Seminar 4.1

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Received: 11 September 2017 Revised: 21 November 2017 Accepted: 27 November 2017
DOI: 10.1002/mbo3.578
ORIGINAL RESEARCH
Candida auris: A systematic review and meta-analysis of current

updates on an emerging multidrug-resistant pathogen
John Osei Sekyere
Department of Pharmaceutics, Faculty
of Pharmacy and Pharmaceutical Abstract
Sciences, Kwame Nkrumah University of From 2009, Candida auris has emerged as a multidrug-resistant ascomycete yeast
Science and Technology, Kumasi, Ghana
pathogen with the capacity for easy transmission between patients and hospitals, as
Correspondence well as persistence on environmental surfaces. Its association with high mortalities,
John Osei Sekyere, Department of
Pharmaceutics, Faculty of Pharmacy and breakthrough and persistent candidaemia, inconsistencies in susceptibility testing re-
Pharmaceutical Sciences, Kwame Nkrumah sults, misidentification by available commercial identification systems and treatment
University of Science and Technology, Kumasi,
Ghana. failure, complicates its management and detection. Within the last nine years, C. auris
Email: jod14139@yahoo.com has been increasingly reported from far-Eastern Asia, the Middle East, Africa, Europe,
South and North America with substantial fatalities and misidentification. Herein, I
provide a systematic and thorough review of this emerging pathogen. Meta-analysis
showed that at least 742 C. auris isolates have been reported in 16 countries, with
most of these being from India (≥243), USA (≥232) and UK (≥103) (p-value = .0355)
within 2013–2017. Most isolates were from males (64.76%) (p-value = .0329) and
blood (67.48%) (p-value < .0001), with substantial crude mortality (29.75%) (p-
value = .0488). Affected patients presented with other comorbidities: diabetes (≥52),
sepsis (≥48), lung diseases (≥39), kidney diseases (≥32) etc. (p-value < .0001).
Resistance to fluconazole (44.29%), amphotericin B (15.46%), voriconazole (12.67%),
caspofungin (3.48%) etc. were common (p-value = .0059). Commonly used diagnostic
tools included PCR (30.38%), Bruker MALDI-TOF MS (14.00%), Vitek 2 YST ID
(11.93%), AFLP (11.55%) and WGS (10.04%) (p-value = .002). Multidrug resistance,
high attributable mortality and persistence are associated with C. auris infections. Two
novel drugs, SCY-078 and VT-1598, are currently in the pipeline. Contact precautions,
strict infection control, periodic surveillance and cleaning with chlorine-based deter-
gents, efficient, faster and cheaper detection tools are necessary for prevention, con-
tainment and early diagnosis of C. auris infections.
KEYWORDS
antifungal resistance, Candida auris, candidaemia, fungemia, molecular epidemiology
1 | INTRODUCTION century (Laxminarayan et al., 2016). Antimicrobial-resistant microbes,

particularly bacteria and fungi, are increasingly being reported in
Antimicrobial resistance (AMR) is inarguably one of the greatest healthcare and community settings, with high attendant morbidities,
threats and challenges to clinical medicine and public health in this mortalities, and healthcare-associated costs that runs into millions of
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Author. MicrobiologyOpen published by John Wiley & Sons Ltd.
MicrobiologyOpen. 2018;7:e578. www.MicrobiologyOpen.com | 1 of 29

https://doi.org/10.1002/mbo3.578
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dollars (Laxminarayan et al., 2016; Osei Sekyere, 2016; Osei Sekyere, Galleria mellonella larvae (Sherry et al., 2017). Currently, C. auris has
Govinden, Bester, & Essack, 2016). Until recently, AMR was mainly re- been reported in 16 countries on five continents: North America
ported in bacteria. Specifically, in medically important Gram-negative (Canada and USA), South America (Colombia and Venezuela), Europe
ones in which plasmid-mediated or horizontally acquired antibiotic re- (Germany, Norway, Spain, UK), Africa (South Africa), Asia (India,
sistance genes were associated (Nordmann, Jayol, & Poirel, 2016; Osei Israel, Japan, Kuwait, Oman, Pakistan, South Korea) (Chowdhary,
Sekyere et al., 2016). Notorious genes encoding antibiotic resistance Sharma, & Meis, 2017).
enzymes including extended-spectrum β-lactamases (ESBLs) such as Early detection of C. auris infections has been shown to be ben-
CTX-M, SHV, TEM, GES, and OXA, carbapenemases such as NDM, eficial as earlier initiation of appropriate antifungal therapy saved
KPC, IMP, VIM, and OXA-48 type, and the MCR colistin resistance many lives (Chowdhary et al., 2014; Todd, 2017). However, the
gene have been raising alerts due to their activity against clinically inability of several available commercial identification systems/
important antimicrobials (Nordmann, 2014; Osei Sekyere, 2016; Osei platforms to quickly diagnose C. auris remains a challenge to early
Sekyere & Amoako, 2017). therapy (European Centre for Disease Prevention and Control, 2016;
While clinicians are still battling with the above-stated resistance Kordalewska et al., 2017). While the MALDI-TOF MS and PCR are
enzymes in Gram-negative bacteria, a new multidrug-resistant asco- currently aiding in this regard with their faster turnaround times,
mycete yeast pathogen emerged in a female patient in Tokyo, Japan, the cost and skill involved in their procurement and operation, re-
in 2009 and contemporaneously in 15 South Korean patients in the spectively, is still a hurdle for most under-resourced mycology lab-
same year (Kim et al., 2009; Satoh et al., 2009). This yeast belonged to oratories (Kathuria et al., 2015; Kordalewska et al., 2017; Prakash
the Candida genus. As it was detected in the external ear canal of the et al., 2016). There are currently no official therapeutic guidelines,
patient, it was named as Candida auris; auris is the Latin word for ear dosage or Clinical Laboratory Standards Institute (CLSI)/European
(Satoh et al., 2009). Satoh et al. (2009), who first described this patho- Committee on Antimicrobial Susceptibility Testing (EUCAST) min-
gen, found that it clustered in the Metschnikowiaceae clade. Further, imum inhibitory concentration (MIC) breakpoints for C. auris in-
it was closely related to Candida lusitaniae, Candida pseudohaemulonii, fections, and studies evaluating these are few (Arendrup, Prakash,
Candida duobushaemulonii and Candida haemulonii. Candida haemulonii Meletiadis, Sharma, & Chowdhary, 2017; Lepak et al., 2017). The
was first isolated from the gut of a blue-striped grunt fish (Haemulon sensitivities and specificities of all the diagnostic tools, kits, and
scirus), and later from the blood of a renal failure patient (Cendejas- media used for detecting this new pathogen are discussed herein.
Bueno et al., 2012). The closer phylogenetic relationship between C. Microscopic and molecular/genomic analysis have established the
auris and Candida krusei, C. lusitaniae, C. haemulonii, C. pseudohaem- presence of phenotypic and genetic/genomic differences between
ulonii, and C. duobushaemulonii, which are inherently multidrug re- different C. auris strains from the same or different regions (Lockhart
sistant to amphotericin B (polyenes) and azoles, has been cited as a et al., 2017; Tsay et al., 2017). These include the ability to exist as ag-
reason for the similarly higher resistance of C. auris to these two drug gregates or nonaggregate cells, biofilm formation ability, clonality of
classes (Cendejas-Bueno et al., 2012; Lepak, Zhao, Berkow, Lockhart, outbreak strains, and genetic variations between strains from different
& Andes, 2017). geographical locations (Borman et al., 2016; Sherry et al., 2017). The
Although C. auris was initially isolated from the external ear virulence characteristics of aggregating and nonaggregating cellular
canal or discharges of patients with otitis media, latter reports have morphologies have been investigated by at least two studies (Borman
shown their involvement in candidaemia/fungemia and other deep- et al., 2016; Sherry et al., 2017). However, there is much to be done
seated invasive infections with very high associated mortalities and to answer several pending questions about this pathogen and these
co-morbidities (Azar, Turbett, Fishman, & Pierce, 2017; Ben-Ami loopholes are highlighted below. There are currently two novel anti-
et al., 2017). Unlike other yeasts, they can be transmitted within fungal drugs that have 100% efficacy against C. auris: SCY-078 from
and between hospitals, patients and the environment. Furthermore, Scynexis pharmaceuticals (Berkow, Angulo, & Lockhart, 2017; Larkin
their resistance to at least one antifungal drug such as the azoles et al., 2017) and VT-1598 from Viamet pharmaceuticals (Anonymous,
(particularly fluconazole and/or voriconazole), polyenes (ampho- 2017).
tericin B), flucytosine, and the echinocandins (caspofungin, mica-
fungin and anidulafungin) is well documented (European Centre for
1.1 | Purpose of this systematic review
Disease Prevention and Control, 2016; Rudramurthy et al., 2017;
Schelenz et al., 2016; Tsay et al., 2017). Various studies have estab- Although there are at least eight excellent reviews addressing this
lished their persistence in clinical environments, including the air new menace (Table S1), this current work aims to provide a more com-
and bedding materials, and even in patients undergoing antifun- prehensive update of C. auris reports available to date, and touches
gal treatment (Schelenz et al., 2016; Vallabhaneni et al., 2016). As on all aspects of the pathogen: phenotypic characteristics, genomic
well, their virulence and pathogenicity have been investigated and characteristics, virulence and pathogenicity, resistance profiles and
found to be almost equal to or a little lesser than that of Candida mechanisms, crude mortality rates, detection tools and their relative
albicans (Ben-Ami et al., 2017; Borman, Szekely, & Johnson, 2016; efficiencies, molecular epidemiology, infection prevention and control
Larkin et al., 2017; Sherry et al., 2017); notably, Sherry et al. (2017) protocols, and management. It is thus hoped that this work shall be-
found aggregative C. auris to be more virulent than C. albicans in come the benchmark reference for all reported findings on C. auris.
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except FLZ, above 1 mg/L were defined as nonsusceptible (i.e., high

1.2 | Databases and keywords used for
and potentially resistant) (Arendrup et al., 2017) and included in the
literature search
statistics (Figure 2c). Studies that were not specific with the MICs of
The PRISMA guidelines and checklists (Figure S1) were used in un- the individual isolates were excluded from the computation of the re-
dertaking this systematic review and meta-analysis. Pubmed, Web of sistance rate.
Science and ScienceDirect were searched for English research papers The following data were extracted from the included articles:
written on Candida auris using the search word, Candida auris, with the country of detection, year of detection, specimen types obtained
year filter turned to 2009-01-01. This returned 157 published articles from, resistance profiles, diagnostic method used, comorbidities and
as at 21/07/2017. Google search, references in returned articles and clinical outcome. These data were imputed into Microsoft Excel and
recently published manuscripts (online) not yet indexed in pubmed used for the collation of frequencies and charts (Figures 2 and 3).
were also added to make up to 163 papers. The abstract was screened Statistical analysis of the data was undertaken with GraphPad Prism®
to remove review articles, non-English articles, and non-Candida auris 5 for Windows, version 5.01 (August 7, 2007). The statistical signifi-
papers (Figure 1). Reports on C. auris detection or prevalence from the cance of the data was computed using the Wilcoxon signed rank test
Centers for Disease Control and Prevention (CDC, Atlanta Georgia, and/or the student’s t test (column statistics or one sample t test). The
USA), Public Health England (PHE) and the European Centres for p-values were two-tailed and calculated with a Gaussian approxima-
Disease Control and Prevention (ECDC Stockholm, Sweden) were tion. A p-value of <.05 was defined as significant. Studies that did not
added. The articles were further categorized into eight as shown in provide the required data in the text were excluded from the statisti-
Table S1. All search was done in triplicate to ensure reproducibility. cal analysis. All statistical analyses were done in triplicates to ensure
reproducibility.
1.3 | Statistical analysis
1.4 | Included articles
Unless otherwise stated, tentative MIC breakpoints proposed by the
CDC (Centers for Disease Control and Prevention, 2017b) were used The literature search yielded 163 published articles in addition to re-
for interpretation of the MICs in the meta-analysis: Resistance to flu- ports from the CDC, PHE, and the ECDC. Further screening and exclu-
conazole (FLZ) ≥32L, amphotericin B (AMB) ≥2, anidulafungin (ANF) sion reduced these to 48 articles that were used for the write-up; 38
≥4, caspofungin (CFG) ≥2 and micafungin (MCF) ≥4. MICs of all azoles, articles were used for the statistical analysis (Figure 1).
Identification
Records identified through Additional records identified

database searching through other sources
(n = 157) (n = 6)
Records after duplicates removed

(n = 158)
Screening
Records screened Records excluded

(n = 158) (n = 85)
Full-text articles assessed Full-text articles excluded:

for eligibility Reviews, C. haemulonii,
Eligibility
(n = 73) news, CRISPR-Cas 9,

laryngology/acoustics
papers
(n = 25)
Studies included in
qualitative synthesis
(n = 48)
Included
F I G U R E 1 PRISMA-adapted flow
diagram of included and excluded studies. Studies included in
quantitative synthesis
Adapted from the PRISMA website (http:// (meta-analysis)
prisma-statement.org/PRISMAStatement/ (n = 38)
CitingAndUsingPRISMA.aspx) and article
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F I G U R E 2 Frequency of Candida auris isolated per country between 1996 and 2007 (a), comorbidities presented by C. auris-infected patients
(b) and crude mortality rates per country (c). Total number of reported isolates, comorbities, and mortalities per study were collated per country
and used to calculate the frequencies. GraphPad was used to calculate the p-values
F I G U R E 3 Frequency of males and females infected with Candida auris per country (a), specimen sources (b), and antifungal resistance rates
(c). Total number of reported cases per male and female patients, specimen sources and antifungal resistance per study were collated per country
and used to calculate the frequencies. GraphPad was used to calculate the p-values
2 | PHENOTYPIC FEATURES grouped ovoid, ellipsoidal to elongate budding cells (Kathuria et al.,
2015; Mohsin et al., 2017; Satoh et al., 2009); on SDA, they appear
Microscopy has been instrumental in providing pictorial images of as smooth white to cream-colored colonies (Prakash et al., 2016).
the shapes, color, size, and population structure (Figure 4) of C. auris However, Kumar, Banerjee, Pratap, and Tilak (2015) (Kumar et al.,
strains growing on different culture media such as Sabouraud’s dex- 2015) saw no characteristic color on CHROMagar with their C. auris
trose agar (SDA), CHROMagar, Brilliance Candida agar, GYPA culture strains, which could be due to the conditions used. The size [(2.0–
plates, CS4 agar medium and cornmeal agar at different tempera- 3.0) × (2.5 × 5.0) μm] and growth rate of C. auris is comparable to
tures and incubation times (Table 1). Particularly on CHROMagar, Candida glabrata than to C. albicans (Borman et al., 2016), although
which is the most common media used, C. auris appear as pale its growth patterns are similar to C. albicans (Larkin et al., 2017).
purple or pink smooth colonies occurring as single, paired and/or The thermoresistance of C. auris that allows it to grow between 30
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F I G U R E 4 Scanning electron
micrograph of Candida auris treated with
no drug (control) (a) and with SCY-078
at 1 × MIC (0.5 mg/L) (b). Adapted with
permission from Emily Larkin et al.
Antimicrob. Agents Chemother. 2017;
61:e02396–16
and 42°C, albeit slowly and weakly at 42°C (Satoh et al., 2009), is a established by several researchers (Table 1). However, Borman et al.
unique characteristic that is unseen in other species of Candida. This (2016) and Sherry et al. (2017), respectively, found the formation of
characteristic can be used in the easy identification of this path- rudimentary and occasional pseudohyphae in C. auris, suggesting that
ogen from other species and has been cited as a possible reason pseudohyphae formation might be strain-specific or condition-specific
for the high survival of this pathogen in humans and its potential (Borman et al., 2016; Sherry et al., 2017); further investigations with
to survive in avian species (Borman et al., 2016; Chatterjee et al., a larger number of strains will be necessary to comprehensively char-
2015; Chowdhary et al., 2014; Satoh et al., 2009). Evidently, this acterize these differences between strains, the underlying genetic
thermoresistance will also enhance persistence in the host, aiding in and epigenetic mechanisms or factors and environmental conditions
the dissemination of this pathogen in the environment (Piedrahita inducing these differences in pseudohyphae formation. The forma-
et al., 2017; Schelenz et al., 2016; Welsh et al., 2017). tion of hyphae, pseudohyphae, and germ tube in species such as C.
In determining the species of this novel Candida pathogen, Satoh albicans, and Candida tropicalis, have been associated with higher
et al. (2009) determined the sugar fermentation and assimilation char- virulence characteristics (Ben-Ami et al., 2017; Borman et al., 2016;
acteristics of C. auris, which has been confirmed by other authors Larkin et al., 2017) while germ tube and chlamydoconidia formation
(Table 1) (Satoh et al., 2009). The differences between sugar fermen- are used in identifying different fungal or Candida spp (Chowdhary
tation and assimilation, nitrogen sources utilization, and high salt tol- et al., 2014; European Centre for Disease Prevention and Control,
erance in C. auris and other species of Candida, has further been used 2016; Kumar et al., 2015). Thus, the absence of germ tubes, chlamydo-
by Welsh et al. (2017) to formulate a highly sensitive and specific Salt conidia/chlamydospores in strains that grow at 42°C, but are unable
Sabouraud dextrose/dulcitol/mannitol and Salt Yeast Nitrogen Base to grow on NAG-containing medium should be indicative of C. auris.
dulcitol/mannitol broths that can easily isolate C. auris from clinical and Furthermore, the higher virulence characteristics of C. auris even in the
environmental specimens (Welsh et al., 2017). Moreover, the inability absence of pseudohyphae and germ tube formation remains a mystery
of C. auris to grow on cycloheximide-containing medium (0.1%–0.01%) yet to be unraveled.
(Table 1) could be a marker for the identification of this pathogenic Borman et al. (2016), Ben-Ami et al. (2017), and Sherry et al. (2017)
yeast. Thus, the phenotypic and biochemical characteristics of have reported of the presence of at least two cellular morphologies of
C. auris, as detailed in Table 1, can be used in designing novel media C. auris: aggregating and nonaggregating cells (Ben-Ami et al., 2017;
and identification kits to enhance the early and efficient detection of Borman et al., 2016; Sherry et al., 2017). Borman et al. (2016) showed
this yeast, particularly as misidentification is a major problem with C. that aggregating C. auris strains could not be separated by mechanical
auris infection management (European Centre for Disease Prevention action using vigorous shaking/vortexing and/or chemical treatment
and Control, 2016; Khillan, Rathore, Kathuria, & Chowdhary, 2014; with detergents. Thus, it is argued that the aggregating cells are not
Lee et al., 2011). due to flocculation or encapsulation of cells in biofilms but rather, to
Furthermore, differences exist between strains from Japan and the inability of daughter cells to separate after budding. Through G.
South Korea on one hand, and those from India, South Africa, and mellonella infection model studies, it has been established that non-
Brazil on the other hand in terms of N-acetyl glucosamine (NAG) utili- aggregating cells are more virulent and pathogenic than aggregating
zation (Table 1). This difference has not been fully investigated to as- cells and equally, highly or a little less virulent than C. albicans (Borman
certain the underlying genetic and/or phenotypic mechanism. Further et al., 2016; Sherry et al., 2017). Moreover, nonaggregating C. auris
research should be undertaken to characterize the genetic basis for cells formed a greater biofilm mass than aggregating ones and C. gla-
these differences to aid in a better typing and description of different brata, and a lower biofilm mass than C. albicans (Sherry et al., 2017).
C. auris strains in future. Besides the G. mellonella infection model studies (Borman et al., 2016;
The inability of C. auris to grow pseudohyphae, germ tube, Sherry et al., 2017), no study has shown a higher pathogenicity for
chlamydoconidia, and chlamydospores on cornmeal agar has been C. auris over C. albicans. Contrasting findings by Larkin et al. (2017)
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T A B L E 1 Phenotypic and genomic characteristics of Candida auris
Phenotypic and genomic

