1. No category

Critical Reviews in Microbiology, 2009; 35(4): 283–309 2009 2009
REVIEW ARTICLE
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Candida parapsilosis: a review of its epidemiology,
pathogenesis, clinical aspects, typing and
antimicrobial susceptibility
Eveline C. van Asbeck1,2, Karl V. Clemons1, David A. Stevens1
Division of Infectious Diseases, Santa Clara Valley Medical Center, and California Institute for Medical Research,
San Jose, CA 95128 USA and Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford,
CA 94305, and 2Eijkman-Winkler Institute for Medical and Clinical Microbiology, University Medical Center Utrecht,
Utrecht, The Netherlands
1
Abstract
The Candida parapsilosis family has emerged as a major opportunistic and nosocomial pathogen. It causes
multifaceted pathology in immuno-compromised and normal hosts, notably low birth weight neonates.
Its emergence may relate to an ability to colonize the skin, proliferate in glucose-containing solutions, and
adhere to plastic. When clusters appear, determination of genetic relatedness among strains and identification of a common source are important. Its virulence appears associated with a capacity to produce biofilm
and production of phospholipase and aspartyl protease. Further investigations of the host-pathogen interactions are needed. This review summarizes basic science, clinical and experimental information about
C. parapsilosis.
Keywords: Candida parapsilosis, epidermiology, strain differentiation, clinical aspects, pathogenesis,
antifungal susceptibility
Introduction
Candida bloodstream infections (BSI) remain an
exceedingly common life-threatening fungal disease
and are now recognized as a major cause of hospitalacquired infection (Douglas 2003; Tortorano et al. 2006;
Tortorano et al. 2004). It is now the fourth most common
organism recovered from blood cultures among hospitalized patients in the USA (Hobson 2003; Pfaller et al.
1998b, Rangel-Frausto et al. 1999; Schaberg et al. 1991).
Some years ago Candida albicans accounted for
70–80% of the Candida isolates recovered from infected
patients (Banerjee et al. 1991; Beck-Sague & Jarvis
1993; Fidel et al. 1999). However, infections due to
non-­albicans species have emerged over the past two
decades, and a shift from C. albicans to species such as
Candida glabrata, Candida parapsilosis, and Candida
tropicalis has occurred (Fidel et al. 1999; San Miguel
et al. 2005). C. parapsilosis is now the second or third
most common cause of candidiasis, behind C. albicans.
The organism was first described in 1928 (Ashford 1928),
and early reports of C. parapsilosis described the organism as a relatively non-pathogenic yeast in the normal
flora of healthy individuals that was of minor clinical
significance (Weems 1992). Important factors that have
contributed to the increasing incidence of C. parapsilosis are the use of life support systems, such as parenteral
nutrition, or central venous catheters (Eggimann et al.
2003, Krcmery & Barnes 2002). The increased incidence
of candidemia due to C. parapsilosis also is associated
with extended hospital stay, which leads to increased
cost of medical care. Its spectrum of clinical manifestations include fungemia, endocarditis, peritonitis,
arthritis, and endophthalmitis. This species displays
many interesting ­biological features that are presumed
to be directly related to its virulence, such as its selective adherence to prosthetic materials and formation of
biofilms on plastic surfaces (Branchini et al. 1994; Pfaller
1995), secrection of extracellular proteases (Fusek
et al. 1993, Merkerova et al. 2006, Pichova et al. 2001),
Address for Correspondence: Karl V. Clemons, Ph.D., Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose,
CA 95128. Tel: (408) 998–4557, Fax: (408) 998–2723. E-mail:[email protected]
(Received 17 March 2009; revised 23 June 2009; accepted 02 July 2009)
ISSN 1040-841X print/ISSN 1549-7828 online © 2009 Informa UK Ltd
DOI: 10.3109/10408410903213393
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284 van Asbeck et al.
colonization of human hands (Bonassoli et al. 2005),
profileration in high concentration of glucose and lipids
(Branchini et al. 1994), phenotypic switching (Laffey &
Butler 2005, Lott et al. 1993), and resistance to drugs and
inhibitors (Camougrand et al. 1986). Unfortunately, we
have much to learn about the virulence of C. parapsilosis and even more about the host defenses directed
against the organism. Therefore, studies increasing our
­knowledge about this pathogen are needed.
Since a previous review was written (Weems 1992),
C. parapsilosis has only increased its standing as a
pathogen. It therefore is highly relevant to review the
recent literature on C. parapsilosis. While this article
was in preparation, last year an updated useful review
of many of the aspects of C. parapsilosis was presented
(Trofa et al. 2008). We review the literature on C. parapsilosis; specific topics discussed include its epidemiology, the molecular epidemiology, clinical perspectives,
pathogenesis, and antimicrobial susceptibility and
treatment.
Epidemiology
C. parapsilosis is a ubiquitous microorganism in the
natural environment. It is not only isolated easily from
soil, seawater, and plants, but also can be isolated from
mucosal surfaces, skin and nails, where it belongs to the
benign commensal flora of humans and mammals (De
Bernardis et al. 1999; Kuhn et al. 2004; Sanchez et al. 1993;
Weems 1992). The epidemiology of C. parapsilosis in the
hospital environment is unique among Candida species,
because it is frequently isolated from physical surfaces.
It is a frequent cause of opportunistic infection, associated with high morbidity and mortality rates in hospitalized immuno-compromised patients (Girmenia et al.
1996; Jarvis 1995). Although C. parapsilosis is an opportunistic pathogen, the majority of patients who develop
disseminated candidiasis due to C. parapsilosis are not
immunosuppressed in the classical sense (Spellberg &
Edwards 2002). Rather, the predominant risk factors for
disseminated candidiasis due to C. parapsilosis, which
are held in common among afflicted patients, are iatrogenic and/or nosocomial factors (Spellberg et al. 2006).
This species has been particularly associated with BSI
in very low birth weight neonates (Campbell et al. 2000;
da Silva et al. 2001; Damjanovic et al. 1993; Huang et al.
1998; Huang et al. 1999; Sarvikivi et al. 2005; Saxen et al.
1995; Solomon et al. 1986; Welbel et al. 1996), but is also
seen frequently in patients with catheter-associated
candidemia and/or with intravenous hyperalimentation
(Cano et al. 2005; Huang et al. 2004; Levin et al. 1998;
Levy et al. 1998; Marais et al. 2004).
Although C. albicans continues to predominate,
several surveillance programs report the emergence
of non-albicans species worldwide as a cause of BSI
(Pfaller & Diekema 2002). The percentage of isolates of
non-albicans species varies considerably from region
to region (Pfaller et al. 2006a; Pfaller et al. 2006b). In a
previous study (Wingard 1995), spanning a period from
1952 to 1992, C. parapsilosis accounted for only 7% of
candidemia in cancer patients. Weems (1992) gave a
summary of C. parapsilosis fungemia cases described
before 1992. From 1962 to 1986, 11 different studies
reported between 3% and 27% prevalence of C. parapsilosis among Candida fungemia. Since 1990 C. parapsilosis showed an increase in incidence and is the second
or third most common yeast species isolated from the
blood in Asia and Latin American countries (Pfaller
et al. 2008a; Pfaller et al. 2000; Sandven 2000), and has
been commonly found in Europe as well (Pfaller et al.
1999; Sandven 2000). Pfaller et al. (2002) reported the
role of sentinel surveillance studies of candidemia and
­demonstrated differences among studies done between
1992 and 2001. The overall incidence in six different
­studies showed a prevalence between 7 and 21 percent
of C. parapsilosis causing candidal BSI. They further
showed that the distribution of C. parapsilosis causing BSI in adults was 5–12% while the distribution in
neonates was 24–45%. C. parapsilosis was most prevalent in patients less than 1 year of age.
Kao et al. (1999) conducted a prospective, active
population-based surveillance for candidemia in two
United States cities, Atlanta and San Francisco, during
1992 to 1993. C. parapsilosis was the second most common Candida species, and was recovered from 21% of
isolates from different patient populations. C. parapsilosis was recovered from 45% of the cases of candidemia
in neonates.
The National Epidemiology of Mycosis Survey
(NEMIS) performed an 18-month prospective study,
in surgical intensive care units (SICUs) and neonatal
intensive care units (NICUs), from several centers in the
United States (Rangel-Frausto et al. 1999). C. ­parapsilosis
was isolated from the blood in 7% of the cases in the
SICU, whereas a prevalence of 29% of C. parapsilosis was
identified in the NICU.
A 10-year study, from 1992 through 2001, recorded
the distribution of BSI isolates of different Candida ­
species (Pfaller & Diekema 2004). Isolates were collected
from 250 medical centers in 32 nations worldwide.
C. parapsilosis accounted for 13% and was the third most
common Candida species isolated from BSI.
Pfaller et al. (1998a) previously reported C. parapsilosis had a higher prevalence in Europe, Canada and Latin
America compared to the United States. In 1997 and
1998 the SENTRY Antimicrobial Surveillance Program
reported 12 months of BSI surveillance in the United
States, Canada and Latin America (Diekema et al.
1999; Pfaller et al. 2000). Of 634 BSI, 8.4% was due to C.
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Candida parapsilosis: a review 285
parapsilosis. There was a difference of frequency of BSI
due to C. parapsilosis between countries and difference
in years. There was a decline in frequency of C. parapsilosis fungemia in both Canada and Latin America
between 1997 (23%; 38% respectively) and 1998 (7%;
19%). An increase in BSI due to C. parapsilosis in the
United States was noted from 9% in 1997 to 15% in 1998
(Diekema et al. 1999; Pfaller et al. 2000). The SENTRY
Antimicrobial Surveillance Program studied candidemia in 20 European medical centers (13 nations) in
1997 (Pfaller et al. 1999). C. parapsilosis was, with 21%,
the second most common Candida species causing BSI
in Europe. The greatest prevalence of C. parapsilosis was
noted in the Latin American hospitals. Over a 3-year
period, from 1995 to 1998, Edmond et al. (1999) reported
C. parapsilosis (21%) as the third most common Candida
species causing nosocomial BSI, in data obtained from
49 hospitals across the United States (1999).
A decreasing trend in the rate (overall decrease, 10 to
11%) of C. albicans isolation was noted over a 6.5 years
period (1997–2003) from the ARTEMIS DISK Global
Antifungal Surveillance Study including 121 different
institutions (Pfaller et al. 2005c). In contrast, C. parapsilosis showed an increase of 3% frequency of isolation
over this time period. From 1997 to 1998, C. parapsilosis accounted for 4%, and in 2003 for 7% (Pfaller et al.
2005c).
Diekema et al. ( 2002) performed prospective surveillance for candidemia at 16 hospitals in the State of Iowa
between 1998 to 2001. C. parapsilosis was ­identified in
7%, the fourth most common Candida species. However,
the percentage of candidemia caused by C. parapsilosis
trended higher among infants less than 1 year of age
(17%) compared to other age groups (6%) (Diekema
et al. 2002).
Between 2001 and 2004 the distribution of Candida
species of clinical isolates (blood or sterile-site) were
tested among 91 medical centers worldwide (AsiaPacific, Europe, Latin America, and North America)
and C. parapsilosis accounted for 14% (Pfaller et al.
2006b). In another report, during the 2001–2002 study
period, a prevalence of 14% was found for C. parapsilosis isolates obtained from 54 different centers worldwide (Pfaller et al. 2005b). Nucci et al. (2001) reported
a study of C. parapsilosis and C. albicans candidemia in
a tertiary hospital in Brazil. Patients with a candidemia
of C. parapsilosis were less ill, more had cancer in complete remission, fewer had antibiotics, were less likely
to be hypotensive and showed a lower mortality compared to patients with a candidemia caused by C. albicans (Nucci et al. 2001).
