Journal of

Fungi
Review
An Overview on Candida auris in Healthcare Settings
Maria Luisa Cristina 1,2 , Anna Maria Spagnolo 1,2 , Marina Sartini 1,2, * , Alessio Carbone 1 , Martino Oliva 1 ,
Elisa Schinca 1,2 , Silvia Boni 3 and Emanuele Pontali 3

1 Department of Health Sciences, University of Genoa, Via Pastore 1, 16132 Genoa, Italy;
cristinaml@unige.it (M.L.C.); am.spagnolo@unige.it (A.M.S.); elisa.schinca@unige.it (E.S.)
2 Hospital Hygiene Unit, E.O. Ospedali Galliera, 16128 Genova, Italy
3 Infectious Disease Unit, Galliera Hospital, 16128 Genoa, Italy
* Correspondence: sartini@unige.it

Abstract: Candida auris has become a major concern in critical care medicine due to the increasing
number of immunocompromised patients and candidiasis is the most frequent cause of fungal
infections. C. auris and other fungal pathogens are responsible for at least 13 million infections and
1.5 million deaths globally per year. In immunocompromised patients, infections can quickly become
severe, causing wound infections, otitis and candidemia, resulting in high morbidity and mortality.
The clinical presentation of C. auris is often non-specific and similar to other types of systemic
infections; in addition, it is harder to identify from cultures than other, more common types of Candida
spp. Some infections are particularly difficult to treat due to multi-resistance to several antifungal
agents, including fluconazole (and other azoles), amphotericin B and echinocandins. This entails
treatment with more drugs and at higher doses. Even after treatment for invasive infections, patients
generally remain colonized for long periods, so all infection control measures must be followed
during and after treatment of the C. auris infection. Screening patients for C. auris colonization enables
facilities to identify individuals with C. auris colonization and to implement infection prevention
and control measures. This pathogenic fungus shows an innate resilience, enabling survival and
Citation: Cristina, M.L.; Spagnolo,
persistence in healthcare environment and the ability to rapidly colonize the patient’s skin and be
A.M.; Sartini, M.; Carbone, A.; Oliva,
easily transmitted within the healthcare setting, thus leading to a serious and prolonged outbreak.
M.; Schinca, E.; Boni, S.; Pontali, E.
An Overview on Candida auris in
Keywords: Candida auris; healthcare infections; antifungal resistance; epidemiology; prevention and
Healthcare Settings. J. Fungi 2023, 9,
control measures
913. https://doi.org/10.3390/
jof9090913

Academic Editors: Carmen

Rodríguez-Cerdeira, Erick 1. Introduction
Martinez-Herrera, Marina
Candida auris has become a major concern in critical care medicine due to the increasing
Romero-Navarrete and Sergeev
number of immunocompromised patients and candidiasis is the most frequent cause
Alexey Yurievich
of fungal infections [1]. Patients hospitalized for COVID-19 are at risk for healthcare-
Received: 26 July 2023 associated infections (HAIs), including candidemia, or bloodstream infections caused by
Revised: 28 August 2023 Candida [2].
Accepted: 6 September 2023 Some isolates of C. auris can form aggregates both in vitro and in vivo that could allow
Published: 8 September 2023 it to evade the host’s immune system, escape attack by neutrophils, persist in host tissues
and have a higher resistance to antifungals [3].
Various studies have described healthcare-associated infections caused by C. auris [4,5].
The aim of this narrative review is to describe C. auris contamination in healthcare set-
Copyright: © 2023 by the authors.
tings, potential risks of infection, epidemiology, diagnostic and treatment, prevention and
Licensee MDPI, Basel, Switzerland.
control measures.
This article is an open access article
To ensure a broad coverage of relevant literature, we undertook a MEDLINE search
distributed under the terms and
conditions of the Creative Commons
for English-language articles using the terms “Candida auris”, “healthcare facilities”, “anti-
Attribution (CC BY) license (https://
fungal resistance” and further relevant studies from reference lists of articles identified.
creativecommons.org/licenses/by/
4.0/).

J. Fungi 2023, 9, 913. https://doi.org/10.3390/jof9090913 https://www.mdpi.com/journal/jof

 J. Fungi 2023, 9, x FOR PEER REVIEW 2 of 15

J. Fungi 2023, 9, 913 2 of 14

“antifungal resistance” and further relevant studies from reference lists of articles
identified.

2.
2. Characteristics
Characteristics of of the
the Microorganism
Microorganism
C.
C. auris
auris is
is an
an opportunistic pathogen that
opportunistic pathogen that can
can cause
cause severe
severeillness
illnessininhospitalized
hospitalized
patients.
patients.
C.
C. auris
auris like
like other Fungi is
other Fungi is aa eukaryotic,
eukaryotic, heterotrophic,
heterotrophic,mainly
mainlyaerobic
aerobicorganism,
organism,
possessing chitin in its cell walls. It is a ubiquitous organism found in association
possessing chitin in its cell walls. It is a ubiquitous organism found in association with with
organic matter. C. auris is a haploid fungus with spherical or oval morphology
organic matter. C. auris is a haploid fungus with spherical or oval morphology with 2–3 with
× 2.5–5
ൈ 2.5–5
2–3 µmµm cells,
cells, which which normally
normally growsgrows as a [6]
as a yeast yeast [6] most
unlike unlike most
other Candida
other species
Candida
species (Figure
(Figure 1). 1).

