Global trends and hotspots in research of carbapenem-resistant Enterobacteriaceae (CRE): a bibliometric analysis from 2010 to 2020

Introduction

Carbapenem-resistant Enterobacteriaceae (CRE) is one of the fastest spreading multi-drug resistant (MDR) bacteria worldwide and is also a major cause of hospital-acquired infections (HAIs) (1). When first isolated from the stool sample of a 57-year-old woman with leukaemia (2), it has become a grave challenge and the all-cause mortality can reach as high as 32–65% (3,4). Therefore, much attention has been given to CRE infections in the fields of epidemiology, drug-resistant gene detection, infection control and antimicrobial therapy (5). However, most of them are still unresolved issues (6).

Research publications play vital roles in the scientific processes of bridging knowledge gaps, improving knowledge uptake, and knowledge application (7). For professionals who share similar interests in specific areas, academic collaborations will be facilitated by trust (8). Bibliometric analysis is an effective tool for quantitatively analysing academic research at the global, national, organizational and individual levels (9). Recently, it has been widely applied in various disciplines to comprehensively identify scientific advances, investigation hotspots, and research trends (10). The Web of Science (WoS) database is frequently chosen for retrieving publications, as it has a wide coverage of literature and provides comprehensive data for bibliometric analyses (11). VOSviewer is extensively used for tabulation, mapping, networking, and visualization to highlight the most influential countries, organizations, authors, sources, and documents (12). In addition, co-word biclustering analysis, a recently emerging bibliometric methodology, can generate a co-occurrence matrix and reveal research hotspots based on published evidence (13).

Therefore, a bibliometric analysis was conducted to overview of relevant publications and to assess the current status of contributors’ linkage and research trends in the field of CRE. Our findings will be valuable for academic and clinical investigators, as well will map the CRE research landscape and forecast the future work.

Methods

Literature search

We conducted a comprehensive search using the Web of Science (WoS) core collection Science Citation Index Expanded (SCI-EXPANDED) database (Thomson Reuters, New York, NY, USA) and EmBase database from 2010 to June 19, 2020. The search strategy syntax included “carbapenem-resistant Enterobacteriaceae”, “carbapenem-resistant Klebsiella pneumoniae”, “carbapenemase producing Enterobacteriaceae” and “carbapenemase producing Klebsiella pneumoniae” searched in both Medical Subject Headings (MeSH) and titles. While different languages cannot be analysed together by the bibliometric analysis, some Chinese database like China national knowledge infrastructure (CNKI) was not included. Thus, the language was restricted to English, and the document type was restricted to original article.

Data collection

Two authors screened the retrieved literature independently and determined eligibility. The full data of included publications, including author, title, abstract, keywords, source, language, citation, etc., were downloaded in a text format from the WoS core collection SCI-EXPANDED and EmBase database.

Bibliometric analysis

WoS core database output analysis

The basic characteristics of the retrieved publications, including the total number of documents, annual, national, institutional, and individual article counts, research field distributions, and top cited literature, were described using the intrinsic functions of the WoS core database and Microsoft Excel (version Microsoft 365). The count of annual national publication and the relevant growth trend were analysed using the online analysis platform of literature metrology (http://bibliometric.com/).

Network analysis

To illustrate the CRE research collaboration network and identify research hotspots and future trends, we conducted a bibliometric analysis using VOSviewer (version 1.6.10, Leiden University, Leiden, the Netherlands) to import the collected data. Subsequently, networks connecting authors, organizations, countries, citations and other factors were generated using co-authorship, co-occurrence, citations, bibliographic coupling and co-citation analysis. Overlay mapping was conducted to show the time scale of themes in the CRE field. In the visual maps, different colours indicate different clusters, and connecting lines indicate collaboration or co-citation. The numbers of documents, citations and keyword occurrences are represented by circle size, while the strength of the links is represented by the thickness of connecting lines.

Keywords biclustering analysis

The connections between high-frequency keywords and source literature and the connections among high-frequency keywords were displayed by co-words biclustering. First, we constructed a co-occurrence matrix of high-frequency keywords with Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) (version 2.0, designed by Professor Lei Cui from China Medical University). Second, the matrix was further clustered by gCLUTO (version 1.0, Graphical Clustering Toolkit, University of Minnesota, Minneapolis, MN, USA). The source literature was displayed in columns, and the high-frequency keywords were displayed in rows, and a binary matrix was generated. Finally, the semantic relationships between typical keywords and source literature in clusters of CRE research were mapped by matrix and mountain visualization.

