Current global status of Candida auris an emerging multidrug-resistant fungal pathogen: bibliometric analysis and network visualization

Abstract

Background

Candida auris is an emerging multidrug-resistant fungal pathogen associated with nosocomial infections and hospital outbreaks worldwide, presenting a serious global health threat. There has been a rapid emergence of scientific research publications focusing on therapeutic compounds, diagnostic techniques, control strategies, prevention, and understanding the epidemiology related to C. auris.

Objective

This study aims to provide the most up-to-date comprehensive and integrated examination of C. auris research subject and demonstrate that C. auris is indeed a topic of increasing interest.

Methods

The search query “candida-auris” was used as a topic term to find and retrieve relevant data published between 2009 and 15 June 2023, from the Web of Science Core Collection (WoSCC) database. In this work, the bibliometric analysis and network visualization were conducted using VOSviewer software, and Biblioshiny interface accessible through the Bibliometrix R-package on RStudio software.

Results

The yearly growth rate percentage (37.91%), along with the strong positive correlations between publications and citations (r = 0.981; p < 0.001), suggests heightened scholarly engagement in this topic. The USA, India, China, and the UK have emerged as pivotal contributors, with the Centers for Disease Control and Prevention (CDC) in the USA being the most productive institution. Current research hotspots in this field mainly focused on identifying and limiting transmission of the clonal strains, epidemiology, antifungal resistance, and in vitro antifungal susceptibility testing.

Conclusion

This detailed bibliometric analysis in C. auris topic shows that this fungal pathogen has garnered growing attention and attracted progressively more scholars. This paper will help researchers to find without difficulty the relevant articles, research hotspots, influential authors, institutions, and countries related to the topic.

Supplementary Information

The online version contains supplementary material available at 10.1007/s42770-023-01239-0.

Introduction

In the kingdom of fungi, Candida genus contains more than 200 species recognized in NCBI taxonomy database to date. With its distinct characteristics, Candida is the largest genus among medically important yeasts [1]. Some species of the Candida genus are commonly found in diverse locations in the human body, including the oral, vulvovaginal, and anorectal regions [2]. Besides, to date, many species of the Candida genus have been identified as causative agents of human infection. Indeed, they range from common superficial mucosal infections to life-threatening invasive infections, particularly among individuals with compromised immune systems [3]. Within these clinically relevant species, we found Candida albicans, Nakaseomyces glabrata (Candida glabrata), Candida tropicalis, Candida parapsilosis, Pichia kudriavzevii (Candida krusei), Candida dubliniensis, Meyerozyma guilliermondii (Candida guilliermondii), Clavispora lusitaniae (Candida lusitaniae), Candida duobushaemulonii, and Candida auris and the list continues to expand [1, 4–6].

Over the past decade, multidrug-resistant microorganisms have caused serious threat to the global population and health-care systems around the world [7]. In 2016, international health agencies and organizations issued alerts regarding C. auris as an emerging multidrug-resistant fungal pathogen that poses a serious threat for the people [8]. It has become a challenging fungal pathogen to control. Since 2009, with the first isolation from the external ear canal sample of a Japanese patient, outbreaks of C. auris have been reported in numerous countries [9–11]. This emerging opportunistic pathogen has become a global public health concern due to its resistance to multiple classes of antifungal drugs, the ability to cause severe invasive infections, high mortality rates, easy transmission and dissemination, problems of misidentification, surface adhesion, and biofilm formation ability [11–14].

C. auris has been characterized both phenotypically and genotypically in many studies. Based on genome sequences and by comparing isolates from different regions, five unique clades of C. auris consisting of South Asian (clade I), East Asian (clade II), South African (clade III), South American (clade IV), and Iranian (clade V) have been identified [9, 15–17]. Every clade shows distinct genetic characteristics, biochemical characteristics, and susceptibility profiles to antifungal agents [11, 18]. Consequently, there has been widespread global attention directed toward research and development efforts aimed at combating this emerging pathogen through the creation of new therapeutic compounds and diagnostic techniques [14]. Additionally, there has been a focus on control strategies, prevention, and understanding the epidemiology, including the incidence and prevalence rates [19, 20].