features Observations References
Fermented sugars Glucose, sucrose (weak) and trehalose (weak) Cendejas-Bueno et al. (2012), Chowdhary
Nonfermented sugars Galactose, maltose, lactose or raffinose et al. (2013, 2014), Emara et al. (2015),
Lee et al. (2011), Satoh et al. (2009)
Assimilated carbon sources Glucose, sucrose, maltose, D-trehalose, D-raffinose, D-melezitose,
inulin (weak), soluble starch, ribitol (weak), galactitol, D-mannitol,
sorbitol and citrate, N-acetyl- D-glucosamine (NAG)a
Nonassimilated carbon sources D-galactose, L-sorbose, D-cellobiose, lactose, melibiose, D-xylose,
L-arabinose, D- arabinose, ribose, L-rhamnose, D-glucosamine,
NAG, methanol, ethanol, glycerol, erythritol, α-methyl-D-
glucoside, salicin, D-gluconate, DL-lactate, succinate, inositol,
hexadecane, 2-keto-D-gluconate and xylitol
Nitrogen sources utilized Ammonium sulfate, cadaverine, and L-lysine
Nitrogen sources not utilized Sodium nitrite, potassium nitrate and ethylamine are not utilized
Growth in vitamin-free medium, Positive
50% glucose, and 10%
NaCl/5% glucose medium
Growth temperature 37–40°C (optimal); 42°C (weak and slow); >42°C (no growth)
Starch formation, urease Negative
activity and diazonium blue B
reaction
Growth in the presence of 0.1% Negative Cendejas-Bueno et al. (2012), Chowdhary
and 0.01% cycloheximide et al. (2014), Emara et al. (2015), Lee et al.
(2011), Rudramurthy et al. (2017), Sarma
and Upadhyay (2017), Satoh et al. (2009)
Virulence factors: Hyphae, Hyphae formation is negative. Some strains form pseudohyphae Azar et al. (2017), Borman et al. (2016),
pseudohyphae, germ tube, and occasionally, but most strains do not. No germ tube formed on Cendejas-Bueno et al. (2012), Chowdhary
biofilm formation; proteinases cornmeal agar. Little adherence to catheter material (compared to et al. (2013, 2014), Kumar et al. (2015,
and phospholipasesb Candida albicans). Phospholipases (Pz) and proteinases production 2017), Larkin et al. (2017), Lee et al.
production; adherence were strain-dependent, at different degrees (0.78–1 and 0.0–5.3, (2011), Satoh et al. (2009), Sherry et al.
respectively) and relatively lower than C. albicans (Pz = 0.66) (2017)
Most strains form biofilms to different degrees while some do not Chatterjee et al. (2015), Chowdhary et al.
form biofilms at allc (2013), Larkin et al. (2017), Oh et al.
(2011), Sherry et al. (2017)
Shape, size, appearance Cells are ovoid, ellipsoidal to elongate, (2.0–3.0) × (2.5–5.0) μm, Ben-Ami et al. (2017), Borman et al.
chlamydospore and chlamydo- single, in pairs, or in groups/aggregates. Smooth, pale purple, (2016), European Centre for Disease
conidia formation pinkish and creamy colonies on CHROMagar. Some studies saw Prevention and Control (2016), Kumar
no characteristic color on CHROMagar. Beige colored colonies et al. (2015), Larkin et al. (2017), Lee
formed on Brilliance Candida Agar. Obverse colonies white cream et al. (2011), Ruiz Gaitán et al. (2017),
on GYPA and Reverse colony milky brown 48 h at 24°C. Obverse Satoh et al. (2009), Schelenz et al. (2016),
colonies nile blue and Reverse light green at 24°C. No chlamydo- Sherry et al. (2017)
spores or chlamydoconidia were formed on cornmeal agar
Misidentification by commercial Vitek 2 YST: Candida haemulonii, Candida duobushaemulonii. API Centers for Disease Control and Prevention
systems 20C: Rhodotorula glutinis, Candida sake, Saccharomyces cerevisae. (2017b), Chowdhary et al. (2014),
BD Phoenix: Candida haemulonii, Candida catenulate. MicroScan: Kathuria et al. (2015), Khillan et al. (2014),
Candida famata, Candida guilliermondii, Candida lusitaniae, Candida Kordalewska et al. (2017), Mizusawa et al.
parapsilosis. Auxacolor 2: S. cerevisae (2017), Ruiz Gaitán et al. (2017)
Genomic features 12.3–12.5 Mb genome, GC content = 44.8%–45.3%, CDSd = 6675, Centers for Disease Control and Prevention
5.8S rRNA, 184 tRNA, 3262 repetitive elements (2017a), Chatterjee et al. (2015), Lockhart
et al. (2017), Schwartz and Hammond
(2017), Sharma et al. (2016), Tsay et al.
(2017), Vallabhaneni et al. (2016)
a
Some strains from India, South Africa, Brazil, etc. are able to assimilate NAG (Prakash et al., 2016).
b
Pz < 0.89 (strong phospholipase activity); Pz = 0.90 to 0.99 (weak phospholipase activity); Pz = 1 (no phospholipase activity).
c
The lack of biofilm formation may be due to several factors: type of substrate and media used, source of isolates (ear/blood), pretreatment with fetal bo-
vine serum (FBS), biofilm measurement/scale used.
d
Coding sequence.
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with murine infection models are described below (Larkin et al., 2017). in virulence and antifungal stress response such as Hog1 protein ki-
Furthermore, the finding of a higher virulence/pathogenicity among nase, 2-component histidine kinase etc., were discovered in the C.
nonaggregating cells than in aggregating cells has only been estab- auris genome. Functional annotation of most C. auris genes remain to
lished in G. mellonella models. Thus, additional studies are necessary to be undertaken and this will be necessary to comprehend the genetic
establish the relative pathogenicity of these two cellular morphologies mechanisms of this pathogens’ MDR and virulence/pathogenicity
in different infection models. (Grahl, Demers, Crocker, & Hogan, 2017).
Summing up, C. auris has a complicated phenotypic plasticity in Thus, the C. auris genome is still not fully characterized and bears
terms of cellular morphology, nitrogen and carbon source assimilation little resemblance to the genomes of other species of Candida. Several
and utilization, virulence and pathogenicity, which can be cellular mor- orthologous efflux and virulence genes are present in the genome, but
phology type-, strain- and/or country of origin-specific. Nevertheless, its actual sexual cycle remains a mystery.
their ability to grow at 40–42°C has been confirmed worldwide.
4 | RESISTANCE PROFILES, RATES

3 | GENOMIC FEATURES AND MECHANISMS
Of the six articles reporting on the use of whole genome sequenc- The antifungal resistance profiles of the estimated 742 C. auris isolates
ing to characterize the genome of C. auris (Chatterjee et al., 2015; were used to compute the resistance frequency and rates of the iso-
Lockhart et al., 2017; Sharma, Kumar, Meis, Pandey, & Chowdhary, lates to the various antifungals (Figure 2c), using tentative breakpoints
2015; Sharma, Kumar, Pandey, Meis, & Chowdhary, 2016; Tsay et al., developed by the CDC (Centers for Disease Control and Prevention,
2017; Vallabhaneni et al., 2016), only three gave detailed genome 2017b) and suggested by Arendrup et al. (2017) (please see Section
characteristics of the sequenced isolates (Chatterjee et al., 2015; 1.3). As seen in Figure 2c, most of the isolates were resistant to FLZ
Sharma et al., 2015, 2016), which were all from India. In a detailed (n ≥ 318; 44.29%), followed by AMB (n ≥ 111; 15.46%), voriconazole
description of sequenced C. auris genomes, Chatterjee et al. (2015), (VRZ) (n ≥ 91; 12.67%), CFG (n ≥ 25; 3.48%), flucytosine (FCN) (n ≥ 14;
and Sharma et al. (2015, 2016) showed that the C. auris genome di- 1.95%), itraconazole (ITZ) (n ≥ 13; 1.81%), isavuconazole (ISA) (n ≥ 11;
verged from that of C. albicans by 99.5% and had a size of 12.3– 1.53%), posaconazole (PSZ) (n ≥ 10; 1.39%), ANF (n ≥ 9; 1.25%), MCF
12.5 Mb with a G+C content of 44.53%–44.8% (Chatterjee et al., (n ≥ 9; 1.25%), SCY-078 (0; 0%) and VT-1598 (0; 0%). Resistance to at
2015; Sharma et al., 2015, 2016). Its genome was closest in homol- least two of these drugs were frequently reported in several studies
ogy or average nucleotide identity to that of C. lusitaniae (85.9%– (Table 2).
86.4%), but it lacked the MATa mating locus allele, although it had Although susceptible C. auris strains, specifically to FLZ, have been
the other allele, MATα. PCR amplification of the MATα gene allowed described (Vallabhaneni et al., 2016), most C. auris strains have been
for easy identification of C. auris from other species of Candida and reported to be resistant to FLZ and/or to other azoles such as VRZ
can thus be used for identification of C. auris, besides the 26S rDNA and to AMB, with a minority being resistant to FCN, other azoles and
D1/D2 domain and 18S rRNA internal transcribed spacer (ITS) re- the echinocandins (Table 2; Figure 2). In several cases, MDR to FLZ
gion DNA (Chatterjee et al., 2015; Satoh et al., 2009; Sharma et al., and AMB or to all three antifungal drug classes (azoles, polyenes and
2016). Although the MATα allele was found in C. auris, its sexual- echinocandins) have been reported (Table 2) (Chakrabarti et al., 2015;
ity, that is, parasexual/asexual or sexual, could not be established Lockhart et al., 2017). The order of resistance as shown in Figure 2
(Chatterjee et al., 2015; Pragasam et al., 2016); further research is namely, FLZ > AMB > echinocandins, is the same in most of the stud-
necessary to reveal its sexual cycle. ies reported so far in most countries (Arendrup et al., 2017; European
Within the C. auris genome, orthologs of several C. albicans ef- Centre for Disease Prevention and Control, 2016; Todd, 2017)
flux genes belonging particularly to the major facilitator superfamily (Table 2). Thus, higher resistance to FLZ in a Candida nonalbicans spe-
(MFS) and the ATP-binding cassette (ABC) transporter families were cies has become one of the distinguishing characteristics indicative of
identified, suggesting that efflux is a potential resistance mechanism a potential C. auris infection (European Centre for Disease Prevention
mediating multidrug resistance (MDR) against azoles, polyenes, and and Control, 2016). Due to the relatively low resistance to echino-
echinocandins in this pathogen (Chatterjee et al., 2015; Sharma et al., candins, it is recommended that an echinocandin empirical therapy
2016). This was phenotypically confirmed by Ben-Ami et al. (2017) be initiated in patients suspected to have C. auris infections prior to
with a rhodamine-based efflux assay (Ben-Ami et al., 2017). Further, antifungal susceptibility testing of collected strains (Lee et al., 2011;
the zinc (II) 2 cys 6 transcription factor family, of which four members Todd, 2017). The echinocandins can then be maintained or changed
are key regulators of MDR1, an efflux pump gene whose upregulation based on the susceptibility results (Lepak et al., 2017; Todd, 2017); it
leads to MDR, was enriched in the C. auris genome (Chatterjee et al., should, however, be noted that some patients have died even while
2015). on echinocandins (Azar et al., 2017; Ruiz Gaitán et al., 2017; Schelenz
Orthologous genes of C. albicans virulence proteins such as STE- et al., 2016). Early initiation of echinocandin therapy has been advised
related proteins, MADS-box, Ste12p, mannosyl transferases, adhes- to cut down on C. auris-mediated mortalities (Chowdhary et al., 2014;
ins, and integrins as well as orthologs of C. albicans kinases involved Lee et al., 2011).
T A B L E 2 Geographical distribution, demographics, specimen sources, resistance profiles, diagnostics and clinical data of Candida auris isolates identified between 2006/9 and 2017
Specimen Resistance Clinical

|
Country (n) Year (n) Age(n)/sex source (n) MICa (μg/ml) mechanisms Diagnostics used Co-morbidity outcome (n) References
8 of 29
b c d f g
Canada (5) 2017 (5) 64 (1)/M Ear discharge FLZ = 128, AMB = 2, ND MALDI-TOF MS, WGS Chronic otitis media, Alive Schwartz and
(1) MCFe = 0.5 odontogenic brain Hammond (2017)
abscess
Colombia (17) 2016 (17) 0–77 (9)/M, Blood (13), FLZ = 16–>64, ND API 20C, VITEK 2 YST Diabetes (3), pancreatitis Demised (6) Morales-Lopez
NSh (6)/Fi peritoneal VRZk < 0.12–2, ID, Phoenix BD, (2), cancer (2), HIV (1) et al. (2017)
fluid (1), CSFj AMB = 8->16, Microscan(Walkaway
(1), bone (1), MCF < 0.06–0.25, and AutoSCAN 4),
urine (1) CFGl < 0.25–0.5 CHROMagar,
MALDI-TOF MS
Germany (2) NS 68 (1)/M Blood (2) SCY-078m = 0.5, ND API 20C AUX, VITEK 2 NS NS Larkin et al. (2017)
FLZ > 64, YST ID, PCR and
ISAn = 0.031, sequencing (of ITS1/4s
ITZo = 0.5,
PSZp = 0.25–0.5,
VRZ = 0.125–0.5,
AMB = 4,
FCNq = 0.5,
ANFr = 0.25,
CFG = 0.5,
MCF = 0.25
Germany (1) 2015 (1) NS Blood (1) NS ND NS NS NS European Centre
for Disease
Prevention and
Control (2016)
India (90) 2010–14 NS Blood (78), AMB = 0.125–8, ND, no MALDI-TOF MS, AFLP, NS NS Kathuria et al.
(90) gangrenous ITZ < 0.03–2, mutations in PCR and sequencing (of (2015), Prakash
tissue (NS), VRZ < 0.03–16 FKS1/2 genes ITS1, LSU and RPB1) et al. (2016)
pleural fluid ISA < 0.015–4,
(NS), PSZ < 0.015–8,
peritoneal FLZ = 4–>64
fluid (NS), FCN < 0.125–>64,
urine (NS), CFG = 0.125–8,
sputum (NS) MCF < 0.015–8
ANF < 0.015–8
India (74) 2011–12 49.7 (Mean Blood (74) R (FLZ = 43), ND VITEK 2 YST ID, PCR Pulmonary (30), renal (16), 41.9%–44.7% Chakrabarti et al.
(74) age); M = 46, R (VRZ = 2), and sequencing (of ITS1 cardiovascular (15), crude (2015),
F = 28, R (ITZ = 3), and D1/D2) gastrointestinal (7), and mortalities Rudramurthy
adults=52 R (CFG = 7), liver (5) diseases (19.6%–27% et al. (2017)
R (AMB = 10) attributable
mortalities)
(Continues)
OSEI SEKYERE
T A B L E 2 (Continued)
OSEI SEKYERE

