency particulate air (HEPA) ltered environ-
ment is recommended (Eckmanns et al. 2006). Revised
guidelines for prevention of nosocomial aspergillosis
have been published by the CDC (Tablan et al. 2004);
however, despite these eorts, IA remains a constant
threat to the survival of immunocompromised patients.
Antifungal susceptibility
Specic antifungal therapy for IA often involves the
administration of amphotericin B or one of its lipid-
based formulations (Walsh et al. 2008). Although the
vast majority of Aspergillus species remain susceptible
to this class of antifungal agents (Table 19), it is impor-
tant to realize that A. terreus, A. lentulus, and A. ustus
are considered to be resistant to amphotericin B, and
infections with these species should be treated with an
alternative agent (Baddley et al. 2003; Balajee et al. 2005;
Iwen et al. 1998; Lass-Florl et al. 2000; Saracli et al. 2007;
Steinbach et al. 2004). e introduction of voriconazole
provides a treatment option that has excellent activity
against the majority of Aspergillus species (Table 19) and
that is more ecacious and less toxic than amphotericin
B (Herbrecht et al. 2002a; Steinbach et al. 2003a; Walsh
et al. 2008). Likewise, the echinocandins (anidulafun-
gin, caspofungin and micafungin), posaconazole, and
itraconazole show excellent activity against Aspergillus
species, including A. terreus (Table 19) (Diekema et al.
2003; Guinea et al. 2008; Pfaller et al. 2008f; Rodriguez-
Tudela et al. 2008). It is important to note that although
rare, A. lentulus and A. ustus may exhibit resistance to
both polyene and azole antifungals (Balajee et al. 2005).
Azole resistance among Aspergillus spp. is uncom-
mon (Diekema et al. 2003; Guinea et al. 2008; Pfaller et al.
2008f; Rodriguez-Tudela et al. 2008); however, multiply
azole-resistant clinical isolates are now well described
(Pfaller et al. 2008f; Rodriguez-Tudela et al. 2008; Verweij
et al. 2002; Verweij et al. 2007). Most studies concerning
mechanisms of azole resistance in Aspergillus have been
performed with A. fumigatus and have demonstrated
that resistance was associated with the modication
of the 14-α sterol demethylase target enzyme (CYP51),
specically, modication corresponding to mutations in
the gene cyp51A (Balashov et al. 2005; Chen et al. 2005;
Garcia-Eron et al. 2005; Mellado et al. 2004; Mellado
et al. 2005; Mellado et al. 2007; Naschimento et al. 2003;
Rodriguez-Tudela et al. 2008). Importantly, mutations
resulting in resistance to posaconazole and itracona-
zole appear to dier from those conferring resistance
to voriconazole and ravuconazole (Mann et al. 2003;
Mellado et al. 2004; Mellado et al. 2005; Mellado et al.
2007; Rodriguez-Tudela et al. 2008; Xiao et al. 2004).
Cross-resistance to itraconazole and posaconazole has
been associated with amino acid substitutions at gly-
cine 54 (G54) (Diaz-Guerra et al. 2003; Mann et al. 2003;
Naschimento et al. 2003; Rodriguez-Tudela et al. 2008),
whereas cross-resistance to voriconazole and ravucona-
zole has been associated with amino acid substitutions
at G448 (Mellado et al. 2004; Xiao et al. 2004). Recently, a
third phenotypic prole of resistance to all azoles (itraco-
nazole, posaconazole, voriconazole, and ravuconazole)
has been described in A. fumigatus (Diaz-Guerra et al.
2003; Mann et al. 2003; Mellado et al. 2007; Naschimento
et al. 2003; Pfaller et al. 2008f; Rodriguez-Tudela et al.
2008). e majority of these strains harbor amino acid
substitutions at methionine 220 (M220) or a substitution
of leucine 98 for histidine (L98H), together with the pres-
ence of two copies of a 34-bp sequence in tandem in the
promoter of the cyp51A gene (TR) (Mellado et al. 2004;
Mellado et al. 2007; Rodriguez-Tudela et al. 2008). ese
various patterns of cross resistance are detectable using
the CLSI or EUCAST standardized broth microdilution
methods. In vitro testing of the susceptibilities of clini-
cal isolates of Aspergillus spp. to each of the triazoles will
allow one to select the most active agent without having
to resort to characterization of the specic mutations
(Mosquera et al. 2002; Pfaller et al. 2008f; Rodriguez-
Tudela et al. 2008).
Infections due to Filamentous Fungi other than
Aspergillus
Although Aspergillus clearly head the list of opportunistic
moulds causing IFI, an expanding array of Zygomycetes,
and previously uncommon hyaline (e.g., Fusarium,
Scedosporium, Acremonium, and Trichoderma) and
dematiaceous (e.g., Bipolaris, Cladophialophora, and
Alternaria) lamentous fungi are being reported with
greater frequency (Alastruey-Izquierdo et al. 2008;
Herbrecht et al. 2002b; Negroni et al. 2004; Nucci et al.
2007; O’Donnell et al. 2008; Perfect et al. 2003; Pfaller
et al. 2004a; Revankar et al. 2002; Revankar et al. 2004;
Roden et al. 2005; Teizeira et al. 2003; Walsh et al. 2004).
A large (N = 5,589) retrospective (1985–1999) review of
records at Fred Hutchinson Cancer Research Center
(Seattle, WA) revealed that the three most common non-
Aspergillus moulds causing IFI among HSCT recipients
were Fusarium, Scedosporium, and Zygomycetes (Marr
et al. 2002a). More recently (2004–2007) Neofytos and
colleagues (Neofytos et al. 2009a; Neofytos et al. 2009b)
found Zygomycetes, Fusarium and Scedosporium spe-
cies to be the most frequent non-Aspergillus moulds
causing IFI in both HSCT (Neofytos et al. 2009a) and
SOT (Neofytos et al. 2009b) recipients in 17 institutions
North American invasive mycoses 27
Table 19. In vitro susceptibilities of opportunistic moulds to systemically active antifungal agents.a
Organism Antifungal agent No. tested
MIC (µg/ml)b
50% 90%
Aspergillus fumigatus Amphotericin Bc1,119 0.5 1
Itraconazole 1,119 0.5 1
Posaconazole 1,119 0.12 0.5
Ravuconazole 256 0.25 0.5
Voriconazole 1,119 0.25 0.5
Caspofungind256 0.03 0.06
Aspergillus avus Amphotericin Bc89 1 2
Itraconazole 89 0.5 1
Posaconazole 89 0.25 0.5
Ravuconazole 30 0.5 1
Voriconazole 89 0.5 1
Caspofungind30 0.03 0.06
Aspergillus niger Amphotericin Bc101 0.12 1
Itraconazole 101 1 2
Posaconazole 101 0.25 0.5
Ravuconazole 29 0.5 2
Voriconazole 101 0.5 2
Caspofungind29 0.03 0.06
Aspergillus versicolor Amphotericin Bc20 1 2
Itraconazole 20 1 2
Posaconazole 20 0.5 1
Ravuconazole 20 0.25 1
Voriconazole 20 0.5 1
Caspofungind20 0.03 0.12
Aspergillus terreus Amphotericin Bc22 2 2
Itraconazole 22 0.5 0.5
Posaconazole 22 0.25 0.25
Ravuconazole 16 0.25 0.5
Voriconazole 22 0.25 0.5
Caspofungind16 0.03 0.06
Aspergillus lentuluseAmphotericin B 14 7.33 12
Itraconazole 14 8 10.25
Posaconazole 14 0.33 0.75
Ravuconazole 14 4 6
Voriconazole 14 5 6
Caspofungind14 0.28 1
Micafungind14 0.03 0.07
Fusarium spp. Amphotericin Bc67 8 32
Itraconazole 67 16 32
Posaconazole 67 16 32