Given the rapid emergence of scientific research publications concerning this fungal pathogen, it is important to have a full view on the literature to understand the evolution of this topic. Bibliometric analysis method is a popular and rigorous statistical and analytical procedure utilized for quantitative analyses of the literature [21]. To the best of our knowledge, there is an absence of any current bibliometric studies providing the most up-to-date comprehensive and integrated examination of C. auris topic as thoroughly as our study. The main goal of this work is to contribute to the existing body of knowledge on this subject and to show that C. auris is really a topic of increasing interest via bibliometric analysis.

Materials and methods

The search query, database search, data collection, and the bibliometric and scientometric tools used to analyze and visualize the data are described as follows.

Building the search query

The key step for obtaining high-quality data and conducting a robust bibliometric study is formulating an effective search query. In our study, the query was built by using the keywords: (candida, auris) and hyphen (-). The use of the hyphen (-) to join the keywords indicate that they are linked, the search engine treats hyphen (-) in keywords as spaces. Therefore, searching for hyphenated query terms candida-auris returns records that contain the terms C. auris. The search query built was (candida-auris), and it was used as a topic term to find documents with this word in the titles, keywords, and abstracts.

Searching database

There are several bibliographic databases including various sorts of publications that are available online. Academicians from many scientific domains frequently use databases such as Web of Science (WoS), Scopus, PubMed, MEDLINE, and others [22]. In this study, Web of Science Core Collection (WoSCC) a subset of the Web of Science database from Clarivate Analytics has been used as the source of raw data. Web of Science (WoS) contains a remarkable treasure of data on scientific content; it is admired by the academicians for indexing high-quality contents [23, 24]. Besides it is the most frequently used database for bibliometric studies.

Data collection

Guided by the approach above, we searched the query (candida-auris) in the WoSCC database to retrieve the data which cover the publications between 2009 and 15 June 2023. A total of 1308 results were obtained initially. After selecting the “document types” refinement option, 1052 results were returned, focusing specifically on articles and reviews as the considered publication categories. Furthermore, the data was downloaded and saved as plain text for further analysis. The flowchart of the data collection, screening, and analysis process is outlined (Supplementary Figure 1).

Analysis tools

Several software tools have been developed and used for data analysis. In this work, metadata analysis was conducted in two parts consisting of “bibliometric analysis” and “network analysis.” The software tools used for this purpose were RStudio and VOSviewer. RStudio is a free software environment for statistical computing and graphics. It compiles and runs on a wide variety of platforms. The open-source “bibliometrix” R-package was installed in this software, which provides a set of tools for quantitative research in bibliometrics and scientometrics [25]. VOSviewer software tool developed by Nees Jan van Eck and Ludo Waltman was used for creating, visualizing, and exploring the maps based on network data [26].

Bibliometric and network visualized analysis

The bibliometric analysis and visualization of information from the metadata were conducted by utilizing the VOSviewer program, and biblioshiny interface. Biblioshiny is accessible through the bibliometrix R-package [25]. The bibliometric analysis and visualization focused on several aspects, including the number of publications, number of citations (total citations and citations per year), most cited countries, productive countries, top productive journals, major contributors, most productive affiliations, international collaborations, co-occurrence keywords, co-authorship, co-cited references, historograph, and thematic evolution [21].

Statistical analysis

GraphPad Prism software, version 8.0.2 for Windows (GraphPad Software, San Diego, California, USA), was used for the calculation of Pearson’s correlation coefficient, to determinate if there is any correlation between the annual publications and citations of the 1052 documents. Microsoft office Excel (Microsoft Corporation, 2019) was used for the calculation of percentages and means.

Ethical approval

This study followed all ethical guidelines. There were no human or animal subjects involved, and the data were obtained from the open database. Therefore, the ethics committee does not need to approve this bibliometric analysis. This research involved the use of Chat GPT 3.5 and Google BARD PaLM 2 AI tools for English proofreading purposes, given that the authors are non-native English speakers.

