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Klebsiella pneumonia and Its Antibiotic Resistance: A Bibliometric Analysis

Pharmacy Department, Jiangsu Vocational College of Medicine, 224005 Yancheng, Jiangsu Province, China Post Graduate Centre, Management and Science University, University Drive, Off Persiaran Olahraga, Section 13, 40100 Selangor, Malaysia Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, Shah Alam, Malaysia School of Electronic and Information Engineering, Suzhou University of Science and Technology, Suzhou, China


Introduction
Klebsiella pneumonia, belonging to the family Enterobacteriaceae, is a natural inhabitant of the gastrointestinal tract microbiome of healthy humans and animals [1]. It has a variety of antibiotic resistance mechanisms and is a common pathogen causing hospital-acquired surgical wound infections, digestive tract infections, and community-onset infections, which can cause outbreaks of nosocomial infection [2]. The global drug resistance rate of K. pneumonia has reached as high as 70%, and the infection-related fatality rate has also reached 40%~70% [3]. In recent years, multipledrug resistance (MDR) K. pneumonia and carbapenem-resistant Klebsiella pneumonia (CRKP) have emerged as a major global public health problem.
In this study, we reviewed the literature on antibiotic resistance of K. pneumonia by bibliometrics [4]. This study is aimed at analyzing the trend of antibiotic resistance research of K. pneumonia in recent 10 years. According to data from the Web of Science Core Collection (WoSCC), the CiteSpace5.8.R3 software system was employed to display the detailed analysis based on visualization of the cooperative network of the countries, coauthors, and co-occurring keywords [5]. The method and results of this paper may provide potential prospects for the study of antibiotic resistance of K. pneumonia in the future.

Results and Discussion
3.1. Publication Characteristics. The Web of Science Core Collection (WoSCC) database shows 9366 publications that use our search terms, with 8398 articles and 968 reviews. In general, the number of papers published in recent years shows an upward trend, which indicates that the number of papers published in antibiotic resistance research in K. pneumonia is receiving more and more attention from researchers. Especially in the past three years, the number of publications has increased sharply, accounting for almost half of the total number of publications. Therefore, the anal-ysis period of this study is from 2012 to 2021, and the research period is divided into one year.

Countries/Regions and Institutions Co-Operation
Analysis. The distribution of studies on antibiotic resistance research in K. pneumonia in different countries can be understood by analyzing the country information according to the affiliation of the authors. Many institutions or universities from different countries around the world have contributed to this research field. Research papers from 178 countries have been published, and we have listed the top 10 most productive and influential countries and institutions in K. pneumonia antibiotic resistance research field, based on the total publications, citations, and H-index during 2012-2021 ( Figure 1). As shown in Table 1, the USA and China ranked first and second, with 1,908 and 1,416 publications, accounting for 20.37% and 15.12% of the total, respectively, ahead of India (664 publications and 7.09%), which ranked third. In regard to institutions (   Besides the total number of publications, the H-index, which represents the cited influence of papers, was given in the tables, too. Sometimes, a high total number of publications or citation number alone does not ensure a high H -index. Therefore, some scientists prefer to use the H-index to rank top countries (institutions), because this bibliometric indicator can more fully evaluate the impact of research [4].
In our case, in terms of "most productive countries," the USA topped the H-index by a wide margin. However, in regard to prolific institutions, LERU is the most prolific institution with an H-index value of 65. We also analyzed the results using the CtieSpace 5.8.R3 to visually show the most productive countries (institutions) and their connections to each other (Figures 2 and 3). Meanwhile, to highlight the attention of core countries (regions) and relevant academic institutions in this field, the VOSviewer 1.6.18 and Scimago Graphica 1.0.17 software were used for analysis [6].