In 2004 and 2005 the Global Surveillance study
reported species distribution of Candida species (clinical isolates from blood or sterile site) among 60 medical centers worldwide, and reported a 14% prevalence
of C. parapsilosis (Pfaller et al. 2005c). C. parapsilosis
and C. tropicalis were predominant in the Asia-Pacific
and Latin American regions but was less so in Europe,
Canada and the United States.
In the surveillance study performed by the European
Confederation of Medical Mycology (ECMM), species distribution of Candida bloodstream infections
of 2089 cases were documented by 106 institutions in
seven European countries from Sept 1997–Dec 1999
(Tortorano et al. 2006, Tortorano et al. 2004). In a range
of patient populations, C. parapsilosis accounted for
13% of the cases of candidemia, with a range of 6–30%,
being the third most common Candida species after
C. albicans (56%) and C. glabrata (14%) (Tortorano et al.
2004). Variation in prevalence was noted and has been
attributed to the different patient populations hospitalized in the different units (Tortorano et al. 2004). In
addition, there was variation between countries noted
(Tortorano et al. 2006). C. parapsilosis was identified in
15% in cancer patients (Tortorano et al. 2004). This study
reported C. parapsilosis the most frequent Candida
species identified in premature neonates (29%). In
another study, the ECMM performed an epidemiological prospective survey of candidemia in one Italian
region, Lombardy, for a 28-month period (September
1997–December 1999) (Tortorano et al. 2002). Fifteen
percent of the cases of candidemia were caused by
C. parapsilosis, and it was the second most common
cause of candidemia, behind C. albicans (59%). C. parapsilosis was isolated with the highest frequency in premature neonates and hematological patients, comprising
44 and 24% of isolates. Another study from the ECMM,
in the same time period from several hospitals widely
distributed throughout Spain, showed a prevalence of
22% of C. parapsilosis isolates from adults (Peman et al.
2005). In pediatric patients C. parapsilosis was the most
prevalent species (50%).
The advent of new medical therapies and procedures to treat cancer, such as steroids, the increase in
surgical procedures, widespread use of broad spectrum
antibiotics and prolonged hospital stay are all linked
to the increase of Candida bloodstream infections
(Eggimann et al. 2003; Sofair et al. 2006). The shift in the
epidemiology towards C. parapsilosis infections may
be especially linked to the increase, which occurred
in the past two decades, in incidence of blood stream
infections associated with intravascular devices (San
Miguel et al. 2005). The majority of the C. parapsilosis
infections are due to exogenous acquisition. An important study that recognized this showed that a series of 13
patients with C. parapsilosis fungemia did not have the
organism isolated from other sites before the fungemia
(Meunier-Carpentier et al. 1981). This is in contrast with
fungemia due to other Candida species. Further to this
point, there is a significantly increased risk of systemic
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286 van Asbeck et al.
disease ­associated with intravascular catheters, prosthetic devices and parenteral nutrition (Levin et al. 1998;
Tortorano et al. 2006; Zancope-Oliveira et al. 2000).
C. parapsilosis has the ability to produce an extracellular
polysaccharide or slime, and this property is believed to
aid adherence and biofilm formation on plastic devices
(Levin et al. 1998; Ramage et al. 2005). The source of the
infection by this yeast species is not always apparent.
In many neonatal intensive care units (NICU),
C. parapsilosis has emerged as the predominant
pathogen causing invasive infection, and significantly
increases the morbidity and mortality of severely ill
infants who require care in a NICU (Kao et al. 1999;
Krcmery et al. 1999; Kuhn et al. 2004; Levy et al. 1998;
Roilides et al. 2004; Saiman et al. 2001; Stamos & Rowley
1995). The proportion of infections due to C. parapsilosis has increased among neonates. C. parapsilosis
comprised less than 10% of isolates in the 1980s and
early 1990s (Baley & Silverman 1988; Faix 1984; Huttova
et al. 1998a). More recently, studies reported proportions of 50–60% of C. parapsilosis infections among
neonates (Benjamin et al. 2000; Kossoff et al. 1998; Levy
et al. 1998; Rodriguez et al. 2006). The proportion of
infections due to C. parapsilosis has increased among
neonates. As neonates mature, the incidence of C. parapsilosis decreases (Pfaller & Diekema 2002; Tortorano
et al. 2006). Changes in neonatal intensive care practices
may be related to the emergence of C. parapsilosis as
an important pathogen in very low birthweight infants
(Clerihew et al. 2007). Cases can persist in units for
years (Sarvikivi et al. 2005) and the case fatality rate can
be high (83%) (Saxen et al. 1995). Cross-transmission
between patients, especially among neonates, through
the hands of healthcare workers plays an important
role in the spread of C. parapsilosis, contributing to the
high isolation rate of C. parapsilosis. C. parapsilosis is
a frequent fungal colonizer of the subungual space of
healthy volunteers (Abi-Said et al. 1997; McGinley et al.
1988; Weems 1992). Several reported outbreaks have
been caused via direct interaction between healthcare
workers and the newborn, through the placement
or manipulation of catheters, the site through which
C. parapsilosis entered the bloodstream, as well as liquid
glycerin suppositories and topical ointments (Barchiesi
et al. 2004; Campbell et al. 2000; Huang et al. 1999; Kuhn
et al. 2004; van Asbeck et al. 2007; Welbel et al. 1996).
Hypoxemia, bradycardia, respiratory distress requiring
incubation and dissemination to secondary sites are
less common with C. parapsilosis fungemia in newborns, compared to C. albicans fungemia (Huang et al.
2000).
Other outbreaks have been reported, such as outbreaks of C. parapsilosis caused by contamination of
hyperalimentation solutions, intravascular pressure
monitoring devices, ophthalmic irrigating solutions
and glucose-containing solutions (Clark et al. 2004;
Deresinski et al. 1995; Levy et al. 1998; Posteraro et al.
2004; Solomon et al. 1986; Solomon et al. 1984; Weems
et al. 1987).
With the use of azoles there has been an
­epidemiological shift of hematogenous candidiasis to
those caused by non-albicans Candida species, especially C. krusei and C. glabrata (Abi-Said et al. 1997; Kao
et al. 1999). The rise of C. parapsilosis correlates with
increased use of caspofungin and voriconazole (Forrest
2008). Girmenia et al. (1996) showed an overall decrease
of isolation of C. albicans with a concomitant increase
in isolation of C. parapsilosis among adult patients with
cancer. This indicates that even among older patients
the incidence of C. parapsilosis may be on the rise. The
crude mortality rate associated with C. parapsilosis
infection has been estimated to be 30%, lower than that
reported for invasive infection with C. albicans (79%)
or other non-albicans Candida spp. (mean 78%) (Horn
et al. 1985; Nucci et al. 2001; Pappas et al. 2003).
Molecular epidemiology
Biochemical methods have traditionally been relied
on to identify C. parapsilosis in the clinical microbiology laboratory, although occasionally these can lead to
misidentification (Fenn et al. 1994; Heelan et al. 1998;
Pfaller et al. 2008a; Ramani et al. 1998; Wadlin et al.
1999). Due to problems in the traditional classification
of yeast within the genus Candida, molecular techniques are needed to classify and identify medically
important yeast species. This will help us to understand the evolutionary relationships between these
organisms. The application of molecular procedures
has already resulted in major reclassification of many
species. Comparative studies with chromosomal DNA
have been very helpful to differentiate Candida species
from each other and also to delineate different strains
within species. The ideal method for differentiating
C. parapsilosis at a subspecies level should be able to
discriminate between strains that are epidemiologically unrelated, should be highly reproducible both
intra- and inter-laboratory, should take minimal time,
should be capable of processing a large number of
strains, should require a minimum of specialized
equipment, and be relatively inexpensive (McCullough
et al. 1996). It is unclear whether the emergence of
pathogenic isolates of C. parapsilosis in varying clinical institutions is due to the genetic diversity and the
virulence of some strains, or to widespread favorable
environmental conditions persisting in compromised
hosts (Dassanayake & Samaranayake 2000). Detailing
the genotypic characteristics are not only important for
a more appropriate taxonomy, it could also greatly contribute to our understanding of the epidemiology and
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Candida parapsilosis: a review 287
the pathogenic mechanisms of this emerging pathogen
(Weems 1992). Hospital outbreaks have been associated with specific strains of C. parapsilosis by use of the
various methods we will discuss (Shin et al. 2001;
Barchiesi et al. 2004; Clark et al. 2004; Garcia San Miguel
et al. 2004; Marais et al. 2004). Molecular typing also has
the utility of discerning “pseudo-outbreaks,” contaminated processing materials leading to false conclusion of
a case cluster (Deresinski et al. 1995; Schar et al. 1990).
Genetic analysis of C. parapsilosis has been hindered by the lack of characterized sexual cycle (Logue
et al. 2005), ploidy (aneuploid and/or diploid) of the
organism (Fundyga et al. 2004) and the unavailability
of appropriate molecular genetic tools (Nosek et al.
2002a). Various DNA typing method studies report that
C. parapsilosis can be divided into three groups based
on isoenzyme analysis, internally transcribed spacer
(ITS) sequences of DNA within the ribosomal cassette,
RAPD profiles, RFLP typing, electrophoretic karyotype
patterns, multilocus enzyme electrophoresis, morphotyping, multilocus sequence typing (MLST), and DNA
relatedness (Lehmann et al. 1992; Lin et al. 1995; Lott
et al. 1993; Roy & Meyer 1998; Scherer & Stevens 1987;
Tavanti et al. 2005). Although division into three groups
can be achieved, when subtyping within the three
groups is performed, it was noted that a large number of
the isolates are indistinguishable.
Scherer and Stevens (1987) described a useful
method for the extraction of DNA from the yeast of
Candida spp., followed by digestion and restriction
endonucleases and electrophoresis of DNA fragments.
Seven C. parapsilosis isolates typed in this manner
could be placed in 3 major DNA groups with, initially,
5 subtypes. As more isolates were studied, greater
genotypic diversity became apparent, for example,
Deresinski et al. (1995) found a unique RFLP subtype, VII-3, identified in a common source outbreak,
and a recent study done by van Asbeck et al. (2008a)
examined the molecular epidemiology of the global
and temporal diversity of C. parapsilosis. In this study
15 new subtypes were observed, with one dominant
subtype, VII-1 (82% of 536 C. parapsilosis isolates).
Dividing the isolates into VII-1 versus non-VII-1
showed temporal variation for the USA pre-1995 versus post-1995 (p < 0.0001) and versus Europe pre-1995
(p < 0.0001). Genotype distribution differed among
localities (p < 0.0001); Mexico was unique (p < 0.05) due
to the high proportion of non-VII-1. The prevalence of
C. parapsilosis RFLP type VII-1 apparently has risen in
the USA and current isolates show some variation in distribution of types in some non-USA locales compared
to the USA. There were no differences in distribution of
types comparing babies versus adults, or blood stream
isolates versus colonizing or environmental isolates. In
contrast to the conserved restriction fragment profiles
in strains from ITS groups I and III, a polymorphism
within group II was observed (van Asbeck et al. 2008a).
Roy and Meyer (1998) studied the DNA relatedness
and RFLP patterns of whole-cell DNA and the general
properties of 14 C. parapsilosis isolates and observed
unrelatedness of the three previously described groups
at the species level. The low degree of the DNA relatedness, less than 25% DNA identity, among the three
­different DNA groups of C. parapsilosis suggested
that they represent distinct species. Various studies
­supported this idea of possible separation of C. parapsilosis isolates (Cassone et al. 1995; De Bernardis et al.
1999; Kurtzman & Robnett 1998; Lin et al. 1995; Pontieri
et al. 2001). The internally transcribed spacer (ITS)
regions flanking the 5.8S rDNA in yeasts have greater
heterogeneity than the 5.8S region itself. Using this
observation, for example, Lin et al. (1995) concluded
there were 3 different genotypes in C. parapsilosis
based on sequence analysis.
