A Bibliometric Review on Candida auris of the First Fifteen Years of Research (2009-2023)

Introduction Candida auris is a relatively novel pathogen first described in 2009 in Japan. It has increased its presence worldwide, becoming a public health concern due to its innate resistance to antifungals and outbreak potential. Methods We performed a query using the word “Candida auris” from the Scopus database, further performing a bibliometric analysis with the open-source R package Bibliometrix. Results 907 original articles were retrieved, allowing us to map the principal authors, papers, journals, and countries involved in this yeast research, as well as analyze current and future trends and the number of published articles. Conclusion C. auris will continue to be a pivotal point in fungal resistance research, either for a better understanding of its resistance and pathogenic mechanisms or for developing novel drugs.


Introduction
Candida auris was first described in 2009 when it was extracted from the external ear canal of a female inpatient in a hospital in Japan.Since then, there have been multiple reports around the globe of the emergence of this multidrug-resistant yeast of the Candida/Clavispora clade closely related to Candida haemulonii and Candida lusitaniae.This fungal pathogen has expanded through six continents and multiple countries, causing nosocomial outbreaks with a fatality ratio as high as 72%.It represents the first example of an emerging pathogenic fungus caused by global warming [1][2][3].
There are many alarming features of the disease caused by this emerging fungal disease, such as its complex recognition by phenotypic and biochemical tests requiring more advanced techniques such as DNA sequencing and matrixassisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry to species-level identification; its thermotolerance, in which C. auris can grow at high temperatures > 40 °C; its ability to tolerate high salt concentrations, both of which characteristics that contribute to its persistence and survival on abiotic surfaces for long periods; and its intrinsic resistance to one or more classes of antifungal drugs [2,3].
Most of the C. auris isolates are resistant to fluconazole.However, five clades have been described as emerging simultaneously worldwide with subtle differences in their de facto antifungal resistance.C. auris South Asia clade I isolates are usually resistant to fluconazole, variably resistant to amphotericin B, and rarely to echinocandins.South American clade IV includes isolates with variable resistance to amphotericin B. South African clade III is commonly resistant to azoles.A fifth clade was reported in Iran as resistant to all three major classes of antifungals.Recently, independently from its intrinsic resistance, C. auris prolonged exposure to antifungals can lead to panfungal drug resistance.Transmission of pan-resistant strains has been documented in Texas and the District of Columbia (DC) in the United States of America (USA).This alarmingly growing resistance constitutes one of the main problems when dealing with this fungal disease [3][4][5].
In the context of the COVID-19 pandemic, multiple hospital outbreaks were described in specialized units.In addition, cases in Brazil, Colombia, Mexico, the USA, and many more countries were reported with a shift in prevalence of this disease from Asia to America and presenting with a mortality as high as 83% [2,[6][7][8][9].
Due to all this is important to keep documenting and studying formally the disease caused by this emergent fungal species, primarily because many of the reports of this disease are descriptive studies.Bibliometric analysis is a method for exploring and analyzing scientific data with the primary objective of presenting the scientific efforts made in studying a specific subject, often used to describe and predict tendencies for the upcoming years in specific research [10].Here, we present to our knowledge the broader bibliometric analysis of information about C. auris presented in the literature.

Materials and Methods
2.1.Data Source and Search Strategy.Data were retrieved on 22 February 2023, from the Scopus database.The query used was "Candida auris" within the article title, its abstract, and its keywords for all the documents in the database (TITLE-ABS-KEY("Candida auris")).This means that we queried all publications where "Candida auris" as words must be together.
Documents were then filtered by document type, considering only original articles, and then by language, including only articles written in English (TITLE-ABS-KEY ("Candida auris") AND (LIMIT-TO(DOCTYPE, "ar")) AND (LIMIT-TO(LANGUAGE, "English"))).Quantitative and qualitative analyses, such as citation information (e.g., author(s), document title, and year), bibliographical information (e.g., affiliations and publisher), abstract and keywords (e.g., author keywords and index keywords), funding details, and other features, were extracted using the export document settings in the Scopus database.

Maps
Based on Bibliographical Data.Most of the analyses carried out in this study were performed with the help of the open-source R package Bibliometrix [11].