India (19), 2012–15 24–69 Blood (n = 27), FLZ = 4–256, ERG11 WGS Diabetes (34), solid tumor Demised (24) Lockhart et al.
Pakistan (19), (53) (53)/M = 26, urine (n = 10), VRZ = 0.03–16, mutations: (12), liver disease (8), (2017)
South Africa F = 15, tissue (n = 5) ITZ = 0.125–2, F126T, Y132F, immunocompromised
(10), NS=13 or other PSZ = 0.06–1, Y132F, (20)
Venezuela (5), (n = 11) CFG = 0.03–16, K143R
ANF = 0.125–16,
MCF = 0.06–4,
FCN = 0.125–128,
AMB = 0.38–4
India (17) 2013–14 NS NS NS ND VITEK 2 YST ID, VITEK 2 NS NS Wattal et al.
(17) MS, PCR and sequenc- (2017)
ing (of 18S rRNA)
India (15) 2011–13 48, 80 &87 Blood (7), pus FLZ = 64, VRZ = 0.5–4, ND CHROMagar, PCR and Diabetes (5), chronic Demised (4) Chowdhary et al.
(15) (3)/F2 (1)/M, (1), CVCt (3), FCN = 0.25–64, sequencing (of ITS and kidney disease (4), (2014)
20–79 (8)/M surgical tissue CFG = 0.25–1, D1/D2) malignancies (3), sepsis
(3), Broncho PSZ = 0.015–0.125, (4), acute renal failure
alveolar lavage ITZ = 0.06–0.25, (2), chronic kidney
(BAL) (1) ISA = 0.06–0.5, disease (3), (broncho-)
AMB = 0.25–1, pneumonia (2),
MCF = 0.06–0.125, peripheral occlusive
ANF = 0.125–0.25 vascular disease (3), IgA
nephropathy, hydrone-
phrosis etc.
India (12) 2009–11 NS Blood (12) FLZ = 16–64, ND API 20C, VITEK 2 YST Immunosuppressive Demised (6) Chowdhary et al.
(12) AMB = 0.25–1, ID, PCR and sequencing conditions (7), diabetes (2013)
ITZ = 0.125–0.25, (of ITS1 and D1/D2), (6), CKDv, cancer
VRZ = 0.125–1 AFLPu chemotherapy (2), HIV
ISA < 0.015–0.25, (1), low birth weight (3),
PSZ = 0.06–0.25, sepsis (1), acute
FCN = 0.125, lymphoblastic leukemia
CFG = 0.125–0.25, (1)
MCF = 0.06–0.125,
ANF = 0.125–0.5
India (5) 2012–14 NS Blood (5) FLZ = 16–64, ND VITEK 2 YST ID, WGS, Sepsis and multiorgan NS Chatterjee et al.
(5) AMB = 4–16, PCR (MFα) dysfunction (1) (2015)
FCN = 1, CFG = 0.25
|
(Continues)
9 of 29
|

10 of 29
India (4) 2013 (4) 43/M Pericardial fluid AMB = 0.125–0.5, ND CHROMagar, Vitek 2, Chronic liver disease Demised (1) Khillan et al.
(1), blood (1), CFG = 1, FLZ > 64, PCR and sequencing (of (2014)
BAL (1) and PSZ ≤ 0.015, ITS and D1/D2)
urine (1) ITZ = 0.03–0.125,
VRZ = 0.06–0.125,
FCN = 0.125–4,
MCF = 0.06,
ANF = 0.125–0.25
India (3) 2013–14 NS Blood (3) NS ND MALDI-TOF MS, PCR NS NS Ghosh et al. (2015)
(3) and sequencing (of ITS1
and D1/D2)
India (2) 2011 (2) NS NS FLZ = 64, VRZ = 2, ND Vitek 2, PCR and NS Demised (≤2) Sarma et al. (2013)
AMB = 16, FCN = 1 sequencing (of ITS and
D1/D2)
India (1) NS 28 (1)/F Vaginal swab ITZ ≥ 2FLZ ≤ 16, ND CHROMagar, PCR and Vulvovaginitis Survived (1) Kumar et al. (2015)
(1) VRZ ≤ 0.5 and sequencing (of ITS1)
AMB ≤ 0.5
India (1) 2015 NS Blood (1) FLZ = 64 ND Vitek 2, PCR and NS NS Sharma et al.
sequencing (of ITS and (2015)
D1/D2, RPB1/2)
Israel, Tel Aviv 2014 (4), NS Blood (5), NS FLZ = 32–64, ND, higher CHROMagar Candida, HIV (1), blood stream Demised (2) Ben-Ami et al.
(6) 2015 (1), (1) ITZ = 0.5, VRZ = 0.5– ABC efflux VITEK 2 YST ID, PCR infections (5) (2017)
2014–15 1, PSZ = 0.12–0.5, activity and sequencing
(1) AMB = 1–2,
ANF = 0.03,
MCF = 0.12–0.25,
CSF = 0.5,
FCN = 0.25–1
Japan (1) 2009 (1) 70 (1)/F Ear discharge FLZ = 2, VRZ = 0.031, ND CHROMagar, Vitek 2, NS Alive Satoh et al. (2009)
(1) ITZ = 0.063, PCR and sequencing (of
FCN = 0.5 ITS and D1/D2)
Kuwait (1) 2014 (1) 27/F Blood (1) FLZ ≥ 256, ND VITEK 2, MAST ID Chronic renal failure, Demised Emara et al. (2015)
AMB = 0.064, CHROMagar, PCR (of lobar pneumonia,
VRZ = 0.38, ITS1 and D1/D2) immotile cilia syndrome,
CFG = 0.0064 bronchiectasis, recurrent
sinusitis
(Continues)
OSEI SEKYERE

OSEI SEKYERE
Norway (1) NS (1) NS Blood (1) NS ND NS NS NS European Centre

for Disease
Prevention and
Control (2016)
Oman (5) 2016–17 62 (2)/M, 71 Blood (5) FLZ = 128->256, ND BD Phoenix Yeast ID Diabetes mellitus (2), Demised (3) Al-Siyabi et al.
(5) (1)/M, 31 VRZ = 0.5–2, panel cerebrovascular accident (2017)
(1)/F, 62 ITZ = 0.12–0.25, (1), chronic kidney
(1)/F PSZ = 0.06–0.12, disease (1), sepsis (1),
ANF = 0.12, acute limb ischemia (1),
CFG = 0.08–0.12, metastatic endometrial
MCF = 0.06–0.12, cancer (1), obstructive
AMB = 1–2, uropathy (1), infected
FCN = 0.06–8 below knee amputation
stump (1), kidney
transplant (1), systemic
lupus erythematosus (1),
pneumonitis (1)
Oman (2) 2016 (1), 70 (1)/F, 77 Blood (2) FLZ ≥ 64, ITZ = 0.125– ND API20C- AUX, MALDI- Diabetes, hypertension, Demised (1) Mohsin et al.
2017 (1) (1)/M 0.031, VRZ = 0.125– TOF MS, PCR and cardiac failure, edema (2017)
1, sequencing (of ITS and and cellutitis (1),
PSZ < 0.016–0.125, LSU rRNA), AFLP diabetes, osteomyelitis
ISA < 0.016–0.125, and septic shock (1)
AMB = 1–2,
ANF = 0.031–0.125,
MCF = 0.063–0.125
South Africa (4) 2012–13 85 (1), 73 (1), Blood (4) FLZ = 64->256, ND API 20C, VITEK 2 YST NS NS Magobo et al.
(4) 60 (1), 27 (1) VRZ = 0.25–2, ID, PCR and sequencing (2014)
PSZ = 0.015–0.06, (of ITS1 and D1/D2)
ITZ = 0.06–0.25,
FCN = 0.06–0.12,
CFG = 0.03–0.25,
MCF = 0.06–0.12,
ANF = 0.06–0.25
South Korea 2006 (15), NS Ear (17), blood FLZ = 2–128, ND VITEK 2 YST ID, PCR Otitis media (17), Survived (17), Kim et al. (2009),
(20) 2007–10 (3) AMB = 0.38–1.5, and sequencing (of ITS1 candidaemia (3) NS (3) Oh et al. (2011),
(5) ITZ = 0.125–4, and D1/D2) Shin et al. (2012)
VRZ = 0.03–2,
CFG = 0.125–0.25,
|
MCF = 0.03
(Continues)
11 of 29
|

12 of 29
South Korea (3) 1996 (1), 1 (1)/F, 1 Blood (3) AMB = 0.5–1, ND API 20C, VITEK 2 YST Hypoxic encephalopathy Demised (2) Lee et al. (2011)
2009 (2) (1)/M, 74 FLZ = 2–128, ID, PCR and sequencing and aspiration pneumo-
(1)/M ITZ = 0.125–2, (of ITS1 and D1/D2) nia (1), laryngeal
VRZ = 0.06–1, carcinoma (1), he-
CFG = 0.06, mophagocytic lympho-
MCF = 0.03 histiocytosis (1)
South Korea (2) 2010–13 NS Ear discharge NS ND Phoenix BD system, NS NS Kim et al. (2016)
(2) (2) VITEK 2 YST ID, MALDI
TOF MS (VITEK MS and
Bruker) PCR and
sequencing (of ITS1 and
D1/D2)
Spain (34) 2016 (34) NS Blood (34) NS ND NS Blood stream infection NS European Centre
(34) for Disease
Prevention and
Control (2016)
Spain (8) 2016 (8) 66 (1)/M, 48 Blood, CVC tip, FLZ > 256, VRZ = 2, ND CHROMagar Candida®, Hepatocellular carcinoma Alive Ruiz Gaitán et al.
(1)/M, 26 urine, susceptible to PSZ, BBL Mycosel agar, API (1), ventricular (2Demised (2017)
(1)/M, 39 peritoneal ITZ, MCF, ANF and ID20C, AuxaColor, dysfunction and multiple (2)
(1)/F, fluid, AMB VITEK MS, PCR & organ dysfunction
pharyngeal, sequencing of ITS syndrome (1),
and rectal poly(thoracic)trauma (2),
culture (4)
UK (53) 2013 (3), NS Blood (7), FLZ = 8−>64, ND PCR (of 28s rRNA/ITS1), NS NS Borman et al.
2014 (1), sputum (2), VRZ = 0.06–2, MALDI-TOF MS (2016, 2017)
2015 (7), groin swab (2), PSZ = <0.03–1,
2016 (4), CSF (1), NS ANF = 0.03–0.5,
2014–16 (18), line (1), FCN = <0.125–0.25,
(7) arterial line (1), AMB = 05–1
pleural fluid
(2), urine (1),
pustule swab
(1), wound
swab (3),
femoral line
(2), swab (2)
(Continues)
OSEI SEKYERE
OSEI SEKYERE

UK (50) 2015–16 19–78 Wound swabs, FLZ > 256, ND Brilliance Candida Agar, Cardiac surgery Survived (50) Schelenz et al.
(50) (50)/M = 33, urine samples, AMB = 0.5–2M, FCN MALDI-TOF, AFLP (2016)
F = 17 vascular <0.06–0.12, ANF/
devices tips, MCF/
blood cultures, CFG = 0.06–0.25
skin (nose,
axilla, groin)
stool samples
United states 2016–17 21–96 Blood (40), Rw (FLZ>32) = 30, ND WGS NS NS Centers for
(224: 104 are (224) (69)/55%M urine (10), R(AMB≥2) = 15, Disease Control
clinical, 120 respiratory R(MCF/ANF/CFG and Prevention
are colonized tract (8), bile >4) = 1 (2017a), Tsay
patients) fluid (4), et al. (2017)
wound (1),
CVC tip (2),
bone (1),
jejunal biopsy
(1)
United States 2013 (1), Not specified Blood (5), urine R (FLZ) = 5 isolates, ND WGS Hematologic malignancies Demised (4), Vallabhaneni et al.
(7) 2015 (1), (NS) (1), external R(AMB) = 1, R (MCF/ (n = 2), bone mar- alive (3) (2016)
2016 (5) ear canal (1) ANF/CFG) = 1 rowtransplantation
(n = 1),acute respiratory
failure (n = 1), peripheral
vascular disease and
skull base osteomyelitis
(n = 1), brain tumor,
villous adenoma
resection (1).
United States, 2017 (1) 71(1)/M BAL FLZ = 4, VRZ = 0.03, ND CHROMagar Candida, Idiopathic pulmonary Demised Azar et al. (2017)
Massachusetts CFG = 0.12, VITEK MS, VITEK 2 fibrosis, chronic
(1) MCF = 0.12, YST ID, MALDI-TOF obstructive lung disease
FCN = 0.12, AMB = 2 MS
(Continues)
|
13 of 29
|
14 of 29

