REVIEW Virulence 3:5, 421–433; August 15, 2012;G 2012 Landes Bioscience Intrinsic and acquired resistance mechanisms in enterococcus Brian L. Hollenbeck and Louis B. Rice* Department of Medicine; Lifespan/Rhode Island Hospital and Alpert Medical School of Brown University; Providence, RI USA Keywords: enterococcus, antibiotic resistance, review, treatment Enterococci have the potential for resistance to virtually all clinically useful antibiotics. Their emergence as important nosocomial pathogens has coincided with increased expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in enterococci may be intrinsic to the species or acquired through mutation of intrinsic genes or horizontal exchange of genetic material encoding resistance determinants. This paper reviews the antibiotic resistance mechanisms in Enterococcus faecium and Enterococcus faecalis and discusses treatment options. Introduction Enterococci are Gram-positive, facultative anaerobic organisms characterized by their ability to grow at 6.5% NaCl concentra- tions and at high pH and to hydrolyze bile-esculin and L- pyrrolidonyl-B-naphthylamide (PYR). Formerly considered mem- bers of Lancefield group D streptococcus, DNA homology studies suggested that they are a distinct genus. Enterococci were previously considered commensal organisms of little clinical importance, but have emerged as serious nosocomial pathogens responsible for endocarditis and infections of the urinary tract, bloodstream, meninges, wounds and the biliary tract, among others.1 Recent surveillance data indicate that the enterococcus is the third most commonly isolated nosocomial pathogen (12% of all hospital infections), behind only coagulase-negative staphylo- coccus and Staphylococcus aureus.2 The rise in prevalence of enterococcal infections in humans is influenced to some degree by the ability of enterococci to escape the action of our most commonly used antibiotics. The influence of antibiotics is most directly seen on the extent to which enterococci colonize the gastrointestinal tract. Animal data have clearly shown the relationship between exposure to parenteral antibiotics, especially extended-spectrum cephalosporins and agents with potent activity against anaerobic bacteria, and high level gastrointestinal colonization by ampicillin-resistant Enterococcus faecium.3 The relationship between colonization and subsequent infection is also *Correspondence to: Louis B. Rice; Email: lrice@lifespan.org Submitted: 04/16/12; Revised: 06/25/12; Accepted: 06/26/12 http://dx.doi.org/10.4161/viru.21282 established. Along with increasing antimicrobial resistance, the acquisition of virulence factors and the ability of enterococcus to form biofilms have also contributed to the rise in nosocomial prevalence.4 This paper reviews the mechanisms underlying antibiotic resistance in enterococci, both intrinsic (universally found within the genome of the species) and acquired (through acquisition of new genetic material or through sporadic mutations to intrinsic genes). Interspecies differences will be addressed as they arise throughout the paper. This paper will additionally provide an overview of current treatment strategies for enterococcal infec- tions. Focus will be on Enterococcus faecalis and E. faecium, as these two species account for the overwhelming majority of human enterococcal infections (Table 1). Intrinsic Resistance β-lactams and cephalosporins. Growth of most bacteria depends upon enzymatic linkage of pentapeptide precursor molecules into a peptidoglycan cell wall. The enzymes responsible for these cross- linking reactions are referred to as penicillin binding proteins (PBPs) because β-lactams (structural analogs of pentapeptide precursors) bind covalently and disrupt normal cell wall growth.5 Attachment of β-lactam agents to PBPs results in impaired cell wall synthesis and, in most cases, programmed cell death via creation of reactive oxygen species.6 Enterococci express low- affinity PBPs (PBP5 in E. faecium, PBP4 in E. faecalis) that bind weakly to β-lactam antibiotics. As a result, minimum inhibitory concentrations (MICs) for penicillins are typically 2–8 mg/ml for E. faecalis and 8–16 mg/ml for E. faecium,7 much higher than MICs for streptococci and related Gram-positive organisms that do not contain chromosomally-encoded low-affinity PBP genes.8 At the population level, enterococcal MICs have increased over time.9,10 Galloway-Pena et al.11 demonstrated two distinct clades of E. faecium. These clades have PBP5 enzymes that vary in affinity, a result of differences in amino acid sequence and transcriptional regulation. Overproduction of non-mutated low- affinity PBPs represents a relatively rare mechanism by which enterococci express low-level resistance to penicillins.7,12 Early studies by Jawetz et al.13 indicated that enterococci were not killed by penicillin when exposed to drug concentrations in the range of the MIC (a phenomenon known as tolerance). Tolerance in E. faecalis has been attributed to removal of reactive oxygen species by the enzyme superoxide dismutase.14 In other www.landesbioscience.com Virulence 421