Based on their ITS (mostly ITS1) region sequences,
Tavanti et al. (2005) proposed to recognize Candida
orthopsilosis and Candida metapsilosis as species separate from C. parapsilosis. Thus far, these sibling species
are phenotypically indistinguishable from C. parapsilosis sensu stricto. DNA sequence analysis showed
conformity of C. parapsilosis with previous group I,
C. orthopsilosis with group II and C. metapsilosis with
group III (Lin et al. 1995; Roy & Meyer 1998; Tavanti
et al. 2005). Based on sequence analysis of four gene
fragments, nine C. orthopsilosis isolates showed nucleotide sequence diversity. This suggests great heterogeneity among the C. orthopsilosis isolates, compared
to the mainly clonal C. parapsilosis. Lack of diversity
among group I isolates had been suggested by karyotyping (Carruba et al. 1991; Lott et al. 1993; Shin et al.
2001). The sequence homogeneity in group I isolates
suggests they emerged more recently than the other
types. Some hospital outbreaks have been related specifically to group II (Lin et al. 1995; Zancope-Oliveira
et al. 2000), although most would appear to be related
to group I.
Our laboratory compared two predominant typing
methods, RFLP and MLST, and reported C. parapsilosis
sensus stricto appear to be nearly identical to the predominant RFLP subtype VII-1, and cannot be subtyped
by RFLP and MLST (van Asbeck et al. in press). However,
C. orthopsilosis can be subtyped by both MLST and RFLP
(van Asbeck et al. in press).
Tavanti et al. (2007) used amplification fragment
length polymorphism (AFLP) to identify C. orthopsilosis
at the species level and efficiently delineate intraspecific genetic relatedness because of the high percentage
of polymorphic bands resulting from the AFLP. Clonal
reproduction and recombination both contribute to
C. orthopsilosis genetic population structure. This
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288 van Asbeck et al.
study also reported the clinical relevance of C. orthopsilosis. Screening a large collection of C. parapsilosis,
5% of the infections/colonizations were identified as
C. orthopsilosis.
Recently, Gomez-Lopez et al. (2008) describe the
prevalence of the two newly described species C. metapsilosis and C. orthopsilosis (described below (Tavanti
et al. 2005)) causing bloodstream infections in Spain. The
prevalence of these species appeared to be important,
representing the fifth and sixth most ­common species
(1.7% and 1.4% for C. metapsilosis and C. orthopsilosis
respectively) (Gomez-Lopez et al. 2008). This study also
provided evidence that these species may behave as
human pathogens. A more recent paper also studied
geographical distribution of the sister species (Lockhart
et al. 2008a). C. orthopsilosis comprised 6.1% and C.
metapsilosis 1.8% of 1,929 isolates. C. orthopsilosis was
most common in South America. Somewhat in contrast to our observations (van Asbeck et al. 2008a),
C. orthopsilosis appeared to have increased in recent
years. Mexico had a high frequency of C. orthopsilosis,
likely a reflection of the same trends as our increase of
non-VII-1 types in that country (van Asbeck et al. 2008a).
Lockhart et al. (2008b) reported that an apparently
closely related species, Lodderomyces elongisporus,
is mislabelled by routine clinical laboratory methods
as C. parapsilosis. Once erroneously considered to be
the teleomorph of C. parapsilosis (van der Walt 1966),
L. elongisporus can be distinguished phenotypically
from C. parapsilosis as they produce different colored
colonies on ChromAgar medium. On cornmeal agar,
L. elongisporus forms short pseudohyphae indistinguishable from C. parapsilosis. On sporulation medium,
only L. elongisporus forms ascospores. The species differentiation is supported by DNA/DNA homology and
sequencing of large-subunit rRNA genes. In their large
population studied (Lockhart et al. 2008b), L. elongisporus could be differentiated as 10/542 isolates from a
collection ostensibly all C. parapsilosis; all of the former
were blood stream isolates.
Camougrand et al. (1988) used restriction analysis of
mitochondrial DNA of C. parapsilosis reference strains
and showed great differences between them. By probing
the restriction patterns with S. cerevisiae mitochondrial
DNA fragments, further differentiation could be made.
Nosek et al. (2004) determined the complete mitochondrial DNA (mtDNA) sequence of C. parapsilosis, represented by linear DNA molecules terminating with arrays
of tandem repeats of a 738 bp unit, varied in number
and size, termed mitochondrial telomeres. Recently,
Kosa et al. (2006) studied the complete sequence of
mitochondrial DNA of the sibling species and observed
C. metapsilosis likely diverged from a common ancestor
prior to the split of C. orthopsilosis and C. parapsilosis
sensu stricto. All three sibling species genomes are highly
compact and encode the same set of genes arranged in
an identical order. However the size of C. orthopsilosis
and C. metapsilosis mtDNA represents about twothirds that of the C. parapsilosis sensus stricto. Earlier,
Rycovska et al. (2004) assessed the polymorphism at the
level of mtDNA and indicated that group II isolates all
have a circular mtDNA, whereas the mtDNA in group
I and III is mostly linear. Kosa et al. (2006) showed
C. orthospilosis and C. metapsilosis differ in the molecular form of the mitochondrial genome, circular—versus
linear—mapping, whereas C. parapsilosis sensus stricto
possesses a linear mitochondrial genome.
Mitochondrial telomeres are unique among
C. ­parapsilosis compared to related species (Nosek
et al. 2002b). Thus, mtDNA enables us to discriminate
between the groups of C. parapsilosis and it represents a
powerful tool to distinguish species.
Similarly, Iida et al. (2005) found that most of the
C. parapsilosis strains from Japan and Brazil tested for
ITS sequences belonged to one of the three genetically
distinct groups (I, II, and III). However, they found that
5 strains showed differences in ITS sequence from those
already reported, and based on this, suggested the presence of a new major DNA group (IV) among the genetic
groups within the C. parapsilosis family.
Dominance of these C. parapsilosis group I isolates,
and its geographic spread, might be due to the clonal
mode of reproduction, shown by the low nucleotide
variability observed within the species (Fundyga et al.
2004; Tavanti et al. 2005; Tavanti et al. 2007).
A new DNA probe, Cp3-13 for DNA fingerprinting,
has been described, which not only discriminated differences between strains, but also identified changes
in a clonal population after a few hundred generations in vitro or changes that have occurred in vivo in
infected persons (Clark et al. 2004; Enger et al. 2001;
Sofair et al. 2006). Recently, a microsatellite method,
with high discrimination and reproducibility, has
been reported that further differentiates group I
C. parapsilosis isolates with high discriminatory
power (Lasker et al. 2006). Microsatellites are short
2- to 10 bp multiple tandem repeats, and have a high
mutation rate. This method makes it possible to detect
microevolutionary variations of isolates obtained
from different body sites, and may facilitate detection
of outbreaks.
Kosa et al. (2007) constructed a collection of replicative shuttle vectors, a system for genetic transformation
of the yeast C. parapsilosis. These vectors, which allow
expression of the cloned genes, intracellular localization
of protein products or monitoring of a promotor activity,
may contribute to the investigation of diverse biological
features related to C. parapsilosis (2007).
A sequencing project of C. parapsilosis nuclear
genome would be important for better understanding
Candida parapsilosis: a review 289
the biology of this pathogenic yeast species at the
molecular level. Understanding the genetic diversity of
the yeast requires further study and may lead to insight
in the pathogenesis of fungal infections, and ultimately
may make it possible to define proper preventive measures (Roy & Meyer 1998).
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Clinical aspects
C. parapsilosis is an important opportunistic pathogen
that causes infections ranging from thrush to invasive
disease such as fungemia, endocarditis, endophthalmitis, arthritis, and peritonitis, all of which usually occur
in association with invasive procedures or prosthetic
devices. We will describe only the most frequent infections caused by C. parapsilosis.
Superficial Infections
Frequent isolation of C. parapsilosis from pathological
lesions of nails and skin, with a distal subungual type
of onychomycosis often occurs with this organism (De
Bernardis et al. 1999; Figueiredo et al. 2007; Mujica et al.
2004; Pfaller et al. 1995; Segal et al. 2000; Strausbaugh
et al. 1994). Risk factors significantly associated with
­colonization in patients are prolonged antibiotic
therapy, parenteral nutrition, duration of stay in the
­hospital, ­surgery, indwelling devices, diabetes, obesity, malignancy, elderly, and neonates of very low birth
weight (Bendel 2003; Dorko et al. 2005; Figueiredo et al.
2007; Jautova et al. 2001).
C. parapsilosis is second to C. albicans as the most
common Candida causing onychomycosis (Brilhante
et al. 2005; Dorko et al. 2002a; Khosravi & Mansouri
2001). However, some studies observed an even higher
prevalence of onychomycosis caused by C. parapsilosis. Segal et al. (2000) reported a high prevalence of
C. parapsilosis among onychomycosis patients obtained
from two different centers in Israel. C. parapsilosis was
the predominant Candida species, recovered from both
fingernail and toenail infections (Segal et al. 2000).
Figueiredo et al. (2007) reported 41% of the 200 samples
recovered from fingernails of Candida species were
C. parapsilosis, which is in agreement with RodriguesSoto et al. (1993), who identified C. parapsilosis as
the prevalent species in onychomycosis involving the
fingernails. In addition, Oliveira et al. (2006) reported
C. parapsilosis as the Candida species most frequently
isolated from onychomycosis lesions. Recently, in a
study among Algerian military personnel, C. parapsilosis
was the predominant yeast species causing both superficial fungal infection and onychomycosis of the foot
(Djeridane et al. 2006; Djeridane et al. 2007). In addition, C. parapsilosis was the most common yeast causing
onychomycosis in Malta (Vella Zahra et al. 2003). One
case of onychomycosis caused by C. parapsilosis, involving both the toenail and the fingernail, in a 35-day-old
patient has been reported (Koklu et al., 2007). With all
positive cultures from nails, supporting histopathological evidence of infection is needed to distinguish infection from colonization. Folliculitis due to C. parapsilosis
has been described by Li et al. (1988).
C. parapsilosis has been associated with disease of the
external or middle ear (Dorko et al. 2004; Garcia-Martos
et al. 1993; Vennewald et al. 2003). The risks appear to
be ocean swimming, trauma and prior antibacterial
therapy.
Mucosal
The primary mucosal infection due to C. parapsilosis
is vaginal. In the majority of women with Candidal
vaginitis it is due to C. albicans, which causes 80% to
92% of all cases of Candida vaginitis worldwide (Singh
et al. 1972; Trama et al. 2005). In immunodeficient
women, vaginal colonization by non-albicans species
is more frequent (Trama et al. 2005). Weems (1992)
concluded that vaginitis caused by C. parapsilosis
is infrequent. However, an increase in frequency of
vaginitis caused by C. parapsilosis has been observed
among healthy women (Nyirjesy et al. 2005; Trama
et al. 2005). C. parapsilosis can be responsible for
vulvovaginal symptoms, such as itching, burning, dyspareunia and vaginal discharge, but can also appear
asymptomatically (Nyirjesy et al. 2005). The change
of species distribution, non-albicans species such as
C. glabrata, C. parapsilosis, and C. tropicalis becoming more frequent, can be related to factors that might
change the vaginal environment and flora (Trama et al.
