Genomic epidemiology of colistin-resistant Escherichia coli in China
Authors: Federico Perez, Robert A Bonomo
Journal: The Lancet Microbe (2020)

The seminal discovery of a mobile genetic determinant of colistin resistance, named mcr-1, among Escherichia coli isolated from food, animal, and human samples in China was first reported in 2015.1Liu Y-Y Wang Y Walsh TR et al.Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.Lancet Infect Dis. 2016; 16: 161-168Summary Full Text Full Text PDF PubMed Scopus (2628) Google Scholar This plasmid-mediated mechanism of resistance was immediately recognised as a threat to human health, given the use of colistin as an antibiotic of last resort to treat infections caused by extensively drug-resistant Gram-negative bacteria. Subsequently, the analysis using whole-genome sequencing (WGS) of 65 isolates from diverse origins discerned that the global population structure of mcr-1-carrying E coli is highly diverse, but dominated by two groups, the largest related to sequence type (ST) 10. Similarly, a high diversity of mobile genetic elements, with 13 plasmid incompatibility types, exists; IncI2, IncX4, and IncHI2 types accounted for 90% of mcr-1-carrying plasmids. While there was no clustering of sequence types by geographical origin or isolation from animal, human, or environmental sources, IncI2 and IncH12 plasmids clustered in Asia and Europe, respectively.2Matamoros S van Hattem JM Arcilla MS et al.Global phylogenetic analysis of Escherichia coli and plasmids carrying the mcr-1 gene indicates bacterial diversity but plasmid restriction.Sci Rep. 2017; 715364Crossref PubMed Scopus (104) Google Scholar China banned the use of colistin as a food additive in animals in 2017—the same year that the use of colistin for the treatment of infections caused by multidrug-resistant Gram-negative bacteria began in Chinese hospitals.3Walsh TR Wu Y China bans colistin as a feed additive for animals.Lancet Infect Dis. 2016; 16: 1102-1103Summary Full Text Full Text PDF PubMed Scopus (120) Google Scholar Thus, an unprecedented natural experiment was launched that eliminated the pressure provided by colistin use in food animals towards the selection of mcr-1-positive E coli, so that changes in the genomic epidemiology of colistin-resistant E coli could be attributed to the ban. In The Lancet Microbe, Cong Shen and colleagues report changes in the prevalence and genomic characteristics of mrc-1 in E coli after China enacted the colistin ban.4Shen C Zhong L-L Yang Y et al.Dynamics of mcr-1 prevalence and mcr-1-positive Escherichia coli after the cessation of colistin use as a feed additive for animals in China: a prospective cross-sectional and whole genome sequencing-based molecular epidemiological study.Lancet Microbe. 2020; 1: e34-e43Summary Full Text Full Text PDF Scopus (24) Google Scholar The prevalence of colistin-resistant mcr-1 harbouring E coli isolated in pigs from 14 Chinese provinces decreased from 45% before (2016) to 19% after (2018) the ban, with significant reductions occurring in ten of 14 provinces surveyed (p<0·0001). Focusing further in the city of Guangzhou, in the southern province of Guangdong, the authors documented a similar significant decrease in the prevalence of mcr-1-harbouring E coli among farm pigs, from 76% in 2016 to 24% in 2018 (p<0·0001). Pronounced reductions were also documented among healthy volunteers and patients colonised or infected with Enterobacteriaceae who were admitted to hospital, as well as in pork, water, and soil samples associated with slaughterhouses, where mcr-1-containing E coli was rarely found in 2018. By contrast, the prevalence of mcr-1 among patients admitted to hospital with infections was low in 2016 (2·1%) and remained so after the ban. These epidemiological observations were complemented with WGS of 755 isolates of mcr-1-containing E coli. This notable effort permitted the analysis of 688 genomes, a third of which belonged to the clonal complex associated with ST10. After the colistin ban, human colonisation with isolates belonging to the ST10 clonal complex declined, and were detected in only a few animal and environmental samples. Genomic analysis suggested that pigs were an important reservoir of mcr-1-producing E coli, since strains obtained from pigs were interspersed among strains from other sources. The exceptions were E coli strains from patients admitted to hospital with infection, where mcr-1 was almost exclusively found in IncH12 plasmids. After the colistin ban, a truncated version of the transposon typically associated with mcr-1 (Tn6330) without the