Multidrug-Resistant Enterobacter cloacae Complex Emerging as a Global, Diversifying Threat

Abstract

The Enterobacter cloacae complex (ECC) includes common nosocomial pathogens capable of producing a wide variety of infections. Broad-spectrum antibiotic resistance, including the recent emergence of resistance to last-resort carbapenems, has led to increased interest in this group of organisms and carbapenem-resistant E. cloacae complex (CREC) in particular. Molecular typing methods based on heat-shock protein sequence, pulsed-field gel electrophoresis, comparative genomic hybridization, and, most recently, multilocus sequence typing have led to the identification of over 1069 ECC sequence types in 18 phylogenetic clusters across the globe. Whole-genome sequencing and comparative genomics, moreover, have facilitated global analyses of clonal composition of ECC and specifically of CREC. Epidemiological and genomic studies have revealed diverse multidrug-resistant ECC clones including several potential epidemic lineages. Together with intrinsic β-lactam resistance, members of the ECC exhibit a unique ability to acquire genes encoding resistance to multiple classes of antibiotics, including a variety of carbapenemase genes. In this review, we address recent advances in the molecular epidemiology of multidrug-resistant E. cloacae complex, focusing on the global expansion of CREC.

Keywords: bacterial genomics; carbapenem-resistant Enterobacter cloacae complex; carbapenem-resistant Enterobacteriaceae; carbapenemase; multidrug-resistance.

FIGURE 1

Global distribution of carbapenem-resistant Enterobacter cloacae complex (CREC). Literature review identified 61 English-language publications identifying carbapenemase subtypes in CREC with a specified geographic location of isolation. The regional emergence of carbapenemases is evident, with KPC and IMI predominant in North America, OXA-48 and VIM predominant in Europe and the Middle East, and NDM and IMP predominant in China and Southeast Asia. Underlying data and referenced publications can be found in Supplementary Table S2. Abbreviations: FRI, French imipenemase; GES, Guiana extended-spectrum β-lactamase; IMI, imipenem-hydrolyzing carbapenemase; IMP, active-on-imipenem carbapenemase; KPC, K. pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; NMC, non-metallo carbapenemase; OXA, oxacillinase; VIM, Verona integron-encoded metallo-β-lactamase.

FIGURE 2

Emergence and spread of CREC. The first reports of KPC were in the mid-1990s. Carbapenem-resistant K. pneumoniae (CRKP) subsequently flourished due to a stable association between CRKP ST258 and bla_KPC, although rare detection of CREC was reported. More recently, the apparent diversification of both KPC and plasmid backbones harboring bla_KPC may have enabled both (1) the emergence of epidemic CREC clones stably associated with bla_KPC -containing plasmids (i.e., ST171, red); (2) sporadic uptake of diverse bla_KPC -containing plasmids by heterogenous E. cloacae complex clones; and (3) emergence of epidemic clones capable of harboring diverse bla_KPC-containing plasmids (i.e., ST78, purple).