Overview
3.1.1.Main Information.A total of 907 original articles on C. auris were found between 2009 and February 2023.Descriptive information regarding the collection can be consulted in Table 1.It is worth to mention that the annual growth rate is 22.93% and the document average age is of 2.76, giving us the understanding that the majority of the research in C. auris has been carried out in the last years and that there are strong collaborations between researchers, because only 37 articles, a 4.08% of the collection, are single-authored documents.Moreover, the average number of coauthors is 7.85, and nearly 1 in every 3 articles has an international coauthorship.
3.1.2.Annual Scientific Production and Prediction.The yearwise distribution of these publications and the prediction of the number of articles for the following 3 years are shown in Figure 1.Between 2009 and 2014, there were only 7 original articles; then, the research interest increased over time.It can 3.2.Sources.Table 2 shows the top 10 sources that generated most of the publications in the study, specifying the number of publications (NP), total number of citations (TC), h-index (h), the year of the first publication for that source (YFP), and the Journal Citation Reports 2021 impact factor and category.
We can see that these journals contribute 33% of the scientific knowledge on the matter.It is important to highlight that even though Emerging Infectious Diseases is the last in this table, it is the third one in total citations and the one with the highest impact factor.Further analysis on the primary focus of the most sources revealed that it is indeed an interdisciplinary research field.For instance, the source with the most publications, Antimicrobial Agents and Chemotherapy, deals with Pharmacology as well as Microbiology.Similarly, Journal of Fungi, Mycoses, and Medical Mycology cover Mycology, Dermatology, and Veterinary Sciences, respectively.3. The features g and m stand for g-index and m-index, respectively.The g-index represents that given a set of articles ranked in decreasing order of the number of citations that they received; the g-index is the unique largest number such that the top g articles received together at least g 2 citations.Meanwhile, the m-index is the h-index divided by the number of years that a scientist has been active and for that reason is more relevant to an earlier career researcher than the h-index.The affiliation information is generated by Scopus and is based on the most recent publication.It is worth highlighting the fact that half of these authors belong to the Centers for Disease Control and Prevention (CDC).This was to be expected because, according to our analyses, the affiliation with most publication is the CDC with 62, followed by the University of Debrecen (51), the University of Delhi (45), the University of the Witwatersrand (34), and the University of Wisconsin (29).Going back to the top 10 authors, 6 of them have affiliations to universities or research centers in the USA, while 2 of them have affiliations in India and 2 in Europe.
3.3.2.Countries.The top 10 countries according to the NP are mentioned in Table 4.The worldwide scenario is led by the USA with 346 publications (38%).To analyze the international collaboration rate, publications were classified according to the country of affiliation of the corresponding author (CA).Records for the publications with a CA of each country were classified as either single country publication (SCP) or multiple country publication (MCP), and the MCP/CA ratio was calculated.Due to a report of missing data by Bibliometrix and inconsistencies in corresponding author information, we proceed to calculate these results without the software.5.It is worth noting that even though Antimicrobial Agents and Chemotherapy had the highest number of citations per source, it does not appear in this table.

Trending Topics.
In a bibliometric study, another important piece of information is to capture trending topics, so future research on C. auris could focus on emerging priorities for this disease.To uncover trending topics, the keywords provided by the authors in the most recent publications were analyzed.Results shown in Figure 2 indicate that the actual trending's are as follows: antifungal activity, Galleria mellonella, and essential oils.On the x-axis, we have the time span in years, and on the y-axis, we have the list of trending topics.The size of the circle indicates the frequency of the term, the position on the circle marks the year with most publications on that topic, and the line defines how long that term has been present.

BioMed Research International
Figure 4 is a thematic evolution map that indicates the evolution of author keywords in three different stages (2009-2014, 2015-2018, and 2019-2023).As we mentioned before from 2009 to 2014, there were only 7 original articles, and obviously, the keyword that most appeared was "candida auris".At the time, when the research on the subject was evolving and being more numerous, it began to diversify, generating more keywords.An important keyword is "multidrug resistance" as this shows up in the last two stages.At the last stage, "fosmanogepix" appears which is an experimental antifungal drug being developed by Pfizer.
Figure 5 shows a thematic map which classifies author keyword groupings according to the quadrant in which they are found.The x-axis corresponds to the relevance and the y -axis to the development of the topic.At the upper right quadrant are the motor themes, at the lower right quadrant the first article ever on C. auris, is at the center of the plot.This paper has a strong edge with the Chowdhary [12] review article about the rapid fungal infections globally, which means that they are frequently cocited.The colors represent clusters.
3.5.4.Social Structure.Figure 9 shows the country collaboration network.Here, we can see 2 main clusters: the blue cluster indicates relationships mainly between European countries while the red cluster highlights the relationships between USA and Asian, Arabic, and Latin American countries.Figure 10 is similar as it indicates country collaboration where the pink color line represents the connection between countries and its thickness identifies the degree of collaboration (minimum edge is 5).The thicker the line, the stronger the collaboration rate.The major collaborations were India-Netherlands 26, USA-Netherlands 22, Brazil-Netherlands 17, USA-Colombia 17, and USA-Brazil 16.