Venezuela (18) 2012–13 <1 year (6)/ Blood (18) FLZ > 64, VRZ = 4, ND VITEK 2 YST ID, PCR Preterm neonates (8), Demised (5) Calvo et al. (2016)
(18) M<1 year AMB = 2, FCN = 0.5, and sequencing (of ITS), cancer (1),
(6)/F14 (1)/ ANF = 0.125 AFLP
F72 (1)/
F21–29 (2)/
M40–48
(2)/M
a
Minimum inhibitory concentration. Tentative MIC breakpoints proposed by the CDC (Centers for Disease Control and Prevention, 2017b) were used for interpretation: Resistance to FLZ ≥ 32L, AMB ≥ 2,
ANF ≥ 4, CFG ≥ 2 and MCF ≥ 4.
b
Male.
c
Fluconazole.
d
Amphotericin B.
e
Micafungin.
f
Not determined.
g
Whole genome sequencing.
h
Not stated.
i
Female.
j
Cerebrospinal fluid.
k
Voriconazole.
l
Caspofungin.
m
A novel orally bioavailable 1,3-β-D-glucan synthesis inhibitor antifungal drug.
n
isavuconazole.
o
Itraconazole.
p
Posaconazole.
q
Flucytosine.
r
Anidulafungin.
s
Internal transcribed spacer region.
t
Central venous catheter.
u
Amplified fragment length polymorphism.
v
Chronic kidney disease.
w
Resistance: R (FLZ) = fluconazole resistance, R (AMB) = amphotericin B resistance.
OSEI SEKYERE
OSEI SEKYERE |
15 of 29
Resistance to other azoles such as ITZ, ISA and PSZ has been Indian and Pakistani strains, were found to be clonally and geograph-
variable (Table 2). Arendrup et al. (2017) suggested that the variable ically related (Lockhart et al., 2017). A comprehensive study on the
resistance to other azoles besides FLZ might be due to a mixed popu- resistance mechanisms of C. auris is required to decipher the MDR
lation of resistant and susceptible (or wild-type and nonwild-type) C. nature of this pathogen.
auris strains or the presence of different resistance mechanisms within Hence, it is obvious that efflux, mutations in the ERG and FKS, and
the population being tested. In other words, the collective resistance biofilm formation are potential C. auris resistance mechanisms. In addi-
mechanism(s) found in the various strains making up the population tion, C. auris is generally resistant to FLZ, moderately resistant to AMB,
can affect the final MIC (Arendrup et al., 2017). Caution should be ex- and variably resistant to other azoles, flucytosine and echinocandins.
ercised in interpreting MIC data for AMB and CFG generated by Vitek
2 as substantial discrepancies (higher AMB and lower CFG MICs) has
been reported between MICs generated by the CLSI’s microbroth dilu- 5 | VIRULENCE AND PERSISTENCE
tion (MBD) method and the Vitek 2 instrument (Kathuria et al., 2015;
Khillan et al., 2014). Kumar et al. (2015) first undertook phospholipase, proteinase, and he-
A comprehensive characterization of C. auris resistance mech- molysin activity assays in C. auris to evaluate their virulence in vitro.
anism(s) is currently unavailable although few researchers have at- Phospholipases, proteinases, and hemolysins are important enzymes
tempted to provide some insights. Oh et al. (2011) earlier reported that are used by fungi to invade and infect the host (Kumar et al., 2015;
that C. auris form no biofilms, an important AMR mechanism. However, Larkin et al., 2017). In that report, substantial phospholipase activity
this has been discounted by several authors (Larkin et al., 2017; Sherry (Pz value = 0.72), proteinase activity (Prz value = 0.66) and hemolysin
et al., 2017) and biofilm-forming genes have been identified in C. auris activity (Hz value = 0.74) were recorded in the single C. auris isolate;
genomes (Chatterjee et al., 2015). The type of substrate and media a Pz, Prz or Hz value of 1 represents no activity (Kumar et al., 2015;
used, source of isolates (ear/blood), pretreatment with fetal bovine Larkin et al., 2017). The presence of several virulence genes in C. auris
serum (FBS), biofilm measurement/scale used etc. are reasons sug- genomes has also been attested to (Chatterjee et al., 2015; Sharma
gested to have led to the different observations recorded by Oh et al. et al., 2016). As already noted, no germ tubes were formed by the
(2011) on the nonformation of biofilms by C. auris (Larkin et al., 2017). isolate on corn meal agar. These findings were recently followed up by
Sherry et al. (2017) showed that C. auris biofilms, just like that of other Larkin et al. (2017) with a larger number (n = 16) of isolates in which
species of Candida, were resistant to CFG and MCF (MIC > 32 mg/L), they observed that not all C. auris strains expressed phospholipases
to FLZ (MIC > 32 mg/L), to VRZ, and AMB (MIC > 4 mg/L); only lipo- and proteinases, and none produced germ tubes (germinated) upon
somal AMB was effective in limiting growth at a lower concentration incubation with fetal bovine serum. Moreover, even among strains
(MIC = 0.25–1 mg/L), albeit up to 16 mg/L was necessary to stop bio- that did express the virulence proteins, the degree of activity was not
film metabolic activity by 90% (Sherry et al., 2017). the same but strain-specific, showing that not all C. auris strains are
The direct role of efflux pumps in C. auris antifungal resistance virulent/pathogenic or equally virulent/pathogenic. As well, two rep-
is yet to be comprehensively characterized although Ben-Ami et al. resentative strains showed relatively poorer adherence to catheters
(2017) used rhodamine, an efflux substrate, to show that C. auris ex- than C. albicans, suggesting that adherence to catheters could not be
pressed a higher ABC-type efflux pump activity than C. glabrata and C. a major means/cause of invasive C. auris infections and persistence in
haemulonii (Ben-Ami et al., 2017). This higher efflux activity suggested patients and hospitals (Larkin et al., 2017). However, there are reports
that efflux pumps play an important role in C. auris MDR mechanisms, on the clearance of C. auris candidaemia upon removal of urinary or
which is corroborated by the several MFS and ABC-type efflux pumps’ central venous catheters from patients (Chowdhary et al., 2014; Lee
orthologous genes identified by Chatterjee et al. (2015) in C. auris ge- et al., 2011; Ruiz Gaitán et al., 2017).
nomes (Chatterjee et al., 2015). It is currently agreed that C. auris forms relatively less biofilms in
Furthermore, the role of mutations in ERG3 and ERG11 genes terms of biomass and metabolic activity than C. albicans, with nonag-
in conferring resistance to azoles in C. auris has been investigated gregating C. auris strains forming more biofilm mass than aggregating
(Chatterjee et al., 2015; Lockhart et al., 2017; Sharma et al., 2016) ones (Larkin et al., 2017; Sherry et al., 2017). Whereas C. auris bio-
by aligning orthologs of these genes in C. auris to that of susceptible films have been shown to be resistant to FLZ, VRZ, echinocandins,
C. auris and/or C. albicans and calling SNPs. The presence of known and AMB (Sherry et al., 2017), the biofilms were found to be com-
resistance-conferring mutations and/or hotspots in C. albicans’ ERG11 posed of very limited extracellular matrix, relatively thin and composed
in C. auris orthologs have been inferred as a possible resistance mech- mainly of yeast cells (Larkin et al., 2017). Notably, orthologous biofilm-
anism (Lockhart et al., 2017). However, transcomplementation or forming genes of C. albicans such as aspartyl proteases genes, the es-
functional studies of these mutated genes have not been undertaken sential phosphatidyl inositol kinase gene (PIK), the essential poly (A)
to establish the effect of these mutations in C. auris, specifically in polymerase gene (PAP), and the nonessential oxysterol-binding pro-
terms of MIC effects. In addition, no known resistance-conferring mu- tein gene (OBP) have been found in C. auris genomes (Chatterjee et al.,
tations in the FKS gene have been identified to date and the ERG11 2015; Sharma et al., 2016).
mutations identified by Lockhart et al. (2017), that is, F126T in South Borman et al. (2016) first reported of two different C. auris cel-
African strains, Y132F in Venezuelan strains, and Y132F or K143R in lular morphologies based on cell aggregation and showed that
|
nonaggregating cells are equally or a little less virulent than C. albicans, susceptible C. auris strains need further investigation. And the poten-
the model pathogenic species of this genus (Borman et al., 2016). This tial of culture-negative but esterase activity-positive (viable) strains to
was seconded by Sherry et al. (2017) that nonaggregating cells can cause infection and hospital spread should be interrogated.
be more virulent and pathogenic than C. albicans (Sherry et al., 2017). Candida auris can colonize, persist and recur in patients several
Further, Borman et al. (2016) showed that hyphae and pseudohyphae months after first detection, allowing it to be distributed or spread to
formation are important virulent factors in Candida in that nonhyphae other patients and in hospitals; even more worrying is the persistent
and nonpseudohyphae-forming species such as C. glabrata, Candida presence of a susceptible C. auris strain in the urine of a patient on
kefyr, C. krusei, and Saccharomyces cerevisiae were less virulent and FLZ treatment (Vallabhaneni et al., 2016). It is estimated that ≥4 hr
pathogenic than hyphae-
forming ones such as C. albicans and C. is the minimum contact period for acquisition of C. auris from an
tropicalis and the rudimentary pseudohyphae-forming pathogen, C. infected person or surface (Schelenz et al., 2016). Moreover, C. auris
auris (Borman et al., 2016). This was evident from the survival times can colonize and be shed from the skin at a rate of approximately
recorded in G. mellonella infection models. Larkin et al. (2017) how- 106 cells/hr, leading to prolonged outbreaks and transmissions in
ever, contend that the use of murine infection models indicates that hospitals (Schelenz et al., 2016; Welsh et al., 2017). It is thus not
C. auris is far less virulent than C. albicans and that the MDR nature of surprising that C. auris has been found on bedding materials, cathe-
C. auris is a fitness cost for its reduced virulence compared to C. albi- ter tips and other medical devices, in the air, on window sills, floors,
cans. Moreover, they asserted that C. auris could not effectively infect on neighboring patients, etc. in infected patients’ wards (European
and disseminate in mice unless they were immunocompromised, and Centre for Disease Prevention and Control, 2016; Schelenz et al.,
7
a larger C. auris inoculum size (3 × 10 yeast cells/animal) was admin- 2016; Tsay et al., 2017; Welsh et al., 2017). During a hospital out-
istered (Larkin et al., 2017). In contrast, a higher virulence and patho- break in the UK, for instance, a nurse who was caring for a heavily
genicity of C. auris in mice was suggested by the findings of Ben-Ami infected patient was found to be colonized with the same C. auris
et al. (2017), but with aggregating cells (Ben-Ami et al., 2017). The strain as that of the patient in the nose, but this was cleared after
possibility that different infection models might yield different viru- receiving oral nystatin, nasal ointment and continual chlorhexidine
lence results should be considered in future virulence and infection washes; the nurse obtained the C. auris colonization from the pa-
model studies. tient. Fortunately, the nurse was only transiently colonized and did
One of the alarming characteristics of C. auris is its ability to per- not transfer the strain to other patients or staff (Schelenz et al.,
sist on both dry and moist surfaces, bedding materials, floors, sinks, 2016). Even among patients on echinocandins therapy, candidaemia
the air, beds, on the skin, in nasal cavities and internal tissues of pa- and skin colonization occurred, showing the difficulty in clearing C.
tients etc. (Piedrahita et al., 2017; Schelenz et al., 2016; Vallabhaneni auris infections (Schelenz et al., 2016). Candida auris has been iso-
et al., 2016; Welsh et al., 2017). Piedrahita et al. (2017) showed lated from the axilla and groins of patients and swabbing of these re-
the ability of C. auris to colonize and spread from hospital environ- gions are recommended for C. auris surveillance (Vallabhaneni et al.,
ments by growing them on moist and dry surfaces for at least 7 days. 2016; Welsh et al., 2017). In all, these show the ability of C. auris to
Moist surfaces produced more C. auris colonies than dry ones and inhabit and persist in various niches, and corroborates the need to
their recovery from dried surfaces was similar to that of other spe- periodically surveil and disinfect healthcare settings previously in-
cies of Candida, methicillin-resistant Staphylococcus aureus (MRSA), fected with C. auris.
vancomycin-resistant Enterococcus (VRE) and carbapenem-resistant In conclusion, C. auris persists in a viable form on dried or moist
Enterobacteriaceae (CRE) (Piedrahita et al., 2017). However, C. auris surfaces for several weeks longer than C. albicans and C. parapsilosis.
was recovered at a higher rate than C. albicans, but significantly less It forms lesser biofilm mass than C. albicans, has poorer adherence to
than Candida parapsilosis (Piedrahita et al., 2017). Further, Welsh et al. catheters, produces no germ tubes and has strain-specific expression
(2017) also evaluated the persistence of C. auris vis-à-vis C. parapsilo- of hemolysins, proteinases and phospholipases virulence factors.
sis on plastic surfaces and found that C. auris can persist for at least
2 weeks on culture and 1 month when their esterase activity (viability)
is measured with a solid-phase cytometer (Welsh et al., 2017). 6 | DEMOGRAPHICS (SEX, AGE), RISK
The higher sensitivity of the esterase activity test, which can FACTORS (COMORBIDITIES), MORTALITY
identify single cells, makes it ideal for testing the sterility of sterile RATES AND SPECIMEN SOURCES
products and determining the presence of C. auris in hospital envi-
ronments; it should thus be used alongside culture-based surveillance. An estimated 742 C. auris isolates from at least 340 patients were
This is because C. auris failed to grow on culture after 2 weeks on calculated from all the published articles (n = 38) and reports of CDC,
plastic surfaces while the esterase activity test continually remained PHE and ECDC up to the time of writing this article (11–27/08/2017).
positive for an additional 2 weeks. Furthermore, while the cultured The five continents and 16 countries with reported C. auris cases con-
C. auris isolates from plastic surfaces grew for 2 weeks, C. parapsilosis sisted of North America (Canada and USA), South America (Colombia
grew for 1 month; however, the esterase activity test showed that C. and Venezuela), Europe (Germany, Norway, Spain, UK), Africa (South
auris persisted for a least a month and was more viable than C. para- Africa), and Asia (India, Israel, Japan, Kuwait, Oman, Pakistan, South
psilosis (Welsh et al., 2017). Persistence times between resistant and Korea) (Figure 2). India (n ≥ 243), the United States (Centers for
OSEI SEKYERE |
17 of 29
Disease Control and Prevention, 2017a; Tsay et al., 2017) (n ≥ 232) prior or continual exposure to broad spectrum antifungal or antibiotic
and the United Kingdom (n ≥ 103) reported the highest number of iso- therapy, or comorbid disease conditions such as diabetes mellitus and
lates and infected and/or colonized patients to date (Figure 2; Table 2) HIV/AIDS (Al-Siyabi et al., 2017; Ben-Ami et al., 2017; Calvo et al.,
(p-value = .0355). 2016; Chowdhary et al., 2013, 2014; Lee et al., 2011; Lockhart et al.,
The reported C. auris isolates were mostly isolated from males 2017; Mohsin et al., 2017; Morales-Lopez et al., 2017; Rudramurthy
(n ≥ 226, 64.76%) while 35.24% (n ≥ 123) were from females (Figure 3) et al., 2017; Ruiz Gaitán et al., 2017; Schelenz et al., 2016; Tsay et al.,
(p-value = .0329). In all countries except South Africa, there were more 2017; Vallabhaneni et al., 2016). It is obvious from these risk factors
male C. auris-infected patients than females. Further, the differences that invasive devices or procedures easily result in the introduction
between male and female C. auris-infected patients were marginal of and re-infection with C. auris in most patients, and the removal of
(<10 patients difference) in all countries except the UK (difference of catheters resolved several candidemia (Chowdhary et al., 2014; Lee
16 patients) and India (difference of 71 patients). No reason has been et al., 2011; Ruiz Gaitán et al., 2017). Hence, removal of catheters is a
provided yet for the sexual differences in terms of frequency of C. necessary first-line strategy for managing and treating acute, recurring
auris infections. However, C. auris case differences between sexes are and persistent C. auris infections (Chowdhary et al., 2014; Lee et al.,
country-specific and local health factors might play a role in the higher 2011; Ruiz Gaitán et al., 2017).
male rates recorded per country and worldwide. In addition, most of Moreover, the suppression of the immune system of patients
the reported cases of C. auris occurred or escalated within the last with immunosuppressive agents such as steroids and malignancies
5 years (2012–2017) and were isolated mainly from blood (n ≥ 361) or medical procedures that require such agents, specifically during
and other deep-seated infections, tissues and/or tips of invasive de- organ transplants (Azar et al., 2017), also reduces the ability of the
vices than from urine (n = 33) and ear discharge (n = 22) (Figure 3) immune system to prevent the easy dissemination of C. auris invasive
(p-value < .0001). infections.
Patients infected or colonized with C. auris almost always pre- In addition, broad-spectrum antimicrobials clear away nonpatho-
sented with several other underlying health conditions or comorbidi- genic but important bacteria and fungi that offer competitive inhibition
ties including diabetes (n ≥ 52), sepsis or blood stream infections (BSI) to C. auris pathogens, allowing the latter to proliferate freely. Thus, an-
(n ≥ 48), pulmonary diseases/pneumonia (n ≥ 39), chronic/acute kid- timicrobial stewardship has been advised to prevent the proliferation
ney failure/pathologies, transplants etc. (n ≥ 32), immunosuppressive of C. auris and related species (Ben-Ami et al., 2017; Chakrabarti et al.,
conditions (n ≥ 29), solid tumor/malignancies (n ≥ 26), cardiovascular 2015; European Centre for Disease Prevention and Control, 2016).
diseases (n ≥ 24), chronic otitis media (n ≥ 18), liver disease (n ≥ 14) Contact precautions are advised by the CDC (Centers for Disease
(Figure 2) etc. (p-value < .0001). Many of the C. auris infections oc- Control and Prevention, 2017a, b; Tsay et al., 2017; Vallabhaneni et al.,
curred in hospitalized patients on prior broad-spectrum antibiotics 2016) because close contact with an infected patient as well as being
and with invasive medical devices and/or procedures such as central in the same hospital or ward is a risk factor for colonization or infec-
venous catheter (CVC), arterial line, urinary catheter, parenteral nutrition with C. auris (Schelenz et al., 2016; Tsay et al., 2017; Vallabhaneni
tion, abdominal surgery, immunosuppressive agents etc. (Azar et al., et al., 2016).
2017; Ben-Ami et al., 2017). Candida auris was first isolated from the ear in 2009 (Kim et al.,
Out of 316 patients, 94 were recorded as demised, which trans- 2009; Satoh et al., 2009), but it has subsequently been reported mostly
lated into 29.75% crude mortality rate (p-value = .0488). Crude mor- in BSIs or sepsis and deep-seated invasive infections (Figure 2). Hence,
tality per country showed that C. auris infections resulted in 33.33% to C. auris infections are currently associated with candidaemia, high
100% crude mortality worldwide, with the least (33%) being recorded mortalities (Figure 3c), persistent fungemia and therapeutic failure as
in South Africa and Israel; p-value = .1789 (Figure 2c). they are difficult to clear from the blood even when they are suscepti-
As shown in Table 2 and Figure 3, C. auris has been isolated from ble (Ben-Ami et al., 2017; Chowdhary et al., 2013, 2014; Vallabhaneni
patients of both sexes and of all age groups. However, preterm or et al., 2016). In the first organ-transplantation-associated C. auris in-
low-birth weight infants as well as geriatrics are known to be highly fection case, Azar et al. (2017) described the dangers involved in un-
at-risk patients due to their weaker immune systems, such that they dertaking organ transplantation without prior investigation into the
have high mortality risk upon being infected with C. auris (Chowdhary donor’s clinical history and species of all Candida identified on the
et al., 2013; Newnam & Harris-Haman, 2017; Ruiz Gaitán et al., 2017; organ (Azar et al., 2017). In India and other areas, C. auris candidaemia
Schelenz et al., 2016; Schwartz & Hammond, 2017; Tsay et al., 2017). ranges between 5% and 30% of all candidaemia cases (Calvo et al.,
As geriatrics are more prone to be hospitalized in acute-care hospitals 2016; Chowdhary et al., 2013, 2014; Rudramurthy et al., 2017) re-
or long-term care facilities, it is more likely that they will be exposed to ported in selected hospitals. These show the rapid emergence of C.
C. auris infections reported from healthcare centers. auris as a lethal pathogen and nosocomial threat. The true prevalence
Risk factors associated with C. auris infections are consistently the of C. auris-mediated candidaemia could be higher if they are rightly
same in almost all the reported cases worldwide and these include detected.
the presence of catheters (urinary, central venous), arterial line, par- In summary, C. auris has been isolated from both sexes in 16 coun-
enteral nutrition, invasive medical procedures (surgeries) and devices, tries and five continents worldwide, with risk factors ranging from the
mechanical ventilation, hospital and intensive care unit (ICU) stays, presence of invasive devices to immunocompromised conditions.
|
7 | DIAGNOSTICS AND TYPING METHODS et al., 2017). Thus, its adoption in other laboratories will facilitate the
easy and quicker detection of this problematic pathogen.
Meta-
analysis showed that conventional PCR was the most used Kumar et al. (2017) combined two culture media, CHROMagar
diagnostic tool in terms of number of studies (29/38) and collec- Candida media supplemented with Pal’s medium, to perfectly distin-
tive sample size (n ≥ 484; 30.38%). Vitek 2 Yeast ID system was the guish between C. auris and C. haemulonii. Pal’s medium was originally
second most common platform used per study (20/38) and third in designed for the identification of Cryptococcus neoformans and has
terms of total sample size analyzed (n ≥ 190; 11.93%) while Bruker been useful in distinguishing C. albicans from Candida dubliniensis. On
MALDI-TOF MS was second in terms of total sample size analyzed this merged medium, C. auris produced no pseudohyphae, grew at
(n ≥ 223; 14.00%) and third most used instrument in all the studies 42°C, and had confluent growth of white-cream colored smooth colo-
(10/38) (p-value = .002). Detailed statistics on the diagnostic tools nies while C. haemulonii did not grow at 42°C, had pseudohyphae, and
used in detecting and typing C. auris are comprehensively summarized showed poor growth of smooth light-pink colonies. This method, while
in Tables 3–4. very sensitive and specific (100%) if used for only these two species, is
The greatest hindrance to effective detection of C. auris in most limited by the fact that an initial identification by available commercial
microbiology laboratories is misidentification by available commercial systems to rule out other nonalbicans species of Candida is required
identification platforms or systems such as the Vitek Yeast ID Panel, (Kumar et al., 2017).
Microscan Walkaway, BD Phoenix, API 20C, Auxacolor, CHROMagar, In an earlier work, Shin et al. (2012) used 38 species of Candida
etc. as C. haemulonii, Candida famata, C. kefyr, C. duobushaemulonii, including 20 C. auris isolates to evaluate the capacity of five pheno-
C. pseudohaemulonii, C. krusei, Rhodotorula glutinis etc. (Table 1). typic tests namely, E-test on Mueller-Hinton agar supplemented with
Furthermore, without an updated database (Mizusawa et al., 2017; glucose and methylene blue (E-test-MH), E-test on RPMI agar sup-
Wattal, Oberoi, Goel, Raveendran, & Khanna, 2017), it is impossible plemented with 2% glucose (E-test-RPG), Vitek 2, as well as CLSI and
for the currently reliable and often used MALDI-TOF MS systems, EUCAST MBD protocols to determine AMB resistance in vitro. The E-
the Bruker Biotyper and the Vitek 2 MS, to correctly identify C. auris test-MH method was adjudged the best in detecting AMB resistance
(Tables 3–4) (Kordalewska et al., 2017). As well, discrepancies between followed by the Vitek 2 among C. haemulonii and C. auris. The CLSI and
MICs obtained from Vitek 2 and the CLSI MBD method have been EUCAST MBD protocols yielded very narrow AMB MICs, which made
reported for antifungal agents such as AMB, azoles, and echinocan- them unable to efficiently discriminate between AMB susceptible and
dins (Arendrup et al., 2017; Kathuria et al., 2015; Khillan et al., 2014). resistant strains (Shin et al., 2012). Further tests will be necessary to
This is a serious observation as the Vitek 2 is a commonly used instru- confirm this preliminary finding.
ment for measuring the MICs of various antifungals against C. auris
(Tables 3–4). Although Shin et al. (2012) have argued that the Vitek
7.2 | Diagnostic tools: MALDI-TOF MS
2 was better than the CLSI and EUCAST MBD protocols in detect-
ing AMB resistance, particularly as the latter two methods yield very The inefficiencies of available diagnostic tools in detecting or misi-
narrow AMB MICs that are unable to efficiently discriminate between dentifying C. auris are already mentioned above (Tables 3–4). Using
AMB susceptible and resistant isolates, the Vitek 2 should not be an updated research use only (RUO) library or database, which can be
used alone to report on the susceptibility of C. auris strains (Shin et al., updated in-house, the two available MALDI-TOF MS platforms, the
2012). This is particularly important as wrong susceptibility results can commonly used Bruker Biotyper™ and the lesser used Vitek MS, can
result in fatal consequences (Chowdhary et al., 2014; Kathuria et al., detect C. auris with 100% sensitivity and specificity within a few min-
2015; Kumar et al., 2015; Ruiz Gaitán et al., 2017; Vallabhaneni et al., utes (Table 3). The Bruker Biotyper™ database 3.1 has spectra of three
2016). For now the gold standard for C. auris MICs is the CLSI MBD C. auris strains (Kathuria et al., 2015). Grenfell et al. (2016) showed
protocol, which is the most widely used (Arendrup et al., 2017). that adding ClinProTools to the Flex Analysis provided higher dis-
criminatory power in detecting biomarker peaks (Grenfell et al., 2016).
Several researchers have also reported of the higher efficiency of the
7.1 | Diagnostic tools: culture-based methods
Bruker Biotyper over the Vitek 2 MS in detecting C. auris and other no-
Welsh et al. (2017) recently reported of two novel in-house diagnostic nalbicans species of Candida, even with an updated database (Ghosh
broths they designed to efficiently screen for and detect C. auris from et al., 2015; Grenfell et al., 2016; Kim, Kweon, Kim, & Lee, 2016). The
clinical and environmental specimens with relative ease, 100% speci- MALDI-TOF MS has thus been used to reidentify 90 C. auris isolates
ficity and sensitivity, and low cost. These broths, consisting of 10% out of 102 strains initially misidentified as C. famata and C. haemulonii
salt, gentamicin, chloramphenicol and either dulcitol, mannitol or dex- by Vitek 2 (Kathuria et al., 2015). Prakash et al. (2016) and Girard et al.
trose in Sabouraud broth or Yeast Nitrogen base (YNB), could inhibit (2016) have both used the MALDI-TOF MS to type C. auris isolates
the growth of all other species when cultivated at 42°C. However, and found it to be as equally effective as genotypic tools such as am-
when the Sabouraud broth with dextrose was used and cultured at a plified fragment length polymorphism (AFLP) and multilocus sequence
lower temperature, C. glabrata could also grow as it has high salinity typing (MLST), which are considered gold standards in molecular typ-
tolerance. This easy-to-prepare and cheaper broth has been useful in ing (Girard et al., 2016; Prakash et al., 2016). The MALDI-TOF MS also
controlling the spread of C. auris in the US and other countries (Welsh holds the potential to discriminate between resistant and susceptible
T A B L E 3 Relative efficiencies of various diagnostics used for the identification of Candida auris
OSEI SEKYERE
Combined Sensitivity Specificity Turnaround Skill level