Figure 1. Morphology of cells of the microbial organism C. auris (Stephanie Rossow/Centers for
Figure 1. Morphology of cells of the microbial organism C. auris (Stephanie Rossow/Centers for
Disease Control and Prevention—https://phil.cdc.gov/Details.aspx?pid=23239, accessed on 13
Disease Control and Prevention—https://phil.cdc.gov/Details.aspx?pid=23239, accessed on 13
February 2023).
February 2023).
Recently, it was discovered that C. auris displays a phenotypic plasticity that allows
Recently, it was discovered that C. auris displays a phenotypic plasticity that allows this
this microorganism to hold a three-way phenotypic switching system. Strikingly, through
microorganism to hold a three-way phenotypic switching system. Strikingly, through this
this new system, C. auris can switch shapes among typical yeast, filamentation-competent
new system, C. auris can switch shapes among typical yeast, filamentation-competent yeast
yeast and filamentous form according to particular circumstances [6]. The latter
and filamentous form according to particular circumstances [6]. The latter morphology
morphology would be inhibited at the normal human body temperature of 37 °C and
would be inhibited at the normal human body temperature of 37 ◦ C and conversely favored
conversely favored at lower◦ temperatures (26 °C). C. auris grows well at 40–42 °C and is
at lower temperatures (26 C). C. auris grows well at 40–42 ◦ C and is able to survive in
the environment and under alkaline conditions, although it cannot tolerate anaerobiosis.
The transformation of C. auris from an environmental fungus to a human pathogen would
be due to the overuse of antimycotics [7] or thermal adaptation due to climate change [8].
J. Fungi 2023, 9, 913 3 of 14

The hypothesis of an environmental origin would arise from the consideration that it is a
fungus which is tolerant to high temperatures and hypersaline conditions before becoming
pathogenic to humans [9]. The thermotolerance of C. auris has been proposed to be a
characteristic that has allowed birds to transport the fungus across the globe to rural areas
where humans and birds are in constant contact and from there it would quickly reach the
urban environment up to healthcare facilities [10].
C. auris is phylogenetically related to Candida haemulonii and Candida ruelliae [11]. Four
distinct clades (South American clade, African clade, South Asian clade and East Asian
clade) have been identified from separate geographic origins, suggesting a recent and
nearly simultaneous emergence of different clonal populations [12]. In 2018, an isolate
representative of a potential fifth clade was identified in Iran, separated from the other
clades by >200,000 single-nucleotide polymorphisms, susceptible to the three major classes
of antifungal drugs. The isolate was cultured from ear swab specimens from a patient who
had never travelled outside the country [13].
The virulence factors associated with C. auris infections are not completely understood.
Probably the most important factor contributing to Candida virulence is the production of
aspartyl proteinases (SAPS), enzymes involved in cell wall formation and adhesion, biofilm
production, the ability to bypass the immune system and degradation and invasion of host
tissues. The latter virulence factor would also be expressed by lipases. The ability of C. auris
to express the various virulence factors is weaker than that of C. albicans, suggesting that
C. auris is not as virulent as C. albicans. This decrease in virulence relative to C. albicans
is likely due to the fact that C. auris, along with C. glabrata and C. haemulonii, is unable
to develop hyphae or pseudohyphae in the mammalian host, which play critical roles in
tissue invasion during infections [3].

3. Infections and Risk Factors

Patients may be colonized asymptomatically by C. auris on the skin, or in the nostrils,
oropharynx, rectum and other body sites. However, unlike most other Candida species,
which colonize the gastrointestinal tract, C. auris predominately colonizes the skin.
The interaction between skin commensal bacteria and fungi (microbiota) and C. auris
can define its colonization level. Proctor et al. [14] investigated the associations between
skin microbiota and C. auris colonization. The difference in both commensal bacteria and
fungi communities present in C. auris-positive and C. auris-negative patients has provided
evidence that the host microbiome may play an important role in the colonization of C. auris
on the skin. Although microbiota dysbiosis was observed in the skin of C. auris-colonized
individuals, it is still not known whether alterations in the microbial community are a
consequence of C. auris colonization or whether microbiota dysbiosis contributes to C. auris
colonization in the skin [15].
Patients with C. auris colonization can spread this yeast to other patients, and colonized
patients can develop invasive as well as superficial infections. C. auris can cause severe
illness and spreads easily among patients in healthcare facilities; it can cause candidemia,
wound infections, otitis, and urogenital tract and respiratory tract infections. Antibiotic use
disrupts the skin and gut microbiome, increasing Candida colonization and risk of invasive
candidiasis [5].
Infections may be severe, and persistently positive blood cultures for >5 days or
recurrent candidemia in those with C. auris candidemia have been reported [16].
Candidemias represent the most serious infections in patients with immunosuppres-
sion or major underlying diseases, such as diabetes mellitus, chronic kidney disease, HIV
infection, solid tumors and hematological malignancies, and neutropenia; some cases have
also been reported in newborns [17]. However, even in the absence of underlying disease,
patients are at risk of invasive disease during intra-hospital outbreaks and depending on
the ward concerned. Almost one third of patients with candidemia develop septic shock.
In a study conducted by Bassetti et al. [18], age and abdominal source of the infection are
J. Fungi 2023, 9, 913 4 of 14