Discussion
C. auris infection has increased over the years, and its poor prognosis, high mortality rate, and rapid spread have drawn the attention of researchers, making it a trending topic.This bibliometric study retrieved 907 original articles published between 2009 and 2023.According to the exponential fitting curve, the annual number of publications showed an upward trend, rocketing up in the first half of the period, especially after 2015.According to the expected function model, the number of publications in 2023 will increase to 552 (or ~552), while in 2025, several 1572 are expected (or ~1572) which will be a higher number of publications in this field.
A total of 285 journals reported research in C. auris, and the top 10 are presented in Table 2. Antimicrobial Agents and Chemotherapy rank first with 64 publications (7.06%), followed by Journal of Fungi (58, 6.39%) and Mycoses  Table 3 shows the top 10 authors in terms of publication volume and centrality.The most prolific author, with 52 papers in this field, is Jacques F. Meis from the Canisius Wilhelmina Hospital at the Netherlands, with a h-index of 92, who has published over 599 articles according to Scopus, in which his most contributed topics between 2017 and 2021 were as follows: isavuconazonium, antifungal agents, and voriconazole (25 documents); Candida spp., antifungal agents, and voriconazole (12 documents); and Cryptococcus gattii, flucytosine, and Cryptococcus neoformans (6 documents).The second-ranked author was Abhay Sadashiv Chowdhary, a professor in Vallabhbhai Patel Chest Institute in New Delhi, India, with a h-index of 17, who has published over 114 articles, in which his most contributed topics between 2017 and 2021 were as follows: human influenza, oseltamivir, and laninamivir (3 documents); dengue, antibody-dependent enhancement, and flavivirus (2 documents); and mutation, isoniazid, and ethambutol (2 documents); this author, even having fewer articles compared to the first author, has received considerably higher citations compared to all authors in the top 10.The third-ranked author was Shawn R. Lockhart from the CDC, with a h-index of 67, who has published over 243 articles, in which his most contributed topics between 2017 and 2021 were as follows: Candida spp., antifungal agents, and voriconazole (33 documents); isavuconazonium, antifungal agents, and voriconazole (10 documents); and candidemia, invasive candidiasis, and antifungal agents (9 documents).It is worth mentioning that within this top 10 authors, 5 of them are affiliated with the CDC; this is to be expected since, being an emerging infection, a national agency like this one, in charge of protecting health and safety, injuries, and -1  These publications came from 77 countries.The top ten countries are distributed in Europe, America, and Asia, mainly in Europe (n = 6) (Table 4).Among them, the country with the largest number of publications is the USA (n = 346), followed by India (n = 129), United Kingdom (n = 82), and Netherlands (n = 75).The top 10 authors are located in 4 countries, with three-fifths of them located in the USA.In the bibliometric study by Ramírez-Malule et al. ( 2020) which covers research on C. auris between 2009 and 2018, China was in the tenth place among the countries with the most studies related to C. auris.Now, China has caught up to where the UK once stood, having advanced exponentially since 2018 from a total of 7 publica-tions to 60; it is important to remember that in contrast to the previous paper, we only considered original articles [14].Now, it is important to look at the collaborations between the different countries.With Bibliometrix software, it was found that the main collaborations were between the following countries: India-Netherlands (n = 26), USA-Netherlands (n = 22), Brazil-Netherlands (n = 17), USA-Colombia (n = 17), and USA-Brazil (n = 16); these countries were also the most productive in terms of publications relating to C. auris.
In the field of research, there are different factors for the existence of advances in medical research; one of them is academic capability, which is determined by the economic status of a country and governmental expenditure on healthcare [15].One country that invests the most in the   BioMed Research International research area is the USA, with USD10,784USD10,202 per resident [16], which could explain in a certain way why it is the country with the most publications on C. auris.
Further, in the analysis, the top cited publications have Lockhart et al.; this paper analyzed 54 isolates from 5 countries, not only collecting clinical data of the patients but also performing molecular techniques into the strains to know antimycotic resistance and whole genome sequencing, demonstrating that each geographical region has unique clades associated with azole resistance [17].The second most cited paper corresponds to Satoh et al., which describes the first case reported in Japan in 2009 [1].Schelenz et al., in 2017, published the first hospital outbreak of C. auris [18].The other seven that conform to the top ten most cited can be divided into outbreak reports [19,20], reviews [21,22], molecular methods to asses resistance and identification [23,24], and a global surveillance report [25].Interestingly at the moment of publication of this latest article, only 6 cases of C. auris have been reported.Therefore, it is slightly mentioned in the document.Furthermore, the three top cited papers have kept this position since a previous bibliometric was published in 2020 by Ramírez-Malule et al. [14].
Regarding the trending topics, it allows us to picture the changes through time in strain research.C. auris is a young pathogen allowing us to map its research efforts and critical themes.Considering previous work, we limited our trending topics to the last five years.Upon the start of 2017-2018, we saw a decline in molecular identification since it became a standard part of the research and a slight spike regarding C. haemulonii; this species represents another emerging pathogen with significant antimycotic resistance worldwide [26].Other pathogens with the same concerns can be found as trending topics in the upcoming years, such as Candida glabrata from 2019 to 2020.Another topic that peaked during 2019 was the "Azoles"; referring to the papers examining resistance, another topic of interest was "MALDI-TOF," which refers to matrix-assisted laser desorption/ionizationtime of flight.While this technique was developed in 1987, it quickly became a potential tool for microbial identification [27].In 2015, this method started identifying C. auris in research and clinical environments when cultures were proved insufficient [28].Antifungal resistance still is a theme of concern.Finally, in 2022, the trending topics include essential oils; this research branch is currently exploring aromatic plants such as Thymus or Cinnamomum [29,30].The oils have shown antifungal activity in resistant strains [31].Another trending topic is "galleria mellonella"; these larvae are currently used as an in vivo model for examining C. auris virulence [32].Finally, "antifungal activity" is another set of words currently trending, mainly due to the novel antifungals researched for this fungus and other mycoses.