Diagnostic tool (usage frequency, n = 38) sample size (%) (%) time (hr) Relative cost required References
Phenotypic and/or culture-based media or methods

CHROMagar Candida at 40–42°C (9/38) 37 40–73 0 24–48 Cheaper Minor Azar et al. (2017), Ben-Ami et al. (2017), Chowdhary
et al. (2014), Emara et al. (2015), Khillan et al. (2014),
Kumar et al. (2015), Morales-Lopez et al. (2017), Ruiz
Gaitán et al. (2017), Satoh et al. (2009)
CHROM Candida supplemented with Pal’s 15 100 100 24–48 Cheaper Minor Kumar et al. (2017)
medium at 37–42 °C (1/38)
MAST ID CHROMagar Candida at 42°C 1 0 100 24–48 Cheaper Minor Emara et al. (2015)
(1/38)
BBL Mycosel agar ± cycloheximide (2/38) 9 0 100 24–48 Cheaper Minor Emara et al. (2015), Ruiz Gaitán et al. (2017)
Brilliance Candida Agar (1/38) 50 0 0 24–48 Cheaper Minor Schelenz et al. (2016)
Salt Sabouraud broth with dextrose (1/38) 77 100 ≤100 24–48 Cheapest Minor Welsh et al. (2017)
Salt Sabouraud broth with dulcitol/mannitol 77 100 100 24–48 Cheapest Minor Welsh et al. (2017)
(1/38)
Salt Yeast Nitrogen base broth + dulcitol/ 77 100 100 24–48 Cheapest Minor Welsh et al. (2017)
mannitol (1/38)
Commercial identification instruments/kits
API 20C (7/38) 48 0 0 18–72 Cheap Minor Chowdhary et al. (2013), Larkin et al. (2017), Lee et al.
(2011), Magobo et al. (2014), Mohsin et al. (2017),
Morales-Lopez et al. (2017), Ruiz Gaitán et al. (2017)
AuxaColor™ 2 (1/38) 8 0 0 24–48 Cheap Minor Ruiz Gaitán et al. (2017)
Microscan Walkaway & AutoSCAN 4 (1/38) 17 0 0 (24+) 2–≤24 Expensive High Morales-Lopez et al. (2017)
BD Phoenix Yeast ID panel (3/38) 24 0 0 (24+) 4–15 Expensive High Al-Siyabi et al. (2017), Kim et al. (2016), Morales-Lopez
et al. (2017)
VITEK 2 YST ID (20/38) 190 0 0 (24+) Expensive High Azar et al. (2017), Ben-Ami et al. (2017), Calvo et al.
(2016), Chakrabarti et al. (2015), Chatterjee et al.
(2015), Chowdhary et al. (2013), Emara et al. (2015),
Khillan et al. (2014), Kim et al. (2009, 2016), Larkin
et al. (2017), Lee et al. (2011), Magobo et al. (2014),
Morales-Lopez et al. (2017), Oh et al. (2011),
Rudramurthy et al. (2017), Sarma et al. (2013), Satoh
et al. (2009), Sharma et al. (2015), Shin et al. (2012),
Wattal et al. (2017)
|
(Continues)
19 of 29
|
20 of 29
Combined Sensitivity Specificity Turnaround Skill level
Diagnostic tool (usage frequency, n = 38) sample size (%) (%) time (hr) Relative cost required References
VITEK MS MALDI-TOF (4/38) 28 100 100 ≤12 Very High Azar et al. (2017), Kim et al. (2016), Ruiz Gaitán et al.
expensive (2017), Wattal et al. (2017)
Bruker Biotyper MALDI-TOF (10/38) 223 100 100 ≤12 Very High Azar et al. (2017), Borman et al. (2016, 2017), Ghosh
expensive et al. (2015), Kathuria et al. (2015), Kim et al. (2016),
Mohsin et al. (2017), Prakash et al. (2016), Schelenz
et al. (2016), Schwartz and Hammond (2017)
Molecular-based methods
Conventional PCR (29/38) 484 100 100 2.5 Expensive Very high Ben-Ami et al. (2017), Borman et al. (2016, 2017), Calvo
et al. (2016), Chakrabarti et al. (2015), Chatterjee et al.
(2015), Chowdhary et al. (2013, 2014), Emara et al.
(2015), Ghosh et al. (2015), Kathuria et al. (2015),
Khillan et al. (2014), Kim et al. (2009, 2016),
Kordalewska et al. (2017), Kumar et al. (2015), Larkin
et al. (2017), Lee et al. (2011), Magobo et al. (2014),
Mohsin et al. (2017), Oh et al. (2011), Prakash et al.
(2016), Rudramurthy et al. (2017), Ruiz Gaitán et al.
(2017), Sarma et al. (2013), Satoh et al. (2009), Sharma
et al. (2015), Shin et al. (2012), Wattal et al. (2017)
AFLP (4/38) 184 100 100 2.5–4 Expensive Very high Calvo et al. (2016), Chowdhary et al. (2013), Prakash
et al. (2016), Schelenz et al. (2016)
Real-time PCR (1/38) 140 100 100 2 Expensive Very high Kordalewska et al. (2017)
WGS (6/38) 160 100 100 8–72 Very Highest Centers for Disease Control and Prevention (2017a),
expensive Chatterjee et al. (2015), Lockhart et al. (2017), Schwartz
and Hammond (2017), Tsay et al. (2017), Vallabhaneni
et al. (2016)
OSEI SEKYERE
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21 of 29
T A B L E 4 Usage characteristics and

Descending order
analyzed sample sizes per diagnostic tool
Descending order of of combined
Methods/tools usage frequency Methods/tools sample size
Conventional PCR 29 Conventional PCR 484