Results

Bibliometric analysis of publication output

In total, 2,303 publications on the topic of CRE were identified in the WoS core database between 2010 and 2020. Thirty-three publications were excluded because they were published in non-English languages. Another 599 publications, included 238 reviews, 151 letters, 130 meeting abstracts, 49 editorials and 60 other types of publications, were also excluded due to non-target article types. Finally, 1,671 original articles were included for eligible quantitative analysis (Figure 1). Most of the publications (1,020, 61.0%) were open access.

Figure 1 Flow diagram of included publications. CRE, carbapenem-resistant Enterobacteriaceae; WoS, Web of Science; SCI-EXPANDED, Science Citation Index Expanded.

The literature counts by country between 2010 and 2020 were ranked to explore the global geographic distribution of publications in the field of CRE (Figure 2). The United States of America (USA) [533], China [234], Italy [133], France [122], and England [88] ranked as the top five prolific contributors in terms of CRE research. The United States Department of Health and Human Services, with 209 studies indexed in the WoS core database, United States National Institutes of Health [180], National Natural Science Foundation of China [122], National Institute of Allergy and Infectious Diseases [86], and United States Centers for Disease Control and Prevention [35] were the top five funding agencies (Figure S1A). Infectious diseases; microbiology; pharmacology and pharmacy; public, environmental, and occupational health; and immunology were the most frequent study areas (Figure S1B). A total of 292 journals have published articles on the topic of CRE, among which 59 journals have published more than 5 manuscripts. Antimicrobial Agents and Chemotherapy (AAC), Infection Control and Hospital Epidemiology, Journal of Antimicrobial Chemotherapy, Diagnostic Microbiology and Infectious Disease, and American Journal of Infection Control were the top five most productive journals in the field of CRE (Figure S1C). Bonomo RA, Kaye KS, Chen L, Kreiswirth BN, and Castanheira M were the most productive authors (Figure S1D). Case Western Reserve University, University of Pittsburgh, Zhejiang University, Tel Aviv University, and the Centers for Disease Control and Prevention were the most productive organizations (Figure S1E).

Figure 2 Bibliometric analysis of WoS core database output. The growth trends of the top 10 productive countries in CRE research from 2010 to 2020. WoS, Web of Science; CRE, carbapenem-resistant Enterobacteriaceae.

Bibliometric analysis of co-authorship

A total of 9,313 authors have published papers on CRE. VOS viewer was used to analyses a total of 239 authors with more than 5 publications in this field (Figure 3A). Among them, Bonomo RA from Case Western Reserve University, whose research mostly focused on ß-lactamase, was the author of 43 documents cited 1,186 times, with a total link strength of 276. The main collaborators were Kaye KS (link strength with Bonomo RA, 21; total link strength, 239) from the University of Michigan and Perez F (link strength with Bonomo RA, 21; total link strength, 184) from Louis Stokes Cleveland VA Medical Center.

Figure 3 Bibliometric analysis of the co-authorship. The cooperation of authors (A), institutions (B), and countries (C,D) in field of CRE research. The color indicated clusters, circle size indicated number of publications, the thickness of lines indicated strength of linkage (A,B,C).

A total of 2,690 organizations have published relevant papers, with 241 of them publishing more than 5 publications (Figure 3B). Case Western Reserve University has published 45 related papers with 1,140 citations, with a total link strength of 180. The main partners of the organization were the University of North Carolina (link strength with Case Western Reserve University, 17; total link strength, 127) and the Cleveland Clinic (link strength with Case Western Reserve University, 15; total link strength, 114).

The bibliometric analysis also showed that 91 countries have published relevant articles, with 52 publishing more than 5 publications (Figure 3C). The USA contributed most to the CRE field, publishing 533 documents that were cited 13,071 times, with a total link strength of 224. The main partners of the USA were China (link strength 21), Italy (link strength 18) and England (link strength 16) (Figure 3D).

The top ten countries, organizations and authors of CRE publications with the strongest co-authorship links are presented in Table S1.