2005). These factors could be increasing use of azole
drugs, an aging population, increased exogenous use
of hormones to manage menopause, and/or more
medical and hospital contact in the patients sampled
(Trama et al. 2005). Cassone et al. (1995) showed that
~10% of vaginal candidiasis is caused by C. parapsilosis. Nyirjesy et al. (2005) reported 9% of vaginitis cases
were caused by C. parapsilosis. C. parapsilosis, like
C. albicans, produces acid proteinases, enzymes which
are associated with vaginopathic potential (Agatensi
et al. 1991; Nyirjesy et al. 2005). Secretion of aspartyl
proteinases is elevated in vaginitis caused by these
vaginopathic strains. Women suffering multiple episodes of vulvovaginitis, and with theoretically compromised integrity of the vaginal mucosa, may be more
susceptible to infection with C. parapsilosis because of
the acid proteinase activity of the organism (Nyirjesy
et al. 2005). Vaginitis caused by this pathogen seems
to respond to a variety of antifungals (Nyirjesy et al.
2005).
290 van Asbeck et al.
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Urinary tract infections
Primary urinary tract infections due to C. parapsilosis
have markedly increased in recent years and are associated with the presence of urinary catheters (Camacho
et al. 2007; Passos et al. 2005; Tamura et al. 2003). The
adherence of microorganisms to the surface is a determining factor in colonization and infection (Tamura
et al. 2003). Recently, in a study of Camacho et al. (2007),
antimicrobial activity of chlorohexidine and gentian
violet reduced the adherence of C. parapsilosis.
Systemic
In contrast to C. albicans infections, C. parapsilosis
­infections may occur without prior colonization, especially in young children (Shin et al. 2001). C. parapsilosis causes 17–50% of fungemia in children (Abi-Said
et al. 1997; Krcmery & Barnes 2002; Krcmery et al. 1999;
Viscoli et al. 1999; Wingard 1995). The clinical picture of fungemia may include shock and renal failure
(Almirante et al. 2006). Direct access to the bloodstream
via indwelling devices might be an explanation of the
cause of infections without prior colonization at other
sites (Levin et al. 1998; Traore et al. 2002; Weems 1992).
Unlike other Candida species, catheter-related fungemia
caused by C. parapsilosis has a higher rate of spontaneous clearance and a much lower rate of establishment at
secondary sites (Levy et al. 1998; Weems 1992).
Breakthrough fungemias during antifungal treatment appear especially common in cancer patients and
are associated with an infected foreign body, such as
catheters, and insufficient antifungal treatment (Safdar
et al. 2002). Krcmery et al. (1999) reported breakthrough
fungemia among neonates during fluconazole therapy
and prophylaxis. The presentation of C. parapsilosis
fungemia in neonates can be subtle including thrombocytopenia and leucopenia (Huang et al. 1999). C. parapsilosis fungemia has a lower mortality than bloodstream
infections due to other Candida species.
Endocarditis
As a cause of endocarditis, C. parapsilosis has demonstrated a tendency to persist, even despite suppressive
therapy, and recrudesce if suppression is discontinued.
This can be misleading, in that patients with C. parapsilosis endocarditis are reported in the literature while
still receiving suppressive therapy (and sometimes with
short follow-up post-surgery, and without attempts to
evaluate fungemia), resulting in a false impression of
cure (Galgiani & Stevens 1977). Serologic follow-up during and after therapy may be useful (Galgiani & Stevens
1977). Weems (1992) described some patients with endocarditis caused by C. parapsilosis before 1992. In the past
two decades fungal endocarditis has increased in incidence, carrying with it a high risk of mortality (Garzoni
et al. 2007; Lopez-Ciudad et al. 2006); this is one of the
most serious manifestations of candidiasis. A long duration of illness has been reported in patients suffering
non-albicans endocarditis, so prolonged treatment is
required to avoid grave consequences (Khan et al. 2007).
Among yeast-related endocarditis, C. parapsilosis is the
most important non-albicans species isolated (Garzoni
et al. 2007; Khan et al. 2007).
Clusters of cases involving prosthetic valves have
been reported (Diekema et al. 1997). Garzoni et al.
(2007) described intraoperative contamination (e.g.
cardiac bypass equipment, tears in surgical gloves) to
be the most common source of infection in outbreaks of
C. parapsilosis infective endocarditis (Diekema et al.
1997; Johnston et al. 1994). The most prevalent predisposing factors for fungal endocarditis caused by
C. parapsilosis are prosthetic valves, then, in this order,
­intravenous drug use, parenteral nutrition, antibiotic
therapy, preexisting valvular heart disease, prior episode of endocarditis and reconstructive cardiovascular
surgery (Brandstetter & Brause 1980; Garzoni et al. 2007;
Khan et al. 2007; Rubinstein et al. 1975; San Miguel et al.
2006; Tonomo et al. 2004; Weems 1992). Abdominal surgery and immunosuppression have also been described
as risk factors. The aortic valve is the first, and mitral valve
the second, most commonly involved valve in infection
of native valves (Garzoni et al. 2007; Weems 1992), with
intravenous drug use the most common predisposing
factor (Garzoni et al. 2007). The overall mortality of these
patients was high (42%). Among those treated with conventional antifungals and adjunctive surgery, mortality
was lower (Johnston et al. 1994). Peripheral embolic and
hemorrhagic events are the most common complications (44%) of C. parapsilosis endocarditis (Garzoni et al.
2007).
Peritonitis
Fungal peritonitis is an uncommon but potentially lifethreatening complication of continuous ambulatory
peritoneal dialysis (CAPD) (Amici et al. 1994; Bren 1998;
Chen et al. 2004; Chen et al. 2006; Johnson et al. 1985;
Kaitwatcharachai 2002). C. parapsilosis has become the
most prevalent pathogen of fungal peritonitis (Chen
et al. 2006). This organism, which is a common skin and
subungual colonizer, has the ability, in high glucose
concentrations, to adhere easily to prosthetic material
by extensive biofilm formation on the surface of the
plastic catheter. The high glucose content of dialysate,
and catheter implantation in peritoneal dialysis patients
causes this high prevalence of fungal peritonitis caused
by C. parapsilosis (Chen et al. 2006). The mechanism of C.
parapsilosis infections is considered to be transmission
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Candida parapsilosis: a review 291
by skin colonization of C. parapsilosis via the catheter
lumen (Kaitwatcharachai 2002).
An earlier study of Manzano- Gayosso et al. (2003)
reported C. albicans and C. parapsilosis as the most common species among 165 patients with peritonitis receiving CAPD treatment. Other studies showed C. parapsilosis the most prevalent pathogen of fungal peritonitis in
patients receiving peritoneal dialysis (Chen et al. 2006;
Wong et al. 2000). Recently, Chen et al. (2006) reported
a percentage of 86% (19 cases), of fungal peritonitis
caused by Candida species, of these, 41% (9 cases) were
C. parapsilosis. Fifty percent of these patients developed
severe complications, with abscess formation and persistent peritonitis after catheter removal (Chen et al.
2006).
Wang et al. (2000) showed that the presence of
abdominal pain, antibiotic use within 3 months before
fungal peritonitis, bowel obstruction and a catheter kept
in situ seems to be associated with the development of
fungal peritonitis and necessitate CAPD discontinuation
(removal of the catheter) (Kaitwatcharachai 2002; Wong
et al. 2000). Kaitwatcharachi (2002) showed that either
abdominal pain or antibiotic use in the previous three
months were risk factors for fungal peritonitis prior to
CAPD discontinuation. Prior gram negative bacterial
peritonitis is also a risk factor for development of fungal peritonitis (Kaitwatcharachai 2002). Whereas there
is no consensus whether or when peritoneal catheters
should be removed, rapid catheter removal has been
recommended in C. parapsilosis peritonitis in CAPD
patients (Bren 1998; Kaitwatcharachai 2002). Chen et al.
(2006) showed that patients with C. parapsilosis peritonitis developed more complications and have a worse
prognosis than those infected with other Candida species in peritoneal dialysis-associated fungal peritonitis.
Because of different severity and prognosis, C. parapsilosis peritonitis in peritoneal dialysis patients should be
treated more aggressively than other Candida species
(Chen et al. 2006).
Endophthalmitis
C. parapsilosis has been known as a cause of epidemic
of post-cataract endopthalmitis caused by intrinsically ­contaminated, intraocular lens-irrigating solution (McCray et al. 1986; O’Day 1985; O’Day et al. 1987;
Stern et al. 1985). In one study 4% of patients exposed
to the contaminated solution developed C. parapsilosis
­endopthalmitis (McCray et al. 1986). Although other
sporadic postoperative intraocular infections with
C. parapsilosis have been reported, hematogenous
endophthalmitis appears to be rare (Feman et al. 2002;
Weems 1992). Recently, Marangon et al. (2004) reported
Candida species as the most common cause of endogenous endophthalmitis in their institution, with C.
albicans the most frequent subspecies (30%). C. parapsilosis accounted for 21% of all Candida endophthalmitis infections.
A few cases of keratitis have been reported, with risk
factors such as corticosteroid use, corneal transplantation and laser in situ keratomileusis (LASIK) (Bourcier
et al. 2003; Muallem et al. 2003; Solomon et al. 2004).
Since treatment, such as surgery and antifungal therapy,
can save vision, evidence of intraocular infection should
be recognized as early as possible (Feman et al. 2002).
Joint diseases
Candida arthritis is most commonly seen among intravenous drug users (Vasquez et al. 2002). Nosocomial
C. parapsilosis arthritis has been reported in only a few
cases, involving the knee, shoulder and wrist (De Clerck
et al. 1988; Diekema et al. 1997; Legout et al. 2006;
Salo et al. 1990; Smith et al. 1987; Vasquez et al. 2002;
Yarchoan et al. 1979) Arthritis caused by C. parapsilosis is associated with joint prostheses, probably due to
the increased ability of this micro-organism to adhere
to plastic (Brooks & Pupparo 1998; Cushing & Fulgenzi
1997; Hennessy 1996; Wada et al. 1998). Arthritis, produced by C. parapsilosis, can result through direct inoculation of the fungus at arthrocentesis and is sporadic
in older individuals (Cuende et al. 1993). Risk factors
for these sporadic incidents include diabetes mellitus,
intravenous drug use, and immunosuppression (Cuende
et al. 1993).
Pancreatitis
There are a growing number of reports of pancreatic
infections due to Candida species, most commonly
C. albicans, mainly with previous abdominal manipulation, such as previous pancreatic drainage procedures
(percutaneous or surgical) (Robbins et al. 1996). Fungal
pancreatitis due to non-albicans species has increased
in incidence and is attributed to several factors, such
as the use of broad-spectrum antibiotics, parenteral
nutrition as well as the increase in use of immunosuppressive agents (Robbins et al. 1996). Only a few cases of
pancreatic infections (infected pancreatic necrosis and
pancreatic abscesses) due to C. parapsilosis have been
described (Ibanez & Serrano-Heranz 1999; Kull et al.
1999; Gautret et al. 1998).
Meningitis
Up to 1992, in the review article by Weems (1992) one
case of meningitis caused by C. parapsilosis was reported
(Faix 1983). Several cases of meningitis caused by this
organism have since been described, especially among
neonates (Dorko et al. 2002b; Huttova et al. 1998b).
292 van Asbeck et al.
Surgery, antibiotic treatment, parenteral nutrition,
skin folliculitis, fungemia and the use of intravascular
and intraventricular catheters are potential risk factors
(Huttova et al. 1998b; Jimenez-Mejias et al. 1993; Weems
1992).
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Pathogenesis
Although very little on this subject has been studied,
in this section we will discuss what is currently known
about virulence factors of C. parapsilosis and host
defense against this organism.
Virulence
C. parapsilosis accounts for a significant proportion of
nosocomial infections, with an increasing prevalence.
As with other Candida species, invasion of C. parapsilosis can result in severe disease, particularly in hosts with
a suppressed immune system. For the development of
more effective containment measures it is necessary to
understand the mechanisms that underlie pathogenicity. The lack of knowledge of virulence factors that play
a role in the pathogenicity of C. parapsilosis may in part
be due to the exclusive use of type-collection strains in
most experiments (Cassone et al. 1995). The paucity of
data on clinical isolates needs to be corrected.
