Global trends and current status in colistin resistance research: a bibliometric analysis (1973-2019)

Background: Colistin resistance is a major breach in our last line of defense and without urgent action, we are heading for a post-antibiotic era, in which common infections and minor injuries can once again kill. To the best of our knowledge, the use of the bibliometric analytical technique for examining colistin resistance-related research does not exist in the literature. Methods: Here, we analyze and present bibliometric indicators of the global literature in colistin resistance research. The Scopus database was searched for articles on colistin resistance. The articles retrieved were analyzed using the bibliometrix R-package. Results: A total of 1105 publications were retrieved. There was a noticeable increase in the number of publications on colistin resistance research in the past decade. Six journals made up the core zone in colistin research and produced 35.83% of the published articles. The analysis across time-intervals revealed several keywords that had increased or decreased in usage when comparing the interval between 1973-2009 and 2010-2019. Authors’ keywords “Acinetobacter baumanii”, and “ Pseudomonas aeruginosa” were the most frequent encountered during the period of 1973-2009, while “ mcr-1”, “ Enterobacteriaceae”, “ Escherichia coli”, and “ Klebsiella pneumoniae” emerged in the past decade. Conclusions: There has been a significant growth in publications on colistin resistance in the past decade, suggesting an urgent need for action by different stakeholders to contain this threat of colistin resistance. Keyword analysis revealed temporal changes in the types of keywords used across time-intervals. These findings summarize a general vision on colistin resistance research and will serve as baseline data for future comparative purposes.


Introduction
According to the World Health Organization (WHO), antibiotic resistance is one of today's greatest threats to global health, food security, and development 1 . The emergence and unprecedented spread of carbapenemases have led to a resurgence in the use of last-line antibiotic colistin as salvage therapy 2-5 .
Colistin or polymyxin E is a polypeptide antibiotic developed in the 1950s. Originally, the antibiotic was isolated from the soil bacterium Paenibacillus polymyxa subsp 6 . Though withdrawn from clinical use in the 1980s owing to its significant toxicity, it has been re-introduced for the treatment of multidrug resistant (MDR) bacteria, particularly carbapenem-resistant Gram-negative bacterial infections 4,5,7,8 . It acts by interfering with bacterial cell membranes and/or the inhibition of bacterial respiration 9,10 .
In 2016, the first plasmid-mediated colistin resistance gene, mcr-1, was detected in Escherichia coli and Klebsiella pneumoniae 11 . Since then, several variants of mcr-1 and novel families of mcr genes have been identified in a variety of samples [12][13][14][15][16][17][18] . Colistin resistance is a major breach in our last line of defense and without urgent action, we are heading for a post-antibiotic era, in which common infections and minor injuries can once again kill.
Bibliometrics is the branch of library science that applies mathematical and statistical techniques to analyze articles, reviews, editorial letters, books, and other documents 19 . This is an important tool to assess new trends in scientific research. To the best of our knowledge, the use of the bibliometric analytical technique for examining colistin resistance-related research does not exist in the literature. Here, we analyze and present bibliometric indicators of the global literature in colistin resistance research.

Literature search
Articles on colistin resistance published in the literature were retrieved from the Scopus database on November 15, 2019. Keywords used for data extraction were obtained from published review articles on colistin resistance 20-22 . The search query used for data extraction was: TITLE-ABS-KEY ("colistin resistance" OR "polymyxin E resistance").

Study selection
Two authors independently performed the literature search using EndNote X9 (Bld 12062) produced by Clarivate Analytics. Papers published between January 1, 1973 and 31 December 2019 were included. After removal of duplicate results, titles and abstracts were reviewed for relevance to the research question. Any disagreement was resolved by consensus of the two authors. Experimental studies and studies that reported colistin sensitive bacteria were not eligible for inclusion. Searches were restricted to studies published in the English language.

Analysis methods
According to similar previously published bibliometric studies, selected documents were analyzed by different standard indicators including total number of publications, document types, countries/territories, authors, sources, total number of citations, h-index, average number of citations per publication, international collaborations and Bradford division analysis using the bibliometrix R-package 23,24 . Furthermore, graphs were plotted for visualization of co-citation networks and keyword co-occurrence of the text corpus extracted from the title and the abstract fields of the articles 25 . Co-citation has been defined as any two items (authors) that have been jointly cited by another item (author). To determine temporal changes in the type of keywords in colistin resistance research, analysis was carried out for two-time intervals of the study period: period 1, representing 1973 to 2009, and period 2, from 2010 to 2019. All data analysis was performed using the opensource bibliometrix R-package 26 on RStudio version 1.2.1335 (Boston, MA). The bibliometrix R-package provides a set of functions for quantitative research in bibliometric, including: (1) data loading and conversion to R dataframe (readFiles(), convert2df()), (2) data analysis (summary() and plot(), citations(), local citations(), Hindex(), lotka(), keywordGrowth(), keywor-dAssociation()), and (3) data visualization (biblioNetwork(), histNetwork()) 26 . Most of the publications were original research studies (n = 862; 78.01%), followed by editorial letters (n = 124; 11.22%), and reviews (n = 65; 5.88%).

Sources analysis
The top 10 cited papers, their citation frequency and titles are listed in Table 1. The most-cited article (n = 1632) was written by Liu et al.  Table 2. Bradford division analysis shows six sources in the core zone. These six sources are Antimicrobial Agents and Chemotherapy, Journal of Antimicrobial Chemotherapy, International Journal of Antimicrobial Agents, Frontiers in Microbiology, Journal of Global Antimicrobial Resistance, and The Lancet Infectious Diseases, which produced 35.83% of the published articles.