Ravuconazole 11 8 >8
Voriconazole 67 16 32
Caspofungind13 >8 >8
Scedosporium apiospermum Amphotericin Bc26 2 8
Itraconazole 26 1 32
Posaconazole 26 0.25 1
Voriconazole 13 0.12 0.25
Micafungind26 >16 >16
Scedosporium prolicans Amphotericin Bc80 16 32
Itraconazole 80 64 64
Posaconazole 80 16 32
Voriconazole 55 4 4
Micafungind17 >32 >32
Table 19. continued on next page
28 M. A. Pfaller, and D. J. Diekema
Organism Antifungal agent No. tested
MIC (µg/ml)b
50% 90%
Zygomycetes Amphotericin Bc86 0.25 2
Itraconazole 86 1 32
Posaconazole 86 0.5 4
Voriconazole 86 16 128
Acremonium spp. Amphotericin Bc33 1 4
Itraconazole 33 >10 >10
Voriconazole 3 1 NAf
Anidulafungind3 >16 NA
Paecilomyces lilacinuseAmphotericin Bc27 32 32
Itraconazole 27 16 16
Posaconazole 27 0.25 0.5
Ravuconazole 27 1 1
Voriconazole 27 0.5 1
Anidulafungind27 32 32
Caspofungind27 32 32
Micafungind27 32 32
Paecilomyces variotiieAmphotericin Bc31 0.03 0.25
Itraconazole 31 0.06 0.25
Posaconazole 31 0.03 0.12
Ravuconazole 31 16 16
Voriconazole 31 8 16
Anidulafungind31 0.016 0.016
Caspofungind31 0.5 2
Micafungind31 0.016 0.016
Trichoderma spp. Amphotericin B 16 2 2
Itraconazole NA ≥4 ≥4
Voriconazole 16 0.5 1
Bipolaris spp. Amphotericin B 10 0.25 0.25
Itraconazole 10 0.06 0.25
Posaconazole 10 0.06 0.12
Voriconazole 6 0.3 NA
Anidulafungind6 2.7 NA
Caspofungind6 1.7 NA
Exophiala spp. Amphotericin B 14 0.5 1
Itraconazole 14 0.5 1
Posaconazole 14 0.25 0.5
Voriconazole 5 1 NA
Alternaria spp. Amphotericin B 13 0.5 4
Itraconazole 13 0.5 1
Posaconazole 13 0.12 0.25
Cladosporium spp. Amphotericin B 11 1 4
Itraconazole 11 0.12 16
Posaconazole 11 0.06 16
Wangiella spp. Amphotericin B 5 4 NA
Voriconazole 5 1 NA
Anidulafungind5 2 NA
aData compiled from Alcazar-Fuoli et al (2008); Castelle et al. (2008); Cortez et al. (2008); Kontoyiannis et al (2008); Pfaller et al(2008f); Sabatelli
et al (2008).
b50% and 90%; minimum inhibitory concentration (MIC) encompassing 50% and 90% of isolates tested, respectively.
cAmphotericin B MICs determined by using Etest.
dMinimum eective concentration (MEC) determined for echinocandins.
eMICs determined by using EUCAST broth microdilution (Alcazar-Fuoli et al [2008]; Castelle et al. [2008)]).
fNA, not applicable.
Table 19. Continued.
North American invasive mycoses 29
participating in the PATH Alliance Fungal Registry (Horn
et al. 2007).
ese organisms tend to cause infections in patients
with neutropenia; the infections are often disseminated
in nature and are almost uniformly fatal in the absence
of immune reconstitution (Baddley et al. 2001b; Marr
et al. 2002a; Neofytos et al. 2009a; Neofytos et al. 2009b).
Both Fusarium and Scedosporium species are capable
of adventitious conidiation (i.e., generation of spores
in tissue), with concomitant hematogenous dissemi-
nation, positive blood cultures, and multiple cutane-
ous lesions (Liu et al. 1998; Pfaller et al. 2004a; Sutton
2008; Walsh et al. 2004). Overall, these non-Aspergillus
moulds are less susceptible to the available systemically
active antifungal agents than are the Aspergillus species
(Table 19) (Alastruey-Izquierdo et al. 2008; Chamilos
et al. 2005; Chamilos et al. 2008; Cortez et al. 2008;
Diekema et al. 2003; Kontoyiannis et al. 2005; Nucci et al.
2007; Roden et al. 2005; Van Schooneveld et al. 2008).
Voriconazole has been approved by the U.S. Food and
Drug Administration (FDA) for the treatment of serious
infections caused by Fusarium spp. and by Scedosporium
apiospermum in patients who are intolerant of or refrac-
tory to other antifungal agents (Perfect et al. 2003).
Posaconazole is FDA-approved for prophylaxis of IFI in
high-risk immunocompromised adults and is currently
being investigated as salvage therapy for zygomycosis,
invasive fusariosis and scedosporiosis (Mellingho et al.
2002; Raad et al. 2006; Van Burik et al. 2006).
Zygomycosis
Zygomycosis is a sporadic disease that occurs worldwide
and is caused by fungi of the class Zygomycetes and the
order Mucorales. Rhizopus spp. are the most frequent
cause of zygomycosis but invasive infections are also
caused by species of Mucor, Cunninghamella, Absidia,
Saksenaea, Rhizomucor, and occasionally other mem-
bers of this class of fungi (Roden et al. 2005).
e Zygomycetes are ubiquitous worldwide in decay-
ing soil and vegetation, and infection may be acquired
by inhalation, ingestion, or contamination of wounds
with sporangiospores from the environment (Spellberg
et al. 2006). As with Aspergillus spp., nosocomial spread
of Zygomycetes may occur by way of air-conditioning
systems, particularly during construction (Roden et al.
2005; Spellberg et al. 2006). Focal outbreaks of zygo-
mycosis have also been associated with the use of con-
taminated adhesive bandages or tape in surgical wound
dressings, resulting in primary cutaneous zygomycosis
(Spellberg et al. 2006).
Infections due to the Zygomycetes are rare, occurring
at an annual rate of 1.7 infections per million population
in the U.S. (Rees et al. 1998). In the past decade, however;
zygomycosis has emerged as an increasingly impor-
tant mycosis, particularly among HSCT recipients and
patients with hematologic malignancies (Kontoyiannis
et al. 2005; Marr et al. 2002a; Roden et al. 2005; Siwek
et al. 2004). Marr et al (Marr et al. 2002a) reported a
doubling in the number of cases of zygomycosis among
HSCT recipients at the Fred Hutchinson Cancer Center
from 1985-1989 to 1995-1999 and other reports have
indicated an increase in incidence since the 1990s
(Chamilos et al. 2006; Kontoyiannis et al. 2005; Neofytos
et al. 2009a). Zygomycosis accounted for 6.3% and 9.8%
of IMI in SOT and HSCT recipients, respectively, in the
PATH Alliance Fungal Registry between 2004 and 2007
(Neofytos et al. 2009a; Neofytos et al. 2009b). As opposed
to IA, the vast majority of cases of zygomycosis occur
very late (more than 100 days) post HSCT. Garcia-Vidal
et al (Garcia-Vidal et al. 2008) found that 88% of HSCT
recipients with invasive zygomycosis received a diag-
nosis very late. Likewise, Neofytos et al (Neofytos et al.
2009a) found that IFIs due to Zygomycetes occurred at a
median of 173 days post HSCT and were late in autolo-
gous (median 412 days) compared to allogeneic HSCT
recipients (median 162 days).
In addition to causing infection in HSCT and SOT
recipients, the Zygomycetes may also cause lethal infec-
tions in a broader and more heterogeneous popula-
tion, such as patients with diabetes, patients receiving
deferoxamine therapy, injection drug users, and indi-
viduals with no apparent immune impairment (Roden
et al. 2005). Invasive zygomycosis is clinically similar
to aspergillosis and is marked by angioinvasion and
tissue infarction (Spellberg et al. 2006). Roden et al.