Results

Main information about data

A total of 1308 documents (docs) were obtained initially. They were composed mainly of 64% of research articles (855 docs), 15% of review articles (197 docs), and 21% of other mixed documents (meeting abstracts, editorial materials, letters, early access, corrections, news items, proceeding papers, book chapters, and reprints) as shown in Supplementary Figure 2. For the final study, 1052 documents in total were collected from WoSCC, by excluding the other mixed documents (21%≈256 docs), and focusing specifically on research articles and review articles using the aforementioned search techniques in Supplementary Figure 1. They were sourced from 298 different journals and books. Furthermore, the data has 4822 distinct writers, which helped to produce the retrieved articles, with an average of 7 co-authors per document and 30 authors of single-authored documents. Besides, approximately 33.37% of the documents have international co-authorship. Concerning the level of impact within the academic community, on average, each document has received 26.76 citations. Besides, the average age of the documents within the data was appointed about 2.64 years. Table 1 offers a thorough summary of the data.

Table 1.

Main information about data

Description	Timespan	Sources (Journals, Books, etc.)	Documents
Results	2009 to 2023 June 15	298	1052
Description	Annual growth rate %	Document average age	H-index of all Doc
Results	37.91	2.64	79
Description	References	Author’s keywords (DE)	Authors
Results	26970	2079	4822
Description	Authors of single authored docs	International coauthorships %	Co-authors per doc
Results	30	33.37	7.2
Description	Doc cited without self-citations	Total times cited Doc	Average citations per Doc
Results	12515	28149	26.76

Annual publication and citation of documents

In the year 2009, the initial document on C. auris was released. It was entitled “Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital.” Afterwards, just a few articles were published between 2009 and 2015. Since 2016, the average of scientific production and citation of articles concerning C. auris began to increase (Fig. 1). In 2021 and 2022, it was seen that the most scientific production was made with 231 and 232 publications, respectively. In addition, the same years had the highest number of citations, with 6657 and 7329, respectively. The total times cited score for all the documents in the data was equal to 28,149, while without self-citations it was equal to 12,555 (citations from external sources). Also, h-index of all the publications was about 79. Besides, the relationship between publications and citations was also investigated. Consequently, the results revealed a statistically significant positive correlation (r = 0.981; p < 0.001). Moreover, the yearly growth rate percentage reveals that scientific production has undergone a dramatic growth rate of 37.91% each year as shown in Table 1.

Fig. 1.

Annual publications and citations from 2009 to 15 June of 2023

Productive and influential countries/regions

The productivity of countries/regions on C. auris research is reflected by the number of publications. Besides, the impact of those countries could be revealed by the total citations cumulated, showing the usefulness of these publications to scientists. The results revealed that 68 countries/regions have contributed to scientific publications. The USA scored the first position, with a total of 317 articles and 10,548 total citations (Table 2 and Table 3). Following, India produced 86 articles, China 60 articles, and the UK 58 articles, which allowed them to be ranked second, third, and fourth, respectively. When considering the impact of published articles, the UK had 3354 total citations, India had 3324 total citations, and China had 1153 total citations, placing these countries in the second, third, and fourth positions, respectively. Spain, Brazil, Canada, and others were also among the productive and most cited countries/regions as shown in Table 2 and Table 3.

Table 2.

The top 10 productive countries/regions

Rank	Country	No. of articles	% from (1052)	Total citations	Citation per publication
1	USA	317	30.13	10548	33.27
2	India	86	8.17	3324	38.65
3	China	60	5.70	1153	19.22
4	UK	58	5.51	3354	57.83
5	Spain	48	4.56	830	17.29
6	Brazil	44	4.18	836	19.00
7	Germany	30	2.85	311	10.37
8	Italy	28	2.66	477	17.04
9	Canada	26	2.47	743	28.58
10	South Africa	22	2.09	405	18.41

Table 3.

The top 10 most cited countries/regions

Rank	Country	No. of articles	% from (1052)	Total citations	Citation per publication
1	USA	317	30.13	10548	33.27
2	UK	58	5.51	3354	57.83
3	India	86	8.17	3324	38.65
4	China	60	5.70	1153	19.22
5	Brazil	44	4.18	836	19.00
6	Spain	48	4.56	830	17.29
7	Japan	20	1.90	758	37.90
8	Canada	26	2.47	743	28.58
9	Netherlands	21	2	646	30.76
10	Denmark	8	0.76	628	78.50