The conceptual structure allows us to make visible research revolving around this pathogen.Divided into colored clusters, we can see how blue, green, pink, red, and brown dots revolt around the resistance and virulence of the strain.In contrast, orange ones focus on outbreaks and places where they occur, such as intense care units (ICUs).Other dots appear less related, like the light blue with mortality and gray ones, which link this strain with the COVID-19 pandemic and antimicrobial resistance.Similarly, the thematic map allows us to see how multiple branches came from a single term, "C.auris," in 2009.From 2015 to 2018, they mainly related once more to outbreaks, how to prevent them, and resistance.Then, it changed again from 2019 to 2023 when the main topics now revolve around virulence and other concerning pathogens.Novel drugs are being researched for their treatment.BioMed Research International All of this past and future can be better understood with the thematic showcasing the pathogen's story.We find declining themes such as MALDI-TOF and decontamination or environment in the lower left quadrant.These themes were relevant in the past but are now common in publications.Niche themes can be found in the upper left quartile.The topics here include echinocandin resistance, which is a motive of concern since some strains have shown innate resistance to all echinocandins.
Furthermore, the test with caspofungin sometimes exhibits an eagle effect which can be confusing in determining resistance [33].Another niche theme is the cell cycle to understand the yeast's physiology better.Moving into the lower right quartile, we find basic themes in C. auris research, such as the name of the pathogen and keywords such as biofilm, resistance, and candidemia.Finally, the upper right quartile showcases the motor themes and topics currently being pushed and will outline future research in this theme.Here, we find a cluster of keywords related to real-time PCR and C. haemulonii.The other method is to identify C. auris and allow for a better delineation from C. haemulonii, a close species complex.Furthermore, commercially available kits allow the identification in clinical settings that lack technology, like the MALDI-TOF [34].
Other keywords encompass other candida species, such as C. glabrata and C. parapsilosis, which are monitored for multidrug resistance [35,36].Finally, the last cluster focuses on the novel antifungal that is being researched.The new drug "fosmanogepix," also known as APX001, has a novel mechanism of action targeting the glycosylphosphatidylinositolanchored protein by inhibiting a fungal enzyme preventing the adherence of the fungal to surfaces, it is also the first broad-spectrum antifungal, and it currently has the fast track status by the US Food and Drug Administration (FDA) for various invasive fungal diseases [37].While not mentioned in our analysis, it is worth mentioning that other drugs, such as ibrexafungerp, olorofim, opelconazole, and rezafungin, are being developed for multi-drug-resistant fungi.
The conceptual structure also complements this perspective.It was divided into four clusters; the red one revolves around virulence factors and properties of the pathogen to avoid immune responses such as biofilms.It also includes risk factors, colonization, and multidrug resistance.Conversely, the green cluster focuses on antifungal drugs like caspofungin and amphotericin B and drug groups like azoles and echinocandins.The blue cluster includes a small number of words, such as candida, echinocandin, and fungal.One of the most interesting findings is "erg11," a gene described in Candida species and codes for azole resistance [38].
Finally, the cocitation network, while challenging to analyze each article by itself, however, is remarkable that the paper published by Satoh in 2009 stays at the center as being the most cocited in all C. auris literature; [1] it has strong relationships with other published papers including a review of the pathogen published by Chowdhary et al. in 2017 [12] and an original article published by Borman et al. in 2016 which compared the pathogenicity of C. auris isolates, as well as other key candida species [39].Finally, another article with a strong relationship was published in 2014 by Magobo et al.; this is a letter to the editor describing four isolates from South Africa which were molecularly identified and compared to other strains [40].Overall, the cocitation network allows us to see that current research is growing and allowing other papers to be created.
Future tendencies in C. auris revolve around the search for new antifungal drugs [41,42] that allow clinicians to increase the effectivity of treatments and reduce adverse effects in patients, while it is still in early developing, new antifungal families such as triterpenoids [43] and olorofim [44] strengthen existing antifungals such as azoles and echinocandins, and the research of new delivery methods like nanoparticles will be on the center of fungal research [45,46].
However, research will also focus on fully understanding how it works, molecular studies into resistant genes, and how they continue to evolve, and the use of molecular sciences to fully understand its pathogenetic abilities will open doors in the mycology field.In vitro studies using various agar combinations have focused on understanding the role and characteristics of biofilm formation, as well as the ability of the yeast to survive high temperatures and enzyme secretion as pathogenic mechanisms [47].On the other hand, in vivo models have also increased; with Galleria mellonella as the some term related this area that appeared in our results, however, the use of murine models with knockout genes also allow us to examine how different strains work within the immune system of a live being [48].
Finally, and due to current conditions, clinical research and epidemiology also have a road ahead; they must both understand factors such as the on-site setting of transmission and the actions that can be taken to control outbreaks and reduce infection rates, as well as understand the complications, coinfections and risk factors of patients by understanding from an on-site setting the transmission and the actions that can be taken to control the outbreaks and diminish infection rates; as well as understand the complications, coinfections and risk factors of the patients.The implications of the bibliometric data limit this article.We can only predict, to a certain extent, future tendencies.