(Roden et al. 2005) recently reviewed 929 case reports
of zygomycosis occurring between 1940 and 2003. e
most common sites of infections were sinus (39%), pul-
monary (24%), and cutaneous (19%) with 23% of the
cases becoming disseminated. Among patients with
disseminated infection, the associated mortality rate
was 96% (Roden et al. 2005). Signicant risk factors for
mortality include disseminated disease, renal failure,
and infection with Cunninghamella. (Roden et al. 2005).
Among HSCT and SOT recipients with zygomycosis in
the PATH Alliance Registry, 12-week mortality was 64%
and 100%, respectively (Neofytos et al. 2009a; Neofytos
et al. 2009b).
Risk factors for zygomycosis include prior corticoste-
rioid and deferoxamine therapy, diabetic ketoacidosis,
renal failure, hematologic malignancy, myelosuppres-
sion, and exposure to hospital construction activity
(Roden et al. 2005; Spellberg et al. 2006). Recent case
series (Imhof et al. 2004; Marty et al. 2004; Siwek et al.
2004) and one case-control study (Kontoyiannis et al.
2005) suggest that exposure to voriconazole prophylaxis
among HSCT recipients (used to prevent IA) may be a
risk factor for zygomycosis. While this phenomenon is
still not completely understood, it is clear that the use of
broader spectrum antifungal agents for prophylaxis will
30 M. A. Pfaller, and D. J. Diekema
inevitably change the epidemiology of fungal infection,
and that selective advantage will accrue to those organ-
isms with intrinsic resistance to the currently available
antifungal agents.
Most of the Zygomycetes appear to be quite suscep-
tible to amphotericin B in vitro and are not susceptible
to the triazoles and echinocandins (Table 19) (Diekema
et al. 2003; Pfaller et al. 2004a). Similar to that observed
for invasive candidiasis (Garey et al. 2007; Morrell et al.
2005), delay in the initiation of amphotericin B therapy
has been shown to increase mortality among hemato-
logic malignancy patients with zygomycosis (Chamilos
et al. 2008). Chamilos et al (Chamilos et al. 2008)
reported that the 12-week mortality was 49% among
patients started on amphotericin B therapy within 6
days following diagnosis versus 83% among those in
which amphotericin B therapy was delayed more than
6 days.
Among the extended spectrum triazoles, posacona-
zole stands apart from voriconazole in that it appears to
be active against most of the Zygomycetes, both in vitro
and in vivo (Diekema et al. 2003; Greenberg et al. 2006;
Sun et al. 2002; Tobon et al. 2003). A recent case series of
91 patients with zygomycosis suggest that posaconazole
appears promising (60% complete or partial response
and 21% with stable disease at 12 weeks) as an oral
therapy for patients who received adjunctive surgical
debridement and other interventions required for con-
trol of their underlying illness (Van Burik et al. 2006). In
contrast, voriconazole is inactive against Zygomycetes
(Diekema et al. 2003), and breakthrough zygomycosis
has been reported in patients receiving voriconazole
prophylaxis (Imhof et al. 2004; Kontoyiannis et al. 2005;
Marty et al. 2004; Siwek et al. 2004; Roden et al. 2005;
Spellberg et al. 2006).
Fusarium
Fusariosis has been recognized with increasing fre-
quency among immunocompromised patients, espe-
cially those with hematologic malignancies and recipi-
ents of allogeneic HSCT (Nucci et al. 2002; Nucci et al.
2003; Nucci et al. 2004; Nucci et al. 2007). e overall
incidence of fusariosis is approximately 6 cases per 1000
HSCTs; the incidence is lowest (1.5 to 2/1000) among
recipients of mismatched related donor allogeneic
HSCTs (Nucci et al. 2004; Nucci et al. 2007). In the allo-
geneic HSCT population, the infection has a trimodal
distribution, with a rst peak in the early post-transplant
period (during neutropenia), a second peak at a median
of 70 days after transplant among patients with acute
GVHD receiving corticosteroids, and a third peak greater
than 1 year after transplant during treatment for chronic
extensive GVHD (Nucci et al. 2004). Locally invasive and
usually late infections may also develop among SOT
recipients (Neofytos et al. 2009b; Sampathkumar et al.
2001), but these appear to be less common than those
among HSCT patients.
Among more than 50 species of Fusarium identied,
only a few have been associated with human infections
(Sutton. 2008); Fusarium solani is the most frequent
(~50% of cases), followed by F. oxysporium (~20%), F.
verticillioides (~10%), and F. moniliforme (~10%) (Nucci
et al. 2002; Nucci et al. 2007). F. solani is also the most
frequent pathogen in fusarial keratitis (Chang et al. 2006;
Doczi et al. 2004; O’Donnell et al. 2007; O’Donnell et al.
2008).
Fusarium species cause a broad spectrum of infec-
tions, including supercial locally invasive and dissemi-
nated infections. Fusariosis in the immunocompro-
mised population is typically invasive and disseminated
and carries a mortality of 79% to 100% (Nucci et al.
2003). Among patients with hematologic malignancies,
the infection occurs most frequently in those with acute
leukemia (56%), and most patients are neutropenic
(83%) at diagnosis (Nucci et al. 2003). Fusarium species
accounted for over half of the non-Aspergillus, non-Zy-
gomycete IMIs in the PATH Alliance Fungal Registry and
carried a mortality of 80% among infected HSCT recipi-
ents (Neofytos et al. 2009a). Among almost 300 reported
cases of fusariosis, receipt of HSCT and presence of neu-
tropenia, disseminated disease, and lung involvement
predicted death (Nucci et al. 2007).
e principal portal of entry for Fusarium spp. is the
airways, followed by the skin at the site of tissue break-
down and possibly the mucosal membranes. Fusarium
spp. can be recovered from hospital water systems (water
storage tanks, shower heads) and from hospital air and
other environments (Nucci et al. 2007). Risk factors for
invasive fusariosis include persistent neutropenia and
corticosteroid therapy (Nucci et al. 2003; Nucci et al.
2007). ere is a strong correlation between immune
reconstitution and outcome, with persistent neutro-
penia and corticosteroid therapy known to negatively
inuence the outcome in cancer patients with fusariosis
(Nucci et al. 2003).
e hallmark of disseminated fusariosis is the
appearance of multiple purpuric cutaneous nodules
with central necrosis (Nucci et al. 2003; Nucci et al. 2004;
Sampathkumar et al. 2001). Biopsy of these nodules
generally reveals branching hyaline and septate hyphae
invading dermal blood vessels. In contrast to patients
with IA, ~75% of patients with fusariosis will have posi-
tive blood cultures (Walsh et al. 2004).
e typical antifungal susceptibility prole of
Fusarium spp. is that of relative resistance to most
antifungal agents (Table 19) (Alastruey-Izquierdo et al.
2008; Nucci et al. 2007; O’Donnell et al. 2008). Fusarium
spp. often appears to be resistant to amphotericin B in
vitro and breakthrough infections occur frequently in
patients treated with this agent (Nucci et al. 2004; Perfect
North American invasive mycoses 31
et al. 2008). Notably, dierent species may have dierent
patterns of susceptibility; F. solani and F. verticillioides
are usually resistant to azoles and exhibit higher ampho-
tericin B MICs than other species whereas F. oxysporum
and F. moniliforme may be susceptible to voriconazole
and posaconazole (Table 19) (Alastruey-Izquierdo et al.
2008; Nucci et al. 2007). Although voriconazole and
posaconazole exhibit only modest activity in vitro (Table
19), both of these triazoles have been used successfully
in some patients with amphotericin B-refractory fusari-
osis (Perfect et al. 2003; Raad et al. 2006). e echinocan-
dins are not active against Fusarium spp. (Diekema et al.
2003; O’Donnell et al. 2008). It is notable that keratitis-
associated isolates of Fusarium form robust biolms
on various types of contact lenses rendering them less
susceptible to both antifungal agents and lens care solu-
tions (Imamura et al. 2008).
Scedosporium
Within the genus of Scedosporium, Scedosporium
apiospermum (S.boydii; teleomorph Pseudallescheria
boydii) and S. prolicans represent two important anti-
fungal-resistant opportunistic pathogens (Cortez et al.
