Bibliometric analysis of Scopus indexed publications on polymyxin resistance (2009-2018)


 Background: Antimicrobial resistance is a serious public health problem that has become a global threat. Special attention should be given to polymyxins (polymyxin B and colistin) which, since their reintroduction into clinical practice, are considered "last resort" drugs. The objective of this study is to perform a bibliometric analysis of scientific research on polymyxin resistance.Methods: Scopus database was used to retrieve documents relevant to polymyxin resistance. At the beginning, all kinds of documents without year restrictions were included. Subsequently, the study period (2009-2018) was limited and analyzed using SciVal. Specifically, the 10 institutions and countries with the highest production, authors, journals, and most cited articles were analyzed. The growth of publications and citations was graphed, in addition to an analysis of the keywords using VOSviewer.Results: A total of 1,306 documents were retrieved (1947-2019). Original articles (76.95%) and letters to the editor (15.47%) were the most frequent types of documents. English was the predominant language with 1,270 documents (97.2%). In the period 2009-2018, there was a significant growth in publications (p-value < 0.001) retrieving 833 (64%) documents. The received citations were 23,974, with a peak in 2016 (8,033 citations). The United States and China lead the scientific production with 146 (17.5%) and 137 (16.4%) publications, respectively. University of Fribourg (Switzerland) was the most productive institution on the subject (44 documents), although University of Zhejiang (China) has caused the greatest impact (73.5 citations/article). Antimicrobial Agents and Chemotherapy ranked first with 140 documents. Most of the documents were published in quartile 1 journals (82.7% and 69.1%, according to Scimago Journal & Country Rank and CiteScore, respectively).Conclusions: The number of documents on polymyxin resistance has increased significantly in the recent years. In the last few years alone, 64% of all documents have been published. The United States and China lead the scientific production. Greater efforts are still needed to tackle this global problem.


Introduction
Although efforts for the development of new antibiotics are constant, their number is still insu cient, many of these are modi cations of existing ones and only ensure temporary control [1]. Meanwhile, antimicrobial resistance (AMR) continues to be one of the main problems in public health, not only because of the high cost at the social level but also because of the high economic cost, therefore urgent actions are necessary to face this global problem [2][3][4]. The AMR, especially in gram-negative bacteria, has led to the rethinking of drugs that, due to their severe adverse effects, namely nephrotoxicity and neurotoxicity, were neglected more than 30 years ago [5]. Such is the case of polymyxins, a group of polypeptide antibiotics composed of 5 different chemical structures (A-E), of which only polymyxin B and E have clinical relevance, the latter being better known as colistin [6].
Since their reintroduction into clinical practice, they are considered "last resort" drugs because they serve as a nal alternative to the ineffectiveness of other drugs [7].
In 2017, the World Health Organization (WHO) in the GLASS (Global Antimicrobial Resistance Surveillance System) report noted that, due to cases of carbapenem resistance, the use of colistin had increased signi cantly. Although cases of colistin resistance are rare in countries that have the possibility of monitoring it, an emerging resistance to this drug has been noted [8], especially reported in Acinetobacter baumannii [9][10][11]. Therefore the WHO developed a technical guide for the detection and reporting of colistin resistance [12], in addition to molecular methods to support AMR surveillance [13,14]. Since then, various efforts have been made by researchers to develop detection mechanisms for polymyxin resistance, mainly in Enterobacteriaceae [15] and gram-negative bacteria [16].
Previously, various drugs have been studied with bibliometric indicators [17,18], as in the case of some antiparasitics such as antimalarial drugs [19], and antifungals such as triazoles [20]. Antibiotic resistance has also been studied in a general way [21] or individually, either focusing on which organ or system is affected, such as antimicrobial resistance to uropathogens [22], or according to the class of antibiotic, for example those resistant to carbapenem [23]. However, no bibliometric studies on polymyxin resistance have been performed. Although colistin is the best-known example, it is preferred to study the class of antibiotics to which it belongs. In such a way, it is necessary to analyze the information published so far in order to understand the current state of the art in relation to polymyxin resistance, as these will serve as the basis for future plans and actions aimed at controlling or reducing the AMR and thereby reduce its impact on health. The objective of this study is to comprehensively analyze research on polymyxin resistance, speci cally, bibliometric indicators such as the types of documents, the top ten institutions, countries, authors, journals, and articles in Scopus.