For a better understanding of the collaboration between countries/regions in C. auris research, co-authorship of countries was analyzed. Supplementary Figure 3 illustrates the global collaborations among countries, visualized through the R-Bibliometrix tool. The minimum threshold for collaboration documents was set at five to ensure significant collaborative efforts are considered. Additionally, Fig. 2 highlights the collaboration network of countries/regions using VOS Viewer, by selecting full counting method, without ignoring articles written by a large number of countries. Countries that met the threshold of at least five collaboration documents were selected, resulting in a selection of 48 countries for network map as shown in Fig. 2. As the largest contributor, the USA collaborates closely with the Netherlands, England, India, Germany, Brazil, France, China, Austria, Spain, and Italy. Besides, five distinct clusters were identified, and each cluster is represented by a specific color and consists of a group of countries/regions, which provide valuable insights into the collaborative patterns and associations among them. As shown in Fig. 2, each node represents a country/region, and the presence of a link between two nodes indicates that those countries/regions have collaborated in publishing scientific literature. The size of each node corresponds to the volume of relevant literature published by the respective country/region. Additionally, the width of the link between two nodes indicates the level of collaboration between them.

Fig. 2.

Network map of collaborations among countries/regions

Most relevant affiliations

To date, many institutions were involved in the C. auris research topic. Table 4 shows the top 10 related affiliations. According to the analyses, the Centers for Disease Control and Prevention (CDC) located in the USA was the most productive institution by 86 published articles. The University of Delhi was the second most contributed institution with 59 published articles. The USA has also gained the third position thanks to the University of Wisconsin–Madison’s contribution of 56 published articles. The University of Debrecen in Hungary has published 55 articles allowing this institution to rank fourth. Besides, the University of the Witwatersrand in South Africa has appeared in the fifth rank by publishing 38 articles. Some affiliations had almost equal numbers of publications. Among them, the Canisius-Wilhelmina Hospital in the Netherlands has contributed 35 articles, Case Western Reserve University in the USA 31 articles, the University of Exeter in England 30 articles, Fudan University in China 28 articles, and the University of São Paulo in Brazil 25 publications.

Table 4.

Top 10 related affiliations

Rank	Affiliation	Country	No. of articles	% from (1052)
1	Centers for Disease Control and Prevention	USA	86	8.17
2	University of Delhi	India	59	5.60
3	University of Wisconsin–Madison	USA	56	5.32
4	University of Debrecen	Hungary	55	5.22
5	University of the Witwatersrand	South Africa	38	3.61
6	Canisius-Wilhelmina hospital	Netherlands	35	3.33
7	Case western reserve university	USA	31	2.94
8	University of Exeter	England	30	2.85
9	Fudan University	China	28	2.66
10	University of São Paulo	Brazil	25	2.37

An analysis of citations involved in C. auris research was performed among institutions. Furthermore, a network map of citations was generated (Supplementary Figure 4). Each node in the network map represents an institution, and the presence of a link between two nodes indicates citation relationships between institutions. The size of each node corresponds to the total number of citations received by all documents published. The CDC and the University of Delhi were the largest contributors in terms of publications and the most cited as revealed in the network map.

Analysis of most productive journals

The top 10 most productive journals based on the number of publications on C. auris topic are summarized in Supplementary Table 5. These journals collectively published 360 research articles and/or reviews which accounts for 34.21% of the 1052 publications. As can be seen, the Journal of Fungi was on the top with 89 relevant publications, which cumulated 1241 total citations with an average of 14 citations per publication. Besides, this journal has an impact factor equal to 5.724 and was classified in the first quartile (Q1). In the second rank, Antimicrobial Agents and Chemotherapy, with an impact factor of 5.938, contributed 64 publications and was classified as Q1. The Mycoses, with an impact factor of 4.931 and classified as Q1, was the third-ranked contributor journal with 40 articles. Among the top 10 journals, the Journal of Clinical Microbiology had the highest impact factor (11.677). It contributed 26 publications, received 1824 citations averaging 70 citations per publication, and was also classified as Q1.