2008). Disease states produced by these organisms range
from cutaneous and subcutaneous infections to dissem-
inated infections in immunocompromised hosts. e
estimated annual incidence of IFIs due to these organ-
isms is one infection per million population (Rees et al.
1998), although serious infections in cancer patients
and recipients of SOT and HSCT have been reported
with increasing frequency in recent years (Cortez et al.
2008; Husain et al. 2003; Husain et al. 2005; Lamaris et al.
2006; Steinbach et al. 2003b; Walsh et al. 1999).
Among transplant recipients, scedosporiosis
accounted for approximately 25% of all non-Aspergillus
mould infections in SOT recipients (Husain et al. 2003)
and 29% of those in HSCT recipients (Husain et al. 2005).
ese infections are now recognized as important com-
plications of immunosuppressive therapy for GVHD,
with 75% of infections in HSCT recipients and 61% of
infections in SOT recipients occurring within 6 months
of transplantation (Husain et al. 2005). Disseminated
infection is common, occurring in 69% and 46% of sce-
dosporiosis cases among recipients of HSCT and SOT,
respectively. Fungemia is present in approximately
one-third of HSCT recipients but in only 11% of SOT
recipients (Husain et al. 2005). Among SOT recipients,
those with S. prolicans infections were more likely to
have fungemia (40%) than those with S. apiospermum
infections (5%). e mortality due to these infections in
transplant recipients is high (58% overall). e mortal-
ity among SOT recipients is 54% (77.8% for those with
S. prolicans infections and 54.5% for those with S.
apiospermum infections). Among HSCT recipients the
overall mortality rate is 68% (77.8% for patients with
S. prolicans infections and 61.5% for those with S.
apiospermum infections) (Husain et al. 2005).
Lamaris et al. (Lamaris et al. 2006) reviewed the cases
of Scedosporium infection among cancer patients at a sin-
gle institution and found that the incidence per 100,000
inpatient days increased from 0.82 cases between 1993
and 1998 to 1.33 cases in 1999 to 2005. Risk factors asso-
ciated with scedosporiosis were lymphopenia (88%),
steroid treatment (80%), serum albumin level of <3mg/
dl (88%), neutropenia (52%; 100% with S. prolicans and
43% with S. apiospermum), diabetes (56%), and cytome-
galovirus reactivation (24%). e majority (76%) of these
infections occurred in the face of antifungal therapy with
74% of the patients receiving amphotericin B. Fungemia
was noted in 69% of the Scedosporium infections and
disseminated infection was found in 67% of patients
with S. apiospermum and 50% of patients with S. proli-
cans. Among those patients with disseminated infection,
88% had pulmonary involvement. Mortality due to S.
apiospermum infection was associated with dissemina-
tion, fungemia, ICU admission, APACHE (acute physi-
ology and chronic health evaluation) score of >11, pro-
longed and persistent neutropenia, and breakthrough
Scedosporium infection (Lamaris et al. 2006).
S. apiospermum is generally considered to be resist-
ant to amphotericin B, the MICs of which are elevated
(Table 19) and to which clinical response is very poor
despite the use of high doses (Cortez et al. 2008). e
extended-spectrum azoles are active in vitro against S.
apiospermum and both posaconazole and voriconazole
have successfully been used for the treatment of CNS
abscesses (Mellingho et al. 2002; Nesky et al. 2000). In
addition to antifungal therapy, restoration of immuno-
competence is essential for survival in these often fatal
infections (Cortez et al. 2008; Walsh et al. 2004).
S. prolicans is considered to be resistant to virtually
all of the systemically active antifungal agents, including
the extended-spectrum azoles and the echinocandins
(Table 19) (Cortez et al. 2008). Although terbinane, an
inhibitor of squalene epoxidase, does not appear to be
active alone, synergy between triazoles and terbinane
against S. prolicans has been demonstrated in vitro
(Cortez et al. 2008), and ve patients with IFI due to S.
prolicans have been successfully managed with a com-
bination of terbinane and voriconazole, in addition to
aggressive surgical debridement and immune recon-
struction (Bhat et al. 2007; Gosbell et al. 2003; Howden
et al. 2003; Singh et al. 2005; Whyte et al. 2005). Despite
these encouraging results, medical therapy for nonre-
sectable or disseminated disease due to S. prolicans is
virtually always ineective (Cortez et al. 2008; Steinbach
et al. 2003b; Walsh et al. 1999; Walsh et al. 2004). Surgical
resection remains the only denitive therapy for infec-
tions caused by S. prolicans (Cortez et al. 2008; Walsh
et al. 2004).
32 M. A. Pfaller, and D. J. Diekema
Mycoses due to other hyaline moulds
e list of hyaline moulds, also known as hyalohy-
phomycetes, is quite long, and it is well beyond the
scope of this review to discuss them all. e taxonomi-
cally diverse agents of hyalohyphomycosis (infection
due to nonpigmented moulds) do share several charac-
teristics, in that many exhibit decreased susceptibility
to a number of antifungal agents and when present in
tissue, they appear as hyaline (nonpigmented), septate,
branching, lamentous fungi that may be indistinguish-
able from Aspergillus. Culture is necessary to identify
these agents and may be critical in determining the most
appropriate therapy.
Although infections caused by most of these fungi
are relatively uncommon, they appear to be increas-
ing in incidence. Most disseminated infections are
thought to be acquired by the inhalation of spores or
by the progression of previous localized cutaneous
lesions. In this review, the discussion of specic gen-
era is limited to selected clinically important hyaline
moulds: Acremonium spp., Paecilomyces spp., and
Trichoderma spp.
Invasive infections due to Acremonium spp are
almost exclusively seen in patients with neutrope-
nia, transplantation, or other immunodeciency and
present in a manner similar to that of Fusarium, with
hematogenously disseminated skin lesions and posi-
tive blood cultures (Foell et al. 2007; Guarro et al. 1997;
Miyakis et al. 2006). Species of Acremonium are com-
monly found in soil, decaying vegetation, and decay-
ing food. Although the genus Acremonium contains
numerous species, relatively few have been implicated
in disease (Sutton 2008). Most of the recent reports of
invasive disease cite A. strictum as the causative agent
(Foell et al. 2007; Miyakis et al. 2006). Many of the same
risk factors seen in fusariosis apply to disseminated dis-
ease with A. strictum. Adventitious conidia seen in these
and other genera are thought to contribute to hematog-
enous dissemination. e optimal treatment for invasive
infections due to Acremonium spp. has not been estab-
lished. In vitro resistance to amphotericin B, itracona-
zole, and the echinocandins is seen, whereas the newer
triazoles, such as voriconazole appear to be active in
vitro (Table 19). Recent reports of successful treatment
of Acremonium fungal osteomyelitis with voriconazole
(Miyakis et al. 2006) and of a pulmonary infection due to
A. strictum with posaconazole (Herbrecht et al. 2002b)
suggest that the new triazoles may be useful in the treat-
ment of Acremonium infections.
Paecilomyces spp are saprobic lamentous fungi that
are found worldwide in soil and as air and water con-
taminants (Castelle et al. 2008; Gutierrez et al. 2005;
Madsen et al. 2007). Among the species in this genus,
P. lilacinus and P. variotii are of clinical importance, as
they are an increasingly reported cause of opportunistic
and usually severe human infections (Carey et al. 2003;
Castro et al. 1990; Chamilos et al. 2005; Gutierrez et al.
2005; Lee et al. 2002; Martin et al. 2002; Orth et al. 1996;
Pastor et al. 2006). e dierentiation between these two
species is important clinically, as they seem to exhibit
marked dierences in their in vitro susceptibilities to
antifungal agents (Table 19).