Conclusions
This pathogen, C. auris, will continue to be a concern in clinical settings and research.Its capability to resist multiple antifungals prompts scientists and the pharmaceutical industry to develop novel treatments and more accurate and accessible identification methods.We also expect an increase in clinical trials for new antifungals.This work presents a trending analysis of topics related to C. auris.While some may not be pursued in the future, others will be the motor themes for researchers worldwide.What is certain is that this strain represents a challenge for hospitals and doctors alike since it continues to increase worldwide.

Data Availability
Data used in the preparation of this article were obtained from the Scopus database.Further inquiries can be directed to the corresponding author.

1 .
Authors.The top 10 authors according to the NP are shown in Table

1 .
Most Global Cited Documents.Out of the 907 original articles published in the 2009-2023 period on C. auris, the top ten articles that received the most citations are shown in Table

Figure 3
is a cooccurrence network, which is a collective interconnection of author keywords based on their presence in C. auris studies.A cooccurrence of two author keywords is when they appear in a particular article which forms an edge.The thicker the edge means a higher frequency of words cooccurring.The different colors used in the plot indicate word clusters.The clusters and their nodal positions were based on the values of the features betweenness, closeness, and page rank using a walk trap clustering method.

Figure 1 :
Figure 1: Estimation of original articles by year on Candida auris.

Table 1 :
Summary of descriptive information on the original articles collection found from 2009 to 2023.

Table 2 :
List of journals with the highest number of publications on the subject in our collection.

Table 3 :
List of authors with the highest number of publications on the subject in our collection.

Table 4 :
List of countries with the highest number of publications on the subject in our collection.
[1].3.Intellectual Structure.Figure8is a cocitation network and represents the frequency with which two documents are cited together by other documents.If at least one other document cites two documents, these documents are said to be cocited.The minimum number of edges is 15 to appear in this network.As we can appreciate in the plot, Satoh[1],

Table 5 :
Publications with the highest number of citations.