the most important factors significantly associated with the development of septic shock in
patients with candidemia.
Regarding extrinsic risk factors, a retrospective analysis of C. auris infections world-
wide from 2009 to 2020 found that the five ones most often found in patients were a history
of broad-spectrum antibiotic treatment (55.9%), central venous catheter (55.1%), intensive
care unit (48.9%), urinary catheter (38.0%) and surgery (37.1%) [19]. Other risk factors
include mechanical ventilation, parenteral nutrition, increased hospital length of stay, and
residence in a high-acuity, skilled nursing facility. Infections have been observed several
days to weeks after hospitalization in susceptible patients, suggesting exogenous sources
of infection [20].
The patient and the environment can be reservoirs of fungal resistance in healthcare
settings. C. auris studies have described widespread contamination of environmental
surfaces and equipment persisting for months, with patient acquisition of C. auris occurring
after as little as 4 h of contact. Ventilators in clinical care units were reported to spread
C. auris infection [20].
This pathogenic fungus therefore shows an innate resilience, enabling survival and
persistence in the clinical environment, and the ability to rapidly colonize the patient’s
skin and be easily transmitted within the healthcare setting, thus leading to a serious and
prolonged outbreak. In this context, the hands of healthcare personnel also play a crucial
role with regard to the possible cross-transmission of Candida from colonized/infected
patients and/or from contaminated surfaces to susceptible patients [21].
Several studies have shown the presence of various microorganisms including C. auris
on different surfaces in healthcare environments [22,23], suggesting that these may be
an important reservoir of contamination. C. auris was detected on the mattress, bedside
table, bed rail, chair and windowsill in the room of a patient who had a C. auris blood-
stream infection 3 months earlier and who remained persistently colonized in multiple
body sites [24]. Contamination in the hospital environment has also been highlighted in
other studies. During an outbreak in a London hospital, environmental sampling of the
clinical area surrounding colonized patients demonstrated the contamination with C. auris
of horizontal surfaces, such as the floor around bed sites, trollies, radiators, windowsills,
equipment monitors and keypads, in addition to one air sample [25]. C. auris was also
detected on reusable patient-monitoring equipment (axillary temperature probes and a
pulse oximeter) and a patient hoist [26]. C. auris can also survive on non-porous plastic
surfaces for at least two weeks, remaining metabolically active for at least 4 weeks [27].
Vallabhanei et al. [24] have highlighted how the persistence—weeks to months after initial
infection—of colonization on skin and other body sites may represent a risk of contam-
ination of the healthcare environment. In a surveillance study on C. auris colonization
conducted by Ferrer Gomez et al. [28] in an ICU, it was found that of 124 colonized patients,
67% of pharyngeal carriers negativized at 1 month compared to 21% of cutaneous carriers,
who negativized after 3–4 months. It has been shown experimentally that C. auris has a
greater ability to survive on surfaces than C. albicans, but not compared with C. parapsilosis
or C. glabrata. Compared with common bacterial pathogens, C. auris was detected with
similar frequencies on dry surfaces and significantly more frequently on wet surfaces
such as sinks. These results support the hypothesis that contaminated surfaces may be an
important source of C. auris transmission [23].
C. auris is able to form biofilms on the surfaces it contaminates. Kean et al. [29] demon-
strated that C. auris biofilms were more resistant to hospital disinfectants (chlorhexidine
and hydrogen peroxide) than C. albicans and C. glabrata biofilms. Sherry et al. [30] demon-
strated that C. auris can differentially adhere to polymeric surfaces, form biofilms and
resist antifungal agents that are active against its planktonic counterparts. Of particular
interest, caspofungin was predominately inactive against C. auris biofilms; this finding
was unexpected because caspofungin is normally highly effective against Candida biofilms.
These features contribute not only to C. auris virulence but also to its survival in hospital
environments, increasing its ability to cause outbreaks.
J. Fungi 2023, 9, 913 5 of 14