Although they are uncommon, Paecilomyces spp. may
cause invasive disease in organ and hematopoetic stem
cell recipients, individuals with AIDS, and other immu-
nocompromised patients (Castro et al. 1990; Chamilos
et al. 2005; Chan-Tack et al. 1999; Lee et al. 2002; Lott
et al. 2007; Martin et al. 2002; Orth et al. 1996; Pastor
et al. 2006; Van Schooneveld et al. 2008). e portal of
entry is often breaks in the skin or intravascular cath-
eters; and dissemination, possibly aided by adventitious
conidiation in tissue, is common (Liu et al. 1998; Orth
et al. 1996). Susceptibility to amphotericin B is variable,
with resistance seen in P. lilacinus but not in P. variotii
(Table 19). In addition to amphotericin B, itraconazole
and the echinocandins show poor activity against P.
lilacinus, while the new triazoles are active (Table 19)
(Castelle et al. 2008). In contrast, P. variotii is susceptible
to most antifungal agents apart from voriconazole and
ravuconazole (Table 19). Voriconazole alone or in com-
bination with terbinane has successfully been used to
treat IFIs due to P. lilacinus (Hilmarsdottir et al. 2000;
Martin et al. 2002; Pastor et al. 2006; Pastor et al. 2007).
Amphotericin B seems to be the treatment of choice for
P. variotii infections, whereas voriconazole resistance
has been described previously (Chamilos et al. 2005).
Trichoderma is another genus of concern in immuno-
compromised individuals. Recent molecular taxonomic
studies have shown that invasive species within this
genus currently appear to be restricted to Trichoderma
longibracheatum and T. citrinoviridae (Kuhls et al. 1999;
Sutton 2008). Trichoderma spp. are excellent examples
of fungi previously labeled as nonpathogenic that have
emerged as important opportunistic pathogens in immu-
nocompromised patients and in patients undergoing
peritoneal dialysis (Chouaki et al. 2002; Guarro et al. 1999;
Munoz et al. 1997; Myoken et al. 2002; Richter et al. 1999;
Sequin et al. 1995). Fatal disseminated infection due to
T. longibracheatum occurs in patients with hematologic
malignancies and following HSCT or SOT (Chouaki et al.
2002; Munoz et al. 1997; Myoken et al. 2002; Richter et al.
1999). Most Trichoderma spp. show decreased suscepti-
bilities to amphotericin B, itraconazole, uconazole, and
ucytosine (Table 19) (Chouaki et al. 2002; Kretzer et al.
2006; Richter et al. 1999). Voriconazole appears to be
active against the few isolates tested (Table 19).
Phaeohyphomycosis
e term “phaeohyphomycosis” is used to designate
infections caused by dematiaceous or pigmented
North American invasive mycoses 33
lamentous fungi that contain melanin in their cell walls
(Revankar et al. 2002). e presence of melanin in their
cell walls may serve as a virulence factor for these fungi
(Jacobsen 2000).
e agents of phaeohyphomycosis are found world-
wide and are predominantly organisms from the soil.
e list of dematiaceous fungi is long and taxonomi-
cally diverse, encompassing more than 100 species
and 60 genera causing a variety of clinical syndromes
ranging from keratitis and solitary subcutaneous nod-
ules to fulminant, rapidly fatal disseminated disease
(Matsumoto et al. 1994; Revankar et al. 2002). Most of
the species are considered to be opportunistic patho-
gens, although some have a marked neurotropism and
may function as true pathogens (Revankar et al. 2002;
Revankar et al. 2004). ose fungi known to be neuro-
tropic include Cladophialophora bantiana, Bipolaris
spicifera, Exophiala spp., Wangiella dermatitidis,
Ramichloridium obovoideum, and Chaetomium atro-
brunneum (Revankar et al. 2004). Brain abscess is the
most common CNS presentation. Bipolaris spp. and
Exerohilum rostratum infections may initially present
as sinusitis, which then extends into the CNS (Revankar
et al. 2004).
In a review of 72 cases of disseminated phaeohy-
phomycosis, Revankar and colleagues (Revankar et al.
2002) found some degree of immune dysfunction in 76%
of the patients, 39 (54%) of which had a malignancy and
half were neutropenic. Interestingly, no immunode-
ciency was apparent in 17 (24%) of the 72 patients. Of
these patients, previous cardiac surgery had been per-
formed in 10, 9 of which received valve replacements.
e overall mortality was 79% (57 of 72 patients); 84% in
patients with a preexisting immunodeciency and 65%
in immunocompetent patients.
e optimal treatment for disseminated or CNS phae-
ohyphomycosis has not yet been established, although
it most often includes administration of amphotericin B
and complete (as much as possible) surgical excision of
the infected focus (Revankar et al. 2004). Despite these
eorts, phaeohyphomycosis does not respond well to
therapy and relapses are common (Negroni et al. 2004;
Revankar et al. 2002; Revankar et al. 2004). Indeed,
Revankar et al (Revankar et al. 2002) found a notable
lack of ecacy for amphotericin B in the treatment
of disseminated phaeohyphomycosis: only 14 (23%)
of 62 patients treated with amphotericin B survived
and no single drug was associated with improved out-
come. Likewise, the use of combination therapy did not
improve the mortality rate.
e in vitro activities of the antifungal triazoles
(itraconazole, voriconazole, and posaconazole) are
superior to that of amphotericin B against many dema-
tiaceous moulds (Table 19). Proia and Trenholme
(Proia et al. 2006) reported a case of chronic refractory
phaeohyphomycosis of the oropharynx due to Alternaria
in which clinical failure was associated with the devel-
opment of in vitro resistance to both itraconazole (MIC
increased from 0.5 to 2.0 µg/ml) and voriconazole (MIC
increased from 0.5 to 8.0 µg/ml). e organism was
susceptible (MIC = 0.5 µg/ml) to posaconazole and the
infection responded rapidly to posaconazole adminis-
tration. e infection relapsed following discontinuation
of posaconazole: reintroduction of the drug produced
a favorable response and the patient was continued
on posaconazole with no evidence of active infection
after 1 year of treatment. Posaconazole has also been
used successfully to treat disseminated infections due
to Exophiala spinifera (Negroni et al. 2004). Long-term
triazole (posaconazole or voriconazole) therapy cou-
pled with repeat surgical resection may be necessary to
prevent recurrences (Proia et al. 2006; Revankar et al.
2004; Walsh et al. 2004).
Systemic mycoses due to endemic
dimorphic fungal pathogens
e dimorphic fungal pathogens are organisms that
exist in a mould form in nature or in the laboratory at
25°C to 30°C and in a yeast or spherule form in tissues
or when grown on enriched medium in the laboratory
at 37°C. e organisms in this group are considered pri-
mary systemic pathogens, owing to their ability to cause
infection in both immunocompromised and immuno-
competent hosts and for their propensity to involve the
deep viscera after dissemination of the fungus from the
lungs following its inhalation from nature. e dimor-
phic pathogens encountered in North America include
Blastomyces dermatitidis, Coccidioides immitis and C.
posadasii, and Histoplasma capsulatum var capsulatum.
Other dimorphic fungal pathogens encountered outside
of North America include Histoplasma capsulatum var
duboisii (Africa), Paracoccidioides brasiliensis (South
America), and Penicillium marneei (ailand). Only
those fungi endemic to North America will be covered
in this review.
ese organisms are also known as endemic patho-
gens, in that their natural habitat is delimited to specic
geographic regions (Table 20), and infection due to a
particular fungus is acquired by inhalation of spores
from that specic environment and geographic loca-
tion. H. capsulatum var capsulatum, C. immitis, and C.
posadasii have emerged as major opportunistic patho-
gens in individuals with AIDS and transplant recipients
receiving immunosuppressive therapy, where primary
infection may progress to fulminant disseminated dis-
ease. Recognition of these endemic mycoses may be
complicated by the fact that they may become manifest
only after the patient has left the area of endemicity
34 M. A. Pfaller, and D. J. Diekema
(Kauman 2001). Often the infection may be quiescent,
only to reactivate when the individual becomes immu-
nosuppressed and is living in an area where the fungus
is not endemic (Kauman 2001; Walsh et al. 1999).