Bibliometric analysis of keywords Co-Occurrence

Of the articles retrieved from the WoS core database, 1,988 author keywords were identified. A total of 142 keywords that occurred more than 5 times were defined as high-frequency keywords and enrolled in the analysis. The most frequent keyword was “carbapenem-resistant Enterobacteriaceae” (occurrences, 247; total link strength, 559), which had strong links to “Klebsiella pneumoniae carbapenemase” (link strength, 39; occurrences, 117), “Klebsiella pneumoniae” (link strength, 30; occurrences, 214), “ceftazidime-avibactam” (link strength, 26; occurrences, 45), “carbapenemase” (link strength, 17; occurrences, 220), and “colistin” (link strength, 16; occurrences, 58) (Figure 4). A word cloud was also generated to show the occurrence rates of high-frequency keywords. “Carbapenem-resistant Enterobacteriaceae”, “Enterobacteriaceae”, “carbapenemase”, “Klebsiella pneumoniae”, and “KPC” were ranked as the top five active keywords (Figure S2).

Figure 4 Bibliometric analysis of keywords. The co-occurrence of highly frequent author keywords. The color indicated clusters, circle size indicated number of occurrences, the thickness of lines indicated strength of linkage.

Bibliometric analysis of citations

The ranking of the top 10 cited articles in the field of CRE is shown in Table 1 (the top 100 cited articles are presented in Table S2). Most of the articles were randomized clinical trials focused on antimicrobial therapies or observational studies on outcomes and risk factors for CRE infection. Additionally, numerous in vitro studies have concentrated on carbapenem-resistance mechanisms, such as the genome of the CRE plasmid and the genotype of carbapenemase. Epidemiological studies revealing the prevalence of and mortality due to CRE infections, as well as methodological studies investigating the rapid detection of CRE, have also been extensively reported. The average number of citations in the top 100 most widely cited articles was 118 (range, 63–503). The article “Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with Whole-Genome Sequencing”, written by Snitkin et al. and published in Science Translational Medicine in 2012, was the most cited document (cited 503 times).

Table 1 The top ten most cited articles in the field of CRE
Full table

The top ten most-cited journals, countries, organizations and authors of CRE publications were ranked. The most cited journal was the AAC (impact factor 4.904), publishing 171 articles on CRE with 5,387 citations. Bonomo RA. from Case Western Reserve University, who published 43 articles, was the most cited author (cited 1,186 times) (Figure S3A). An institution analysis revealed that the University of Pittsburgh was the most cited institution, publishing 44 articles that were cited 1,636 times (Figure S3B). The USA was ranked highest for citations (13,071 times), publishing a total of 533 papers, with a total link strength of 3,508 (Figure S3C).

Bibliometric analyses of bibliographic coupling and co-citation

Bibliographic coupling analysis assesses links between documents that cite the same literature. The bibliographic coupling networks for authors, documents, journals and countries are shown in Figure S4. For document analysis, 9 clusters were formed; the largest cluster (277 items) focused on CRE infection outbreaks and relevant intervention strategies (shown in red). The representative paper was published in Science Translational Medicine in 2012 by Evan S. Snitkin. Co-citation analysis evaluates the link between two documents that are both cited in the same manuscript. The co-citation networks for authors, references and journals are shown in Figure S5. For authors, 17 clusters were identified, and Patrice Nordmann was the most co-cited author. For journals, 37 clusters were generated, and the largest cluster included 115 items. Amongst them, AAC was the representative journal.

Bibliometric analyses of theme terms and topic trends

There were 1,019 terms that occurred more than 10 times in the retrieved articles. In total, 10 CRE-related theme clusters were identified. The red cluster represents clinical trials of antimicrobial therapies for CRE infection, and the green cluster represents underlying mechanistic investigations of CRE. The blue cluster represents in vitro studies on CRE susceptibility or the activity of agents against CRE (Figure 5A). Figure 5B shows the overlay of the theme terms representing the topic trends of CRE research. The colour of the circle indicates the average year of publication. Recent frequent theme terms are marked in yellow. It was demonstrated that “ceftazidime-avibactam” (occurrences, 85; average publication year, 2018.26) and “whole-genome sequencing” (occurrences, 97; average publication year, 2017.94) are emerging hot topics.

Figure 5 Bibliometric analysis of theme terms. (A) Distribution of the theme terms. (B) Overlay visualization map of the topic trends. The size of the circles indicated the occurrences of theme terms. The distance between circles indicated their relationship, different colors indicated variety of clusters (A) and average publication year (B) respectively.