Vitek 2 Yeast ID 20 Bruker Biotyper 223
MALDI–TOF (10/38)
Bruker Biotyper 10 Vitek 2 Yeast ID 190
CHROMagar 9 AFLP 184
API 20C 7 WGS 160
WGS 6 Real-time PCR 140
Vitek MS 4 Salt SAB/NBB 77
AFLP 4 Brilliance Candida Agar 50
API 20C 48
CHROMagar 37
C. auris strains as done for CRE (Osei Sekyere, Govinden, & Essack, were 10 CFU/reaction (Ct = 28.61 ± 0.25) for C. auris-specific assays
2015), and should be further investigated to unleash this potential for and 1,000 CFU/reaction (Ct = 27.83 ± 0.87) for C. auris-related spe-
MDR C. auris testing. cies (Kordalewska et al., 2017).
In terms of specimen preparation protocols, Ghosh et al. (2015) Besides using the sequenced amplicons to identify an isolate as C.
showed that the on-plate formic acid extraction method is the most auris by comparing the sequence to available sequences at GenBank,
cost and time efficient (Ghosh et al., 2015). Mizusawa et al. (2017) also they can also be used in phylogenetic analysis to draw evolutionary or
observed that the direct extraction method enabled the perfect de- phylogenetic trees. These phylogenetic dendrograms has been instru-
tection of C. auris on the Vitek MS system while the full-length or par- mental in tracing the sources and clonality of the isolates in relation to
tial extraction method was necessary for 100% identification by the other isolates from the same or different hospital, region, or country.
Bruker MS system (Mizusawa et al., 2017). Using the direct on-plate Other PCR-based typing tools such as AFLP and MLST have been used
extraction method resulted in only 50% identification of C. auris with to identify and type C. auris strains (Tables 2–4). As well, other molec-
low score match, with 50% being unidentified (Mizusawa et al., 2017). ular but non-PCR-based or restriction enzyme-based techniques such
Girard et al. (2016) also used the direct smear protocol to identify C. as PFGE and REAG-N have been used occasionally to aid in the typing
auris with the Vitek MALDI-TOF MS (Girard et al., 2016). of C. auris (Oh et al., 2011). However, these above-mentioned (PCR-
based and non-PCR-based) typing tools are labor intensive with longer
turnaround times.
7.3 | Diagnostic tools: PCR, real-time PCR and whole
WGS is increasingly being used to aid in the simultaneous identifi-
genome sequencing (WGS)
cation and typing or evolutionary analysis of C. auris cases (Chatterjee
The use of conventional PCR to amplify the ITS and/or D1/D2 DNA et al., 2015; Lockhart et al., 2017; Sharma et al., 2016; Tsay et al.,
sequences, followed by sequencing of the amplicons is currently the 2017; Vallabhaneni et al., 2016). Due to its higher resolution, it can
gold-standard and most commonly used technique to identify, confirm provide a better evolutionary and epidemiological analysis of C. auris
the identity and type C. auris strains (Tables 3–4) with 100% specific- cases than all other methods within a comparatively short turnaround
ity and sensitivity, and shorter turnaround time (Kordalewska et al., time (8–72 hr), except that it is more expensive and requires higher
2017). Recently, Kordalewska et al. (2017) developed a conventional skill and data processing capacity (Table 3–4) (Lockhart et al., 2017).
PCR and real-time assay that could respectively identify C. auris as
well as C. auris, C. duobushaemulonii and C. lusitaniae with 100% sensi-
7.4 | CLSI and EUCAST MIC protocols
tivity and specificity, and shorter turnaround time of 2.5 and 2 hr re-
spectively. This protocol was also used in direct colony PCR to achieve Arendrup et al. (2017) used 123 C. auris isolates of international ori-
the same optimum results. Either gel electrophoresis (for conventional gin to evaluate the MIC of common antifungals as obtained by the
PCR) or melting temperature (Tm) analysis (real-time PCR) was used most commonly used CLSI MBD protocol and the less used EUCAST
for final confirmation or differentiation of the results respectively. The MBD protocol. They established a good correlation between both
amplicons covered a fragment of 5.8S, ITS2 and a part of 28S riboso- methods for FLZ and VRZ MICs. However, lower MICs were obtained
mal DNA using CauF/R primers, which yielded a 163 bp long (conven- by the EUCAST protocol for AMB, ANF, MCF, and PSZ. In terms of
tional) PCR amplicon for C. auris. Further, CauRe1R primers (real-time geometric MIC, there were slightly different values except for AMB
PCR) selectively amplified regions in either C. auris, C. duobushaemulo- for which the EUCAST MIC values were higher. Further experimenta-
nii, C. haemulonii or C. lusitaniae. The limit of detection of these assays tion with a larger number of isolates will be necessary to confirm this
|
finding. Thus, although the MIC differences from both protocols are D2 and ITS sequences, they showed that this new pathogen phyloge-
relatively minor, researchers should be mindful of the specifics when netically clustered in the Metschnikowiaceae clade (Satoh et al., 2009).
comparing MICs obtained from both methods (Arendrup et al., 2017). Thus far, this first work by Satoh et al. (2009) is the only reported case
Notwithstanding these little differences in MIC values, it is expected of C. auris in Japan to date. Later in the same year, Kim et al. (2009)
that the CLSI protocol will continue to hold preeminence among re- also reported of a novel yeast species with close phenotypic similarity
searchers because of the large number of available MIC data gener- to C. haemulonii from the ear of 15 otitis media patients who visited
ated from this protocol, which will facilitate easy comparison with five hospitals in South Korea between 2004 and 2006. These histori-
already available data from other works. cal isolates, some of which were later found to be clonally related (Oh
The authors observed that the collective MIC values from any pop- et al., 2011), were actually C. auris, with elevated FLZ, VRZ and AMB
ulation will be influenced by the presence of wild-type and nonwild- MICs or resistance.
type colonies as well as by the collective resistance mechanisms of the Thus, it is obvious that C. auris first appeared in South Korea as
various strains (Arendrup et al., 2017). This might explain the variable early as 1996 (Table 2), but was misidentified and undescribed until
resistance of C. auris to the other azoles besides FLZ. A low acquired Satoh et al. (2009) did so in Japan. Moreover, the Japanese isolate was
resistance to AMB and echinocandins was recorded in the C. auris later found to be very closely related phylogenetically to some of the
strains. isolates from South Korea (Ben-Ami et al., 2017; Mohsin et al., 2017;
Summing it up, PCR and MALDI-TOF are the commonly used di- Schelenz et al., 2016) and they all assimilated NAG while those from
agnostic tools and the CLSI MBD remains the most commonly used other countries did not (Table 1) (Prakash et al., 2016); thus, the pos-
protocol for MIC determination. sibility of transfer from South Korea to Japan or otherwise, should be
investigated further. It is notable that almost all the isolates recov-
ered from Japan and South Korea were from the ear (Table 2), except
8 | MOLECUL AR EPIDEMIOLOGY a few (n = 6) that were obtained from blood; at least two patients with
candidaemia demised (Lee et al., 2011; Shin et al., 2012). Fortunately,
While the above-mentioned methods have enabled the easy descrip- no C. auris cases, either from the ear or blood (fungemia), have been
tion of the molecular epidemiology and phylogenetic relationship be- reported in South Korea since 2013.
tween strains of the same or different hospitals and/or countries, their
resolution power is relatively weaker than that of WGS, which has
8.2 | South Asia: India and Pakistan
recently been used by Lockhart et al. (2017) to comprehensively de-
scribe the genomic evolution of 53 C. auris strains from India, Pakistan, Chowdhary et al. (2013) were the first to report on a clonal out-
South Africa and Venezuela. A further retrospective analysis of histor- break of C. auris candidaemia in India and worldwide involving 12
ical isolates (n = 15,271) from a SENTRY surveillance program showed patients from two different hospitals in Delhi. Although reported
that C. auris is less likely to have emerged prior to 2009 (Lockhart in 2013, these isolates were collected between 2009 and 2011,
et al., 2017). and were clonally different from those from Japan and South
Due to misidentification of C. auris by most commercial identifi- Korea, suggesting an independent emergence of C. auris in India
cation systems and the nonspecies identification of many species (Chowdhary et al., 2013). The isolates were highly resistant to FLZ
of Candida in many mycology laboratories, the true prevalence and and 50% of the patients died. Subsequently, India has recorded the
epidemiology of C. auris infections in most countries and the world largest number of C. auris candidaemia worldwide between 2009
is not known and is likely to be underestimated than overestimated and 2015 (Figure 2) (Table 2), including MDR isolates (Chakrabarti
(Kordalewska et al., 2017; Todd, 2017). Moreover, blood, fluid and et al., 2015; Chowdhary et al., 2014; Prakash et al., 2016). There is
tissue cultures for detecting C. auris grow slowly and they could be a higher prevalence of C. auris infections in the public sector than
falsely negative in cases of low-
level or intermittent candidaemia private sector hospitals in India due to overcrowding and possible
(Todd, 2017). The molecular epidemiology of all reported C. auris cases compromise in infection control (Rudramurthy et al., 2017), with C.
are described below under their continents and countries according to auris prevalence ranging from 5% to 30% of all candidaemia cases
the order of detection. in certain hospitals (Chowdhary et al., 2013; Rudramurthy et al.,
2017). WGS, AFLP, MLST and MALDI-TOF MS typing of several
Indian strains showed their closer evolutionary or phylogenetic
8.1 | Far East Asia: Japan and South Korea
relationship and wider evolutionary or phylogenetic distance from
The earliest C. auris case was misidentified and undetected as far back those of other countries (Lockhart et al., 2017; Prakash et al., 2016).
as 1996 in South Korea (Lee et al., 2011), prior to the first reported Lockhart et al. (2017) showed that the genomes of isolates from
case of C. auris by Satoh et al. (2009), which was isolated from a 70- India differed from that of other countries by >10,000 SNPs, in-
year old female Japanese patient. Satoh et al. (2009) were thus the dicating the independent emergence of C. auris in this country
first to describe and name the new pathogen as C. auris due to its (Lockhart et al., 2017). However, strains from the Pakistan, USA and
closer phylogenetic, phenotypic and genotypic (Table 1) relationship UK have very close phylogenetic relationship with those from India,
to the Candida genus and its isolation from the ear. Using the D1/ suggesting that they were possibly imported from India (Borman,
OSEI SEKYERE |
23 of 29
Szekely, & Johnson, 2017; Vallabhaneni et al., 2016). Further, the with chronic renal failure who was admitted to the ICU in May 2014.
first C. auris case in Canada was in a patient previously hospitalized The isolate was highly resistant to FLZ (MIC of >256 μg/ml), but was
in India (Schwartz & Hammond, 2017). susceptible to AMB (MIC of 0.064 μg/ml), VRZ (MIC of 0.38 μg/ml),
The higher prevalence of C. auris cases (Figure 2) and clonal out- and CFG (MIC of 0.064 μg/ml). The patient involved unfortunately ex-
breaks in India is very concerning, particularly as many were multi- pired from multiorgan failure.
drug resistant and can spread to other countries as already reported Two different research groups simultaneously reported of sepa-
(Borman et al., 2017; Schwartz & Hammond, 2017; Vallabhaneni rate C. auris incidence at different hospitals in Oman in the same year
et al., 2016). In one study, there was interhospital and intrahospi- (Al-Siyabi et al., 2017; Mohsin et al., 2017), one of which described
tal spread of clonal C. auris strains, even though there were no ex- two clonal strains from two old (70 and 77 years) patients from the
change of healthcare personnel between these hospitals and wards same hospital; one patient died (50% mortality) (Mohsin et al., 2017).
(Chowdhary et al., 2013). Resistance to FLZ has been found to be me- Al-Siyabi reported of five C. auris candidaemia cases involving mostly
diated by known mutations (Y132F and K143R) in ERG11 (Lockhart old patients in another hospital, of which three died (Al-Siyabi et al.,
et al., 2017). Recommended infection control protocols should be 2017). All the C. auris candidaemia cases were detected between
instituted and strictly followed to reduce the incidence of this MDR August 2015 and February 2017, and the isolates expressed high re-
pathogen and its attendant mortalities (Centers for Disease Control sistance to FLZ; some patients died even though they were on ANF
and Prevention, 2017b; European Centre for Disease Prevention therapy. The onset of infection after hospitalization ranged from 22 to
and Control, 2016; Schelenz et al., 2016; Todd, 2017). 62 days, showing that these candidaemia cases were nosocomially ac-
The incidence of C. auris in Pakistan (n = 19) was first reported quired. The phylogenetic relationship between the isolates from these
by Lockhart et al. (2017) and characterized using WGS (Table 2). The two reports has not been undertaken, albeit this is necessary to show
Pakistani isolates were collected between 2012 and 2015 and were if the isolates from the two reports are clonally related, and if these
found to be very closely related to those from India, with <60 SNPs cases were locally acquired or imported. The two clonally related iso-
between isolates. Notably, they resulted in very high crude mortali- lates (Mohsin et al., 2017) however seem to have been locally acquired
ties (72%; 13/18) and also shared the same FLZ resistance mechanism as the patients had never traveled outside Oman; notwithstanding,
(Y132F and K143R in ERG11) as that of the Indian strains (Lockhart they clustered phylogenetically between isolates from India and UK.
et al., 2017). There are no reports of C. auris infections in Pakistan be- Further investigations might be necessary to show whether they had
sides this, but the higher mortality rate is worrying. Further surveil- contacts with persons from some of these countries. However, no fur-
lance and prompt report of C. auris cases are necessary to detect cases ther reports of C. auris have been published from Oman.
as early as possible.
8.4 | Africa: South Africa

8.3 | Middle East: Israel, Kuwait and Oman
Candida auris candidaemia was detected in four male South African
Only a single report of C. auris candidaemia in six patients from two patients between October 2012 and October 2013, with high
hospitals in Tel-Aviv has been published to date in Israel (Ben-Ami resistance to FLZ (Magobo, Corcoran, Seetharam, & Govender,
et al., 2017). These strains were collected between May 2014 and 2014). Except for one patient aged 27, the ages of the patients
May 2015 and were phylogenetically different from those from were between 60 and 85 years. Lockhart et al. (2017) subsequently
East Asia, Africa, and the Middle East. They formed aggregates in reported of an additional 10 isolates collected from South Africa
the kidneys of mice infection models and were less virulent than C. between 2012 and 2014, which were closely related to each other
albicans, but more virulent than C. haemulonii. The formation of ag- with <70 SNPs, but very distant phylogenetically to those from
gregates by these Israeli strains is akin to that reported by Borman Pakistan, India and Venezuela (Lockhart et al., 2017). Borman et al.
et al. (2016) and Sherry et al. (2017), and corroborates the asser- (2017) showed that isolates from the UK had very close sequence
tion that some C. auris cells form aggregates, which are less viru- similarity with those from South Africa, the first and only African
lent/pathogenic than nonaggregating ones and C. albicans (Ben-Ami country to report of a C. auris mediated candidaemia (Borman et al.,
et al., 2017; Borman et al., 2016; Sherry et al., 2017). In addition, 2017). Prakash et al. (2016) also reported that the South African
these strains were found to have higher ABC efflux activity than C. strains clustered with other isolates of diverse geographical origin
glabrata and C. haemulonii, which agrees with the enriched efflux (Prakash et al., 2016).
genes reported by Chatterjee et al. (2015) in the C. auris genome
and explains the MDR nature of this pathogenic yeast (Chatterjee
8.5 | Europe: Germany, Norway, Spain and UK
et al., 2015). The phylogeny of these strains indicates that they
emerged independently in Israel and were not imported as they did Reports of C. auris fungemia and colonization have been rare in con-
not have a close relationship with other isolates from the Middle tinental Europe, with most C. auris cases being reported in the UK,
East, South or East Asia (Ben-Ami et al., 2017). which was the first country in Europe to report of C. auris incidence
The first and only C. auris candidaemia case in Kuwait was re- as well as a clonal outbreak involving 50 patients in a cardiothoracic
ported by Emara et al. (2015). This case was in a 27-year old woman center in London (Borman et al., 2016, 2017; Schelenz et al., 2016).
|
The first reported case (candidaemia) of C. auris in the UK was in CVC (n = 16), a urinary catheter (n = 15) and a mechanical ventila-
2013 from three unrelated patients in distant geographical locali- tor (n = 10), which are important risk factors for acquiring C. auris
ties (Borman et al., 2016, 2017). PHE reports that at least 200 C. infections. A similar exposure to invasive instruments was found
auris infection cases and colonizations have so far been recorded in by Calvo et al. (2016) (Morales-Lopez et al., 2017). The 17 isolates
the UK, although an estimated number of ≥103 cases were found were from 17 patients from six different hospitals, and were col-
in published literature (Figure 2) (Public Health England). The UK lected from February through July 2017, with misidentification
isolates were of two different phenotypes, which had distinct viru- and delayed diagnosis resulting in the death of 35.2% of patients.
lence characteristics: aggregate-forming strains with lesser virulence The C. auris outbreak case in Venezuela resulted in C. auris being
and nonaggregate-forming strains with higher virulence (Borman the 6th most common cause of fungemia in that hospital that year
et al., 2016; Sherry et al., 2017). Borman et al. (2016) and Sherry (Morales-Lopez et al., 2017). Vallabhaneni et al. (2016) added that
et al. (2017) observed respectively that the UK isolates formed ru- isolates from Illinois, USA, were closely related (identical sequence
dimentary and occasional pseudohyphae, a characteristic that has homology with <150 SNPs apart) to those from Venezuela (Calvo
never been reported in any other C. auris strain worldwide (Table 1) et al., 2016). On the contrary, Lockhart et al. (2017) showed that
(Borman et al., 2016; Sherry et al., 2017). Phylogenetic analysis isolates from Venezuela emerged independently (Lockhart et al.,
showed that the UK strains were of international origin due to their 2017).
close sequence similarity with strains from India, Japan, Kuwait,
Malaysia, Korea, South Africa etc.
8.7 | North America: USA and Canada
Further, Schelenz et al. (2016) found C. auris in the air, floors, beds,
bedding materials, window sills, environmental surfaces as well as the Beginning from 2013 when the first US case of C. auris was iden-
nostrils, stools, axilla and groins of patients during the outbreak that tified in New York, at least 232 C. auris candidaemia (n = 112) and
occurred between April 2015-July 2016 among 50 patients admit- colonization (n = 120) incidences have been recorded by the CDC
ted to a cardiothoracic center in London, UK (Schelenz et al., 2016). (Figure 2) in nine states (Connecticut, Florida, Illinois, Indiana,
Daily chlorhexidine washes could not eradicate C. auris colonization, Maryland, Massachusetts, New Jersey, New York, and Oklahoma)
possibly due to reinfection from patients’ bedding and clothing. Some (Azar et al., 2017; Centers for Disease Control and Prevention,
patients on echinocandins still developed candidaemia, and the echi- 2017a; Vallabhaneni et al., 2016), making it the largest recorded C.
nocandins could not clear/reduce C. auris colonization on the skin. A auris incidence so far, after India. Most of these reported candidae-
nurse caring for a heavily infected patient was also transiently col- mia cases are from New York, which have been shown by WGS to be
onized, but healthcare workers were generally not colonized. The closely related to isolates from New Jersey and Maryland with <70
persistence of C. auris on several surfaces and materials made their SNPs apart. Notably, there were overlapping stays at long-term and
complete eradication from the hospital difficult despite thorough de- acute care facilities within these states; for instance, isolates from
colonization and decontamination with chlorhexidine-based products Maryland and New Jersey differed by <10 SNPs (Tsay et al., 2017;
and hydrogen-peroxide vapor. Hence, positive patients can shed C. Vallabhaneni et al., 2016). The lung donor-derived C. auris isolate
auris into the hospital environment, posing a risk of continuous trans- from Massachusetts was very closely related to that from Illinois,
mission (Schelenz et al., 2016). from where the lung donor was based (Azar et al., 2017; Tsay et al.,
The first incidence of C. auris infections in continental Europe oc- 2017). WGS showed that isolates from the same state were very
curred in Spain among four patients, two of whom died (Ruiz Gaitán closely related to each other than to those from other states. As well,
et al., 2017). ANF therapy could not clear candidaemia from one pa- some cases from New York and all the cases in Oklahoma and Indiana
tient and all the strains were highly resistant to FLZ and resistant to were from patients who had been earlier treated abroad; some of the
VRZ. The ECDC (European Centre for Disease Prevention and Control, New York cases were in patients who had returned from the Middle
2016) reported of single C. auris cases in Germany and Norway while East. It is thus believed that C. auris was introduced into the US from
Larkin et al. (2017) used two C. auris isolates obtained from the blood abroad followed by local transmission. For instance, isolates from
of a German male patient (Larkin et al., 2017). Such sporadic reports of Illinois were of the same clade as those from South America while
C. auris infections should motivate public health officials to undertake those from New York and New Jersey were of the same clade as
periodic comprehensive surveillance of patients and hospital environ- those from South Asia (Tsay et al., 2017).
ments to determine the true prevalence of C. auris in Europe. Interestingly, only two C. auris cases had been reported by 2015 in
the US, but this number shot up afterwards, suggesting a recent and
rapid emergence or higher detection of this menace possibly due to
8.6 | South America: Colombia and Venezuela
increased awareness and education on detection methods. The min-
Three invasive C. auris reports, one from Colombia (n = 17) imum time from hospital admission to first isolation of C. auris was
(Morales-Lopez et al., 2017) and another two involving an out- 18 days in the first seven cases; and five out of the seven patients
break case (n = 18) and additional cases (n = 5) from Venezuela died. In one case, a C. auris candidaemia that was susceptible to FLZ
(Calvo et al., 2016; Lockhart et al., 2017), have been published from persisted in the patient even though the patient was on the same drug.
South America. In the report from Colombia, most patients had a In two cases, the C. auris candidaemia recurred for 3–4 months while
OSEI SEKYERE |
25 of 29
some patients remained colonized months after first detection (Tsay 2017). Particularly, SCY-078 is not affected by common mutations in
et al., 2017). This shows that C. auris can easily spread through hospi- protein targets, is orally bioavailable and active against echinocandin-
tals and patients from colonized or infected persons. resistant strains (Berkow et al., 2017). It is not advisable however, to
Only a single C. auris case has been detected in Canada in a patient offer antifungal therapy to colonized patients (Todd, 2017).
who was initially admitted in a hospital in India (Schwartz & Hammond,
2017). The isolate was continually obtained from repeated swabbing
of the same ear of the patient over a 6-week period. No other C. auris 10 | INFECTION CONTROL
isolate has been reported in Canada afterwards. AND PREVENTION
The persistence and recurrence of C. auris in the hospital environment