We suspect that the lower virulence of C. parapsilosis
compared to C. albicans and some other non-albicans
Candida species is a reason for the lower mortality and
morbidity rates observed in adults and neonates (Faix
1992; Sullivan et al. 1995; Weems 1992). Comparing
C. parapsilosis with C. albicans has made it possible to
define some putative virulence factors. These virulence
factors, present in both species, include adherence to
epithelial and endothelial cells, proteinase production
(Cassone et al. 1987; Ross et al. 1990), pseudohypha
formation (Sobel et al. 1984), phospholipase production
(Ibrahim et al. 1995) and phenotypic switching (Soll
1992).
The lower virulence of C. parapsilosis compared
to C. albicans can also be attributed to the lack of formation of hyphae. Most Candida species, including
C. parapsilosis (Laffey & Butler 2005) exist as spherical to
ovoid blastospores or yeast cells. Many Candida species
are capable, to various degrees, of producing chains of
elongated blastospores termed pseudohyphae, both in
vivo, and under certain conditions, in vitro. The hyphal
forms are more difficult to ingest, and the cell walls may
be more resistant to digestion. In addition, hyphal forms
have been defined as more adhesive than pseudohyphae
(Hostetter 1994).
The ability of a micro-organism to adhere to
mucosal surfaces is the critical first step for successful
c­ olonization and subsequent infection of host tissues
by a ­potentially pathogenic Candida spp. C. parapsilosis, which is thought to be acquired from exogenous
sources, adheres to indwelling devices, and after adherence invades the host (Kuhn et al. 2004). C. albicans and
other non-albicans Candida species adhere to a greater
extent to mucosal tissue than does C. parapsilosis (Klotz
et al. 1983, Wingard 1995). A decreased adherence to
epithelial cells by C. parapsilosis compared to C. albicans and C. tropicalis has been observed (Krcmery &
Barnes 2002, Weems 1992) and the reduced pathogenic
potential of C. parapsilosis related to its adhesive properties (Branchini et al. 1994). However, Panagoda et al.
(2001) observed adhesion by C. parapsilosis skin isolates to human buccal epithelial cells was higher than
that of systemic isolates, and also found an association
between relative cell surface hydrophobicity and adhesion to acrylic surfaces. The high adherence to human
buccal epithelial cells noted among certain of the
C. parapsilosis isolates used in this study might be attributed to variation in strains and culture conditions, or
aggregation among yeast cells, but implies the potential
for colonization of mucosal surfaces, possibly equal to
that of C. albicans (Panagoda et al. 2001).
de Bernardis et al. (1999) found isolates from blood
and skin adhered about equally to plastic, but that
greater adhesion to plastic was found among isolates showing a fringed colony morphology versus a
nonfringed morphology. In addition, these authors
reported higher secreted aspartic protease (Sap) production among isolates from skin, which were better
able to cause experimental rat vaginitis than were low
Sap-producing fungemia isolates. However, the skin
isolates were less virulent than were the blood isolates
in a model of systemic infection in neutropenic mice
(De Bernardis et al. 1999). These data indicate that
different biotypes may thus differ in virulence. Sap
enzymes are considered a putative virulence factor of C.
albicans (Gokce et al. 2007; Naglik et al. 2004). They may
have a role in disrupting mucosal surfaces or destroying
host defense proteins. These enzymes also have been
strongly associated in superficial, but not with systemic
invasion, caused by C. parapsilosis (Cassone et al. 1995;
De Bernardis et al. 1999; Gokce et al. 2007). However,
Dagdeviren et al. (2005) observed a higher production
of acid proteinase among blood isolates compared to
non-blood isolates. A proteinase inhibitor can reduce
tissue damage due to this species (Gacser et al. 2007b).
Although C. parapsilosis possesses fewer Sap enzymes
than C. albicans (De Bernardis et al. 1999), Lin et al.
(1995) reported differences in proteinase activity
within the major DNA groups of C.parapsilosis. Group I
showed strong to moderately strong proteinase production, whereas group II and III isolates had low proteinase activity.
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Candida parapsilosis: a review 293
One potential virulence factor for C. parapsilosis
includes slime production. This is of special importance
for adhesion to foreign body material and in formation
of biofilms (microbial communities that are associated
with solid surfaces such as intravascular catheters) (Nett
et al. 2007), which results in the increase of catheterrelated candidemia and antifungal resistance related to
catheter insertion (De Bernardis et al. 1999; Hawser &
Douglas 1994). The molecular mechanisms that regulate
biofilm development in C. parapsilosis is not yet understood (Girmenia et al. 1996; Laffey & Butler 2005; Levy
et al. 1998; Viscoli et al. 1999), although quorum-sensing
mediated through farnesol has been implicated (Laffey
& Butler 2005).
Song et al. (2005) also observed differences in biofilm
formation among the three groups of C. parapsilosis.
They only observed biofilm production among the
group I C. parapsilosis isolates, the group preferentially
associated with bloodstream isolates and those from
healthcare workers. Kuhn et al. (Kuhn et al. 2004) also
indicated less biofilm production among non-group I
strains, and reported a greater biofilm production by outbreak isolates compared to sporadic isolates. Recently,
Melo et al. (2007) demonstrated biofilm production in
all three groups. Tavanti et al. (2007) reported no biofilm production among C. orthopsilosis (former group II
C. parapsilosis) and 95% of the C. metapsilosis (formerly
group III C. parapsilosis) were unable to produce biofilm. Differences in the results of the three studies are
likely due to differences in methods of inducing biofilm
production and the quantification methods (Melo et al.
2007). The failure to produce extracellular matrix could
contribute to the lower frequency of group II and III
(C. orthopsilosis and C. metapsilosis) in the clinical setting (Tavanti et al. 2007). Parenteral nutrition and high
glucose environments seems to play a role promoting
the development of biofilm production (Branchini et al.
1994; Kuhn et al. 2004). Recently, Ruzicka et al. (2007)
described a discrepancy of biofilm production between
C. parapsilosis blood isolates and C. parapsilosis isolated
from the skin. Biofilm production was found among 59%
of the bloodstream isolates and just 39% in those from
the skin. Studies also reported that biofilms can also
reduce susceptibility to antifungal agents (Ruzicka et al.
2007; Shin et al. 2002).
Although phenotypic switching was largely studied
in C. albicans, recently it was determined that phenotypic switching does occur in C. parapsilosis (Enger et al.
2001; Lott et al. 1993). This specific phenotypic instability allows strains to switch colony phenotype without
affecting the identifiable genotype (Fidel et al. 1999;
Soll 1992). Laffey & Butler (2005) found a correlation in
phenotypic switching and biofilm formation. The concentric phenotype generates up to twofold more biofilm
than crepe or crater phenotypes. Of the four phenotypes
identified, smooth phenotypes produce the least biofilm. The molecular mechanisms that regulate phenotypic switching in C. parapsilosis are not yet understood
(Laffey & Butler 2005).
Another enzyme that seems to play an important
role in the pathogenesis of C. parapsilosis is phospholipase. This group of enzymes affect adhesion to
and penetration of host cells. Phospholipase activity
was detected in 51% of C. parapsilosis strains in a study
done by Ghannoum et al. (2000). Dagdeviren et al.
(2005) described phospholipase activity among 26% of
the blood isolates. As with C. albicans, C. parapsilosis
isolated from blood cultures were found to be stronger
phospholipase producers than isolates from other body
sites (Ibrahim et al. 1995). One study indicated no statistical difference between phospholipase production
and adherence, possibly due to the small sample size
(Dagdeviren et al. 2005).
The enzyme lipase seems to be another important
virulence factor. These enzymes affect adhesion and may
deny the host nutrients. Gacser et al. (2007a) showed that
lipase inhibitors significantly reduce tissue damage during infection of reconstituted human tissues. Recently,
Gacser et al. (2007b) studied targeted gene deletion on
the lipase genes CpLIP1 and CpLIP2. Their data support
the idea that lipase, secreted by C. parapsilosis, is involved
in disease pathogenesis. Extracellular lipase proteins
are important for optimal growth of C. parapsilosis in
lipid solutions, such as lipid-rich total parenteral nutrition, frequently used for very low birth weight neonates.
Another finding of the study was the correlation between
biofilm formation and lipase. Biofilm formation of the
C. parapsilosis lipase-negative mutant was decreased
dramatically (Gacser et al. 2007b). This enzyme seems to
be involved in survival of C. parapsilosis after phagocytosis by macrophages. Lipase-negative mutants were more
readily phagocytosed and killed by macrophages, compared to the parental strain and reconstituted mutants
(mutants of C. parapsilosis showing lipase activity). The
lipase –negative strain of C. parapsilosis was tested in a
murine intraperitoneal infection model and showed less
virulence compared to the parental and reconstituted
strains (Gacser et al. 2007b).
Cassone et al. (1995) reported that C. parapsilosis is
markedly heterogeneous in experimental pathogenicity
and made a ranking of biotype. They assessed the various differential characteristics of colony morphology
(morphotype), resistance to various chemicals (resistotype), and correlated these with virulence in a systemic
murine infection model. These authors were able to
place isolates into groups on the basis of these traits,
although virulence in murine models showed a wide
range within a group. In addition, these authors found
no correlation of virulence in systemic infection with
Sap production (Cassone et al. 1995).
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294 van Asbeck et al.
Gacser et al. (2007a) investigated pathogenicity of
different C. parapsilosis strains in vitro using reconstituted human epidermal and oral tissues. Reconstituted
epidermal human tissues are extremely useful for modeling host interactions with C. parapsilosis and studying
virulence factors of this organism (Gacser et al. 2007a).
Their results showed that C. orthopsilosis caused damage similar to C. parapsilosis, while C. metapsilosis was
less virulent.
Earlier studies on pathogenicity may have been
confusing because C. parapsilosis is a group of three
sibling species, as we now know. Thus comparisons of
traits may have been across species lines rather than
within a single species. Since we are now able to distinguish these 3 species, it will be important for future
studies first to identify the organism to species level, so
that the ­appropriate comparisons can be made. Hostparasite interaction studies will benefit by recognizing
the genetic diversity of strains. Extensive genetic studies
(microarrays, the whole genome sequence) may make
it possible to define the virulence factors and the rising importance of C. parapsilosis makes these studies
necessary. In addition, there is a need for models that
enable the study of interaction of this fungus in human
tissue, because of the rising importance of C. parapsilosis among humans.
Host Response
Important to the relative virulence of C. parapsilosis is the
host response to infections caused by C. parapsilosis. In
contrast to the vast body of work that has been described
on host defense against C. albicans, little is known about
specific host defense mechanisms against C. parapsilosis. C. parapsilosis has been described as a relatively
low-grade pathogen for humans. However, infections
and death due to C. parapsilosis have increased steadily
during the last decade, particularly among immunocompromised adults, but are also common in the nonneutropenic hosts (i.e., premature infants and surgical
patients). The differences in pathogenicity in different
host groups indicate that some level of host defense
does indeed exist. Better understanding of the mechanisms of host defense against C. parapsilosis may enable
us to support or deploy these mechanisms against this
opportunistic pathogen and improve treatment (Marodi
et al. 1991b).
Mononuclear phagocytes, macrophages and polymorphonuclear leukocytes (PMN) have been studied
and shown to be a critical component of host defense
that protects against candidemia and candidiasis
(Aybay & Imir 1996; Marodi et al. 1991a; Marodi
et al. 1991b; Roilides et al. 1995a; Takao et al. 1996;
Vecchiarelli et al. 1985). C. parapsilosis is not as difficult for macrophages to kill compared to several other
pathogenic fungi, such as C. albicans, Blastomyces dermatitidis and Paracoccidioides brasiliensis (Brummer
et al. 1991). The mechanism of killing C. parapsilosis
by peritoneal macrophages, activated in vitro by
lymphokines or recombinant gamma-interferon was
studied by Brummer et al. (Brummer & Stevens 1989).