Although exposure to each of these endemic fun-
gal pathogens is common in their respective areas of
endemicity, overt clinical disease is considered to be
uncommon (Kauman 2006; Parish et al. 2008). As
such, any attempt to dene the true incidence of infec-
tion is largely incomplete. Chu et al (Chu et al. 2006)
has conducted a population-based national study of
the more severe cases of endemic mycoses, namely
those requiring hospitalization during the year 2002
in the U.S. (Table 20). ese investigators reported that
an estimated 332 pediatric and 6,003 adult cases of
endemic fungal infections (blastomycosis, coccidioid-
omycosis, and histoplasmosis) required hospitaliza-
tion in the U.S. in 2002. e rate of all endemic mycoses
requiring hospitalization was 22.5 cases per million
persons in the U.S. (4.6 cases per million in children <18
years of age and 28.7 cases per million in adults aged
≥18 years). Notably, only 17% of hospitalized children
and 13% of hospitalized adults with endemic mycoses
had a reported underlying immunocompromising
condition, reecting the more overt pathogenic nature
of these fungi versus the opportunistic fungal patho-
gens. Chu et al. (Chu et al. 2006) also identied a large
burden of hospital charges (total hospital charges were
$18 million for children and > $240 million for adults)
and a considerable mortality rate (5% among children
and 7% among adults) among persons requiring hospi-
talization for endemic mycoses. e majority (87%) of
all persons who died were immunocompetent, which
reinforces the incidence data showing that otherwise
healthy individuals account for most of the burden of
these infections (Chu et al. 2006). It is important to
understand that although impressive, these statistics
do not reveal the substantial morbidity produced by
these infections, which may require a prolonged dura-
tion of treatment, have relapsing courses, and cause
permanent disability from pulmonary, osteoarticular,
and neurological involvement (Anstead et al. 2009;
Chu et al. 2006).
Blastomycosis
Blastomycosis is a systemic pyogranulomatous infec-
tion, primarily of the lungs, which arises after inhala-
tion of the conidia of the dimorphic fungus Blastomyces
dermatitidis. Blastomycosis of the lung can be an
asymptomatic infection or manifest as acute or chronic
pneumonia. Hematogenous dissemination frequently
occurs; extra pulmonary disease of the skin, bones,
and genitourinary system is common, but almost any
organ can be infected. Like other endemic mycoses,
this infection is conned to specic geographic regions,
with most infections originating in the Mississippi River
basin, around the Great Lakes, and the Southeast region
of the U.S. (Table 20).
Our understanding of the epidemiology of blas-
tomycosis remains incomplete, owing largely to the
lack of well characterized antigens for skin testing or
seroepidemiologic studies. Current information on
the epidemiology of blastomycosis is based upon the
population-based national survey of hospitalized cases
conducted by Chu et al. (Chu et al. 2006) as well as clin-
ical reports of sporadic cases in humans and dogs and
the study of point source outbreaks of disease (Klein
et al. 1986).
e ecologic niche of B. dermatitidis appears to be in
decaying organic matter, although growth of the organ-
ism from soil or leaf litter is dicult. Hyperendemic foci
within the endemic regions are characterized by areas
of warm, moist, sandy, acidic soil in wooded areas rich
in organic debris and at low elevation in proximity to
bodies of water (Baumgardner et al. 2001; Klein et al.
1986; Klein et al. 1987). Outbreaks of infection have
been associated with occupational or recreational con-
tact with soil and infected individuals include all ages
and both genders (Armstrong et al. 1987; Baumgardner
et al. 1992; Klein et al. 1987). Among individuals hos-
pitalized with blastomycosis, the rates of infection are
much higher for adults than children (Table 20) (Chu
et al. 2006). Females accounted for 54% of pediatric
cases and 42% of adult cases. e overall crude mortal-
ity rate was 0% among children and 6% among adults
hospitalized with blastomycosis; 11% of adults were
immunocompromised versus 0% of children (Chu
et al. 2006).
Blastomycosis is relatively uncommon among indi-
viduals with AIDS or other immunocompromising con-
ditions. However, when it occurs in these individuals,
it tends to be acute, involve the CNS, and have a much
poorer prognosis (Kauman 2006; Pappas et al. 1993).
In North America, the area of endemicity overlaps
that of histoplasmosis (Table 20) and includes the
Southeastern and South central states, especially those
bordering the Ohio and Mississippi River basins; the
Midwest states and Canadian provinces bordering the
Great Lakes; and an area in New York and Canada along
Table 20. Cumulative incidences of cases of histoplasmosis,
blastomycosis, and coccidioidomycosis requiring hospitalization in
the United States, 2002.a
Region
No. hospitalized patients per 1 million U.S. persons per year
Histoplasmosis Blastomycosis Coccidioidomycosis
Children Adults Children Adults Children Adults
Northeast 0.00 4.04 0.84 0.49 0.00 1.41
Midwest 1.98 27.08 2.28 7.39 1.74 4.40
South 3.05 21.40 0.59 3.96 1.33 6.04
West 0.0 4.42 0.29 0.71 5.29 28.65
aData compiled from Chu et al. (2006).
North American invasive mycoses 35
the St. Lawrence River (Kauman. 2006). Although
blastomycosis is typically associated with rural areas,
urban foci of the disease, also near waterways, have
been recently reported (Baumgardner et al. 2006). It is
estimated that three to six cases of blastomycosis requir-
ing hospitalization occur per 1 million persons each
year in endemic areas (Chu et al. 2006). Among animals,
dogs are most susceptible; the infection rate is estimated
to be 10 times that for humans (Armstrong et al. 1987;
Baumgardner et al. 1990).
e decision to treat blastomycosis must take into
consideration the clinical form and severity of the dis-
ease, as well as the immune status of the patient and the
toxicity of antifungal agents (Kauman 2006; Pappas
et al. 1993). It is estimated that one to two cases of symp-
tomatic blastomycosis requiring antifungal therapy
occur per 100,000 population each year in areas with
endemic disease. Clearly, pulmonary blastomycosis in
immunocompromised patients and those with progres-
sive pulmonary disease should be treated (Chapman
et al. 2008). Likewise, all patients with evidence of
hematogenous dissemination (e.g., skin, bone, all non-
pulmonary sites) require antifungal therapy (Chapman
et al. 2008).
In vitro antifungal susceptibility testing has not
proven useful in directing therapy in cases of blastomy-
cosis. Practice guidelines for the management of blas-
tomycosis were updated in 2008 (Chapman et al. 2008)
and indicate that amphotericin B (a lipid formulation
is preferred) remains the agent of choice for the treat-
ment of life-threatening or CNS disease. Mild or mod-
erate (pulmonary or extrapulmonary, but excluding
CNS disease) disease may be treated with itraconazole.
Fluconazole may be an alternative for those patients
unable to tolerate itraconazole. Voriconazole is active
against B. dermatitidis in vitro, and has proven eec-
tive in murine models of blastomycosis (Li et al. 2000;
Sugar et al. 2001). Voriconazole has been used with
success for treatment of refractory blastomycosis and
for treatment in immunosuppressed patients including
patients with CNS disease (Bakleh et al. 2005; Borgia
et al. 2006; Lentnek et al. 2006; Panicker et al. 2006).
Posaconazole and the echinocandins exhibit variable
activity against B. dermatitidis but have not been used
in the treatment of human cases of blastomycosis
(Espinel-Ingro 1998; Nakai et al. 2003; Sugar et al.
1996; Zhanel et al. 1997).
Depending on the severity of the disease and the
status of the host, therapeutic success rates with
amphotericin B or azole therapy range from 70% to 95%
(Chapman et al. 2008). Survival for AIDS patients and
other immunocompromised patients is about half this
gure. e latter patients may require long-term sup-
pressive therapy with itraconazole in an eort to avoid
relapses of infection (Chapman et al. 2008).