9 | MANAGEMENT AND CLINICAL in the face of rigorous decontamination, disinfection and decoloniza-
OUTCOMES (MORTALITIES) tion protocols, as occurred in the UK over a one-year period, should
be a wake-up call to all infection control personnel in all healthcare
An official management protocol for C. auris infections is yet to be centers (Schelenz et al., 2016). Due to issues with misidentification,
concluded, an optimal antifungal agent(s) or dosing regimen for C. it is necessary that all microbiology (mycology) laboratories update
auris infections is not defined and CLSI/EUCAST breakpoints for this their commercial identification softwares to enable them to easily and
pathogen is wanting (Lepak et al., 2017), making researchers resort efficiently identify C. auris cases. Specifically, C. famata, C. haeumolo-
to that established for closely related species of Candida (Arendrup nii, C. sake, C. krusei, R. glutinis, etc. strains should be further analyzed
et al., 2017; Lockhart et al., 2017). Interestingly, the efficacy of this with PCR or MALDI-TOF to confirm they are not misidentified. Or
approach was recently established by Lepak et al. (2017) for FLZ and where such systems are unavailable, to quickly transport such speci-
AMB using neutropenic disseminated candidiasis murine models in- mens to local or foreign reference laboratories, isolate the patient
fected with C. auris (Lepak et al., 2017). Pharmacokinetic and phar- under contact precautions and start empirical echinocandin therapy
macodynamic (PK/PD) data showed that the MICs breakpoints of while awaiting the outcome of the laboratory tests (Azar et al., 2017;
these two antifungals for other species of Candida, will hold for C. Centers for Disease Control and Prevention, 2017a, b; Lepak et al.,
auris as the concentrations (exposure target) associated with optimal 2017; Todd, 2017). In cases of organ transplants, donor organs should
outcomes were similar. Furthermore, there was a strong relationship be scrutinized for sterility from C. auris prior to transplantation (Azar
between the PK/PD parameters and treatment outcome for each et al., 2017). Antifungal stewardship is necessary and prophylactic an-
drug (including MCF) and the dose-effect against C. auris for each tifungal therapy or broad-spectrum antibiotics prescription should be
drug was proportional to the MIC (Lepak et al., 2017). A tentative administered with caution (Ben-Ami et al., 2017; European Centre for
breakpoint for some selected antifungals has however been proposed Disease Prevention and Control, 2016) as they can select for resistant
by the CDC and was used in analyzing some of the data in this re- C. auris and other drug-resistant Candida spp (Ben-Ami et al., 2017;
view (Table 2; Figure 2) (Centers for Disease Control and Prevention, Chakrabarti et al., 2015).
2017b; Schwartz & Hammond, 2017). Clinicians currently advise on Patients with C. auris infections, persons colonized with or sus-
the use of echinocandins empirical therapy when C. auris is expected pected to have such infections or patients transferred from hospi-
as it is the current antifungal with the most effective activity against tals with a history of C. auris infections or outbreaks should be kept
this pathogen. However, this can be changed when subsequent sus- in separate wards under strict contact precautions as detailed by the
ceptibility results show other antifungals to be potent against the pa- CDC, ECDC, and PHE (Bishop et al., 2017; Centers for Disease Control
tient’s isolate (Lepak et al., 2017; Todd, 2017). and Prevention, 2017b; European Centre for Disease Prevention and
Liposomal AMB has also been shown to be very effective against Control, 2016; Public Health England, 2016; Schwartz & Hammond,
C. auris including the inhibition of biofilm formation and potency 2017; Seiffert et al., 2014). Such contact precautions have proved ef-
against C. auris biofilms. It is also used in combination therapies with fective in the containment of outbreaks by other multidrug-resistant
an echinocandin (Azar et al., 2017; Emara et al., 2015; Ruiz Gaitán organisms, particularly CRE, and was useful in the UK C. auris outbreak
et al., 2017; Sherry et al., 2017; Vallabhaneni et al., 2016). The higher case (Schelenz et al., 2016). Patients or healthcare workers coming in
toxicity of AMB in comparison with the much tolerated azoles and close contact with infected persons should also be placed under strict
echinocandins limits its use clinically (European Centre for Disease contact precautions until they consistently provide negative cultures
Prevention and Control, 2016). Due to the relatively higher efficacy over 3 weeks (Schelenz et al., 2016). The wards of patients found to be
of the other less used azoles such as ITZ, ISA, and PSZ as well as FCN colonized or infected with C. auris should be thoroughly disinfected as
against C. auris, they can still be used either alone or in combinations described (Schelenz et al., 2016).
when susceptibility testing proves their potency. The emergence of MICs should ideally be measured using the CLSI MBD protocol
novel antifungal drugs, SCY-078 and VT-1598, which have so far to ensure accurate susceptibility results, which can inform correct
demonstrated 100% efficiency against C. auris infections is a welcom- therapeutic choices (Khillan et al., 2014; Lepak et al., 2017). Clinicians
ing news for clinicians as it bolsters the available antifungal arsenals should also consider removing CVCs and other catheters where pos-
(Anonymous, 2017; Berkow et al., 2017; CDC, 2017; Larkin et al., sible as certain studies have found such options useful in resolving
|
persistent candidaemia (Calvo et al., 2016; Lee et al., 2011; Ruiz Gaitán This review was limited by the fact that several studies failed to
et al., 2017). detail the year, sex, age(s), mortality, antifungal MICs, total number
Besides culture-based methods in surveillance studies, esterase ac- of isolates and patients, comorbidities, and specimen of the reported
tivity as measured by a solid-phase cytometer should be considered to C. auris infections. This made the meta-analysis challenging as such
enhance the detection of viable but nonculturable strains (Welsh et al., studies had to be excluded.
2017). Hospital wards, bedding materials, beds, invasive and nonin-
vasive medical devices, clothing of patients, skin and surface wounds
AVAI L AB I L I T Y O F M AT ER I AL S AND DATA
etc. should be decontaminated, using chlorine-based detergents such
as chlorhexidine (0.2%–4%) and hydrogen peroxide vapor (Schelenz Supplementary data is included in this manuscript.
et al., 2016; Sherry et al., 2017). As well, chlorhexidine-impregnated
protective discs for all CVC exit sites can aid reduce line-associated
AC KNOW L ED G M ENT
C. auris BSIs (Schelenz et al., 2016). Oral nystatin plus nasal ointments
have proved effective in decolonizing healthy nasal carriers (Schelenz None.
et al., 2016). Soap and handwashing followed by alcohol-based hand
sanitizer is recommended by PHE. Admission screening of patients
AU T HO R CO NT R I B U T I O NS
from infected sites or areas, active surveillance to identify carriers and
prompt notification of the clinical infection control team are important JOS designed and undertook the meta-analysis, systematically re-
(European Centre for Disease Prevention and Control, 2016). viewed the literature and wrote the paper.
ET HI C AL AP P ROVAL
11 | CONCLUSIONS, FUTURE
PERS PECTIVES AND STUDY LIMITATIONS Not applicable.
It is evident from this review that C. auris infections are more com-
T R ANS PAR ENC Y D EC L AR AT I O N
monly reported in India, the USA and the UK, with fewer or isolated
cases in South America, Africa, and continental Europe. Phylogenetic The author declares no conflict of interest in the publication of this
data show the independent emergence of C. auris in several coun- manuscript.
tries. Misidentification, intrahospital transmission, poor treatment
outcomes and higher crude mortalities between 33.33% and 100%
O RC I D
are associated with C. auris infections worldwide. An official treatment
guideline for C. auris infections is lacking and empirical treatment in- John Osei Sekyere http://orcid.org/0000-0002-9508-984X
volving an echinocandin is advised. Contact precautions and effective
disinfection with chlorine-based agents are advised for hospitals with
C. auris cases. PCR and MALDI-TOF MS remain the most efficient and REFERENCES
commonly used diagnostic tools. Al-Siyabi, T., Al Busaidi, I., Balkhair, A., Al-Muharrmi, Z., Al-Salti, M., &
Todd (2017) has suggested that the variations in C. auris- Al’Adawi, B. (2017). First report of Candida auris in Oman: Clinical
and microbiological description of five candidemia cases. Journal of
associated mortalities could emulate those of other emerging in-
Infection, 75, 373–376. https://doi.org/10.1016/j.jinf.2017.05.016
fections in which initial cases are most severe, but tend to drop in Anonymous. (2017). Viamet’s VT -1598 demonstrates potent activity
severity over time (Todd, 2017). It would be welcoming should this against Candida auris and other life-threatening fungal species. 1–2.
be the case with C. auris. Efficient identification tools such as the Retrieved from http://www.viamet.com/docs/PR_2017_6-5-17.pdf
(accessed August 23, 2017).
MALDI-TOF MS, PCR and WGS are still beyond the reach of many
Arendrup, M. C., Prakash, A., Meletiadis, J., Sharma, C., & Chowdhary,
mycology laboratories worldwide, defeating efficient and prompt A. (2017). Comparison of EUCAST and CLSI reference microdi-
detection, earlier initiation of therapy and effective surveillance lution MICs of eight antifungal compounds for Candida auris and
of C. auris in hospitals. Without efficient detection, the true prev- associated tentative epidemiological cutoff values. Antimicrobial
alence of this menace will never be known, effective management Agents and Chemotherapy, 61, e00485–17. https://doi.org/10.1128/
AAC.00485-17
of potential cases will be elusive and mortalities will continually rise.
Azar, M. M., Turbett, S. E., Fishman, J. A., & Pierce, V. M. (2017). Donor-
Thus, designing a simple, low-cost detection technique, kit or tool derived transmission of Candida auris during lung transplantation. Clinical
with a shorter turnaround time is the key to defeating this deadly Infectious Diseases, 65, 1040–1042. https://doi.org/10.1093/cid/cix460
pathogen. Furthermore, the possibility of this yeast also spreading Ben-Ami, R., Berman, J., Novikov, A., Bash, E., Shachor-Meyouhas, Y., Zakin,
S., … Finn, T. (2017). Multidrug-resistant Candida haemulonii and C.
into the community, farms and the general environment should not
auris, Tel Aviv, Israel. Emerging Infectious Diseases, 23, 195. https://doi.
be lost sight of. Evidence from CRE and MCR-1-positive bacteria org/10.3201/eid2302.161486
should advise mycologists of the potential of this yeast to also infect Berkow, E. L., Angulo, D., & Lockhart, S. R. (2017). In vitro activity of a novel
livestock. glucan synthase inhibitor, SCY-078, against clinical isolates of Candida
OSEI SEKYERE |
27 of 29
auris. Antimicrobial Agents and Chemotherapy, 61, e00435–17. https:// European Centre for Disease Prevention and Control. (2016). Candida
doi.org/10.1128/AAC.00435-17 auris in healthcare settings, Europe. Stock. ECDC 19 December, 1–8.
Bishop, L., Cummins, M., Guy, R., Hoffman, P., Jeffery, K., & Jeffery-Smith, Retrieved from https://ecdc.europa.eu/sites/portal/files/media/
A., … Brown, C. (2017). Guidance for the laboratory investigation, man- en/publications/Publications/Candida-in-healthcare-settings_19-
agement and infection prevention and control for cases of Candida Dec-2016.pdf (Accessed July 24, 2017).
auris. Retrieved from www.gov.uk/phe (Accessed August 24, 2017). Ghosh, A. K. K., Paul, S., Sood, P., Rudramurthy, S. M. M., Rajbanshi, A.,
Borman, A. M., Szekely, A., & Johnson, E. M. (2016). Comparative pathoge- Jillwin, T. J. J., & Chakrabarti, A. (2015). Matrix-assisted laser desorp-
nicity of United Kingdom isolates of the emerging pathogen Candida tion ionization time-of-flight mass spectrometry for the rapid identi-
auris and other key pathogenic Candida species. mSphere, 1, e00189– fication of yeasts causing bloodstream infections. Clinical Microbiology
16. https://doi.org/10.1128/msphere.00189-16 & Infection, 21, 372–378. https://doi.org/10.1016/j.cmi.2014.11.009
Borman, A. M., Szekely, A., & Johnson, E. M. (2017). Isolates of the emerg- Girard, V., Mailler, S., Chetry, M., Vidal, C. C. C., Durand, G. G. G., van
ing pathogen Candida auris present in the UK have several geographic Belkum, A., … Chowdhary, A. (2016). Identification and typing of the
origins. Medical Mycology, 55, 563–567. https://doi.org/10.1093/mmy/ emerging pathogen Candida auris by matrix-assisted laser desorption
myw147 ionisation time of flight mass spectrometry. Mycoses, 59, 535–538.
Calvo, B., Melo, A. S. A. A., Perozo-Mena, A., Hernandez, M., Francisco, E. https://doi.org/10.1111/myc.12519
C., Hagen, F., … Colombo, A. L. (2016). First report of Candida auris in Grahl, N., Demers, E. G., Crocker, A. W., & Hogan, D. A. (2017). Use of RNA-
America: Clinical and microbiological aspects of 18 episodes of can- protein complexes for genome editing in non-albicans Candida species.
didemia. Journal of Infection, 73, 369–374. https://doi.org/10.1016/j. mSphere, 2, e00218–17. https://doi.org/10.1128/mSphere. 00218-17
jinf.2016.07.008 Grenfell, R. C., da Silva Junior, A. R., Del Negro, G. M. B., Munhoz, R. B.,
CDC. (2017). Potent in vitro Activity of SCYNEXIS’ SCY-078 Against Gimenes, V. M. F., Assis, D. M., … Benard, G. (2016). Identification of
Multidrug-Resistant Fungal Pathogen Candida auris Further Confirmed Candida haemulonii complex species: Use of ClinProTools(TM) to over-
in an in vitro Study Conducted by the Centers for Disease Control and come limitations of the Bruker Biotyper(TM), VITEK MS(TM) IVD,
Prevention. Retrieved from http://files.shareholder.com/downloads/ and VITEK MS(TM) RUO databases. Frontiers in Microbiology, 7, 940.
AMDA-2NFFBT/5043574146x0x942485/06E785B0-3542-4512- https://doi.org/10.3389/fmicb.2016.00940
A294-1FD3B0F5719A/SCYX_News_2017_5_11_General_Releases. Kathuria, S., Singh, P. K., Sharma, C., Prakash, A., Masih, A., Kumar, A., …
pdf (Accessed August 23, 2017). Chowdhary, A. (2015). Multidrug-resistant Candida auris misidenti-
Cendejas-Bueno, E., Kolecka, A., Alastruey-Izquierdo, A., Theelen, B., fied as Candida haemulonii: Characterization by matrix-assisted laser
Groenewald, M., Kostrzewa, M., … Boekhout, T. (2012). Reclassification desorption ionization-time of flight mass spectrometry and DNA se-
of the Candida haemulonii complex as Candida haemulonii (C. haemulonii quencing and its antifungal susceptibility profile variability by Vitek
group I), C. duobushaemulonii sp. nov. (C. haemulonii group II), and C. 2, CL. Journal of Clinical Microbiology, 53, 1823–1830. https://doi.
haemulonii var. vulnera var. nov.: Three multiresistant human patho- org/10.1128/JCM.00367-15
genic yeasts. Journal of Clinical Microbiology, 50, 3641–3651. https:// Khillan, V., Rathore, N., Kathuria, S., & Chowdhary, A. (2014). A rare case of
doi.org/10.1128/JCM.02248-12 breakthrough fungal pericarditis due to fluconazole-resistant Candida
Centers for Disease Control and Prevention. (2017a). Candida auris, Case auris in a patient with chronic liver disease. JMM Case Reports, 1, 1–5.
Count Updated: July 14, 2017. Retrieved from https://www.cdc.gov/fun- https://doi.org/10.1099/jmmcr.0.T00018
gal/diseases/candidiasis/candida-auris.html, Accessed 3 August 2017. Kim, T.-H., Kweon, O. J., Kim, H. R., & Lee, M.-K. (2016). Identification of
Centers for Disease Control and Prevention. (2017b). Recommendations uncommon Candida species using commercial identification systems.
for Identification of Candida auris | Fungal Diseases | CDC. Retrieved Journal of Microbiology and Biotechnology, 26, 2206–2213. https://doi.
from https://www.cdc.gov/fungal/diseases/candidiasis/recommenda- org/10.4014/jmb.1609.09012
tions.html (Accessed August 2, 2017). Kim, M.-N. M. M.-N., Shin, J. H. H. H., Sung, H., Lee, K., Kim, E. E.-C. E.,
Chakrabarti, A., Sood, P., Rudramurthy, S. M., Chen, S., Kaur, H., Capoor, M., Ryoo, N., … Kim, S. H. (2009). Candida haemulonii and closely related
… Kindo, A. J. (2015). Incidence, characteristics and outcome of ICU- species at 5 university hospitals in Korea: Identification, antifungal
acquired candidemia in India. Intensive Care Medicine, 41, 285–295. susceptibility, and clinical features. Clinical Infectious Diseases, 48, e57–
https://doi.org/10.1007/s00134-014-3603-2 e61. https://doi.org/10.1086/597108
Chatterjee, S., Alampalli, S. V., Nageshan, R. K., Chettiar, S. T., Joshi, S., & Kordalewska, M., Zhao, Y., Lockhart, S. R., Chowdhary, A., Berrio, I., &
Tatu, U. S. (2015). Draft genome of a commonly misdiagnosed multi- Perlin, D. S. (2017). Rapid and accurate molecular identification of the
drug resistant pathogen Candida auris. BMC Genomics, 16, 686. https:// emerging multidrug resistant pathogen Candida auris. Journal of Clinical
doi.org/10.1186/s12864-015-1863-z Microbiology, 55, 2445–2452. https://doi.org/10.1128/JCM.00630-17
Chowdhary, A., Anil Kumar, V., Sharma, C., Prakash, A., Agarwal, K., Babu, Kumar, D., Banerjee, T., Pratap, C. B., & Tilak, R. (2015). Itraconazole-
R., … Meis, J. F. (2014). Multidrug-resistant endemic clonal strain resistant Candida auris with phospholipase, proteinase and hemolysin
of Candida auris in India. European Journal of Clinical Microbiology activity from a case of vulvovaginitis. Journal of Infection in Developing
and Infectious Diseases, 33, 919–926. https://doi.org/10.1007/ Countries, 9, 435–437. https://doi.org/10.3855/jidc.4582
s10096-013-2027-1 Kumar, A., Sachu, A., Mohan, K., Vinod, V., Dinesh, K., & Karim, S. (2017).
Chowdhary, A., Sharma, C., Duggal, S., Agarwal, K., Prakash, A., Singh, P. Simple low cost differentiation of Candida auris from Candida haem-
K., … Meis, J. F. (2013). New clonal strain of Candida auris, Delhi, India. ulonii complex using CHROMagar Candida medium supplemented
Emerging Infectious Diseases, 19, 1670–1673. https://doi.org/10.3201/ with Pal’s medium. Revista Iberoamericana de Micología, 34, 109–111.
eid1910.130393 https://doi.org/10.1016/j.riam.2016.11.004
Chowdhary, A., Sharma, C., & Meis, J. F. (2017). Candida auris: A rapidly Larkin, E., Hager, C., Chandra, J., Mukherjee, P. K., Retuerto, M., Salem, I., …
emerging cause of hospital-acquired multidrug-resistant fungal infec- Wring, S. (2017). The emerging pathogen Candida auris: Growth phe-
tions globally. PLoS Pathogens, 13, e1006290. https://doi.org/10.1371/ notype, virulence factors, activity of antifungals, and effect of SCY-078,
journal.ppat.1006290 a novel glucan synthesis inhibitor, on growth morphology and biofilm
Emara, M., Ahmad, S., Khan, Z., Joseph, L., Al-Obaid, I., Purohit, P., & Bafna, formation. Antimicrobial Agents and Chemotherapy, 61, e02396–16.
R. (2015). Candida auris candidemia in Kuwait, 2014. Emerging Infectious https://doi.org/10.1128/AAC.02396-16
Diseases, 21, 1091–1092. https://doi.org/10.3201/eid2106.150270 Laxminarayan, R., Amábile-Cuevas, C. F., Cars, O., Evans, T., Heymann, D.
L., Hoffman, S., … Røttingen, J. A. (2016). UN High-Level Meeting on
|
antimicrobials—what do we need? Lancet, 388, 218–220. https://doi. facilities are a potential source for transmission of Candida auris and
org/10.1016/S0140-6736(16)31079-0 other Candida species. Infection Control and Hospital Epidemiology, 1–3,
Lee, W. G., Shin, J. H., Uh, Y., Kang, M. G., Kim, S. H., Park, K. H., & Jang, H. https://doi.org/10.1017/ice.2017.127
C. (2011). First three reported cases of nosocomial fungemia caused by Pragasam, A. K., Sahni, R. D., Anandan, S., Sharma, A., Gopi, R., Hadibasha,
Candida auris. Journal of Clinical Microbiology, 49, 3139–3142. https:// N., … Veeraraghavan, B. (2016). A pilot study on carbapenemase detec-
doi.org/10.1128/JCM.00319-11 tion: Do we see the same level of agreement as with the CLSI obser-
Lepak, A. J., Zhao, M., Berkow, E. L., Lockhart, S. R., & Andes, D. R. (2017). vations. Journal of Clinical and Diagnostic Research, 10, DC09–DC13.
Pharmacodynamic optimization for treatment of invasive Candida auris https://doi.org/10.7860/JCDR/2016/16417.8152
infection. Antimicrobial Agents and Chemotherapy, 61, AAC-00791. Prakash, A., Sharma, C., Singh, A., Kumar Singh, P., Kumar, A., Hagen, F., …
https://doi.org/10.1128/AAC.00791-17 Chowdhary, A. (2016). Evidence of genotypic diversity among Candida
Lockhart, S. R., Etienne, K. A., Vallabhaneni, S., Farooqi, J., Chowdhary, A., auris isolates by multilocus sequence typing, matrix-assisted laser de-
Govender, N. P., … Berkow, E. L. (2017). Simultaneous emergence of sorption ionization time- of-
flight mass spectrometry and amplified
multidrug-resistant Candida auris on 3 continents confirmed by whole- fragment length polymorphism. Clinical Microbiology & Infection, 22,
genome sequencing and epidemiological analyses. Clinical Infectious 277.e1–277.e9. https://doi.org/10.1016/j.cmi.2015.10.022
Diseases, 64, 134–140. https://doi.org/10.1093/cid/ciw691 Public Health England. (2016). Candida auris identified in England - GOV.
Magobo, R. E., Corcoran, C., Seetharam, S., & Govender, N. P. (2014). UK. Retrieved from https://www.gov.uk/government/publications/
Candida auris-associated candidemia, South Africa. Emerging Infectious candida-auris-emergence-in-england/candida-auris-identified-in-en-
Diseases, 20, 1250–1251. https://doi.org/10.3201/eid2007.131765 gland (Accessed August 1, 2017).
Mizusawa, M., Miller, H., Green, R., Lee, R., Durante, M., Perkins, R., … Public Health England. Candida auris within the United Kingdom: updated
Zhang, S. X. (2017). Can multidrug-resistant Candida auris be reli- guidance published - GOV.UK. Retrieved from https://www.gov.uk/
ably identified in clinical microbiology laboratories? Journal of Clinical government/publications/candida-auris-emergence-in-england/can-
Microbiology, 55, 638–640. https://doi.org/10.1128/JCM.02202-16 dida-auris-within-the-united-kingdom-updated-guidance-published
Mohsin, J., Hagen, F., Al-Balushi, Z. A. M., de Hoog, G. S., Chowdhary, A., (Accessed September 3, 2017).
Meis, J. F., & Al‐Hatmi, A. (2017). The first cases of Candida auris can- Rudramurthy, S. M., Chakrabarti, A., Paul, R. A., Sood, P., Kaur, H., Capoor,
didaemia in Oman. Mycoses, 60, 569–575. https://doi.org/10.1111/ M. R., … Das, S. (2017). Candida auris candidaemia in Indian ICUs:
myc.12647 Analysis of risk factors. Journal of Antimicrobial Chemotherapy, 72,
Morales-Lopez, S. E., Parra-Giraldo, C. M., Ceballos-Garzon, A., Martinez, 1794–1801. https://doi.org/10.1093/jac/dkx034
H. P., Rodriguez, G. J., Alvarez-Moreno, C. A., & Rodríguez, J. Y. (2017). Ruiz Gaitán, A. C., Moret, A., López Hontangas, J. L., Molina, J. M. J. M.,
Invasive infections with multidrug- resistant yeast Candida auris, Aleixandre López, A. I., Cabezas, A. H. H., … Canton, E. (2017).
Colombia. Emerging Infectious Diseases, 23, 162–164. https://doi. Nosocomial fungemia by Candida auris: First four reported cases in
org/10.3201/eid2301.161497 continental Europe. Revista Iberoamericana de Micología, 34, 23–27.
Newnam, K. M., & Harris-Haman, P. (2017). Noteworthy professional news. https://doi.org/10.1016/j.riam.2016.11.002
Advances in Neonatal Care, 17, 233–234. https://doi.org/10.1097/ Sarma, S., Kumar, N., Sharma, S., Govil, D., Ali, T., Mehta, Y., & Rattan, A.
ANC.0000000000000419 (2013). Candidemia caused by amphotericin B and fluconazole resis-
Nordmann, P. (2014). Carbapenemase-producing Enterobacteriaceae: tant Candida auris. Indian Journal of Medical Microbiology, 31, 90–91.
Overview of a major public health challenge. Medecine et maladies https://doi.org/10.4103/0255-0857.108746
infectieuses, 44, 51–56. https://doi.org/doi: 10.1016/j.medmal.2013.11. Sarma, S., & Upadhyay, S. (2017). Current perspective on emergence, diag-
007 nosis and drug resistance in Candida auris. Infection and Drug Resistance,
Nordmann, P., Jayol, A., & Poirel, L. (2016). Rapid detection of polymyxin 10, 155–165. https://doi.org/10.2147/IDR.S116229
resistance in Enterobacteriaceae. Emerging Infectious Diseases, 22, Satoh, K., Makimura, K., Hasumi, Y., Nishiyama, Y., Uchida, K., & Yamaguchi,
1038–1043. https://doi.org/10.3201/eid2206.151840 H. (2009). Candida auris sp. nov., a novel ascomycetous yeast iso-
Oh, B. J., Shin, J. H., Kim, M.-N., Sung, H., Lee, K., Joo, M. Y., … Ryang, lated from the external ear canal of an inpatient in a Japanese
D. W. (2011). Biofilm formation and genotyping of Candida haemulonii, hospital. Microbiology and Immunology, 53, 41–44. https://doi.
Candida pseudohaemulonii, and a proposed new species (Candida auris) org/10.1111/j.1348-0421.2008.00083.x
isolates from Korea. Medical Mycology, 49, 98–102. https://doi.org/10. Schelenz, S., Hagen, F., Rhodes, J. L., Abdolrasouli, A., Chowdhary, A., Hall,
3109/13693786.2010.493563 A., … Armstrong-James, D. (2016). First hospital outbreak of the globally
Osei Sekyere, J. (2016). Current state of resistance to antibiotics of emerging Candida auris in a European hospital. Antimicrobial Resistance
last-resort in South Africa: A Review from a public health perspec- & Infection Control, 5, 35. https://doi.org/10.1186/s13756-016-0132-5
tive. Frontiers in Public Health, 4, 209. https://doi.org/10.3389/ Schwartz, I., & Hammond, G. (2017). First reported case of multidrug-
FPUBH.2016.00209 resistant Candida auris in Canada. Canada Communicable Disease
Osei Sekyere, J., & Amoako, D. G. (2017). Genomic and phenotypic Report, 6, 150–153. Retrieved from http://www.phac-aspc.gc.ca/publi-
characterisation of fluoroquinolone resistance mechanisms in cat/ccdr-rmtc/17vol43/dr-rm43-7-8/assets/pdf/17vol43_7_8-ar-02-
Enterobacteriaceae in Durban, South Africa. PLoS ONE, 12, e0178888. eng.pdf (Accessed July 21, 2017).
https://doi.org/10.1371/journal.pone.0178888 Seiffert, S. N., Marschall, J., Perreten, V., Carattoli, A., Furrer, H., &
Osei Sekyere, J., Govinden, U., Bester, L. A., & Essack, S. Y. (2016). Colistin Endimiani, A. (2014). Emergence of Klebsiella pneumoniae co-
and tigecycline resistance in carbapenemase- producing gram neg- producing NDM-1, OXA-48, CTX-M-15, CMY-16, QnrA and
ative bacteria: Emerging resistance mechanisms and detection ArmA methyltransferase in Switzerland. International Journal of
methods. Journal of Applied Microbiology, 121, 601–617. https://doi. Antimicrobial Agents, 44, 260–262. https://doi.org/10.1016/j.
org/10.1111/jam.13169 ijantimicag.2014.05.008
Osei Sekyere, J., Govinden, U., & Essack, S. Y. (2015). Review of established Sharma, C., Kumar, N., Meis, J. F., Pandey, R., & Chowdhary, A. (2015). Draft
and innovative detection methods for carbapenemase- producing genome sequence of a fluconazole-resistant Candida auris strain from
Gram-negative bacteria. Journal of Applied Microbiology, 119, 1219– a candidemia patient in India. Genome Announcements, 3, e00722–15.
1233. https://doi.org/10.1111/jam.12918 https://doi.org/10.1128/genomeA.00722-15
Piedrahita, C. T., Cadnum, J. L., Jencson, A. L., Shaikh, A. A., Ghannoum, Sharma, C., Kumar, N., Pandey, R., Meis, J. F. F., & Chowdhary, A. (2016).
M. A., & Donskey, C. J. (2017). Environmental surfaces in healthcare Whole genome sequencing of emerging multidrug resistant Candida
OSEI SEKYERE |
29 of 29
auris isolates in India demonstrates low genetic variation. New Wattal, C., Oberoi, J. K., Goel, N., Raveendran, R., & Khanna, S. (2017).
Microbes and New Infections, 13, 77–82. https://doi.org/10.1016/j. Matrix-assisted laser desorption ionization time of flight mass spec-
nmni.2016.07.003 trometry (MALDI-TOF MS) for rapid identification of micro-organisms
Sherry, L., Ramage, G., Kean, R., Borman, A., Johnson, E. M., Richardson, in the routine clinical microbiology laboratory. European Journal of
M. D., & Rautemaa-Richardson, R. (2017). Biofilm-forming capabil- Clinical Microbiology and Infectious Diseases, 36, 807–812. https://doi.
ity of highly virulent, multidrug-resistant Candida auris. Emerging org/10.1007/s10096-016-2864-9
Infectious Diseases, 23, 328–331. https://doi.org/10.3201/ Welsh, R. M., Bentz, M. L., Shams, A., Houston, H., Lyons, A., Rose, L. J.,
eid2302.161320 & Litvintseva, A. P. (2017). Survival, persistence, and isolation of the
Shin, J. H., Kim, M.-N., Jang, S. J., Ju, M. Y., Kim, S. H., Shin, M. G., … Ryang, emerging multidrug-resistant pathogenic yeast Candida auris on a plas-
D. W. (2012). Detection of amphotericin B resistance in Candida hae- tic healthcare surface. Journal of Clinical Microbiology, 55, 2996–3005.
mulonii and closely related species by use of the Etest, Vitek-2 yeast https://doi.org/10.1128/JCM.00921-17
susceptibility system, and CLSI and EUCAST broth microdilution
methods. Journal of Clinical Microbiology, 50, 1852–1855. https://doi.
org/10.1128/JCM.06440-11
Todd, B. (2017). Clinical alert: Candida auris. American Journal of Nursing, S U P P O RT I NG I NFO R M AT I O N
117, 53–55. https://doi.org/10.1097/01.NAJ.0000515233.51795.b3
Tsay, S., Welsh, R. M., Adams, E. H., Chow, N. A., Gade, L., Berkow, E. L., … Additional Supporting Information may be found online in the sup-
Jackson, B. R. (2017). Notes from the field: Ongoing transmission of porting information tab for this article.
Candida auris in health care facilities - United States, June 2016-May
2017. Morbidity and Mortality Weekly Report, 66, 514–515. https://doi.
org/10.15585/mmwr.mm6619a7
How to cite this article: Osei Sekyere J. Candida auris: A
Vallabhaneni, S., Kallen, A., Tsay, S., Chow, N., Welsh, R., Kerins, J., …
Ridgway, J. (2016). Investigation of the first seven reported cases of systematic review and meta-analysis of current updates on an
Candida auris, a globally emerging invasive, multidrug-resistant fun- emerging multidrug-resistant pathogen. MicrobiologyOpen.
gus - United States, May 2013-August 2016. Morbidity and Mortality 2018;7:e578. https://doi.org/10.1002/mbo3.578
Weekly Report, 65, 1234–1237. https://doi.org/10.15585/mmwr.
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Received: 11 September 2017 Revised: 21 November 2017 Accepted: 27 November 2017