They observed killing of C. parapsilosis by non-activated peritoneal macrophages. Superoxide dismutase
blocked and dimethyl sulfoxide partially blocked this
killing, which suggested a mechanism depending on
the presence of superoxide anion is involved in the
killing of C. parapsilosis by macrophages. Killing by
activated macrophages was not inhibited by superoxide dismutase or dimethyl sulfoxide, suggesting
that activated macrophages probably depend on the
myeloperoxidase systems. In addition, Brummer et al.
(1991) observed no inhibition of killing of C. parapsilosis by the macrophages by the use of cycloheximide
and hydrocortisone.
Takoa et al. (1996) examined the role of reactive oxygen metabolites in phagocytosis and killing by murine
peritoneal macrophages incubated with C. parapsilosis,
by the use of a fluorochromatic vital staining technique.
The relative contribution of reactive oxygen metabolites,
depending on NADPH oxidase or xanthine oxidase,
was determined using selective inhibition of each of
these enzyme systems. Generation of reactive oxygen
metabolites by xanthine oxidase and NADPH oxidase­dependent pathways were found to be important for
phagocytic killing by murine peritoneal macrophages.
Although there is a difference in pathogenicity of
the species C. albicans and C. parapsilosis, Marodi
et al. (1991b) found no difference in the biochemical
basis of phagocytosis by human monocytes or monocyte derived macrophages between these two Candida
species. In a separate study, C. parapsilosis was killed
significantly better by human monocytes than was
C. albicans; however monocyte derived macrophages
did not require the yeast to be opsonized, and killed
both species to an equivalent extent (Marodi et al.
1991a). The greater killing of C. parapsilosis by monocytes may be due to the sensitivity of the yeast to
toxic oxygen metabolites, hypochlorite, etc., which
is required for the killing of Candida species (Marodi
et al. 1991a). In addition, opsonization was required
for phagocytosis by monocytes for both C. albicans and
C. parapsilosis, and used both the classical pathway
and alternative pathway (Marodi et al. 1991b). Potoka
et al. (1998) studied phagocytosis and phagocytic killing of C. parapsilosis by rat Kupffer cell alone and by
Kupffer cells in coculture with hepatic endothelial
cell-enriched fraction of non-parenchymal cells. They
also reported both the NAPD oxidase and the xanthine
oxidase dependent pathways are important in Kupffer
cell killing of C. parapsilosis.
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Candida parapsilosis: a review 295
PMNs damage pseudohyphae, the invasive form of
Candida species, by attachment and secretion of oxidative burst metabolites (Roilides et al. 1995a, Roilides
et al. 1995b). Candida species differ in resistance to killing by PMNs. Roilides et al. (1995a) showed that nonopsonized pseudohyphae of C. parapsilosis were more
resistant to PMN induced damage than were C. albicans
or C. tropicalis; GM-CSF and interferon-gamma significantly enhanced the killing activity of PMN against
C. parapsilosis. Possibly these differences in the Candida
species susceptibility to PMNs may contribute to host
susceptibility to infection (Roilides et al. 1995a).
However, Lyman and Walsh (1994) obtained a similar
percentage of phagocytosis by PMN of serum-opsonized
C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata.
Vecchiarelli et al. (1985) showed equal killing of Candida
species by murine PMN and bone marrow cells, however C. guilliermondii, C. krusei, and C. parapsilosis
were killed by these phagocytic cells more rapidly and
at significantly lower effector to target ratio compared to
C. albicans, C. tropicalis, and C. viswanathii.
Cytokines,
such
as
granulocyte-macrophage
­colony-stimulating factor (GM-CFS) and interferon-γ,
enhance the ability of phagocytic cells to damage or kill
Candida cells (Roilides et al. 1995a). GM-CSF has the ability to affect monocyte complement production (Hogasen
et al. 1995). Hogasen et al. (1995) determined the release of
GM-CSF by monocytes after exposure to different Candida
species and compared the stimulation of production of
complement components C3 and factor B by monocytes.
C. albicans, C. tropicalis, and C. parapsilosis were the more
effective inducers of C3, factor B and GM-GSF production
compared to C. krusei, T. glabrata (C. glabrata), C. kefyr,
C. guilliermondii, and T. candida (Hogasen et al. 1995).
Hogasen et al. (1995) concluded that monocyte responses
are associated with specific yeast species, related to pathogenicity, and may explain predilection of some yeasts for
particular underlying diseases.
The major components of the cell wall of Candida
yeast are mannan, an α-linked polymer of mannose;
glucan, a β-linked branched chain polysaccharide of
glucose; and chitin, a cellulose-like biopolymer consisting predominantly of N-acetyl-D-glucosamine
(Zhang et al. 2006). Mannose binding lectin (MBL),
produced in the (human) liver is an important component of innate immunity (serum) (Jack & Turner
2003). Candida mannan is a likely target for MBL
binding (Lillegard et al. 2006). Mannose binding protein binds to carbohydrate structures on microbial
surfaces, leading to direct killing via complement activation or via enzymes linked to MBL, or via enhancing phagocytosis by acting as an opsonin or chemotactic factor (Ip & Lau 2004; Brummer & Stevens, in
press). Opsonin-independent phagocytosis could
be blocked by mannan, suggesting the mannose
receptor may play a role in the clearance of Candida
in opsonin-poor conditions, especially by macrophages. High avidity binding was shown between MBL
and C. parapsilosis (van Asbeck et al. 2008c). MBL
increased the deposition of C4 and C3b, and enhanced
the uptake of C. parapsilosis by neutrophils. Recently,
Zhang et al. (2006) demonstrated a protective role for
human antimannan antibody-mediated immunity
and of murine antimannan antibody-mediated immunity against experimental murine systemic candidiasis
due to C. albicans. Furthermore, these authors demonstrated a mannan epitope, M1g1, which is common
to Candida spp., including C. parapsilosis (Zhang
et al. 2006). These data are suggestive that antimannan
antibodies, while protective against C. albicans infection, might also be protective against infection due to
C. parapsilosis.
Animal models
Experimental animal models are a critical component
of understanding the pathogenesis and host resistance
to infection with Candida spp., as well as to development of more efficacious antifungal therapies (Capilla
et al. 2007). There has been very little development of
animal models of C. parapsilosis, despite the emerging
importance of C. parapsilosis infections, both systemic
and mucosal. Those models that have been developed
have included mucosal models in mouse and rat (oral
or vaginal), and systemic murine models in normal or
immunocompromised animals. In various experimental
models, C. parapsilosis has been shown to be less pathogenic than Candida albicans and other Candida species
(Bistoni et al. 1984, Edwards et al. 1977; Howlett 1976).
However, animal models have been used to examine different aspects of infection due to C. parapsilosis and for
preclinical antifungal trials.
Mucosal models
In humans, C. parapsilosis has been associated most
often with vaginal or gastrointestinal colonization and
disease and much less frequently with oral mucosal disease (Weems 1992). Several models of mucosal infection
have been developed.
In an early study, Howlett et al. (1976) described
the varying abilities of five different Candida species
to invade the orthokeratinized mucosa from the dorsal
surface of neonatal rat tongue, reflecting their different
degree of pathogenicity. C. parapsilosis showed only
slight invasion of the connective tissue, compared to
C. albicans, which was the only species able to invade
all the tissues present. The keratin layer of the rat tongue
mucosa appeared to act as a barrier to invasion of
the underlying epithelium by anything but a virulent
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296 van Asbeck et al.
species. These data appear to correlate with the relative
infrequency of C. parapsilosis as a cause of oral mucosal
disease.
Mellado et al. (2000) used adult mice given tetracycline and glucose and intragastric inoculation of yeasts
to model gut colonization and described the virulence
difference among species. C. parapsilosis showed persistent colonisation but lacked the capacity for systemic
spread from the gut tissues, whereas C. albicans did disseminate from the gut.
de Bernardis et al. (1999) have described the importance and increase of C. parapsilosis vaginal infections,
which emphasize the need for vaginal models of C. parapsilosis. de Bernardis et al. (1989a) developed an estrogen-dependent rat vaginitis model for C. parapsilosis.
In those studies one isolate was found to cause vaginitis
similar in extent to a C. albicans isolate, whereas two
other isolates of C. parapsilosis were unable to cause
vaginitis in the rat model. Thus, differences in pathogenic potential were demonstrated among different isolates of C. parapsilosis. In further studies using this same
model, they suggested that C. parapsilosis is a true cause
of human vaginitis (de Bernardis et al. 1989b).
Systemic models
The association of C. parapsilosis with indwelling
catheters and fungemia underscores the importance
of systemic models of infection due to this organism.
Murine models have been established in normal or
immunosuppressed mice by intravenous inoculation
of the organism. Mortality and fungal burden in the
organs are followed as parameters of disease severity.
Cassone et al. (1995) used normal or neutropenic mice
to study systemic models for pathogenicity of different
C. parapsilosis isolates (blood, vaginal and environmental). They found a range of virulence by the isolates
including one incapable of causing lethality in the neutropenic model. Interestingly, and unlike the results of
other authors, they found no correlation between Sap
and pathogeneicity in the systemic infection models
(Cassone et al. 1995). In further studies, this group
examined the pathogenicity of skin and blood isolates
of C. parapsilosis, showing that the skin isolates did not
cause disease in the systemic model, whereas some of
the blood isolates were highly virulent (de Bernardis
et al. 1999). Although both the organism and the host
determine relative virulence of a pathogen, there are
also differences of virulence among different strains of
C. parapsilosis (Cassone et al. 1995).
Systemic murine models have also been used to
compare virulence among species of Candida. Bistoni
et al. (1984) used cyclophosphamide immunodepressed
mice and normal mice to study pathogenicity of different Candida species and reported that C. parapsilosis
was unable to cause disease in either normal or cyclophosphamide immunosuppressed mice. In contrast,
Arendrup et al. (2002) using immunocompetent mice in
a similar study, reported C. parapsilosis did show some
virulence, with parameters such as weight loss, kidney
weight, inflammation and infection and number of eyes
infected. Like C. krusei and C. guilliermondii, C. parapsilosis showed less virulence compared to the ­species
C. albicans, C. tropicalis, C. glabrata, C. kefyr, and
C. lusitaniae. In other studies, Andriole and Hasenclever
(1962) found mortality of diabetic mice infected with
C. albicans, C. tropicalis, or C. parapsilosis.
A recent report of Nett et al. (2007) proposed β-1,3
glucan as a marker for C. albicans, C. parapsilosis, and
C. glabrata biofilm using a central venous catheter
(CVC) biofilm rat model. This model closely mimics a
patient with CVC infection. This model has been used for
diagnostic purposes, where animals with experimental
CVC infection showed significantly higher serum levels
of β-1,3 glucan in C. parapsilosis and C. albicans biofilm
infections, compared with a model of systemic disease
using tail-vein infection, representing disseminated or
nonbiofilm disease.
Although in humans C. parapsilosis is associated with
endophthalmitis Edwards et al. (1977) were unable to
recover C. parapsilosis from the eyes in a rabbit model
of haematogenous Candida endopthalmitis. They studied ocular pathogenicities of species of Candida (e.g.,
C. krusei, C. parapsilosis, C. guilliermondii, C. tropicalis,
C. stellateoidea, and C. albicans) and found a relative
resistance of ocular tissues to haematogenous Candida
infections with species other than C. albicans. Thus, this
model would not appear useful for the study of endophthalmitis due to C. parapsilosis.