Keywords biclustering analysis and CRE research hotspots

A total of 2,066 keywords were obtained from the 1,671 retrieved studies. The total number of keywords including repeats was 5,782. Keywords that appeared more than 20 times were defined as high-frequency keywords. There were 38 high-frequency terms, which are listed in Table S3. The cumulative proportion of these terms was 43.9% (2,538/5,782). The high-frequency keyword/source article matrix and high-frequency keyword co-word matrix were generated by BICOMB (Table S4 and Table S5). According to subsequent biclustering, 38 terms were divided into 5 clusters, and the results are shown in the mountain diagram (Figure 6) and matrix diagram (Figure 7). Clustered keywords were analysed to determine the theme of each cluster.

Figure 6 Mountain visualization of biclustering of highly frequent keywords and literatures on CRE. Each peak represented a cluster. The distance between the peaks indicated the similarity between clusters. The height of the peak indicated the internal similarity of keywords in the cluster. The volume of the peak represented the number of high-frequency keywords in a cluster. The color of the peak top revealed internal standard deviation of a cluster, the red indicated low internal standard deviation, while blue means high. CRE, carbapenem-resistant Enterobacteriaceae.

Figure 7 Visualized matrix of biclustering of highly frequent keywords and identify numbers of literatures on CRE. The highly frequent keywords were shown as row labels, the sequence number of source articles were shown as column labels. The connection between highly frequent keywords were represented in the left cluster tree. The connection between source articles were exhibited in the above cluster tree. The color of the blocks indicated the frequency of keywords occurred in articles. Darker color revealed higher frequency. CRE, Carbapenem-resistant Enterobacteriaceae.

Cluster 0: carbapenemases associated with CRE antibiotic resistance.

Cluster 1: the role of plasmids in carbapenem or colistin resistance in Enterobacteriaceae.

Cluster 2: first-line antimicrobial agents against CRE and their efficacy and safety.

Cluster 3: epidemiology, clinical features and outcomes of CRE infections.

Cluster 4: genome sequencing of CRE and infection control.

Discussion

In our bibliometric analysis of CRE, a total of 1,671 publications on CRE were finally included in the bibliometric analysis and 5 related theme clusters were identified which mainly focused on epidemiology, resistance mechanisms, antibiotics treatment and infection control. A total of 142 keywords that occurred more than 5 times and the most frequent keyword was “carbapenem-resistant Enterobacteriaceae” with 247 occurrences and the total link strength was 559. The output on CRE has gradually increased during the last decade, and the USA has made the greatest contribution due to the 533 research papers. Agents that act against CRE, especially ceftazidime-avibactam (occurrences, 85; average publication year, 2018.26), and the early detection of CRE by genome sequencing techniques (occurrences, 97; average publication year, 2017.94) were emerging hot topics would probably attract future research interest.

Top-cited contributors in the CRE field

Citation analysis is extensively used to evaluate the quality of research work, as citation counts generally represent scientific acknowledgement by professionals (14). This study showed that the USA produced the highest number of publications and had the highest citation rate. A majority of the top 10 most-cited academic institutions and authors were located in the USA. This superior contribution by the USA can be attributed to the large number of prolific researchers and funding sources. Robert A. Bonomo was the top-cited author. His focus areas included antibacterial resistance, genetic epidemiology, CRE outbreaks, CRE treatment, surveillance and antimicrobial stewardship; therefore, he was the author most widely cited by scholars (15).

International collaborations

Co-authorship analysis showed that the USA played a leading role in the field of CRE research and was involved in the most collaborations worldwide. European countries such as France, Italy and England produced a large number of publications and gradually increased their collaboration with other countries. The number of research about CRE from China has increased rapidly since 2018 and therefore it has become the second most productive country. However, the total link strength of China ranked only 15th, reflecting moderate collaboration between China and other countries. A variety of practices have facilitated collaboration between China and other developed countries, such as increasing international collaboration funding, importing outstanding expatriate scientists, and promoting academic visits or exchanges with outstanding institutions.

Research hotspots and trends

Epidemiology of CRE

CRE is a serious pandemic with the isolation rate of 10.32 per 100,000 in hospital days and most of them were isolated from airway secretion and urinary samples (16). Klebsiella pneumoniae (K. pneumoniae) was the most prevalent organism, followed by E. coli and E. cloacae which were also with high all-cause mortality. Therefore, the epidemiology and prevention of CRE is highlighted.