insertion sequence (ISApl1) became more prevalent. By contrast, IncH12-carrying isolates were found to retain ISApl1, which a key mediator of mobilisation of mcr-1-harbouring plasmids. To further investigate the differences in the population structure of mcr-1-producing E coli before and after the ban, additional typing was undertaken with core genome single nucleotide polymorphism (cgSNP) and accessory gene distributions. Seven cgSNPs leading to missense mutations in four genes were significantly different, and 30 gene clusters with 49 genes out of 5700 accessory genes were distributed differently before and after the ban. Taken together, these data indicate that a major change in the population structure occurred. The remarkable work of Shen and colleagues illustrates how WGS can be harnessed to provide maximal strain discrimination and complete analysis of bacterial pathogens, including their core and accessory genomes, to understand changes in the epidemiology of mcr-1-producing E coli in China. Such comprehensive analysis of almost 700 genomes of mcr-1-positive E coli is only possible through the refinement of WGS as an epidemiological tool over the past decade, increasing its rapidity and improving the informatic platforms for analysis and interpretation, while lowering its cost.5Heather JM Chain B The sequence of sequencers: the history of sequencing DNA.Genomics. 2016; 107: 1-8Crossref PubMed Scopus (385) Google Scholar There are important limitations to this study. On the epidemiological level, information about the use of colistin in Chinese hospitals after 2017 was not analysed. Additionally, we are uncertain whether there have been infection control measures to prevent the dissemination of colistin-resistant E coli in the nosocomial setting. At the genomic level, a comparison with mcr-negative strains was not provided. Crucially, the epidemiological meaning of changes in novel genomic markers such as cgSNPs and accessory genes is difficult to interpret on a clinical level. Ultimately, such unprecedented level of genomic resolution might not clarify some of the fundamental epidemiological questions. Where and how did mcr-1-producing E coli enter the hospital population? What are the transmission dynamics, and what determines the pathogenicity of mcr-1-producing E coli?6Grad YH Lipsitch M Epidemiologic data and pathogen genome sequences: a powerful synergy for public health.Genome Biol. 2014; 15: 538Crossref PubMed Scopus (53) Google Scholar Notwithstanding these limitations, this study provides strong additional evidence of changes in the prevalence and genomic characteristics of mcr-1-producing E coli in China attributable to the ban of colistin use in food animals.7Wang Y. Changes in colistin resistance and mcr-1 abundance in E coli of animal and human origin following the ban of colistin-positive additives in China: an epidemiological comparative study. Lancet Infect Dis. [In press].Google Scholar Moreover, this unique study advances the use of genomic tools that can applied to future analyses of mcr-1-producing E coli and other pathogens of public health concern, furthering the momentum of genomic epidemiology in infectious diseases.8Armstrong GL MacCannell DR Taylor J et al.Pathogen genomics in public health.N Engl J Med. 2019; 381: 2569-2580Crossref PubMed Scopus (43) Google Scholar We declare no competing interests. Dynamics of mcr-1 prevalence and mcr-1-positive Escherichia coli after the cessation of colistin use as a feed additive for animals in China: a prospective cross-sectional and whole genome sequencing-based molecular epidemiological studyA rapid, ecosystem-wide, decline in mcr-1 was observed after the use of colistin in animal feed was banned, with associated genetic changes in MCRPEC. Withdrawal of antimicrobials from animal feed should be an important One Health measure contributing to the wider control of antimicrobial resistance globally. Full-Text PDF Open AccessPathogenicity of mcr-1-positive Escherichia coli from human infectionsYan Jiang and colleagues1 announced that mcr-1-positive Escherichia coli isolates from human infections were associated with low prevalence, fewer outbreaks, low mortality rates, and a scattered genetic background. Our previous study2 found that the genome structure of mcr-1-positive E coli from human infections is different from other sources, which could be associated with the ability of these isolates to cause infection. As Federico Perez and Robert Bonomo3 commented in regard to our study,2 the pathogenicity of mcr-1-positive E coli remains unexplored. Full-Text PDF Open Access