4. Diagnosis
The clinical presentation of C. auris is often non-specific and similar to other types
of systemic infections. Candidemia usually causes fever but no specific symptoms. Some
patients develop a syndrome reminiscent of bacterial sepsis, with a fulminant course that
may include shock, oliguria, renal failure and disseminated intravascular coagulation.
As Candida are commensals, their isolation from cultures of sputum, mouth, vagina,
urine, faeces or skin does not necessarily indicate invasive and progressive infection.
In addition, a characteristic clinical lesion must be present and histopathological tissue
invasion documented, and other aetiologies must be excluded. Positive cultures of sample
obtained from normally sterile sites, such as blood, cerebrospinal fluid, pericardial fluid or
biopsy tissue provide definitive proof that systemic therapy is required [1].
Serum beta-glucan is often positive in patients with invasive candidiasis; in contrast, a
negative result indicates a low probability of systemic infection.
Like other Candida infections, C. auris infections are diagnosed by culturing blood or
other bodily fluids [1]. However, C. auris is harder to identify from cultures than other,
more common types of Candida. For example, it can be confused with other types of yeasts,
particularly Candida haemulonii [31].
Although new chromogenic media are available that further facilitate the identification
of C. auris, the culture criterion cannot be the only method of identification [31]. From a
laboratory point of view, the identification of C. auris is complex; in 2019, the Center for
Disease Control and Prevention (CDC) developed an algorithm to identify C. auris based
on phenotypic laboratory methods and initial species identification [32]. As a matter of fact,
traditional phenotypic methods frequently misidentify C. auris. The proposed algorithm
shows in detail the steps needed to determine the correct Candida spp. based on the tests
and equipment available in laboratories (Table 1).

Table 1. Summary of CDC algorithm ([32], modified).

C. auris Is Confirmed If C. auris Is Possible If the Following

Identification Method Database/Software, Initial Identification Is Initial Identifications Are Given.
If Applicable C. auris Further Work-Up Is Needed to
Determine If the Isolate Is C. auris

RUO libraries (v2014 [5627] and Yes n/a

Bruker Biotyper MALDI-TOF more recent)
CA System library (vClaim 4) Yes n/a

RUO library (with Saramis v4.14 database

Yes n/a
and Saccharomycetaceae update)
bioMérieux VITEK MS IVD library (v3.2) Yes n/a
MALDI-TOF C. haemulonii
Earlier than IVD libraries (v3.2) n/a C. lusitaniae
No identification

C. haemulonii
Software version 8.01 * Yes C. duobushaemulonii
Candida spp. not identified
VITEK 2 YST C. haemulonii
Earlier than version 8.01 n/a C. duobushaemulonii
Candida spp. not identified

Rhodotorula glutinis (without

API 20C n/a characteristic red color)
C. sake
Candida spp. not identified

C. intermedia
API ID 32C n/a C. sake
Saccharomyces kluyveri

C. catenulata
BD Phoenix n/a C. haemulonii
Candida spp. not identified
J. Fungi 2023, 9, 913 6 of 14

Table 1. Cont.

C. auris Is Confirmed If C. auris Is Possible If the Following

Identification Method Database/Software, Initial Identification Is Initial Identifications Are Given.
If Applicable C. auris Further Work-Up Is Needed to
Determine If the Isolate Is C. auris

C. lusitaniae **
C. guilliermondii **
MicroScan n/a C. parapsilosis **
C. famata
Candida spp. not identified

RapID Yeast Plus n/a C. parapsilosis **

Candida spp. not identified

GenMark ePlex Yes n/a

BCID-FP Panel
n/a: not applicable. * There have been reports of C. auris being misidentified as C. lusitaniae and C. famata on
VITEK 2. A confirmatory test such as cornmeal agar may be warranted for these species. ** C. guilliermondii,
C. lusitaniae, and C. parapsilosis generally make hyphae or pseudohyphae on cornmeal agar. If hyphae or pseudo-
hyphae are not present on cornmeal agar, the isolate should raise suspicions of being C. auris, as C. auris typically
does not make hyphae or pseudohyphae. However, some C. auris isolates have formed hyphae or pseudohyphae.
Therefore, it would be prudent to consider any C. guilliermondii, C. lusitaniae and C. parapsilosis isolates identified
on MicroScan and any C. parapsilosis isolates identified on RapID Yeast Plus as possible C. auris isolates, and
further work-up should be considered.

It is fundamental to apply phenotypic system and molecular techniques such as PCR

and matrix-assisted laser desorption ionisation–time of flight (MALDI-TOF) platforms,
VITEK2™ with the suitable updated databases and DNA sequencing [6]. Other identifica-
tion methods include molecular tests such as DNA sequencing and WGS [9]. All C. auris
strains from clinical isolation must be tested for susceptibility to antifungals to exclude
therapy with drugs to which it is resistant.