Contributions of authors

The top 10 productive authors with the highest number of publications among 4822 authors were listed (Supplementary Table 6). According to the list, four authors were from the USA, two from India, one from the Netherlands, one from Georgia, one from England, and one from Spain. Moreover, Supplementary Figure 5 shows the network map of co-authorship. Each node in the network map represents an author, and the size of each node corresponds to the total number of published documents. Besides, the presence of a link between two nodes indicates the co-authorship relationship between authors. Wide links indicate more co-authored documents between the two authors. Three clusters (blue color, red color, and green color) and 15 items (authors) were identified with strong co-authorship relationships.

Analysis of cited references

The top 15 cited references related to C. auris are listed in Supplementary Table 7. That table highlights influential works in the field, providing information on the title, first author, publication year, local citations, global citations, total citations per year, and the ratio of the local citations divided by global citations (% LC/GC). The most highly cited article entitled “Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses,” written by Shawn R. Lockhart et al., was published in 2017. It has received 544 local citations and 787 global citations, with an average of 112.43 citations per year. In the second rank, the article entitled “Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital” by Kazuo Satoh et al. was published in 2009. It has accumulated 474 local citations and 611 global citations, with an average of 40.73 citations per year. In the third rank, the article entitled “First hospital outbreak of the globally emerging Candida auris in a European hospital” by Silke Schelenz et al. was published in 2016. It has obtained 328 local citations and 428 global citations, with an average of 53.50 citations per year. It is seen that the remaining references listed in Supplementary Table 7 significantly contribute to C. auris research. Except for the research articles mentioned above, the remaining articles in Supplementary Table 7 have obtained at least 159 local citations and 188 global citations. These most cited articles offer valuable insights and knowledge to the readers and play a crucial role in understanding and studying C. auris. The full counting method was selected for a more comprehensive visualization of the network of co-cited references. To this, the minimum number of citations of a cited reference was set to 100 and then analyzed by VOS Viewer. Of the 26,970 cited references, 40 meet the threshold and the results are shown in Supplementary Figure 6. The visualization mapping done via VOS Viewer showed that the network map of co-cited references was dominated in the center by Shawn Lockhart (2017), Kazuo Satoh (2009), and Silke Schelenz (2016). The density map of co-cited references revealed the same results (Supplementary Figure 7), showing that the same references were in a central position and disposed of the reddish kernel as a result of the higher number of total link strength (tlc) (Shawn Lockhart,4862 tlc; Kazuo Satoh, 4469 tlc; and Silke Schelenz, 3693 tlc).

Historiography analysis

Historiography analysis was conducted using the R-Bibliometrix tool. The results of the analysis are presented in Fig. 3, which depicts the historiography of 15 early scholarly publications. Each node in the historograph represents an article, and the size of each node corresponds to the total citations received. Moreover, the presence of a link between two nodes indicates the citation of the oldest article by the newest one. As mentioned above, Kazuo Satoh et al. published the first article related to C. auris in 2009. Two years later, Lee et al. published the second article entitled “First three reported cases of nosocomial fungemia caused by Candida auris” in 2011. Following this, Chowdhary et al. published the third article related to C. auris entitled “New Clonal Strain of Candida auris, Delhi, India” in 2013. The same authors published the fourth article in the field in 2014 entitled “Multidrug-resistant endemic clonal strain of Candida auris in India.” Another article was published about multidrug-resistant C. auris misidentified as Candida haemulonii by Kathuria et al. in 2015. 2016 was the year where research concerning C. auris began to appear in Europe and America. In the following years, publications on C. auris began to increase exponentially.

Fig. 3.