An alternative nonmammalian model has been
described by Chamilos et al. (2006b), who developed a
model of candidiasis of Toll (Tl)-deficient Drosophila
melanogaster. In agreement with mammalian animal
model studies, C. parapsilosis was less virulent than
C. albicans when injected into Tl mutant flies. This alternative model using D. melanogaster is promising for
large-scale studies of virulence mechanisms of candidiasis (Chamilos et al. 2006b).
Antifungal susceptibility and therapy
Antifungal susceptibility
Widespread use of antifungal agents could be an explanation for the emergence of the more resistant non-albicans species of Candida (Pfaller et al. 1995). Low levels
of azole resistance in vitro have been observed for C.
parapsilosis, suggesting that the emergence of this species may be influenced by one or more confounding risk
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Candida parapsilosis: a review 297
factors in contrast to selection of species, such as C. glabrata and C. krusei, which are much less susceptible to
azole drugs (Kao et al. 1999). Identification of Candida
species and antifungal susceptibility provide important
information for the development of recommendations
for empirical antifungal therapy and can affect therapeutic choices (Fluckiger et al. 2006; Krcmery & Barnes
2002; Pfaller & Diekema 2002; Pfaller et al. 2002). In
addition, antifungal resistance surveillance programs
provide important information for the development of
recommendations for empirical antifungal therapy and
for the design of programs for the control of antifungal
resistance (Pfaller & Diekema 2002).
C. parapsilosis isolates are quite susceptible to
most systemic antifungal agents including polyenes
(amphotericin B) and azoles (fluconazole, ketoconazole, itraconazole, voriconazole, and posaconazole)
(Fluckiger et al. 2006; Mokaddas et al. 2007; Nakamura
& Takahashi 2006; Ostrosky-Zeichner et al. 2003;
Pappas et al. 2004; Pfaller et al. 2002; Pfaller et al.
2005c; Pfaller et al. 2000; Pfaller et al. 1995; Rex et al.
1995; Weems 1992). Bille and Glauser (1997) tested
30 isolates of C. parapsilosis, Laverdiere et al. (2007)
tested 14, and Fleck et al. (2007) tested 19 isolates; all
were susceptible to fluconazole and amphothericin B.
However, Seidenfeld et al. (1983) reported tolerance to
amphotericin B in C. parapsilosis, with minimal fungicidal concentrations more than 32-fold higher than
the MIC. Resistance to amphotericin has been noted
(Ostrosky-Zeichner et al. 2003).
Global surveillance studies, reported by Pfaller et al.
(Pfaller & Diekema 2004), indicated that reduced susceptibility to fluconazole is uncommon among bloodstream isolates of C. parapsilosis, most frequent in
surgical ICU’s (Pfaller et al. 2008b). Similarly, Sarvikivi
et al. (2005) observed fluconazole resistance in only one
C. parapsilosis isolate during a 10-year period of fluconazole prophylaxis and Kovacicova et al. (2000) reported
resistance in only two strains of C. parapsilosis, over a
period of 3 years. However, in addition to fluconazole
resistance, resistance to itraconazole and voriconazole
has been noted (Arias et al. 1994; Ostrosky-Zeichner
et al. 2003; Pfaller et al. 2007).
In an experimental study, Segal et al. (1975) described
the development of resistance to flucytosine by 23%
of strains of C. parapsilosis. However, in the European
Confederation of Medical Microbiology (ECMM) survey of candidemia in Italy, only one of the 99 isolates of
C. parapsilosis tested showed resistance to flucytosine
(Tortorano et al. 2003). Lin et al. (1995) showed a difference in susceptibility to flucytosine between group
I and II isolates of C. parapsilosis, with a tendency for
increased resistance to flucytosine among the group II
isolates.
The emergence of yeast species with decreased susceptibility to contemporary antifungal regimens demonstrates the need for new antifungal agents (Capoor
et al. 2005, Nguyen et al. 1996). The echinocandin
class of antifungals offers an alternative to the standard regimens of azole or polyene agents and provides
additional advantages of reduced toxicity (Messer et al.
2004). Caspofungin, micafungin and anidulafungin,
echinocandin antifungal agents, compromise cell wall
structural integrity through non-competitive inhibition of the synthesis of 1,3-ß-D-glucan (Cappelletty
& Eiselstein-McKitrick 2007; Denning 2003; Pfaller
et al. 2006b). Compared to other Candida species,
C. parapsilosis tends to be associated with a higher MIC
of echinocandins (Cappelletty & Eiselstein-McKitrick
2007; Fleck et al. 2007; Laverdiere et al. 2007; Marco et al.
1998; Messer et al. 2004; Nakamura & Takahashi 2006;
Ostrosky-Zeichner et al. 2003; Pfaller 2004; Pfaller et al.
2005a; Pfaller et al. 2006a; Pfaller et al. 2006b; Reboli
et al. 2007). The meaning of these higher MICs is still
being investigated, but changes in the glucan synthase
subunit Fks1 might explain the reduced activity of echinocandins against C. parapsilosis (Park et al. 2005; Reboli
et al. 2007). A recent report indicated the C. parapsilosis complex has a naturally occurring polymorphism
resulting in the substitution of alanine at position 660
for a conserved proline, which is present in other fungal
Fks1 (Garcia-Effron et al. 2008). The unique mitochondrial respiratory network of C. parapsilosis might play
an important role for its decreased susceptibility to the
echinocandins (Chamilos et al. 2006a). Chamilos et al.
(2006a) observed a decrease in caspofungin MICs after
simultaneous inhibition of all respiratory pathways.
From early studies, anidulafungin was demonstrated
to have a minimal inhibitory concentration range for
90% of C. parapsilosis strains [MIC90] of <2-4 mg/L
(Arevalo et al. 2003; Marco et al. 2003; Marco et al. 1998;
Ostrosky-Zeichner et al. 2003; Pfaller et al. 1997). Marco,
et al. (1998) reported a discrepancy between caspofungin and anidulafungin susceptibility for C. parapsilosis.
Anidulafungin showed less activity against C. parapsilosis than did caspofungin (MIC90, >2 versus 1 µg/mL).
Messer, et al. (2004) reported only 36% of 106 C. parapsilosis strains tested were inhibited by anidulafungin
at < 1 mg/L; however, nearly all isolates were inhibited
at ≤ 4 mg/L. Reboli et al. (2007) directly compared the
efficacy of anidulafungin with that of fluconazole for the
treatment of candidemia and other forms of invasive
candidiasis. In that study, anidulafungin showed higher
MICs for C. parapsilosis compared to other species of
Candida, and patients with a C. parapsilosis infection
treated with fluconazole showed a somewhat better
response rate compared to anidulafungin. However,
the absolute difference in rate of successful response
against C. parapsilosis was not significant. Recently, a
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298 van Asbeck et al.
prospective sentinel surveillance determined the in vitro
activity of all three echinocandins against 5346 invasive
isolates of Candida, 14% consisting of C. parapsilosis
from 90 medical centers worldwide from 2001 to 2003. C.
parapsilosis showed less susceptibility to all three agents
in each of the four regions, compared to C. albicans,
C. glabrata, C. tropicalis, C. krusei and C. kefyr (Pfaller
et al. 2008a).
For antifungal susceptibility testing it is important
to identify the organism to species level, so that appropriate comparisons can be made. Differences in antifungal susceptibility might be explained by comparison of traits and mechanistic pathways across species
lines rather than within a single species. Recently, our
laboratory determined the susceptibility patterns of the
strongly related species C. parapsilosis sensu stricto (formerly C. parapsilosis group I), C. orthopsilosis (formerly
C. parapsilosis group II), and C. metapsilosis (formerly
C. parapsilosis group III) to fluconazole, caspofungin
and anidulafungin (van Asbeck et al. 2008b). C. parapsilosis sensu stricto had significantly higher caspofungin and anidulafungin MICs than C. orthopsilosis or
C. metapsilosis. C. metapsilosis was the least susceptible
of the species to fluconazole. This observation showed
us that significant differences in drug susceptibility
occur among the sibling species. In addition, C. parapsilosis sensu stricto was significantly more susceptible
to caspofungin than anidulafungin. Gomez-Lopez et al.
(2008) studied the susceptibility profile of C. orthopsilosis and C. metapsilosis, which were highly susceptible
to all antifungals tested in this study (amphotericin B,
flucytosine, fluconazole, voriconazole, ravuconazole,
posaconazole, caspofungin, micafungin, and anidulafungin). C. orthopsilosis and C. metapsilosis were
more susceptible to amphotericin B and echinocandins, although no significant conclusions could be made
because few isolates were tested. There was a trend for
C. parapsilosis sensu stricto and C. orthopsilosis to be
more susceptible to caspofungin than the other two
echinocandins, consistent with our significant differences for the former (van Asbeck et al. 2008b), and
prior studies of the C. parapsilosis family (Marco et al.
1998; Pfaller et al. 2006a; Pfaller et al. 2006b). Others
(Lockhart et al. 2008a) have also reported echinocandin MICs higher for C. parapsilosis sensu stricto
than the sister species, also true for amphotericin B.
Tavanti et al. (2007) determined susceptibility patterns of amphotericin B, ketoconazole, voriconazole
and caspofungin for C. orthopsilosis. Only one strain
showed resistance to flucytosine and was dose-dependently susceptible to itraconazole. No resistance
to caspofungin was found. In biofilms, C. parapsilosis
MICs to azoles rise, whereas echinocandin susceptibility is similar to that for planktonic growth (Katragkou
et al. 2008).
Paradoxical growth of some C. albicans isolates was
observed in high concentrations of caspofungin (i.e.,
those above the minimal inhibitory concentration)
(Stevens et al. 2004, Stevens et al. 2005). The effect
was very reproducible, but re-test of cells growing at
high concentrations showed the parental phenotype
(paradoxical effect again), not resistance development.
Chamilos et al. (2007) recently reported this phenomenon also among the other echinocandins, anidulafungin, and micafungin in Candida species. Paradoxical
growth was seen in 90% of isolates (n = 10) of C. parapsilosis tested against caspofungin. However, no paradoxical growth of C. parapsilosis was observed with anidulafungin or micafungin. We (van Asbeck et al. 2008b)
studied paradoxical growth among the closely related
species C. parapsilosis sensu stricto, C. orthopsilosis, and
C. metapsilosis. Thirty-seven percent of the C. parapsilosis sensu stricto isolates tested displayed paradoxical
growth in caspofungin. Despite close similarities among
sibling species, only C. parapsilosis sensu stricto seemed
to have a high capability to avoid caspofungin inhibition.
Melo et al. (2007) indicated paradoxical growth was more
common in Candida cells grown as biofilms, compared
to planktonic growth. All 3 species in the C. parapsilosis
family demonstrated paradoxical growth in biofilms,
and the paradoxical growth was more prominent in biofilms. Those cells demonstrating the paradoxical effect
appear to be more resistant to host defenses (van Asbeck
et al. 2009), possibly related to cell wall changes (Stevens
et al. 2006), and thus this phenomenon may prove to be
a factor in poor therapeutic response to echinocandins
in some infections with this organism. Animal model
studies with Candida have not shown a consistent relationship of the paradoxical effect in vitro with in vivo
resistance, though a “flattening” of the in vivo clearance
despite increasing doses could be an in vivo expression
of the effect (Clemons, et al. 2006).
Unconventional drug development pathways have
included inhibitors of aspartic proteinases, as several
known antiretroviral protease inhibitors have this property, and congeners may be developed that could be
useful in arresting fungal pathogenesis.
Preclinical antifungal drug trials
Animal models provide a rapid way to test experimental
therapies or examine approved drugs for new indications (Capilla et al. 2007). Few preclinical trial data for
infections due to C. parapsilosis have been published.
Longman et al. (1990) described the efficacy of fluconazole for therapy, as well for prophylaxis, of endocarditis
due to C. albicans and C. parapsilosis in a rabbit model.
