High rates of human faecal carriage of mcr-1-positive multi-drug resistant isolates emerge in China in association with successful plasmid families

Zhong, L.-L.; Phan, H. T.; Huang, X.; Vihta, K.-D.; Sheppard, A. E.; Zheng, K.-J.; Li, H.-Y.; Zhang, X.-F.; Patil, S.; Zhang, Y.-F.; Shen, C.; Crook, D. W.; Walker, A. S.; Xing, Y.; Chen, Q.-y.; Lin, J.-l.; Feng, L.-Q.; Doi, Y.; Stoesser, N.; Tian, G.-B.

doi:10.1101/106575

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bioRxiv · 10.1101/106575

High rates of human faecal carriage of mcr-1-positive multi-drug resistant isolates emerge in China in association with successful plasmid families

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Abstract

SynopsisO_ST_ABSBackgroundC_ST_ABSmcr-1-mediated transmissible colistin resistance in Enterobacteriaceae is concerning, given colistin is frequently used as a treatment of last resort in multidrug-resistant Enterobacteriaceae infections. Reported rates of human mcr-1 gastrointestinal carriage have historically been low.\n\nObjectivesTo identify trends in human gastrointestinal carriage of mcr-1 positive and mcr-1-positive/cefotaxime-resistant Enterobacteriaceae in Guangzhou, China, 2011-2016, and investigate the genetic contexts of mcr-1 in a subset of mcr-1-positive/cefotaxime-resistant strains using whole genome sequencing (WGS).\n\nMethodsOf 8,022 faecal samples collected, 497 (6.2%) were mcr-1- positive, and 182 (2.3%) mcr-1-positive/cefotaxime-resistant. Trends in carriage were assessed using iterative sequential regression. A subset of mcr-1-positive isolates was sequenced (Illumina), and genetic contexts of mcr-1 were characterised.\n\nResultsWe observed marked increases in mcr-1 (now ~30% prevalence) and more recent (since January 2014) increases in mcr-1-positive/third-generation cephalosporin-resistant Enterobacteriaceae human colonisation (p<0.001). Sub-cultured mcr-1-positive/third-generation cephalosporin-resistant isolates were commonly multi-drug resistant.\n\nWGS of 50 mcr-1/third-generation cephalosporin-resistant isolates (49 Escherichia coli; 1 Klebsiella pneumoniae) demonstrated bacterial strain diversity (39 E. coli sequence types); mcr-1 in association with common plasmid backbones (IncI, IncHI2/HI2A, IncX4) and sometimes in multiple plasmids; frequent mcr-1 chromosomal integration; and loss of the mcr-1-associated insertion sequence ISApl1 in some plasmids. Significant sequence similarity with published mcr-1 plasmid sequences was consistent with spread amongst pig, chicken and human reservoirs.\n\nConclusionsThe high positivity rate (~10%) of mcr-1 in multidrug-resistant E. coli colonising humans is a clinical threat; the diverse genetic mechanisms (strains/plasmids/insertion sequences) associated with mcr-1 have likely contributed to its dissemination, and will facilitate its persistence.

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Zhong, L.-L., Phan, H. T., Huang, X., Vihta, K.-D., Sheppard, A. E., Zheng, K.-J., Li, H.-Y., Zhang, X.-F., Patil, S., Zhang, Y.-F., Shen, C., Crook, D. W., Walker, A. S., Xing, Y., Chen, Q.-y., Lin, J.-l., Feng, L.-Q., Doi, Y., Stoesser, N., Tian, G.-B.. 2017-02-07. High rates of human faecal carriage of mcr-1-positive multi-drug resistant isolates emerge in China in association with successful plasmid families. https://doi.org/10.1101/106575

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