Historograph of 15 early scholarly publications

Keywords analysis

Co-occurrence analysis was performed for the identification of essential keywords. All keywords including both author keywords and keyword Plus were selected. Besides, the minimum number of occurrences of keywords was set to 30 and then analyzed by VOS Viewer. Among 3365 keywords, 47 meet the threshold and are displayed in Fig. 4. The nodes in the network of keyword co-occurrence represent the keywords, and the size of each node corresponds to the number of occurrences of a keyword. Moreover, the links between two keywords indicate keywords co-occurred in a research study. Three clusters were identified; the first one was composed of 22 items in red color, and the most significant items were antifungal activity, amphotericin-b, antifungal resistance, azole resistance, fluconazole resistance, echinocandins, caspofungin, biofilms, in vitro, and virulence. The second cluster was mainly composed of 16 items in green color, and the most significant items were emergence, transmission, outbreak, nosocomial fungemia, antifungal susceptibility, flight mass-spectrometry, identification, clonal strain, disinfectants, and infection control. As seen in Fig. 4, the third cluster was mainly composed of 9 items identified in blue color, and the most related items were epidemiology, management, surveillance, invasive candidiasis, diagnosis, fungemia, infections, and candidemia. The authors’ keywords were also used to examine the thematic evolution via the R-Bibliometrix tool. Period parameters were set as from 2009 to 2023. Also, three cutting years 2012, 2018, and 2022 were applied. The result was represented as a Sankey diagram in Supplementary Figure 8. Hence, the C. auris research field changed and evaluated over time. Moreover, the Sankey diagram was also used to indicate the relationships among countries (left), authors (middle), and authors’ keywords (right), as illustrated in Supplementary Figure 9.

Fig. 4.

Network map of keyword co-occurrence

Discussion

The bibliometric analysis was used to map the scientific landscape of C. auris research topic, which has emerged globally as a multidrug-resistant fungal pathogen, and has become a severe problem in recent years. Regarding the number of publications, there has been a significant increase from a single publication in 2009 to over 230 publications in 2021 and 2022, with a parallel growth in citation (Fig. 1). Also, the scientific production has undergone a strong growth rate of 37.91% (Table 1). Furthermore, the Pearson’s correlation indicates a strong positive correlation between publications and citations (r = 0.981; p < 0.001). All this implies that more scholars are interested in the C. auris research topic, and it is expected that more scientific data will be published shortly concerning this fungal pathogen.

Based on the statistical analysis of productive and influential countries/region, the USA, India, China, and the UK emerge as leaders in both publication and citations among 68 countries/regions that have contributed to scientific production (Table 2 and Table 3). Certainly, their substantial research efforts and valuable contributions toward understanding this emerging pathogen make them the largest contributor. Moreover, these countries have experienced outbreaks of this multidrug-resistant fungal pathogen [5, 27]. The most recent publication provided by these countries have focused on understanding the pathogenicity and virulence, with special attention to drug and multidrug resistance, effective treatments, and prevention strategies. The collaboration among countries reveal five distinct clusters, showcasing the close ties with the USA (Fig. 2). It is notable that more institutions and collaboration between countries promote knowledge production [28]. The collaborations between countries and institutions are initiated by active researchers. Considering the importance of scientific interactions, it is notable that researchers tend to collaborate frequently with colleagues with whom they share mutual research interest and knowledge [29].

Author keywords and keyword plus were used for co-occurrence analysis to identify high-frequency keywords in the C. auris research topic, reflecting the hotspots in this field. Among 3365 keywords, 47 met the threshold, revealing three clusters (Fig. 4) that contain the research hotspots.

Some research hotspots are predominantly focused on antifungal resistance and in vitro antifungal susceptibility testing. Recently, it was shown that C. auris is resistant to multiple classes of antifungal drugs. Indeed, 90% of isolates exhibit resistance to fluconazole, and a significant number of isolates show cross-resistance to more than one of the three major classes of antifungals, including azoles (e.g., fluconazole), echinocandins (e.g., caspofungin), and polyenes (e.g., amphotericin B) [30, 31]. In response to this challenge, the combination of drugs appears to hold promise against the C. auris fungal pathogen. Many drug combinations including antifungals, non-antifungals, and natural compounds have been investigated for the treatment of C. auris [32]. This fungal pathogen carries extensive mutations and copy number variations in genes associated with several virulence factors [13]. These virulence factors (such as expression of extracellular hydrolases, immune evasion, biofilm formation, antifungal drug, and environmental stress resistance) have been the subject of evaluation in both in vitro and in vivo studies [11, 31, 33, 34]. Recently, alternative models have been used for pathogenicity studies such as Caenorhabditis elegans and Galleria mellonella invertebrate hosts [34]. These new invertebrate model hosts could aid in advancing studies to avoid ethical and economic concerns.

