Mechanisms of antibiotic resistance in enterococci

Abstract

Multidrug-resistant (MDR) enterococci are important nosocomial pathogens and a growing clinical challenge. These organisms have developed resistance to virtually all antimicrobials currently used in clinical practice using a diverse number of genetic strategies. Due to this ability to recruit antibiotic resistance determinants, MDR enterococci display a wide repertoire of antibiotic resistance mechanisms including modification of drug targets, inactivation of therapeutic agents, overexpression of efflux pumps and a sophisticated cell envelope adaptive response that promotes survival in the human host and the nosocomial environment. MDR enterococci are well adapted to survive in the gastrointestinal tract and can become the dominant flora under antibiotic pressure, predisposing the severely ill and immunocompromised patient to invasive infections. A thorough understanding of the mechanisms underlying antibiotic resistance in enterococci is the first step for devising strategies to control the spread of these organisms and potentially establish novel therapeutic approaches.

Keywords::

• antimicrobial resistance
• enterococcus
• mechanisms of resistance
• vancomycin-resistant enterococci

Financial & competing interests disclosure

JM Munita is supported in part by a grant from the Chilean Ministry of Education and by Clinical Alemana de Santiago and Universidad del Desarrollo School of Medicine, Chile. CA Arias is supported by NIH-NIAD grant R01 AI093749. CA Arias has received lecture fees, research support and consulting fees from Pfizer Inc. Lectures and consulting honoraria from Novartis, Cubist, Forest Pharmaceuticals, Astra-Zeneca and Bayer Pharmaceuticals. Research support to CA Arias has been provided by Forest Pharmaceuticals and Theravance Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Enterococci are increasingly common nosocomial pathogens. The changing epidemiology of enterococcal infections with the rise of multidrug-resistant Enterococcus faecium in hospitals worldwide has important therapeutic implications.

• Ampicillin plus an aminoglycoside (gentamicin or streptomycin), the traditional combination for severe enterococcal infections, is increasingly ineffective due to emergence of resistance.

• Resistance to ampicillin in E. faecium is mediated by PBP5, a transpeptidase that functions in the presence of high concentrations of β-lactams.

• Resistance to cephalosporins is an intrinsic feature of enterococci and is mediated in part by CroRS, a two-component signaling pathway, and a system with competing kinase and phosphatase activity (IreK and IreP) that function to control expression of resistance while preserving fitness.

• Glycopeptide resistance is mediated by the van operons, of which nine have currently been described in enterococci. In general, they consist of genes that encode two-component signal transduction systems, which activate the genes responsible for the synthesis of modified peptidoglycan precursors and destruction of ‘normal’ (d-alanine ending) precursors.

• The vanA gene cluster, conferring resistance to vancomycin and teicoplanin, is the most commonly encountered cause of resistance to glycopeptides in the clinical setting and can be transferred between enterococci.

• Enterococci are often intrinsically resistant to most aminoglycosides due to the presence of the 6′-acetyltransferase enzyme AAC(6′)-Ii. As such, only gentamicin or streptomycin should be used to achieve synergy with cell-wall agents.

• Ampicillin plus ceftriaxone is a β-lactam combination against Enterococcus faecalis that appears to be as good as the ‘standard of care’ (ampicillin plus gentamicin) but with much less toxicity.

• Daptomycin (DAP) resistance is associated with multiple mutations but usually involves genes encoding regulatory systems that control cell envelope homeostasis and enzymes that synthesize cell membrane phospholipids and/or are involved in phospholipid metabolism.

• The combination of DAP with β-lactams may offer promise in the future to restore DAP susceptibility and prevent emergence of resistance.

• Linezolid resistance in enterococci continues to be low, but increasing reports in enterococci have been associated with longer duration of therapy.

• Quinupristin/dalfopristin retains bactericidal activity in vitro against in E. faecium (not E. faecalis), but the presence of Erm methylases (which are frequently found in clinical isolates) may decrease the bactericidal effect in vivo and reduce therapeutic efficacy as monotherapy.

• Enterococci are often resistant to quinolones with several mechanisms of resistance including mutation of the quinolone targets, efflux pumps and a transferable plasmid containing qnr, a gene similar to plasmid-borne quinolone resistance in the Enterobacteriaceae.

• Continued research focused on understanding the mechanisms of resistance in enterococci is important to develop novel combination therapies or new antimicrobial compounds.

Notes