Treatment of enterococcal infection can be challenging to clinicians due to the fact that enterococci are frequently resistant to various antibiotics. Traditionally, therapy for systemic enterococcal infections consists of the combination of a cell-wall active antibiotic (eg, ampicillin or vancomycin) with an amino glycoside. However, some cell-wall active antibiotics (eg, oxacillin and cephalosporins) have no activity against enterococci. In addition, enterococci have developed resistance against some of the commonly used cell-wall active antibiotics (eg, vancomycin). While newer antibiotics have been developed, including linezolid, quinupristin–dalfopristin, daptomycin, enterococci quickly developed resistance to some of these newer antibiotics as well. E. faecium is usually much more resistant to anti biotics when compared to E. faecalis. Antimicrobial resistance is classified as either intrinsic or acquired; intrinsic resistance is related to inherent or natural chromosomally encoded resistance patterns, many of which are present in all or most of the enterococci.

A. Intrinsic Resistance

 Enterococci are intrinsically resistant to cephalosporins, penicillinase-resistant penicillins, and monobactams. They have intrinsic low-level resistance to many aminoglycosides, are of intermediate susceptibility or resistant to fluoroquinolones, and are less susceptible than streptococci (10- to 1000-fold) to penicillin and ampicillin. Enterococci are inhibited by β-lactams (eg, ampicillin) but generally are not killed by them. High-level resistance to penicillin and ampicillin is most often due to altered penicillin-binding proteins; β-lactamase producing strains have been rarely identified. In addition, few enterococci (ie, E. casseliflavus and E. gallinarum) are considered to be intrinsically resistant to vancomycin. This is a low level, constitutive resistance which is chromosomally encodes by the VanC gene.

B. Resistance to Aminoglycosides

 Therapy with combinations of a cell wall-active antibiotic (a penicillin or vancomycin) plus an aminoglycoside (streptomycin or gentamicin) is essential for severe enterococcal infections, such as endocarditis. Although enterococci have intrinsic low-level resistance to aminoglycosides (MICs < 500 µg/mL), they have synergistic susceptibility when treated with a cell wall-active antibiotic plus an aminoglycoside. However, some enterococci have high-level resistance to aminoglycosides (MICs > 500 µg/mL) and are not susceptible to the synergism. This high-level aminoglycoside resistance is due to enterococcal aminoglycoside-modifying enzymes. The genes that code for most of these enzymes are usually on conjugative plasmids or transposons. The enzymes have differential activity against the aminoglycosides. Resistance to gentamicin predicts resistance to the other aminoglycosides except streptomycin. (Susceptibility to gentamicin does not predict susceptibility to other aminoglycosides.) Resistance to streptomycin does not predict resistance to other aminoglycosides. The result is that only streptomycin or gentamicin (or both or neither) is likely to show synergistic activity with a cell wall active antibiotic against enterococci. Enterococci from severe infections should have susceptibility tests for high-level aminoglycoside resistance (MICs > 500 µg/mL for gentamicin and >1000 µg/mL for streptomycin in broth media) to predict therapeutic efficacy.

C. Vancomycin Resistance

 The glycopeptide vancomycin is the primary alternative drug to the beta-lactam/aminoglycoside combination (eg, penicillin plus gentamicin or streptomycin) for treating enterococcal infections. In the United States, enterococci that are resistant to vancomycin have increased in frequency. These enterococci are not synergistically susceptible to vancomycin plus an aminoglycoside. Vancomycin resistance has been most common in E. faecium, but vancomycin-resistant strains of E. faecalis also occur.

There are multiple vancomycin resistance genotypes and phenotypes. The VanA phenotype is manifested by inducible high-level resistance to vancomycin and teicoplanin. VanB phenotypes are inducibly resistant to vancomycin but susceptible to teicoplanin. VanC strains have intermediate to moderate resistance to vancomycin. VanC is constitutive in the less commonly isolated species, E. gallinarum (VanC-1) and E. casseliflavus (VanC-2/VanC-3). The VanD phenotype is manifested by moderate resistance to vancomycin and low level resistance or susceptibility to teicoplanin. The VanE phenotype is classified as low-level resistance to vancomycin and susceptibility to teicoplanin. VanG and VanL isolates (usually E. faecalis) have low-level resistance to vancomycin and are susceptible to teicoplanin.

Teicoplanin is a glycopeptide with many similarities to vancomycin. It is available for patients in Europe but not in the United States. It has importance in investigation of the vancomycin resistance phenotype of enterococci.

Vancomycin and teicoplanin interfere with cell wall synthesis in Gram-positive bacteria by interacting with the d-alanyl-d-alanine (d-Ala-d-Ala) group of the pentapeptide chains of peptidoglycan precursors. The best-studied vancomycin resistance determinant is the VanA operon. It is a system of genes packaged in a self-transferable plasmid containing a transposon closely related to Tn1546 (Figure 1). There are two open reading frames that code for transposase and resolvase; the remaining seven genes code for vancomycin resistance and accessory proteins. The vanR and vanS genes are a two-component regulatory system sensitive to the presence of vancomycin or teicoplanin in the environment. vanH, vanA, and vanX are required for vancomycin resistance. vanH and vanA encode for proteins that manufacture the depsipeptide (d-Ala-d-lactate) rather than the normal peptide (d-Ala-d-Ala). The depsipeptide, when linked to UDP-muramyl-tripeptide, forms a pentapeptide precursor that vancomycin and teicoplanin will not bind to. vanX encodes a dipeptidase that depletes the environment of the normal d-Ala-d-Ala dipeptide. vanY and vanZ are not essential for vancomycin resistance. vanY encodes a carboxypeptidase that cleaves the terminal d-Ala from the pentapeptide, depleting the environment of any functional pentapeptide that may have been manufactured by the normal cell wall building process. vanZ’s function is unclear.

Fig1. Schematic map of transposon Tn1546 from E. faecium that codes for vancomycin resistance. IRL and IRR indicate the left and right inverted repeats of the transposon, respectively. (Adapted and reproduced with permission from Arthur M, Courvalin P: Genetics and mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother 1993;37:1563.)

Similar to vanA, vanB, and vanD code for d-Ala-d-Lac, but vanC and vanE code for d-Ala-d-Ser.

Because enterococci that are resistant to vancomycin frequently carry plasmids that confer resistance to ampicillin and the aminoglycosides, newer agents such as daptomycin, linezolid, quinupristin–dalfopristin, and tigecycline (among others) are used for treatment of vancomycin-resistant enterococci (VRE) infections.

D. Trimethoprim–Sulfamethoxazole Resistance

 Enterococci often show susceptibility to trimethoprim sulfamethoxazole by in vitro testing, but the drugs are not effective in treating infections. This discrepancy is because enterococci are able to utilize exogenous folates available in vivo and thus escape inhibition by the drugs.

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مواضيع ذات صلة

Characterization of the Sulfonamide-Resistant Dihydropteroate Synthase in N. meningitidis

Resistance to Sulfonamides in Neisseria meningitidis

Streptomycin: The Second Antibiotic in The History of Antibacterial Agents

Drug Resistance

Agents Used to Treat Bacterial Infections

Antimicrobial Susceptibility Testing and Therapy for Bacillus and Similar Organisms

Penicillin- resistant bacteria

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