Genomic and Geographic Context for the Evolution of High-Risk Carbapenem-Resistant Enterobacter cloacae Complex Clones ST171 and ST78.

Angela Gomez-Simmonds,Zheng Wang,Nenad Macesic,Aidan O’Malley,Nora C Toussaint,Yue Hu,Medini K Annavajhala,Marla J Giddins,Anne-Catrin Uhlemann,Victor J Torres,Susan Whittier

doi:10.1128/mbio.00542-18

Abstract

ABSTRACTRecent reports have established the escalating threat of carbapenem-resistant Enterobacter cloacae complex (CREC). Here, we demonstrate that CREC has evolved as a highly antibiotic-resistant rather than highly virulent nosocomial pathogen. Applying genomics and Bayesian phylogenetic analyses to a 7-year collection of CREC isolates from a northern Manhattan hospital system and to a large set of publicly available, geographically diverse genomes, we demonstrate clonal spread of a single clone, ST171. We estimate that two major clades of epidemic ST171 diverged prior to 1962, subsequently spreading in parallel from the Northeastern to the Mid-Atlantic and Midwestern United States and demonstrating links to international sites. Acquisition of carbapenem and fluoroquinolone resistance determinants by both clades preceded widespread use of these drugs in the mid-1980s, suggesting that antibiotic pressure contributed substantially to its spread. Despite a unique mobile repertoire, ST171 isolates showed decreased virulence in vitro. While a second clone, ST78, substantially contributed to the emergence of CREC, it encompasses diverse carbapenemase-harboring plasmids, including a potentially hypertransmissible IncN plasmid, also present in other sequence types. Rather than heightened virulence, CREC demonstrates lineage-specific, multifactorial adaptations to nosocomial environments coupled with a unique potential to acquire and disseminate carbapenem resistance genes. These findings indicate a need for robust surveillance efforts that are attentive to the potential for local and international spread of high-risk CREC clones.

Highlights

Recent reports have established the escalating threat of carbapenemresistant Enterobacter cloacae complex (CREC)
To assess the diversity of 125 E. cloacae complex isolates collected at a northern Manhattan hospital system, we constructed a phylogenetic tree based on core genome single nucleotide polymorphisms (SNPs) (Fig. 1)
Our study provided robust evidence for the spread of two distinct ST171 clades across the United States, including a successful blaKPC-3-harboring sublineage demonstrating multiple foci of rapid, regionalized clonal proliferation in the Northeastern and northern Midwestern United States

Summary

Introduction

Recent reports have established the escalating threat of carbapenemresistant Enterobacter cloacae complex (CREC). CREC demonstrates lineage-specific, multifactorial adaptations to nosocomial environments coupled with a unique potential to acquire and disseminate carbapenem resistance genes. These findings indicate a need for robust surveillance efforts that are attentive to the potential for local and international spread of high-risk CREC clones. ST171 and ST78 isolates harbored the plasmid-encoded K. pneumoniae carbapenemase (KPC), while diverse resistance mechanisms were detected in other clonal backgrounds [7, 8] Taken together, these data suggest that the emergence of CREC has a complex history, driven in part by its ability to acquire and maintain blaKPC-harboring plasmids. We considered the potential contribution of resistance and virulence determinants to the recent emergence of CREC in the United States and worldwide

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Conclusion