5. Therapy and Antifungal Resistance

The Centers for Disease Control and Prevention do not recommend the treatment of C.
auris isolated from non-invasive sites (e.g., respiratory tract, urine and skin) when there is
no evidence of infection.
Currently, azoles (e.g., fluconazole; itraconazole; isavuconazole; posaconazole; ser-
taconazole; voriconazole), polyenes (e.g., amphotericin B; nystatin) echinocandins (e.g.,
anidulafungin; caspofungin; micafungin) and nucleoside analogues (e.g., 5-flucytosine) are
the main drugs used to treat fungal infections. The choice of antimycotic depends on the
type and anatomical site of infection and fungal susceptibility. The CDC recommends the
use of echinocandins as empirical therapy in the treatment of patients infected with C. auris,
pending the availability of sensitivity test results [33]. Fluconazole and the echinocandins
are the antifungal agents most used for the treatment of Candida bloodstream infection (can-
didaemia). Both are better tolerated than amphotericin B, which is less often prescribed due
to the risk of toxicity [34]. Caspofungin and micafungin are recommended in the treatment
of adults and children over 2 months of age, while anidulafungin is only recommended
for adults. It is very important to follow the clinical course of these patients by repeating
sensitivity tests to assess a possible acquisition of resistance. If the patient is not responsive
to treatment with echinocandins or if the infection is persistent for more than five days, a
switch to liposomal amphotericin B is recommended. In neonates and infants under two
months of age, the initial choice of treatment is amphotericin B deoxycholate. If this is not
effective, a switch to liposomal amphotericin B may be considered. Echinocandins may
only be used in exceptional circumstances and only after ruling out central nervous system
involvement (Figure 2) [33,35].
 J. Fungi 2023, 9, x FOR PEER REVIEW 7 of 15
J. Fungi 2023, 9, 913 7 of 14

Figure 2. Flowchart of recommendations for treatment of C. auris infections ([33], modified).

Figure 2. Flowchart of recommendations for treatment of C. auris infections ([33], modified).
Some infections are particularly difficult to treat due to multi-resistance to several anti-
fungalSome infections
agents, including arefluconazole
particularly difficult
(and to treat amphotericin
other azoles), due to multi-resistance to several
B and echinocandins.
antifungal
This agents, including
entails treatment with morefluconazole
drugs and at (and
higher other azoles),
doses. amphotericin
In vitro, the interaction B and
be-
echinocandins. This entails treatment with more drugs and at higher
tween voriconazole and micafungin showed an interesting synergy against multi-resistant doses. In vitro, the
interaction between voriconazole and micafungin showed an interesting
C. auris strains. These promising results, however, were not found for the combination of synergy against
multi-resistant
other azoles with C.echinocandins
auris strains. These
[36]. promising results, however, were not found for the
combination
There areofcurrently
other azoles with echinocandins
no established [36]. susceptibility breakpoint; therefore,
C. auris-specific
There are
breakpoints are defined
currently
based noonestablished C. auris-specific
those established susceptibility
for closely related breakpoint;
Candida species and
therefore,
on breakpoints
expert opinion. The are
CDC defined based
attempted toon those established
establish breakpointsfor thatclosely
couldrelated Candida
be considered
species
as and on
a general butexpert opinion. guide
not definitive The CDCto C.attempted to establish
auris resistance breakpoints
patterns. Based on that could
these MICbe
considered asmany
breakpoints, a general butresulted
isolates not definitive guide to
as resistant to multiple
C. auris resistance
classes of patterns.
drugs. SomeBasedU.S.on
C. aurisMIC
these breakpoints,
isolates have beenmanyfoundisolates resultedtoas
to be resistant allresistant to multiple
three classes classes
of antifungal of drugs.
drugs. The
CDC
Somereceived reports
U.S. C. auris of pan-resistance
isolates have been found found
to beinresistant
other countries
to all threeas classes
well. According
of antifungal to
the CDC’s
drugs. Thelatest
CDCupgrade,
receivedinreports
the United States, about 90%
of pan-resistance found C. other
of in auris isolates
countrieshaveas been
well.
resistant
According to to
fluconazole, aboutupgrade,
the CDC’s latest 30% haveinbeen resistant
the United to amphotericin
States, about 90% ofBC.and less
auris than
isolates
5% have been resistant to echinocandins. These proportions may include
have been resistant to fluconazole, about 30% have been resistant to amphotericin B and multiple isolates
J. Fungi 2023, 9, 913 8 of 14