Other research hotspots are mostly focused on identifying and limiting transmission of the clonal strains of C. auris. Indeed, there is a need for the development of potentially more effective approaches to reduce C. auris transmission and prevent infections in long-term care facilities, given the significant impact of illness caused by this pathogen [35]. These approaches should be focused more on healthcare provider hygiene and environmental disinfection. Furthermore, misidentification of C. auris may result in a delay in infection prevention, leading to an increased rate of transmission [36]. Commercially available identification tests like VITEK 2 YST^a, API-20C, API-ID 32C, BD Phoenix, and MicroScan often misidentify C. auris as other phylogenetically related pathogens [37, 38]. The correct identification requires more complex analyses such as matrix-assisted laser desorption ionization–time of flight mass spectrometry, DNA sequencing, and real-time PCR [36, 39, 40]. Furthermore, a novel chromogenic agar called “CHROMagar™ Candida Plus” could be an option for rapid identification tests. Indeed, among over 50 different species of Candida spp. tested on CHROMagar™ medium, only Candida diddensiae, a rare species, gave a similar colonial appearance to C. auris as a pale cream with a distinctive blue halo in the surrounding on the agar plate [41].

Regarding the size of nodes in some clusters, it is evident that research hotspots are also concentrated on epidemiology. There is a growing need for genomic epidemiology to incorporate whole-genome sequencing (WGS) to investigate the genetic diversity of C. auris isolated from the environment and clinics [42]. Furthermore, genomic epidemiology helps identify the geographical phylogenetic clades of isolate origin [11]. By this means, five unique clades of C. auris consisting of South Asian (clade I), East Asian (clade II), African (clade III), South American (clade IV), and Iranian (clade V) have been identified [9, 15–17]. Furthermore, three C. auris isolates detected in Singapore, and an independent WGS submission from Bangladesh in the NCBI database, which are genetically distinct from all known clades (I–V) reveal the discovery of a new clade of C. auris as clade VI from Singapore and Bangladesh [43, 44]. The worldwide dissemination of C. auris could be associated with the travel of individuals who have previously encountered C. auris in healthcare environments [45]. Phylogeographic mixing was observed in four predominant clades [46, 47]. Indeed, widespread dissemination of clade I was found in many countries, including the United Arab Emirates, Saudi Arabia, the USA, the UK, France, Pakistan, India, Kenya, Germany, and Canada. Clade II was identified in Canada, Japan, South Korea, and the USA. Clade III was detected in Australia, Canada, Kenya, South Africa, Spain, and the USA. Clade IV was present in Columbia, Israel, Panama, the USA, and Venezuela. Meanwhile, clade V remains confined to Iran, and clade VI recently established is found in Singapore and Bangladesh [43, 44, 47]. These clades possess distinct genetic and biochemical characteristics, and susceptibility profiles to antifungal agents [11, 18]. Specifically, C. auris clade I isolates are extremely resistant to fluconazole, and cross resistant to echinocandins and amphotericin B [48–50], while C. auris clade II isolates exhibit lower resistance to antifungal agents [45, 46, 50]. C. auris clade III isolates are commonly resistant to azoles with some displaying pan-resistance [46, 50, 51]. Clade IV isolates resist fluconazole, amphotericin B, and micafungin, and some are pan-resistant [35, 46, 50–52]. Clade V isolates resistant to fluconazole [15] and clade VI require further antifungal investigations.

The WGS analysis helps to identify the genes that harbor mutations responsible for antifungal resistance. Indeed, fluconazole resistance in C. auris was associated with different mutations in the ERG11 gene known as amino acid substitutions at some specific positions (e.g., F126T or F126L or V125A in South Africa, Y132F or K143R in India, Y132F in Venezuela) [11, 51, 53, 54]. Mutations in the zinc-cluster transcription factor-encoding gene TAC1B, which cause increased expression of efflux pumps such as Cdr1p, also contribute to clinical fluconazole resistance [55, 56]. Furthermore, a mutation in the ERG3 gene of C. auris has been reported to increase MIC₅₀ for caspofungin and fluconazole resistance [30, 51]. In addition, mutations in hot spot regions of the FKS genes, especially FKS1 (e.g., S639F, S639P, S639Y), cause echinocandin resistance in C. auris [30, 51, 57]. Recently, a novel mutation in the C. auris ERG6 gene was found to be associated with amphotericin B resistance, conferring a >32-fold increase in amphotericin B resistance [58].