Candida auris: A systematic review and meta-­analysis of current

John Osei Sekyere

1 | INTRODUCTION century (Laxminarayan et al., 2016). Antimicrobial-­resistant microbes,

MicrobiologyOpen. 2018;7:e578. ﻿ www.MicrobiologyOpen.com | 1 of 29

except FLZ, above 1 mg/L were defined as nonsusceptible (i.e., high

Records identified through Additional records identified

Records after duplicates removed

Records screened Records excluded

Full-text articles assessed Full-text articles excluded:

(n = 73) news, CRISPR-Cas 9,

T A B L E 1 Phenotypic and genomic characteristics of Candida auris

Phenotypic and genomic

4 | RESISTANCE PROFILES, RATES

Specimen Resistance Clinical

Specimen Resistance Clinical

Specimen Resistance Clinical

Specimen Resistance Clinical

Norway (1) NS (1) NS Blood (1) NS ND NS NS NS European Centre

Specimen Resistance Clinical

Specimen Resistance Clinical

Specimen Resistance Clinical

Combined Sensitivity Specificity Turnaround Skill level

Phenotypic and/or culture-­based media or methods

T A B L E 4 Usage characteristics and

Conventional PCR 29 Conventional PCR 484

8.4 | Africa: South Africa

The persistence and recurrence of C. auris in the hospital environment

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Candida auris: A systematic review and meta-analysis of current

1 | INTRODUCTION century (Laxminarayan et al., 2016). Antimicrobial-resistant microbes,

MicrobiologyOpen. 2018;7:e578. www.MicrobiologyOpen.com | 1 of 29

Phenotypic and/or culture-based media or methods