Carbapenemases

The alarmingly rapid worldwide spread of carbapenemase-producing Enterobacteriaceae (CPE) is another research hotspot (16). According to amino acid sequences, carbapenemases are divided into different Ambler classifications (A, B and D) on the basis of a variety of carbapenem-hydrolysing activities (4). Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo (NDM), and oxacillinases (OXA)-type beta-lactamases are the dominant carbapenemases detected in CRE (17). Among them, KPC is frequently identified in mobile genetic elements and is potentially being widely disseminating (17).

Emerging CRE detection technology

The early detection of carbapenemase-producing Enterobacteriaceae (CPE) is a critical issue in preventing CPE dissemination (18) and genetic methods for detection have been extensively investigated. WGS is a superior discriminatory typing technology used in pathogen transmission research (19). Nucleotide-level variations within and the horizontal spread of carbapenemases can be determined by short/long-read genetic sequencers (20). The Xpert Carba-R kit, a well-adapted genetic measurement tool, is able to detect five major carbapenemases with high accuracy (21). The BD MAX instrument with Check-Direct CPE screen was also used for the detection of carbapenemase genes, reducing the turn-around time to only 3 h (22). In addition, rapid and affordable phenotypic assays are available for CPE detection, including matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), carbapenem hydrolysis assays that can detect the disappearance of the original carbapenem and/or the hydrolysis of the carbapenem after incubation with Enterobacteriaceae isolates (23). Future tests should be quick and simple (i.e., with a point-of-care device), providing physicians enough information for immediate action. They can then prescribe antibiotics more appropriately and avoid unnecessary antibiotic use.

Current therapies for CRE

There are limited treatment options for CRE-induced infection (4). Novel high-affinity carbapenemase inhibitors, including AVI, relebactam and vaborbactam, have been recently developed to overcome this dilemma (24). Among them, CAZ-AVI has been marketed in many countries and can be used as a salvage therapy for CRE-related infections, including complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) (25). Plazomicin is a novel aminoglycoside maintaining activity against CPE, with good efficacy in patients with serious infection due to CRE (26). Eravacycline is a new fluorocycline antimicrobial agent in the tetracycline class that has shown in vitro activity against CRE and has demonstrated noninferior efficacy in patients with cIAI compared to ertapenem (27). Furthermore, polymyxins, which are considered “old antibiotics”, have re-emerged in the clinic as an option for CRE infection, and combination therapy has been suggested to be superior to monotherapy in reducing mortality (28).

Strengths and limitations

Our study is the first bibliometric analysis evaluating publications on CRE extracted from the WoS core database. The data analysis is objective and comprehensive. The present study provides a large quantity of information illustrating the current status, hotspots and future outlook of CRE research. Additionally, the results were visualized by a variety of tools demonstrating the bibliometric results clearly. Nevertheless, some limitations are inevitable. First, while different languages cannot be analysed together by the bibliometric analysis, some Chinese database like CNKI was not included. Thus, the language was restricted to English which led to the neglection of some high-quality work in non-English media. Second, we attempted to avoid bias due to updated publications by conducting all the database searches in one day. There might be some new data missing, although the impact on citation frequency is likely minimal. Third, there might be some inaccurate data or deficiencies in the databases that we cannot identify. Finally, some keywords were presented as singular and plural and as abbreviations and full names; such inconsistent information can reduce the accuracy of bibliometric analyses. To account for this, time-consuming data combing was necessary.

Conclusions

The bibliometric analysis revealed that development of antibacterial agents, early etiological detection and genome sequencing techniques were the hotspots and would probably direct the future research directions which would also facilitate a better understanding of the epidemiology of drug-resistant bacteria and implementing the antibiotic stewardship program.

Acknowledgments

Funding: This study was funded by WU JIEPING medical foundation (320.6750.2020-04-31), Research Funds of Shanghai Health and Family Planning commission (20184Y0022, 20194Y0007), Program for Key but Weak Disciplines of Shanghai Municipal Commission of Health and Family Planning (2016ZB0304), Shanghai “Rising Stars of Medical Talent” Youth Development Program - Youth Medical Talents – Clinical Pharmacist Program (SHWJRS (2019)_072, Cultivation fund of clinical research of Renji hospital (PY2018-III-06), Clinical Pharmacy Innovation Research Institute of Shanghai Jiao Tong University School of Medicine (CXYJY2019ZD001) and China International Medical Foundation (Z-2018-35-2003).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-21-87). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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