The rise of the Enterococcus: beyond vancomycin resistance

Abstract

The genus Enterococcus includes some of the most important nosocomial multidrug-resistant organisms, and these pathogens usually affect patients who are debilitated by other, concurrent illnesses and undergoing prolonged hospitalization. This Review discusses the factors involved in the changing epidemiology of enterococcal infections, with an emphasis on Enterococcus faecium as an emergent and challenging nosocomial problem. The effects of antibiotics on the gut microbiota and on colonization with vancomycin-resistant enterococci are highlighted, including how enterococci benefit from the antibiotic-mediated eradication of Gram-negative members of the gut microbiota. Analyses of enterococcal genomes indicate that there are certain genetic lineages, including an E. faecium clade of ancient origin, with the ability to succeed in the hospital environment, and the possible virulence determinants that are found in these genetic lineages are discussed. Finally, we review the most important mechanisms of resistance to the antibiotics that are used to treat vancomycin-resistant enterococci.

Key Points

  • Enterococci are some of the most versatile organisms found to infect hospitalized patients. The epidemiology of enterococcal infections has evolved since the emergence of these pathogens and has seen the rise of Enterococcus faecium as a nosocomial pathogen with serious clinical implications.

  • The effect of antibiotics on the microbiota of the gastrointestinal tract and subsequent alterations in the regulation of the gut immune system can favour colonization by multidrug-resistant enterococci.

  • Enterococcal genomes are extremely malleable, with the ability to exchange large fragments of chromosomal DNA. In addition, the lack of CRISPR (clustered regularly interspaced short palindromic repeats) elements has a potential role in the adaptation of hospital-associated enterococci.

  • Specific pathogenicity factors contribute to the ability of enterococci to produce disease and/or survive in the gastrointestinal tract of mammals. The major factors include secreted and cell surface-associated determinants.

  • Antibiotic resistance is widespread for the anti-enterococcal antibiotics that are most commonly used in clinical practice, and the mechanisms of resistance for many of these antibiotics are known. These antibiotics include ampicillin, linezolid, daptomycin and quinupristin–dalfopristin, and there is also high-level resistance to aminoglycosides. Such resistances have important therapeutic implications.

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Figure 1: The crucial role of the gastrointestinal tract in enterococcal infection and spread.
Figure 2: The effects of antibiotic administration on the gastrointestinal microbiota and the emergence of vancomycin-resistant enterococci.
Figure 3: Major routes of nosocomial transmission of vancomycin-resistant enterococci.
Figure 4: Main mechanisms of enterococcal antibiotic resistance.

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Acknowledgements

The authors have been supported by US National Institutes of Health grants R01 AI067861 and R37 AI47923 (B.E.M.), and R00 AI72961 and R01 AI093749 (C.A.A.) from the US National Institute of Allergy and Infectious Diseases (NIAID). The authors are grateful to J. Sillanpaa and S. Nallapareddy for discussions and insights.

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Correspondence to Cesar A. Arias or Barbara E. Murray.

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Glossary

Probiotics

Microorganisms such as bacteria and yeasts that, when ingested, are thought to provide a beneficial effect to the host.

Third-generation cephalosporins

β-lactam compounds with broad-spectrum activity against Gram-positive cocci (except enterococci) and many Gram-negative bacteria. These antibiotics include ceftazidime, ceftriaxone, cefotaxime and cefpodoxime.

Lipopolysaccharide

An important component of the outer membrane of Gram-negative organisms, composed of a membrane lipid (lipid A) and a polysaccharide chain.

Flagellin

A protein that forms the flagellum of Gram-negative bacteria.

Toll-like receptors

Receptors that are found on and in eukaryotic cells and recognize molecular patterns which are shared by bacterial pathogens.

Lectin

A protein that binds to carbohydrate moieties.

Clonal complexes

Groups of bacterial isolates, as derived from multilocus sequence typing (MLST) analysis. A clonal complex usually includes isolates that differ from one another at only one of the seven loci analysed by MLST.

Clade

A group of bacterial isolates that are genetically related and probably share a common ancestor.

Pheromone-responsive plasmids

Plasmids that are known to respond to a peptide pheromone produced by a recipient cell, which initiates the mating process.

Aggregation substance proteins

A family of surface-localized proteins that are encoded by pheromone-responsive plasmids. These proteins mediate binding of donor bacterial cells to recipients cells.

LPXTG-like motifs

Specific amino acid sequences (X refers to any amino acid) that are found in surface proteins and are necessary for the specific attachment of the protein to the cell wall peptidoglycan.

Immunoglobulin-like folds

Structural domains of immunoglobulins, consisting of two sheets of antiparallel strands that form a sandwich-like structure. These folds are shared by some bacterial surface proteins.

Pseudogene

A gene that has lost its ability to be expressed or to be functional.

Pili

Hair-like projections that are present on the bacterial surface.

Pilin subunits

Proteins that form the pilus.

Sortase

An enzyme for which the main function is to attach surface proteins to the cell wall peptidoglycan or to other proteins after recognition of an LPXTG motif.

Opsonic

Referring to the ability of a moiety to increase phagocytosis of an invading pathogen.

Lipoteichoic acid

An important structure of the cell wall of Gram-positive bacteria. It is composed of cell membrane-anchored teichoic acids (chains of ribitol phosphate).

β-lactam antibiotics

Naturally produced antimicrobials encompassing several classes, including penicillins, cephalosporins, cephamycins, monobactams and carbapenems, all of which contain a ß-lactam ring.

Streptogramins

Naturally occurring antibiotics that are produced by soil bacteria and inhibit protein synthesis. A mixture of the streptogramins quinupristin and dalfopristin is currently available for clinical use and is approved by the US Food and Drug Administration for the treatment of vancomycin-resistant Enterococcus faecium infections.

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