Coccidioidomycosis
Coccidioidomycosis is an endemic mycosis caused by
either of two indistinguishable species, Coccidioides
immitis and C. posadasii (Bailek et al. 2004). e disease
is caused by the inhalation of infectious arthroconidia
and may range from asymptomatic infection (in ~60%
of those infected) to progressive infection and death
(Crum et al. 2004). e two species dier in geographic
distribution and genotype: C. immitis is localized to
California and C. posadasii accounts for the majority of
infections outside of California (Fisher et al. 2002). Aside
from these dierences, there does not appear to be any
additional dierence in phenotype or pathogenicity. As
such, the more familiar name C. immitis will be used in
this review.
Coccidioidomycosis is endemic to the desert south-
western U.S., northern Mexico, and scattered areas
of Central and South America. C. immitis is found in
soil, and the growth of the fungus in the environment
is enhanced by bat and rodent droppings (Fisher et al.
2007). e organism thrives in warm sandy soil in a
climate characterized by hot summers, mild winters,
and fewer than 20 inches of rainfall per year (Fisher
et al. 2007); it does not grow at altitudes greater than
3700 feet.
Exposure to the infectious arthroconidia is greatest
in late summer and fall when dusty conditions prevail.
Cycles of drought and rain enhance the dispersion of
the organism because heavy rains facilitate the growth
of the organism in the nitrogenous soil, and subsequent
drought and windy conditions favor aerosolization of
arthroconidia (Kolivras et al. 2003). Outbreaks of coc-
cidioidomycosis may follow natural events that result
in atmospheric soil dispersion, such as dust storms,
earthquakes, and droughts (Pappagianis 1994). Notable
epidemics of coccidioidomycosis occurred in the San
Joaquin Valley in the 1990s (Pappagianis. 1994) and
after the 1994 Northridge earthquake north of Los
Angeles (Schneider et al. 1997). Factors responsible for
the California epidemic were: (1) a drought-rain cycle;
(2) new construction, resulting in soil dispersion; and
(3) an inux of susceptible individuals into the area
(Pappagianis 1994). A surge of new cases was also noted
in southern and central Arizona, where the incidence
of coccidioidal infections increased from approxi-
mately 12 new cases per 100,000 population in 1995 to
58.2 new cases per 100,000 population in 2005 (Parish
et al. 2008).
ere are as many as 100,000 to 300,000 new cases of
coccidioidomycosis in the U.S. each year (Ampel et al.
1998; Chiller et al. 2003). Although the incidence of coc-
cidioidomycosis is approximately 15 cases per 100,000
annually in the endemic areas, it is known to dispropor-
tionately aect persons aged >65 years (approximately
36 per 100,000) (Galgiani et al. 2005). e incidence of
36 M. A. Pfaller, and D. J. Diekema
coccidioidal infections serious enough to require hos-
pitalization has been estimated to be as high as 22.36
infections per million in the western region of the U.S.
(5.29 per million among children and 28.65 per mil-
lion among adults) and ranges from 1 to 5 per million
throughout the rest of the country (Table 20) (Chu et al.
2006).
C. immitis is probably the most virulent of all human
mycotic pathogens. e inhalation of only a few arthro-
conidia produces primary coccidioidomycosis, which
may include asymptomatic pulmonary disease (60% of
the patients), an acute respiratory illness, chronic pro-
gressive pneumonia, pulmonary nodules and cavities,
extrapulmonary nonmeningeal disease, and meningi-
tis (Parish et al. 2008). It is notable that in one study of
community-acquired pneumonia in Tucson, AZ, 29%
of 55 cases were serologically positive for coccidioidal
infection, suggesting the concept that this organism is a
common cause of community-acquired pneumonia in
endemic areas (Valdivia et al. 2006).
Extrapulmonary disease is said to occur in 1% to
5% of all persons infected with C. immitis (Crum et al.
2004). Extrapulmonary sites of infection include skin,
soft tissues, bones, joints, and meninges (Crum et al.
2004; Parish et al. 2008). e risk is higher among males
(9:1), those with cellular immuno-deciencies, specic
racial groups (African American, Filipino, and Hispanic)
(Table 21) and in pregnancy (Crum et al. 2004). Among
223 patients found to have coccidioidomycosis at the
Naval Medical Center in San Diego, CA, 58% presented
with isolated pulmonary disease, 14% had high com-
plement xation titers (>1:16) without clear evidence
of dissemination, 22% had disseminated disease, and
5% had unclassied disease (Crum et al. 2004). Among
those with disseminated disease, 77% were male, 45%
were African American, and 29% were Filipino. African
American and Filipino patients had a signicantly higher
risk for disseminated disease than white patients (Table
21). Hispanics also appeared to have an increased risk,
but the sample size was small.
Although ethnicity is a signicant risk for dissemi-
nated coccidioidomycosis, persons with occupations
that have soil exposure (agricultural workers, excavators,
military personnel, and archeologists) are at the great-
est risk to acquire coccidioidomycosis (Crum et al.
2004; Peterson et al. 2004). Immunocompromised indi-
viduals at high risk include those with AIDS, transplant
recipients (especially those who received Coccidioides-
infected organs), patients treated with TNF-α antago-
nists, pregnant women (especially in the 3rd trimester),
and cancer patients (Ampel. 2005; Bergstrom et al. 2004;
Blair et al. 2005; Peterson et al. 1993; Wright et al. 2003).
e mortality of disseminated disease exceeds 90% with-
out treatment, and chronic infection is common (Parish
et al. 2008).
Guidelines for the treatment of coccidioidomycosis
have been published (Galgiani et al. 2005). Antifungal
agents used in the treatment of coccidioidomycosis
include uconazole, itraconazole, voriconazole, posa-
conazole, amphotericin B, or lipid formulations of
amphotericin B (Cantanzaro et al. 2007; Crum et al. 2004;
Galgiani et al. 2005; Proia et al. 2004; Stevens et al. 2007).
Most infections requiring therapy can be managed using
either uconazole or itraconazole. Amphotericin B
should be considered when patients are rapidly progress-
ing in their clinical course and are hospitalized because
of the infection (Parish et al. 2008). De-escalation to an
oral azole is recommended for prolonged maintenance
therapy. Voriconazole has been used with success in the
treatment of coccidioidal meningitis (Cortez et al. 2003;
Proia et al. 2004) and posaconazole has shown promise
in a small open-label trial (Cantanzaro et al. 2007) and
as salvage therapy in patients with chronic pulmonary
coccidioidomycosis (Stevens et al. 2007).
Information on the long-term follow-up and death
rates of a cohort of patients with coccidioidomycosis
is limited. In the large epidemic that occurred in Kern
County, CA, it was noted that 29% of patients were hos-
pitalized; 3% were on chronic therapy and 3% died after
1 year (Johnson et al. 1996). Among 223 patients with
coccidioidomycosis at the Naval Medical Center in San
Diego, CA, only 2 died; both were elderly women (72
and 89 years of age, respectively) who died of respiratory
failure (Crum et al. 2004). e crude mortality rate was
8% among 153 children and 6% among 2041 adults with
coccidioidomycosis in the population-based national
study of Chu et al. (Chu et al. 2006).
Histoplasmosis
Histoplasmosis in North America is caused by
Histoplasma capsulatum var capsulatum (histoplasmo-
sis capsulati). For purposes of this review we will refer to
this organism as H. capsulatum.
H. capsulatum is localized to the broad regions of the
Ohio and Mississippi River Valleys in North America
(Table 20) (Kauman 2007). e natural habitat of the
mould form of H. capsulatum is soil with a high nitro-
gen content, such as that found in areas contaminated
Table 21. Relative risk (RR) of coccidioidomycosis based on race.a
Raceb
Pulmonary disease Disseminated disease
RR P value RR P value
African American 1.5 0.11 41.9 <0.0001
Filipino 1.6 0.08 9.6 <0.0001
Hispanic 1.0 0.97 6.0 0.0004
Asian/Pacic
Islander
1.1 0.81 NAcNAc
aData compiled and table adapted from Crum et al. (2004).
bCompared with white.
cNot applicable; no Asian/Pacic Islander other than Filipino had
disseminated disease.