from the same individuals and may change as more isolates are tested. The correlation
between microbiologic breakpoints and clinical outcomes is not known at this time [37].
The mechanisms of molecular resistance involved in C. auris are many and differ
depending on the class of antifungals being used. The mechanisms of resistance to azoles
are mainly the overexpression of two efflux pumps: the ATP Binding Cassette (ABC) and
the Major Facilitator Superfamily (MFS) transporters. One of the possible targets of azoles is
the enzyme Lanosterol 14-alpha-demethylase (LD), encoded by the ERG11 gene, which con-
verts lanosterol to ergosterol, a key component of the C. auris membrane. Point mutation or
overexpression of the ERG11 gene has been shown to be responsible for reduced sensitivity
to azoles. Echinocandins inhibit the enzyme Beta(1,3)D-glucan synthase which is encoded
by the FKS1 and FKS2 genes, being composed of two subunits. Analyzing several isolates
revealed numerous mutations in the FKS1 and FKS2 genes that confer resistance to this class
of antifungals. Resistance to polyenes and in particular amphotericin B is mainly due to the
modification of the sterol composition of the membrane. Finally, a molecular mechanism
of resistance was also found among nucleoside analogues such as 5-Fluorocytosine. In a
single Flucytosine-resistant isolate, an amino acid substitution (F2111I) was found in the
FUR1 gene, which is involved in the metabolism of 5-Fluorocytosine. Especially for the
latter classes of these drugs, given their reduced use compared to the others, little is still
known about the molecular mechanisms that confer resistance to these fungi, so further
research is needed [38].
In a recent 2023 study by Raschig et al., five new azobenzene derivatives were
identified that were shown in vitro to inhibit growth in both fluconazole-sensitive and
fluconazole-resistant C. auris isolates. These derivatives showed promising results both in
terms of antifungal activity and cytotoxicity. Further in vivo studies are required to confirm
this therapeutic potential [39].
In recent years, the increasing percentages of C. auris isolates resistant to the main
classes of antifungals and the “high” mortality rate associated with it have posed a great
challenge in the search for new therapeutic compounds and new approaches such as
the use of nanoemulsions/nanoformulations that could complement or replace current
antifungal therapies [40]. In a paper by Marena et al. [41] from 2023, nanoemulsions (NE)
containing micafungin were developed to combat C. auris infections. Numerous in vitro
evaluations were performed, including, for instance, the determination of the minimum
inhibitory concentration (MIC). Nanoemulsions demonstrated efficacy both against biofilm
and in an in vivo infection model, but not in planktonic cells. Here too, further studies are
needed [41]. In another study from 2023 by Rosato et al., the in vitro efficacy of an essential
oil of Cinnamomum cassia (CC-EO) both alone and formulated with polycaprolactone
nanoparticles (nano CC-EO) was evaluated in 10 clinical strains of C. auris. Both compounds,
both in free form and in nanoformulation form, showed interesting fungicidal activity and
were therefore potential new resources in the fight against C. auris [42]. Recently, in the
fight against disseminated candidiasis, the intravenous use of human immunoglobulins
alone or in combination with amphotericin B have shown protective efficacy in prolonging
the survival of mice with invasive candidiasis [43].

6. Epidemiology
C. auris and other fungal pathogens are responsible for at least 13 million infections and
1.5 million deaths globally per year, primarily in those with some compromised immune
function [44]. C. auris has caused outbreaks on ICUs worldwide. It is the third most
common cause of candidaemia in South Africa, with 88% of cases associated with ICU
stays [5]. Due to lack of surveillance and limited capacity for laboratory detection, the
worldwide prevalence of C. auris is likely to be underestimated [34].
Cases of Candida non-albicans spp. in the care setting have been found worldwide,
presumably related to the prophylactic use of antifungal drugs in high-risk populations;
however, C. auris appears to be unique in its ease of transmission between patients and in
causing, therefore, outbreaks in the care setting and particularly in hospitals. In this respect,
 Cases of Candida non-albicans spp. in the care setting have been found worldwide,
presumably related to the prophylactic use of antifungal drugs in high-risk populations;
however, C. auris appears to be unique in its ease of transmission between patients and in
J. Fungi 2023, 9, 913 causing, therefore, outbreaks in the care setting and particularly in hospitals. In9 of this
14
respect, several molecular biology studies have confirmed intra- and inter-hospital
transmission. It was first described in 2009 after being isolated from an external ear canal
discharge
several of an inpatient
molecular in a Japanese
biology studies hospitalintra-
have confirmed and and
since then has rapidly
inter-hospital reported
transmission. It
was first described in 2009 after being isolated from an external ear canal dischargeon
globally [11]. Cases of C. auris have been reported in more than 40 countries of six
an
continentsin[34].
inpatient Because
a Japanese the identification
hospital and since then of has
C. auris
rapidly requires
reported specialized laboratory
globally [11]. Cases
methods,
of C. aurisinfections
have beenhave likelyinoccurred
reported more than in other countries
40 countries on but have not been
six continents [34].identified
Because
or reported
the [31]. of C. auris requires specialized laboratory methods, infections have likely
identification
C. auris
occurred has been
in other recognized
countries but have as majorly
not beenresponsible
identified or forreported
candidemia
[31]. across the globe,
surpassing
C. auris has been recognized as majorly responsible for candidemiaPichia
the number of cases caused by C. glabrata, C. tropicalis and acrosskudriavzevii
the globe,
in South Africa [2].
surpassing the number of cases caused by C. glabrata, C. tropicalis and Pichia kudriavzevii in
SouthThis organism
Africa [2]. poses a risk for patients in healthcare facilities due to its ability to
causeThis
infections
organism in poses
critically
a riskillfor
patients
patientsand its resistance
in healthcare to several
facilities due toantifungal
its ability toagents,
cause
which makes
infections infectionsilldifficult
in critically patientstoandtreat.
itsPatients
resistance hospitalized
to severalwith severe agents,
antifungal COVID-19 are
which
at risk infections
makes of healthcare-associated
difficult to treat. infections, including candidaemia,
Patients hospitalized and various
with severe COVID-19 areoutbreaks
at risk of
healthcare-associated
of C. auris among COVID-19 infections, including
patients havecandidaemia,
been reported andworldwide
various outbreaks of C. 2021,
[34]. During auris
among
the USCOVID-19
reported patients
over 3700 have beenof
cases reported
C. auris worldwide [34]. During
colonization and over 2021, the probable
1200 US reported or
over 3700 cases
confirmed cases.of C. auris colonization and over 1200 probable or confirmed cases.
In Europe
Europe and and the
the European
European Economic
Economic Area Area (EU/EEA),
(EU/EEA), 670 cases were reported in
the period January 2013—December 2018. In the period 2019 to 2021, another 1142 cases
were
were reported
reported (Figure
(Figure 3) 3) [45].
[45].