Given the challenges of resistance, there is an urgent need for innovative antifungal medications to effectively treat C. auris infections. Some of the newest antifungal agents, demonstrating potential therapeutic effects against C. auris, are in various stages of clinical trials [50, 59]. Among them, ibrexafungerp, a new glucan synthase inhibitor, is the most promising, possessing potent activity against various Candida spp., including C. auris and C. auris isolates with FKS mutations [60, 61]. Fosmanogepix (a prodrug of its active moiety, manogepix) belongs to a new class of antifungals. It inhibits Gwt1, an enzyme localized in the endoplasmic reticulum necessary for the glycosylphosphatidylinositol (GPI) biosynthesis pathway, required for the anchorage of mannoproteins to the fungal cell wall [60, 62, 63]. Indeed, manogepix, the active moiety of fosmanogepix, has shown excellent activity against C. auris isolates [63, 64]. Reazafungin, a novel echinocandin with a prolonged half-life (130 h) and an inhibitor of (1,3)-β-d-glucan synthase, also shows promising activity against C. auris isolates both in vitro and in vivo [59, 60, 65]. New antifungal compound pyrimidinedione derivative MYC-053 [66] inhibits intracellular nucleic acid synthesis and synthesis of cell wall chitin [59]. It is known that the pyrimidinedione derivative MYC-053 has a broad range of antifungal effects against Cryptococcus spp., Pneumocystis spp., and Candida spp., including C. auris [66, 67]. New tetrazoles (VT-1129, VT-1161, and VT-1598) have a similar mechanism of action to other azole compounds, and these tetrazoles are under development [65]. VT-1598 selectively inhibits fungal Cyp51A (lanosterol demethylase) compared to mammalian cytochrome P-450 enzymes. It has demonstrated great anti-fungal activity against C. auris both in vitro and in vivo [68]. Although the PC945 is a novel triazole antifungal agent specifically formulated for the inhaled treatment of Aspergillus fumigatus infections [67], it was found to be a more potent inhibitor against a collection of 50 C. auris clinical isolates [69], but it still needs laboratory and clinical evaluations. SCY-247 is a second-generation fungerp compound with a broad spectrum antifungal activity. It has potent in vitro antifungal activity against various fungal species, including C. auris [70]. Furthermore, the efficacy of SCY-247 for treating C. auris needs further evaluation, as the in vivo potency has not been reported yet.

Conclusion

In this paper, we proceeded to a bibliometric and visualization analysis of publications indexed in the Web of Science (WoS) concerning the C. auris fungal pathogen as the main topic. This detailed bibliometric analysis of C. auris topic shows that this fungal pathogen has garnered growing attention and has progressively attracted more scholars worldwide. Furthermore, scientific production has undergone a dramatic growth rate of 37.91% concerning the C. auris topic. All this implies more documents will be published shortly about C. auris in every aspect.

Genomic epidemiology has unveiled six different clades, their widespread dissemination, and phylogeographic mixing. We know each clade possesses distinct characteristics and a profile of antifungal resistance. For this reason, it is significant to focus on each clade in detail, as the data obtained from one clade are different from the others and may not be extrapolated to all six clades. On the other hand, the challenges posed by pan-resistance to azoles, echinocandins, and polyenes drugs highlight the continuous need for new innovative antifungal molecules to effectively treat this emerging fungal pathogen and strategies to control transmission and overspreading of C. auris. Besides, unveiling the mechanisms and potent mutations implicated in diverse environmental resistances is crucial for novel treatment strategies. Much more studies should be done to figure out the behaviors of this yeast in biotic and abiotic conditions, even though current efforts have been focused on understanding the pathogenicity, drug resistance, and virulence factors. With this perspective, we foresee that the infection and high mortality rate caused by this yeast can be effectively controlled with a holistic approach.

Author contribution

Hamza ETTADILI: responsible for conceptualization; resources; methodology; data analysis; writing—original draft; writing—review and editing. Caner VURAL had roles in the conceptualization, visualization, reporting, drafting, reviewing, validation, writing—original draft and editing. The published version of the work has been reviewed and approved by both authors.

Declarations

Ethics approval

This article does not contain any studies with humans or animals.

Competing interests

The authors declare no competing interests.