Therapeutically, 14 doses of fluconazole eradicated cardiac vegetations of C. parapsilosis and a two-dose prophylactic regimen prevented experimental endocarditis
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Candida parapsilosis: a review 299
by C. parapsilosis and C. albicans. Similarly, Witt et al.
(1993) used a rabbit model of Candida endocarditis
(both C. parapsilosis and C. tropicalis) and reported
amphotericin B or fluconazole effective therapeutically;
prophylactic efficacy of fluconazole and amphotericin B
has also been demonstrated in the same model (Bayer
et al. 1996).
Barchiesi et al. (2006) observed in a neutropenic
murine model of systemic candidiasis the efficacy
of caspofungin against different Candida species.
Depending on the isolate tested, mice infected with C.
parapsilosis required relatively high drug doses of caspofungin, 1 and/or 5 mg/kg/day to show efficacy. More
recently, Barchiesi et al. (2007) described the efficacy of
combination therapy and obtained synergistic interaction of caspofungin and amphothericin B against C. parapsilosis tested in the same murine model. Other combination studies using amphotericin B and the monoclonal
antibody to heat shock protein 90, Mycograb, have been
done in a systemic murine model and demonstrated no
enhanced efficacy of the combination in reduction of
fungal burden due to C. parapsilosis, in contrast to significant enhancement of efficacy against C. albicans, C.
krusei, or C. glabrata (Matthews et al. 2003). Additional
studies of the efficacy of various antifungal drugs alone
or in combination will be required in the future.
As a result of the data with the echinocandins and in
particular caspofungin, it is not clear consequently that
these should be the drugs of first choice for treating infections with this organism. Whether the higher MICs for
caspofungin will affect clinical outcomes is unknown. In
vivo human data do not clearly yet correlate with the in
vitro data for the echinocandins for C. parapsilosis, and
still support the efficacy of echinocandins for invasive
candidemia (Safdar et al. 2002).
Treatment
Mora-Duarte et al. (2002) performed a double-blind
trial to compare caspofungin with amphothericin B
deoxycholate for the primary treatment of invasive
candidiasis. C. parapsilosis caused only 19% of cases
of fungemia in the caspofungin-treated group in this
study, but was associated with 42% of cases in the subset of patients with persistent fungemia. Conversely,
the species distribution in cases of persistent fungemia
in the amphotericin B-treated group more closely paralleled the overall distribution of infecting species in all
types of fungemia. The overall rate of favorable response
for C. parapsilosis was similar for caspofungin versus
amphotericin B, 70% versus 65% (2002). Treatment
failures for caspofungin were most commonly from
blood. This suggested that caspofungin may be used
successfully for treatment of C. parapsilosis fungemia,
but physicians should be aware of the possibility that
this species might respond less readily to this antifungal drug.
Candidemia and acute hematogenously disseminated
candidiasis caused by C. parapsilosis may be treated
with amphotericin B deoxycholate (0.6 mg/kg per day),
fluconazole (6 mg/kg per day) or caspofungin (70 mg
loading dose followed by 50 mg/day) (Pappas et al.
2004). Therapy for candidemia should be continue for
2 weeks after the last positive blood culture results and
resolution of symptoms and signs (Pappas et al. 2004).
In situations involving slime producing organisms, such
as vascular catheter related infection, the organism is
difficult to eradicate using antifungal therapy alone,
but several studies recommend removal of the infecting
device to prevent invasive mycoses and their complications (Nakamura & Takahashi 2006; Pfaller et al. 1995).
When feasible, it may prove useful in initial management to remove indwelling catheters, which is likely to
particularly affect the prevalence of secondary infections caused by C. parapsilosis (Nakamura & Takahashi
2006). This maneuver needs to be studied in randomized
trials.
Very low birth weight neonates and premature
neonates with disseminated cutaneous neonatal candidiasis who are at risk for developing acute disseminated candidiasis should be considered for systemic
therapy, as is the approach in those with disseminated
visceral candidiasis. Little information on pharmacokinetics and response rates is available for this group
of patients. However, amphothericin B deoxycholate
appears to be first choice in treatment, primarily due
to the lack of experience with other antifungal agents
(Pappas et al. 2004). Fluconazole may be used as a
second line agent for very low birth weight neonates
and premature neonates with disseminated cutaneous neonatal candidiasis who are at risk for developing
acute disseminated candidiasis (Pappas et al. 2004).
Although prevention of nosocomial fungal infections
in premature infants is desirable, long-term use of fluconazole may lead to the emergence of resistance in
C. parapsilosis. Thus, fluconazole prophylaxis should
be undertaken with caution (Chapman 2007; Sarvikivi
et al. 2005; Yoder et al. 2004). Very low birth weight
children, during the first six weeks of life, have an
increased risk for candidemia caused by C. parapsilosis
(Kaufman et al. 2001). Prevention of fungal colonization
and invasive infections by fluconazole prophylaxis has
been shown effective in these infants (Kaufman et al.
2001; Kicklighter et al. 2001). In neonates, Krcmery
et al. (2001) reported a better outcome and less mortality for breakthrough fungemias (fungemias which
occurred during fluconazole therapy), compared to
non-breakthrough fungemias. Although not much is
described about caspofungin treatment in neonates,
Odio et al. (2004) showed successful treatment with
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300 van Asbeck et al.
caspofungin of invasive candidiasis due to C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata,
in neonates who were resistant to or intolerant of
amphotericin B. Caspofungin might be an appropriate alternative for treatment of invasive candidiasis in
premature neonates when there is decreased response
to the other antifungals such as amphothericin B or
fluconazole (Odio et al. 2004).
No treatment for Candida endocarditis has been formally tested in prospective randomized controlled studies
(Garzoni et al. 2007). Combined medical and surgical therapy appears to be the best treatment for Candida endocarditis. The Infectious Diseases Society of America (IDSA)
and another study recommend surgical valve replacement of either native valve or prosthetic valve infections
(Garzoni et al. 2007; Pappas et al. 2004). Amphotericin B
deoxycholate was the most frequently prescribed antifungal drug in previous studies, then flucytosine and fluconazole (Garzoni et al. 2007). Rapid and efficient treatment
is important, because this may improve the outcome of
fungal endocarditis (Garzoni et al. 2007).
Endophthalmitis caused by Candida species can be
treated with amphotericin B (Pappas et al. 2004; Stern
et al. 1985). A good alternative choice of treatment is
fluconazole and it is particularly useful for follow-up
therapy (Pappas et al. 2004; Torres Perez et al. 2004).
In addition, fluconazole may be effective for the treatment associated with an intraocular lens implant,
however, removal of the implant is required (Kauffman
et al. 1993). Since treatment can save vision, evidence
of intraocular infection should be sought as soon as
possible (Feman et al. 2002). Marangon et al. (2004)
showed sensitivity to amphotericin B, fluconazole, itraconazole, ketoconazole, flucytosine, and voriconazole
of Candida isolates, including C. albicans, C. parapsilosis, and C. tropicalis recovered from patients with
endophthalmitis. Voriconazole may play a role in the
therapeutic ­management of endophthalmitis caused
by Candida ­species, because of the highest potency
of this drug against Candida species (Marangon et al.
2004). Vitrectomy appears to be an important therapeutic maneuver in treatment of endophthalmitis (Stern
et al. 1985; Stevens 1983). All patients with candidemia
should undergo an ophthalmological examination to
exclude the possibility of endophthalmitis. Therapy for
endophthalmitis should be continued until complete
resolution of visible disease (Pappas et al. 2004).
Peritonitis caused by C. parapsilosis should be
treated more aggressively than other Candida spp,
since C. parapsilosis peritonitis has a higher complication rate (complications such as abscess formation
and persistent peritonitis after catheter removal) than
other Candida spp. (Chen et al. 2006). Intravenous
amphotericin B, oral or intravenous fluconazole
remain the drugs of choice for peritoneal candidiasis
and are recommended therapy by the IDSA (Pappas
et al. 2004). Both agents are also effective for peritoneal
candidiasis caused by C. parapsilosis (Chen et al. 2004,
Kaitwatcharachai 2002). Chen et al. (2004) observed in
a retrospective study comparable efficacy of treatment
with fluconazole alone to intraperitoneal amphotericin
B alone or intraperitoneal amphotericin B combined
with intravenous fluconazole. However, combination
of fluconazole and amphotericin B should be used
cautiously, because of the possibility of antagonism
(Kaitwatcharachai 2002). Recently Chen et al. (2006)
showed that when fluconazole is used as initial therapy, complications are significantly higher in patients
with C. parapsilosis peritonitis than patients with peritonitis caused by other species. In disease associated
with catheters used for peritoneal dialysis, early catheter removal is often required for successful therapy for
peritoneal candidiasis (Bren 1998; Kaitwatcharachai
2002; Pappas et al. 2004).
In general, management of Candida arthritis depends
on site of infection (Pappas et al. 2004). Intravenous
amphotericin B and fluconazole have been used for
medical therapy of Candida arthritis (Brooks & Pupparo
1998; Pappas et al. 2004). Arthritis caused by Candida
species that involves prosthetic joints requires removal
of the primary prosthesis to eradicate the infection
(Brooks & Pupparo 1998).
Vaginal candidiasis due to C. parapsilosis is cleared
from subsequent culture relatively easily (Nyirjesy et al.
2005). Short-courses of treatment such as topical boric acid
(600 mg/day for 14 days), oral fluconazole 200 mg twice
weekly for 1 month or topical antimycotic therapy, such
as topical flucytosine, successfully clear the vaginitis infections caused by C. parapsilosis (Nyirjesy et al. 2005; Pappas
et al. 2004). Other choices in treatment are “over the counter” clotrimazole, buconazole, or miconazole as vaginal
applications (Nyirjesy et al. 2005, Pappas et al. 2004).
Not much about treatment of candiduria due to
C. parapsilosis has been described. Following the IDSA
guidelines (Pappas et al. 2004), candiduria should be
treated in symptomatic patients, neutropenic patients,
very low birth weight infants, patients with renal allografts and patients undergoing urologic manipulation.
Therapy with fluconazole (oral or intravenous), amphotericin B (intravenous), or flucytosine (oral) are effective
and require 7–14 day courses to be successful. When
possible, removal of a urinary catheter might be helpful.
Itraconazole, fluconazole, and terbinafine are effective in treating onychomycosis due to Candida species
(Gupta & Shear 2000). The IDSA indicated itraconazole
to be the most appropriate treatment for onychomycosis caused by Candida species (Pappas et al. 2004).
Terbinafine may be more effective against C. parapsilosis compared to C. albicans (Gupta & Shear 2000).
Higher doses of drugs and longer duration of therapy are
Candida parapsilosis: a review 301
required for onychomycosis caused by Candida species
than is the case for nail infections caused by dermatophytes (Gupta & Shear 2000).
Treatment of otomycosis involves local debridement and topical antifungal therapy for up to 14 weeks,
depending on the depth and extent of infection.
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For personal use only.
Summary and conclusions
In this review we have discussed various aspects of epidemiology, clinical manifestations, pathogenicity, and
antifungal susceptibility of C. parapsilosis. C. parapsilosis has emerged as a major pathogen in the past two
decades. Earlier studies on different aspects of C. parapsilosis may have been made more difficult because
C. parapsilosis appears to be a group of three sibling species. Thus, comparisons of traits may have been across
species lines rather than within a single species. Since
we are now able to distinguish these species, C. parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis,
it will be important for future studies first to identify the
organism to species level, so that the appropriate comparisons can be made. Our knowledge of the pathogenic
siblings is an incomplete, yet evolving story, much as
the pathogen itself is emerging. Therefore, comprehensive studies of their epidemiology, pathogenesis and
resistance must be performed in the future.
Declaration of interest: None to declare for any
author.
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