Figure 3. Reported cases of C. auris infection or carriage in thirty EU/EEA countries, 2013–2021 ([45],
Figure 3. Reported cases of C. auris infection or carriage in thirty EU/EEA countries, 2013–2021 ([45],
modified).
modified).

Moreover, between 2019 and 2021, five countries (Denmark, France, Germany, Greece
and Italy) reported 14 C. auris outbreaks defined as two or more cases with an epidemiolog-
ical link, with 327 affected patients in total. The number of patients affected per outbreak
ranged from two to 214. Inter-facility transmission occurred in eight outbreaks, and three
outbreaks were reported as ongoing at the time of the survey (Table 2) [45].
J. Fungi 2023, 9, 913 10 of 14

Table 2. C. auris outbreaks in five EU/EEA countries detected in 2019–2021 (total of 14 outbreaks)
([45], modified).

Year * No of Cases Duration (Weeks) Inter-Facility Transmission Ongoing at Time of Survey

2019 214 149 Yes Yes
2020 50 80 Yes Yes
2020 15 44.5 Yes No
2020 11 49 No No
2021 10 5 Yes No
2021 5 28 Yes Yes
2021 4 3.5 Yes No
2021 4 4 No No
2021 3 4 Yes No
2021 3 11 No No
2021 2 8 No No
2021 2 8 No No
2021 2 39 Yes No
2021 2 9 No No
Total 327
EEA: European Economic Area; EU: European Union. * year when the outbreak was detected, while the number
of cases is reported for the whole duration of the outbreak.

In Italy, the first case of invasive C. auris infection was identified in 2019, followed by
an outbreak in northern regions in the pandemic period 2020–2021 [46]. In particular, in
February 2020, C. auris was detected in an intensive care unit treating patients with severe
COVID-19 in the same hospital, with a subsequent increase in case numbers throughout
2020 and 2021, and as of February 2022, a total number of 277 cases occurring in at least
eight healthcare facilities in a region in northern Italy and a neighboring region [34].
The difficulty in its identification at laboratory level and the lack of knowledge of this
species may delay early diagnosis, increasing the risk of horizontal transmission. According
to data from the European Centre for Disease Prevention and Control, the number of C. auris
cases reported in European countries has increased significantly in the last 2 years [34]. An
increase in infections due to unidentified Candida species, including increases in isolation
of Candida from urine specimens, should prompt suspicion of C. auris since C. auris can be
transmitted in healthcare settings [31].
Since the start of the COVID-19 pandemic, outbreaks of C. auris have been reported
in COVID-19 units of acute care hospitals. These outbreaks may be related to changes in
routine infection control practices during the COVID-19 pandemic, including the limited
availability of gloves and gowns, the reuse or extended use of these items and changes in
cleaning and disinfection practices. Patients with COVID-19 who developed candidemia
were less likely to have certain underlying conditions and procedures commonly associated
with candidemia and more likely to have acute risk factors linked to COVID-19 care,
including medicines that suppress the immune system [47].
The crude mortality rate in C. auris infections appears to be comparatively higher
than for other species of Candida, ranging from 33% to 72% [48] and is associated with
prolonged hospitalization (10–50 days), thus facilitating the spread of the pathogen in the
hospital environment [28]. C. auris candidemia is associated with mortality rates of about
30–60%, depending on the setting [16]. However, as invasive Candida infections often occur
in severely ill patients with multiple comorbidities, attributable mortality is difficult to
determine [19,34].