Authors' Coanalysis.
Among the top 10 authors with publications, four are from China, three from the USA, two from Australia, and one from France, respectively, as shown in Table 3. Li of Monash University, Australia, tops  Generating a productive author collaboration network is shown in Figure 4. The size of the circle indicates the number of papers the author has published, and the lines between the circles indicate the connections between the authors. The group of primary core authors is the most representative and provides centralized information. From the centrality analysis, Paterson (0.25) ranked the highest followed by Hsueh (0.15), Badal (0.09), and Bonomo (0.09), which reflect their emphasis on this field.     meanings were combined, such as "antibiotic resistance," "antimicrobial resistance," and "drug resistance." Table 5 shows the top 10 keywords for frequency and centrality in this field over the past 10 years. We also developed networks for the analysis in Figure 5. It can be seen that the top five keywords of co-occurrence were Klebsiella pneumonia, antibiotic resistance, Escherichia coli, Enterobacteriaceae, and infection. In order of centrality, the top five keywords were biological activity (0.17), synergy (0.14), penetration (0.14), antimicrobial peptide (0.12), and high prevalence (0.12). Centrality refers to the ratio of the shortest path that passes through a certain point and connects the two points to the total number of shortest path lines between the two points, which is used to describe the importance of a node. The larger the value is, the more influential the node is in the key position in the network [8].
3.5.2. Clustering Analysis. Keyword clustering analysis can cluster similar points together and identify clusters that represent relevant research areas. We use CiteSpace to summarize the clustering of the keyword timeline map. Cluster size is the number of terms contained in each cluster. CiteSpace gives cluster ID 0 to the largest cluster, cluster ID 1 to the second largest, and so on. As shown in Figure 6, the main research directions can be classified as follows: #0 whole genome sequencing, #1 antibacterial activity, #2polymyxin b, #3 identification, #4 combination therapy, #5 virulence, #6 drug resistance, #7 United States, #8 bactericidal activity, #9 mortality, #10 sequence, #11 liver abscess, #12 mgrb, #13 Escherichia coli, and # 14 carbapenem resistance: these clusters can summarize the development of antibiotic resistance research in K. pneumonia and reveal the current research hotspots.
3.6. Keyword and Reference Burst Detection. Keyword burst detection refers to a significant increase in the frequency of keywords in a short period of time. If we understand the studies with high attention in this period, we can judge the hot topics and frontiers of research in the field accordingly. Keyword burst detection of antibiotic resistance research in 10 years in K. pneumonia is shown in Figure 7(a). Sorted by emergence time, it can be seen that the research frontier is whole genome sequencing, activation, phage therapy, gut microbiota, and care associated infection. To some extent, this result represents the trend of the future research.
According to Figure 7(b), it can be seen that in the past 10 years that the research hotspot changes and advances the process of antibiotic resistance research in K. pneumonia. Depending on the burst strength, the first t papers are reviewed from two high-level journals: Lancet Infections Diseases and Clinical Microbiology Reviews [9][10][11][12]. The  [13]. Another three papers show that the heat continues to this day. Two of them are reviews about K. pneumonia [14][15][16][17]. Another article was published in PNAS in 2015 which sequenced the genomes of 300 diverse K. pneumonia and performed a pan-genome-wide association study (PGWAS) to look for associations between gene profiles associated with virulence and antibiotic resistance and the differing disease outcomes seen for K. pneumonia [18].  References marked in red indicate that the keyword usage frequency increases suddenly during this period. Blue represents a period of relative unpopularity.

Conclusion
This paper provides a visual and comprehensive literature review of antibiotic resistance research in K. pneumonia. We examined the characteristics of publications, collaboration between countries, institutions, and authors, and cooccurrence analysis of journals and keywords. In the past 10 years, there have been 9366 journal articles related to this field, and the number of publications increased rapidly, which showed that scientists are paying increasing attention to this area. Antibiotic resistance in K. pneumonia has emerged as a significant threat to global public health problems [19].
We find several interesting keywords with high cooccurrence frequency through co-word analysis. According to recent research, carbapenem-resistant Klebsiella pneumonia (CRKP) has been paid much attention. Carbapenems have strong antibacterial activity and a wide antibacterial spectrum. Carbapenems are the preferred drugs for the treatment of serious Enterobacteriaceae bacterial infections [20]. However, the emergence and prevalence of CRKP pose a serious threat to patients with low immune function and have become an independent risk factor leading to the death of patients with nosocomial infections [21].
Drug efflux, biofilm formation, enzymatic inactivation of the drug, alteration of drug targets, and reduced permeability due to porin loss or modification are the major mechanisms conferring antibiotic resistance to K. pneumonia [22]. For combating antibiotic resistance in K. pneumonia infections, several therapies are currently being developed. Phage therapy, phytotherapy, photodynamic therapy, antimicrobial peptides, and nanoantibiotics are the potential of some alternatives.
Phages have low natural toxicity and high strain specificity. Due to the specificity of phages, their action is limited to the site of infection and can prevent the destruction of the inherent microbiome [23]. This reduces the development cost of phage therapy compared to antibiotics [24].
Additionally, we highlight the highly cited papers and reveal the research hotspots on antibiotic resistance research in K. pneumonia. This paper uses CiteSpace software to perform bibliometrics and visualization analysis on antibiotic resistance research in K. pneumonia data from the Web of Science database. This work presents direct and specific ways to describe existing information in different perspectives to the reader and can provide reference and reference for the relevant scientific research workers in the topic selection and development direction of the research.

Data Availability
All data generated or analyzed during this study are included in this published article. Other data may be requested through the corresponding author.

Conflicts of Interest
The authors have no conflicts of interest to declare.