Methods
The search and data extraction was done in Scopus, due to the fact that it has a greater number of peer-reviewed journals [24].
When performing the search, terms used were extracted from the Medical Subject Headings (MeSH) from Pubmed and Emtree from Embase and from these a complex search strategy was generated: ( ( ( TITLE ( colistin W/1 resist* ) ) OR ( TITLE ( colistimethate W/1 resist* ) ) OR ( TITLE ( colimycin W/1 resist* ) ) OR ( TITLE ( "pol?m?x?n E" W/1 resist* ) ) OR ( TITLE ( "pol?m?x?n B" W/1 resist* ) ) OR ( TITLE ( pol?m?x?n W/1 resist* ) ) ) OR ( KEY ( "colistin resist*" OR "colistimethate resist*" OR "colimycin resist*" OR "polymyxin E resist*" OR "polymyxin B resist*" OR "polymyxin resist*" OR "polymixin resist*" ) ) ) OR ( TITLE-ABS-KEY ( "mobilized colistin resistance" OR "mobile colistin resistance" ) ) AND ( LIMIT-TO ( SRCTYPE, "j" ) ) AND ( EXCLUDE ( PUBSTAGE, "aip" ) ) AND ( EXCLUDE ( DOCTYPE, "er" ) ) AND ( EXCLUDE ( PUBYEAR, 2020 ) ) The asterisk (*) was used as a truncator or wildcard to collect all the variants of the word that have a root in common. For example, when you enter resist*, the search engine will show results for both resist-ent and resist-ance. On the other hand, some articles, especially the oldest ones, reported their research with different versions of the same word, such as polymyxin, polymixin, polymyxin, polymyxin, etc. In order to retrieve the largest number of documents, vowels Y and I of "polymyxin" were replaced with the question mark (?), which allows replacing a single character, nally being written as pol?m?x?n. The W/1 was used to search for variants that have a maximum of 1 term or none among the searched words, for example when searching for TITLE (colistin W/1 resist*), titles such as: colistin resistance, resistant to colistin, and resistance to colistin, among others, will be retrieved. The use of acronyms like "mcr" was avoided when formulating the search strategy since they were confused with false positive results such as "Multivariate Curve Resolution (MCR)". The search excluded 2020 results and was performed on 05/18/20. Erratum, articles in press and inde nite articles were also excluded. Field-Weighted Citation Impact (FWCI) was used as a bibliometric indicator and is de ned as the ratio of the total citations received by a document to the expected number of citations for similar documents [25]. Similar documents include those in the same discipline or area of study, the same type of document, and the same year of publication. It is calculated for the same year of publication and the following three years. Its basal value is 1, that is, if the FWCI is greater than 1, the result is more cited than expected according to the global average [25]. The number of documents per quartile was also counted according to Scimago Journal & Country Rank (SJR) and CiteScore (CS).
VOSviewer (version 1.6.10) was used to create a visual representation of the co-occurrence of the most relevant keywords [26]. For these frequently encountered terms, a minimum of 100 occurrences was placed as a limit.

Results
A total of 1,306 results were obtained (1947-2019). Most of the documents (Table 1) were articles (76.95%), followed by letters to the editor (15.47%) and then reviews (4.29%). The 1,306 documents were published in 13 languages. English was the predominant language with 1,270 (97.2%) documents, followed by Chinese with 12 (0.9%) documents. Since 1994, there has been at least one publication per year on polymyxin resistance, either colistin or polymyxin B. Before that year, the publications were not consecutive and the most frequently cited article discussed the rst mechanisms discovered on polymyxin resistance [27].   Table 2. Of these publications, 2 documents are reviews, the rest are articles, within which is the most cited document on polymyxin resistance. This document was published in The Lancet Infectious Diseases and its number of citations quadruples those received by the second place.  FWCI eld-weighted citation impact Table 4 shows the authors with the highest production on polymyxin resistance. Nordmann P. and Poirel L., both with the same a liation (University of Fribourg), dominate the list with the largest number of documents (43 each) and a similar number of citations (1,510 and 1,560, respectively). It is important to note that the most in uential authors on polymyxin resistance were Doi Y. from the USA and Wang Y. from China with 2,753 and 2,486 citations, respectively.    Table 7 shows the number of documents sorted by the quartile of the journal in which they were published, showing that more documents are published in journals with better quartiles.