Countries/regions analysis
The top 10 most productive territories included two Asian countries, seven European countries and one country in North   China also had the highest citation frequency (Figure 2). International collaboration analysis for active countries is shown in Figure 3.

Keywords analysis
Temporal changes in the type of keywords were observed between the period 1 (1973 to 2009) and period 2 (2010 to 2019) (Table 3).

Discussion
The aim of this study was to analyze the global scientific outputs of colistin resistance research and show the trends and current status in colistin resistance research. The publication    trend showed a significant increase in the number of publications, particularly in the past decade, from 2010 to 2019, which corresponds with the peak clinical interest in its use as antibiotic of choice against MDR Gram-negative bacteria. This trend reflects the increasing attention paid by different stakeholders to concerns about colistin resistance worldwide and shows that research aiming to reduce the threat of colistin resistance is gaining attention in the scientific community.
Bradford division analysis showed a high concentration (35.83%) of publications in a few journals, namely Antimicrobial Agents and Chemotherapy, Journal of Antimicrobial Chemotherapy, International Journal of Antimicrobial Agents, Frontiers in Microbiology, Journal of Global Antimicrobial Resistance, and The Lancet Infectious Diseases. Four of these six sources are exclusively dedicated to antimicrobials, which is consistent with the global effort against antimicrobial resistance.
China was the leading country for publications related to colistin resistance, contributing 19.18% of all Scopus database articles published during the period of study. This may be due to the widespread use of colistin in animal feedstock and agriculture in China 45 . Moreover, the fact that China was the first country where a plasmid-mediated mechanism of colistin resistance, the mobilizable colistin resistance gene-1 (mcr-1), was reported, may be a contributing factor to China's commitment 11 . The majority of publications on colistin resistance research were produced by high-income countries, with a negligible contribution from low-and middle-income countries, particularly Africa, no countries in which were on the list of the top ten most productive countries. Several previous bibliometric studies of the literature have also reported a similar distribution of research publications in different fields from high-income countries 23,46,47 . This poor research output from African countries could be due to the lack of funding and poor facilities.
With regards to keywords, the analysis across time-intervals revealed that several keywords have increased or decreased in usage when comparing the interval between 1973-2009 and 2010-2019. This shows a temporal change in the type of keywords. Keywords "mcr-1", "Enterobacteriaceae", "Escherichia coli", and "Klebsiella pneumoniae", which were absent from 1973 to 2009, have emerged in the past decade. This could be attributed to the fact that until the first report of mcr-1 gene, colistin resistance in Enterobacteriaceae was believed to be chromosomally mediated 36 . However, since 2016, the mcr-1 gene was reported in Enterobacteriaceae recovered from food, animals, and human specimens in China, and it has subsequently been reported worldwide 11,48-53 . The wide spread of the mcr-1 dramatically challenges the newly renewed interest in colistin for clinical use and opens a new research topic on colistin. Currently, eight new mcr genotypes (mcr-2 to mcr-9) have been reported since the discovery of mcr-1 [14][15][16][17][18]33,54,55 . Furthermore, colistin-resistant bacteria without prior colistin exposure, possibly due to cross-resistance between colistin and cationic antimicrobials such as LL-37 and lysozyme, have also been reported 56,57 .
Unsurprisingly, the article "Emergence of plasmid-mediated colistin resistance mechanism mcr-1 in animals and human beings in China: a microbiological and molecular biological study," published by the Lancet 11 was the most cited article.
Country collaboration in colistin resistance research remains relatively weak. This raises the fundamental question of global collaboration to slow the development and spread of colistin resistance 58 . Country collaboration may be the most practical solution to this transmissible plasmid-mediated resistance in the era of globalization, with increased migration, trade and travel. Indeed, horizontal transfer of mcr-mediated colistin resistance is a rapid phenomenon, and can not only occur at a rather high frequency but can also disseminate across different bacterial species. Following its first description, plasmid-mcr has now been reported across all seven continents 59 .

Strengths and limitations of research
To the best of our knowledge, this study is the first to initiate baseline data on bibliometrics in colistin resistance research.
The study was not limited by language and a large literature including original articles, reviews, editorial letters and meeting abstracts published over a long period was included. The Scopus database covers the vast majority of online research, particularly broader biomedical research, and it has been established that it is the most user-friendly and easiest tool to use for bibliometric analysis services 60,61 . Furthermore, comprehensive and relatively objective data analysis was performed, which clearly highlighted the past and current status of colistin resistance research and predicted the future research frontier.
However, this global study is characterized by a number of limitations that are inherent in bibliometric analysis 62 . The main limitation of the present data is the reliance solely upon the Scopus database, which did not represent all the literature. Despite the fact that the Scopus database is considered an excellent source for bibliometric analysis, there are some journals that contain publications on colistin resistance but are not indexed in Scopus and therefore were not counted. Furthermore, we included papers where colistin resistance or polymyxin E resistance was used in the title or abstract or keywords; that inclusion of search items gives a much lower sensitivity to the search.

Conclusions
There has been a significant growth of publications on colistin resistance in the past decade, suggesting an urgent need for action by different stakeholders to contain this threat of colistin resistance. Unsurprisingly, an article on mcr-1 gene research ranked first among the top ten most cited articles on colistin resistance. Keyword analysis revealed temporal changes in the types of keywords used across time-intervals. These findings summarize a general vision on colistin resistance research and will serve as baseline data for future comparative purposes.