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

Introduction

According to the World Health Organization (WHO), antibiotic resistance is one of today's greatest threats to global health, food security, and development¹. 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 subsp⁶. Though withdrawn from clinical use in the 1980s owing to its significant toxicity, it has been re-introduced for the treatment of multidrug resistant (MDR) bacteria,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 pneumoniae¹¹. Since then, several variants of mcr-1 and novel families of mcr genes have been identified in a variety of samples^12–18. 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 documents¹⁹. 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.

Methods

Results

Publications outputs and trends

A total of 1578 non duplicate publications indexed in Scopus were retrieved on November 15, 2019. Of the 1578 studies, 1105 met the inclusion criteria and were used for the bibliometric analysis (Figure 1)²⁷. The result of distribution by time indicates that the literature in this field was first published in 1973. A significant increase occurred in the number of publications from 35 in the period 1973-2009 to 1070 in the past decade (P value <0.001). 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%).

Figure 1. Flow diagram of the selection process of the included studies.

Countries/regions analysis

The top 10 most productive territories included two Asian countries, seven European countries and one country in North America. China dominated the literature in colistin resistance research with 212 items (19.18%), followed distantly by the USA (n = 166; 15.02%) and France (n = 120; 10.85%). China also had the highest citation frequency (Figure 2). International collaboration analysis for active countries is shown in Figure 3.

Figure 2. Top 10 countries with the most publications

Figure 3. International collaboration analysis for top 30 active countries.

Each node in the figure symbolizes a different country’ collaboration with other countries. The node’s diameter corresponds to the strength of collaboration. Links represent international collaboration pathways between countries. Cluster of countries having similar cluster color most probably represents a closely related research group. Links represent the strength of collaboration.

Author analysis

The 1105 publications were written by 5141 authors working on this subject. Author analysis highlighted 0.215 documents per author, 4.65 authors per document, and 7.37 co-authors per document, with a collaboration index of 4.74. A co-citation network of authors showed four clusters: the blue cluster dominated by Liu 2016; the red cluster dominated by Olaitan 2014; the green cluster dominated by Falagas 2005 and the purple cluster dominated by Xavier 2016 (Figure 4).

Figure 4. The co-citation network map of references from publications in colistin resistance research

Each node in the network symbolizes a different author’ co-citation. The node’s diameter corresponds to the strength of co-citation. Links represent co-citation pathways between authors. Co-citation network of authors showed four clusters. Links diameter represent the strength of co-citation.

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 China⁴⁵. 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 commitment¹¹. 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 mediated³⁶. 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^{14–18,33,54,55}. 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 resistance⁵⁸. 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 continents⁵⁹.

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.

Data availability