7. Prevention and Control Measures

To decrease the risk of transmission in acute care settings, healthcare personnel should
use standard and contact precautions as outlined by the CDC [49].
J. Fungi 2023, 9, 913 11 of 14

Even after treatment for invasive infections, patients generally remain colonized for
long periods, so all infection control measures must be followed during and after the
treatment of the C. auris infection [46].
If colonized or Candida-infected patients are to be transferred to other healthcare
facilities, these must be informed of the presence of this multidrug-resistant microorganism
to ensure that appropriate precautions are maintained.
Healthcare facilities must ensure thorough daily and terminal cleaning of rooms
housing patients with C. auris infections, including the use of an EPA-registered disinfectant
with an indication of efficacy against fungal microorganisms [24], such as chlorine-based
disinfectants (at a concentration of 1000 ppm).
Cadnum et al. [50] demonstrated that hydrogen-peroxide-based disinfectants also
have a high level of efficacy against different Candida species including C. auris, while
quaternary ammonium compounds have relatively poor activity against all Candida species.
UV-C devices could be useful as an adjunct to standard cleaning and disinfection to provide
disinfection of any surfaces that are missed or inadequately covered by manual disinfection.
In a study by Sherry et al. [30], chlorhexidine was found to be effective at a concentration
of 0.02% in eradicating both planktonic and sessile cells of C. auris. The authors had
underlined that the use of this disinfectant can be advocated for the topical control of
C. auris at standard concentrations used for skin and wound cleansing and disinfection
(0.05–4.0%) [30,51]. Biswal et al. pointed out that the adoption of multiple strategies was
efficient against C. auris. In particular: elimination from colonized sites using chlorhexidine
body and mouth washes; elimination from the environment using disinfectants; elimination
from the hands of healthcare workers by training and improvements in hand hygiene
compliance [51]. If possible, it is preferable to use disposable and dedicated equipment
for each patient or cohort of patients with C. auris infection or colonization. Cleaning
and disinfection of reusable equipment (e.g., monitoring devices, thermometers, pulse
oximeters, blood pressure measuring instruments) according to manufacturer’s instructions
should be ensured [34].
Although there is no evidence of a specific benefit of antimicrobial stewardship on
the emergence and spread of C. auris, it is likely that an environment with a high use of
broad-spectrum antibacterials and antimycotics favors the development of multi-resistant
yeasts such as C. auris. Therefore, the implementation of antimicrobial stewardship, as well
as it being an essential component of antimicrobial resistance reduction strategies, would
mitigate the risk of C. auris spreading. The ECDC recalls the need to review prophylaxis in
terms of risk–benefit analysis in settings with evidence of C. auris transmission [34].

8. Candida auris Surveillance Measures

Colonized patients may not only be able to transmit C. auris to other patients within
healthcare facilities but may also be at risk of invasive infections. Screening patients for
C. auris colonization enables facilities to identify individuals with C. auris colonization and
to implement infection prevention and control measures [52].
According to the CDC, it is important to screen in those situations that place patients
at high risk of contracting C. auris, such as close care contacts with patients with newly iden-
tified C. auris infection or colonization. The indication to carry out screening also applies
to patients who have been admitted to a healthcare facility within the last year, especially
if in a country with documented cases of C. auris, and to those who, admitted abroad,
present infection or colonization with carbapenemase-producing Gram-negative bacteria
as co-colonization of C. auris with these microorganisms has been observed regularly [53].
Screening is also recommended for patients who have had contact with a patient infected or
colonized with C. auris (index patients) and for roommates in healthcare facilities, including
nursing homes, where the index patient has resided in the previous month. Ideally, index
patient roommates should be identified and screened even if they have been discharged
from the facility. The CDC emphasizes that patients who require higher levels of care (e.g.,
mechanical ventilation) and who have stayed in the ward or unit with the index patient
J. Fungi 2023, 9, 913 12 of 14

for 3 or more days should also be considered for screening as these patients are also at
substantial risk of colonization. Patients with newly identified C. auris infection or colo-
nization may have been colonized for months before the organism was detected. Therefore,
when devising a screening strategy, it is also important to consider the patient’s previous
health exposures and contacts [53]. Healthcare facilities should consider conducting more
extensive screening, such as a point prevalence survey, if there is evidence or suspicion
of ongoing transmission in a facility (e.g., C. auris detected in multiple patients through
contact screening or clinical cultures, or increased infections with unidentified Candida
species). Point prevalence surveys, especially when periodically repeated, yield a great
deal of information on the size of the phenomenon and its trend over time, highlighting the
potential effects of strategies adopted [54]. In a case-point prevalence survey, it is necessary
to screen all patients in a given unit or floor where transmission is suspected and to consider
performing a case-point prevalence survey even if all patients with known C. auris have
been discharged. It is important to screen for C. auris colonization using a composite swab
of the patient’s bilateral axilla and groin. Available data suggest that these represent the
most common and recurrent sites of colonization. Although patients have been colonized
by C. auris in the nose, mouth, external ear canals, urine, wounds and rectum, these sites
are usually less significant for colonization screening [52].
Finally, surveillance systems for healthcare-associated infections should consider
updating their definitions to include C. auris in the list of reportable pathogens linked with
healthcare-associated infections [34].

Author Contributions: Conceptualization, M.L.C. and E.P.; Literature research, A.C. and M.O.;
Writing—original draft preparation, M.L.C. and A.M.S.; Writing—review and editing, M.S., E.S., S.B.
and M.L.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data sharing not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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