Discussion
In other bibliometric studies [19,22] in which the document type is reported, the reviews are in second place after the articles. In our study, although letters represent the second type of document with the highest percentage of publications, only articles and reviews are among the 10 most cited documents on polymyxin resistance. An underlying explanation is that The Lancet Infectious Diseases and to a lesser extent other journals (Antimicrobial Agents and Chemotherapy, International Journal of Antimicrobial Agents and Journal of Antimicrobial Chemotherapy) accept research for publication under the category of research letter as a form of rapid communication, especially on relevant topics. An example of this is the most cited letter (173 citations) in the period 2009-2018 that belongs to Falgenhauer L. et al. [28] published in 2016 in The Lancet Infectious Diseases and which deals with the mcr-1 gene that confers resistance to colistin in carbapenemase-producing gram-negative bacteria and betalactamases that spread in Germany.
In 2016, there was a peak in the number of citations, exactly 8,033 citations, this is probably due to the great impact that the publication dealing with the paradigm shift had on the transfer mechanism of colistin resistance, which was considered only as a rare chromosomal mutation up to that time. Liu Y-Y et al. [29] demonstrated plasmid-mediated colistin resistance thanks to the mobilized colistin resistance (mcr-1) gene identi ed in pigs in China. Interestingly, in the same year another gene called mcr-2 was isolated in Eschericihia coli (E.coli) in Belgium [30]. In the following years other mcr genes were identi ed: in 2017 the mcr-3 gene in E.coli in China [31], mcr-4 in E.coli and Salmonella enterica serovar Typhimurium in three countries (Italy, Spain and Belgium) [32], mcr-5 in E.coli and Salmonella Paratyphi B in Germany [33], and mcr-6 in Moraxella pluranimalium in the United Kingdom [34]; in 2018 the mcr-7.1 and mcr-8 gene, both in Klebsiella pneumoniae in China [35,36]; in 2019 the mcr-9 gene in Salmonella enterica serovar Typhimurium in the USA [37]; and to date, the mcr-10 gene was isolated in Enterobacter roggenkampii in China [38]. This has contributed to the continuous growth of the scienti c literature relevant to polymyxin resistance, although they did not cause the same impact after 2016, as citations decreased (Fig. 1).
As in our study, other bibliometric studies reported that the USA ranked rst in the amount of scienti c production in resistance to other antimicrobials [19,20,22,23]. Likewise, the USA also obtained the rst place in those studies that analyzed the scienti c production of a certain drug, such as tramadol [39], aspirin [40] or clavulanic acid [17]. Given the large number of documents from the USA (n = 146), it is logical to expect them to obtain the highest number of citations (6,513). However, the UK achieved a signi cant number of citations (3,587) with fewer documents (n = 44). This may be due to their great international collaboration Although Antimicrobial Agents and Chemotherapy, Journal of Antimicrobial Chemotherapy and Eurosurveillance were the journals in which the 10 most cited documents were published three times, twice and twice, respectively, The Lancet Infectious Diseases with only 26 documents was 16.91 times more cited than the world average, achieving 137.9 citations/article, which triples the number of citations/article obtained by the journal with the largest number of documents in our study (Antimicrobial Agents and Chemotherapy). However, Antimicrobial Agents and Chemotherapy is the only one that has remained among the 5 journals with the highest scienti c production in other bibliometric studies, ranking rst on carbapenem resistance [23] and antifungal triazole resistance [20], second in antimalarial drug resistance [19], and third in antimicrobial resistance among uropathogens [22].
Finally, there are some limitations and strengths in our research. First, like other bibliometric studies, some results may have been missing due to publication in non-indexed journals in Scopus. However, this is the rst study on polymyxin resistance applying bibliometric indicators. Second, it was not possible to discern between articles related to humans and animals. Despite this, the relationship is closer than it seems because colistin is used as a growth promoter in the veterinary eld [43]. Furthermore, horizontal transmission of mcr genes occurs through multi-resistance plasmids from animals, humans, and retail meat [43,44].

Conclusion
The number of documents on polymyxin resistance in Scopus has increased in the last decade. Most of the documents come from high-income countries, with the USA and China being the countries with the highest scienti c activity in polymyxin resistance. This, together with the high-impact journals in which they were published, demonstrates the great importance of the subject and the rapid spread of AMR. Greater joint effort by clinicians, researchers and the pharmaceutical industries is still needed to confront this old enemy, which has become a global threat.

Funding
This study was self-funded.

Availability of data and materials
All data analyzed with SciVal in this study is included in Dataset 1: Data obtained from Scopus, a .CSV that contain list of studies analyzed.
Ethics approval and consent to participate Not applicable. Research topics clustered by mapping of co-occurrences of terms for publications related to polymyxin resistance. Of the 5,731 terms, 69 terms occurred at least 100 times. The size of the circles represents the occurrences of terms in title/key. The largest set of connected terms consists of 68 terms in three clusters. The three clusters can be interpreted as: "bacteria commonly associated with an emerging polymyxin resistance (red cluster, 26 items)", "drugs used in combination for multidrug-resistant organisms (green cluster, 23 items)", and "genetics of polymyxin resistance (blue cluster, 19 items)"

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