North American invasive mycoses 37
with bird or bat droppings, and heavy exposures to the
organism has been associated with caves, bird roosts,
and dilapidated buildings (Kauman 2007). Outbreaks
of histoplasmosis have been associated with exposure to
these reservoirs as well as with urban renewal projects
involving excavation and demolition (Gustafson et al.
1981; Luby et al. 2005; Ward et al. 1979; Wheat et al.
2004). Aerosolization of microconidia and hyphal frag-
ments in the disturbed soil, with subsequent inhalation
by exposed individuals, is considered to be the basis for
these outbreaks (Kauman 2007; Wheat et al. 2004).
It is estimated that up to 50 million people in the
U.S. have been infected by H. capsulatum, and up to
500,000 new infections occur each year (Hammerman
et al. 1974). Studies show that histoplasmosis, among
the endemic mycoses, is the most common cause for
hospitalization (ranging from 16.7 to 20.6 hospitalized
persons per million in the endemic areas) (Table 20),
with a crude mortality of 7.5% (5% among children and
8% among adults) and a cost of $20,300 per hospitaliza-
tion (Chu et al. 2006).
Although the attack rate approaches 100% in certain
endemic areas, most (~90%) cases remain asympto-
matic and are detected only by skin testing (Kauman
2007; Wheat et al. 2004). Immunocompromised indi-
viduals and children are more prone to develop symp-
tomatic disease after primary infection. In a study of
HIV-infected persons with histoplasmosis, those with
occupational exposure to soil had a 3.3 times greater
risk of acquiring the infection (Hajjeh et al. 2001).
Reactivation of the disease and dissemination is com-
mon among immunosuppressed individuals, espe-
cially those with AIDS (Assi et al. 2007; Kauman 2007;
Sathapatayavongs et al. 1983). Persons receiving TNF
antagonists, children with cancer, and pregnant women
represent newly recognized susceptible hosts for histo-
plasmosis (Adderson 2004; Wallis et al. 2004; Whitt et al.
2004; Zerbe et al. 2005).
e clinical presentation of histoplasmosis is depend-
ent upon the intensity of exposure and immunologic sta-
tus of the host (Kauman 2007). Asymptomatic infection
occurs in 90% of individuals following a low-intensity
exposure. In the event of an exposure to a heavy inocu-
lum, however, most individuals exhibit some symptoms
ranging from a self-limited form of acute pulmonary
histoplasmosis to progressive pulmonary disease (1 in
100,000 cases of acute infection) to disseminated histo-
plasmosis (1 in 2000 adults following acute infection).
Disseminated disease may assume a chronic, subacute
or acute course and is much more common in children
younger than 1 year and in immunocompromised
(AIDS, organ transplant recipients, those receiving ster-
oids or other immunosuppressive chemotherapy) adults
(Goodwin et al. 1980; Kauman. 2001; Sathapatayavongs
et al. 1983; Wheat et al. 1990). Subacute disseminated
histoplasmosis, if untreated, progresses to death in 2 to
24 months whereas untreated acute disease is usually
fatal within weeks (Kauman 2007).
In disseminated histoplasmosis in AIDS patients,
mortality may approach 50% and is especially high in
those persons with the severe disease manifestations of
sepsis, respiratory failure, acute renal failure or multior-
gan failure (Baddley et al. 2008; Couppie et al. 2006; De
Francesco Daher et al. 2006; Wheat et al. 2000). Baddley
et al. (Baddley et al. 2008) recently reported outcomes
and prognostic factors using a cohort of 46 HIV-infected
patients with histoplasmosis (93.5% of which had dis-
seminated disease). Death occurred in 39% of patients
within 3 months of diagnosis of histoplasmosis. Of those
patients who died, only 18% were receiving HAART at
the time of death. Independent predictors of poor prog-
nosis included fungemia (odds ratio [OR], 12.1), renal
insuciency (OR, 11.3), and age (OR, 0.9). ese nd-
ings underscore the fact that HIV-related histoplasmosis
in endemic areas is a serious infectious disease associ-
ated with poor outcomes. In most instances the infec-
tion presented as advanced disease among individuals
with limited access to healthcare (Baddley et al. 2008).
It is notable that among patients hospitalized with
endemic mycoses in the U.S. (Chu et al. 2006), immu-
nocompromising conditions were more prevalent
among patients with histoplasmosis (14-32%) than
among patients with other infection types (0–14%)
(Chu et al. 2006). Among patients with histoplasmo-
sis, there was a greater proportion of children than of
adults with underlying immunodeciencies (32% vs.
14%, respectively); however, children with underlying
immunodeciencies were more likely than adults to be
discharged alive to home (86% vs. 71%, respectively)
(Chu et al. 2006).
Practice guidelines for the treatment of histoplas-
mosis were updated in 2007 (Wheat et al. 2007). e
optimal treatment for histoplasmosis varies according
to the patient’s clinical syndrome. Most infections are
self-limited and require no therapy. However, patients
who are exposed to a large inoculum of H. capsulatum
and those who are immunocompromised or at the
extremes of age usually require therapy (Kauman 2001;
Wheat et al. 2007). Itraconazole, uconazole, vorico-
nazole, posaconazole, and amphotericin B all have in
vitro activity against H. capsulatum (Li et al. 2000; Wheat
et al. 2006). Itraconazole is generally preferred for mild
to moderate histoplasmosis, whereas amphotericin B
(lipid preparations preferred) has a role in the treatment
of moderately severe and severe infections (Wheat et al.
2007). Itraconazole is also recommended for step-down
therapy in patients who have improved with initial treat-
ment with amphotericin B (Dismukes et al. 1992; Wheat
et al. 1995). Fluconazole is not as active in vitro against
H. capsulatum as itraconazole, has been associated
38 M. A. Pfaller, and D. J. Diekema
with the emergence of resistance, and has not been as
eective when used for treatment (McKinsey et al. 1996;
Wheat et al. 1997a; Wheat et al. 1997b; Wheat et al. 2001).
H. capsulatum is highly susceptible to posaconazole
and this expanded-spectrum triazole has been shown
to be ecacious in an experimental model (Connolly
et al. 1999; Connolly et al. 2000) and as salvage therapy
in patients who failed other regimens (Restrepo et al.
2007). Voriconazole is slightly less active in vitro than
either itraconazole or posaconazole (Li et al. 2000; Wheat
et al. 2006); however, it has been used successfully in
combination with amphotericin B to treat Histoplasma
meningitis (Hott et al. 2003) and as salvage therapy of
disseminated disease in SOT recipients (Freifeld et al.
2005). e echinocandins do not appear to have a role
in the treatment of histoplasmosis (Freifeld et al. 2005;
Kauman 2007).
Summary and conclusions
Given the ever-expanding number of individuals at risk
for both opportunistic and endemic fungal infections, it
is essential that physicians keep fungal infections high
on the dierential when faced with a potentially infected
patient. e list of documented fungal pathogens is
extensive, and one can no longer ignore or dismiss fungi
as contaminants or clinically insignicant when they are
isolated from clinical material. It is also apparent that
the prognosis and response to therapy may vary with
the type of fungus causing the infection, as well as with
the immunological status of the host. e antifungal
armamentarium has been expanded signicantly with
the availability of the extended-spectrum triazoles and
the echinocandins; however, several of the “emerging”
opportunists as well as endemic fungal pathogens dis-
cussed herein are not susceptible to these newer agents.
us, fungi with intrinsic resistance to even the newest
antifungal agents already exist in our environment and
some are emerging as these agents are used broadly in
the high-risk patient groups. Knowledge of the local and
regional epidemiology as to the prevalent species and
their susceptibility to the available antifungal agents
is now more important than ever. Both clinicians and
microbiologists must become familiar with the various
fungi, their epidemiologic and pathogenic features, and
the optimal approaches to diagnosis and therapy in
order to make inroads in the management of these dif-
cult infections.
Acknowledgements
Declaration of interest: Drs. Pfaller and Diekema have
received research grant support and served on speakers
bureaus and advisory boards for Astellas, Merck, Pzer,
and Schering-Plough.
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