Although enterococcal resistance to vancomycin constitutes a serious problem, even more dreaded is the possibility that enterococci may transport resistance traits to more pathogenic organisms such as Staphylococcus aureus (SA), Staphylococcus epidermidis (SE), pneumococci, and Clostridia species. Since the only effective antimicrobial treatment for methicillin resistant SA (MRSA) infection is vancomycin, the impact of vancomycin resistant MRSA would be disastrous to many institutions. Knowledge of how enterococci become resistant to vancomycin, appropriate infection control precautions in the case of VRE isolation, and proper selection of treatment options, will aid in limiting the evolution and spread of VRE.

Enterococci and Antimicrobial Resistance

Enterococci are gram-positive coccoid bacteria that reside as normal flora within the gastrointestinal tract of humans and other animals. There are several species of the genus Enterococcus. However, 85%-90% of the clinical isolates are E. faecalis, and 5%-10% are E. faecium. They are the causative agents in urinary tract infections, abdominal and pelvic infections, wound abscess, endocarditis, bacteremia, and rarely, pneumonia and meningitis. Enterococci are reported to cause 12% of nosocomial infections.

Even though enterococci are not particularly virulent organisms and typically cause disease in patients with impaired host defenses, they are very resilient organisms and are intrinsically (naturally) resistant to a broad range of antibiotics. Enterococci, like other gram-positive cocci, use specific enzymes called penicillin binding proteins (PBPs) to catalyze cross-linking of precursors that make their rigid cell walls. B-lactam antibiotics work by binding these PBPs thereby preventing cross-linking of the cell wall. By modifying these enzymes, enterococci are resistant to all cephalosporins and have developed decreased susceptibility to penicillin and ampicillin without compromising cell wall synthesis. Up to 100 times the concentration of penicillin or ampicillin is required to inhibit enterococci than to inhibit a strain of S. pyogenes (Group A streptococcus). This relative insensitivity of enterococci to the penicillins yields organisms that are inhibited but not killed by penicillin. To achieve adequate killing of infections outside of the urinary tract, an aminoglycoside is added in combination with a penicillin to obtain synergistic bactericidal activity.

Enterococci have also acquired plasmid or chromosomal based genes that convey resistance to aminoglycosides, chloramphenicol, tetracyclines and other agents. The most important of these is high-level aminoglycoside resistance (HLAR) to streptomycin and gentamicin defined as minimum inhibitory concentrations (MICs) of >2,000 Fg/mL and 500 Fg/mL, respectively. An enterococcal strain that has HLAR will not be synergistic when used in combination with penicillin, ampicillin or vancomycin. The 1980's have seen an increase in HLAR strains that are also highly resistant to ampicillin and penicillin. Vancomycin then would be the only clinically useful antibiotic in treating infections caused by such isolates. The increasing prevalence of MRSA, as well as the increase in enterococcal infections caused by resistant enterococci, resulted in unprecedented utilization of vancomycin in the hospital setting. With increased use of vancomycin, reports of vancomycin resistance began to appear.

Vancomycin binds to and forms a glove-like fit over the boundary of the cell wall precursor which prevents the formation of the cell wall. Resistance to vancomycin is associated with the bacterial production of a new membrane-associated protein that prevents access of vancomycin to its target. The ensuing resistance may be high level, intermediate or low level (designated as vanA, vanB, and vanC, respectively). Strains with the high and intermediate level resistance traits are clinically most important and are likely to fail treatment when vancomycin is given as a single agent.

Risk Factors for VRE

Epidemiologic studies have defined the major modifiable risk factors for VRE infection as prior exposure to oral or parenteral vancomycin or broad spectrum antibiotics. One study reported 96% of VRE infected patients had prior exposure to vancomycin or broad spectrum antibiotics compared to only 47% of non-VRE infected patients in the control group who had been exposed to antibiotics. Other risk factors included length of hospital stay (59.9 vs.28.6 days), and more invasive procedures, i.e., abdominal surgery, Foley catheters, colonoscopy, sigmoidoscopy, and central venous catheters (40 vs. 9 procedures). Another study compared patients with VRE positive cultures to those with negative cultures. Those with positive cultures were more likely to have received parenteral vancomycin (10 vs. 5), oral vancomycin (4 vs. 0), parenteral aminoglycoside (13 vs. 5), or cephalosporin (26 vs. 11), within the previous two weeks. Other risk factors identified were length of antibiotic therapy (26.7 vs. 16.2 days) and length of hospital stay (64.3 vs. 26.9 days).

Recommendations for Controlling Emergence of VRE

Because vancomycin administration is a major risk factor for developing VRE, the prudent use of vancomycin may be the most effective step in decreasing the emergence of VRE.

HICPAC developed recommendations for preventing the emergence of vancomycin resistance. The guidelines, which focus on eliminating inappropriate or unnecessary vancomycin use, are summarized below (Centers for Disease Control and Prevention. Recommendations for preventing the spread of vancomycin resistance. MMWR 1995;44:1-11).

Situations in which the use of vancomycin is appropriate

Situations in which the use of vancomycin should be discouraged

When a suspected VRE is isolated from a clinical specimen, confirmatory MIC testing should be performed by the microbiology laboratory. While performing confirmatory susceptibility tests, the lab should notify the patient’s primary care giver, patient care unit, and the Hospital Epidemiology and Infection Control staff regarding the presumptive identification of VRE. Appropriate isolation precautions should be initiated promptly based upon the HICPAC guidelines for preventing the nosocomial transmission of VRE. The guidelines are summarized below.

Preventing Nosocomial Transmission of VRE

Eradication of VRE from hospitals is most likely to succeed when VRE infection or colonization is confined to a few patients on a single ward. In the event of VRE identification, the following measures should be taken to prevent nosocomial transmission of the organisms.

Hospital Infection Control staff should arrange for supply packs to aid in the implementation of the VRE isolation procedures. The pack contains the isolation procedures, signs to be posted on the patient’s door, antiseptic soap, a disposable stethoscope and blood pressure cuff, as well as other required supplies.

Treatment of VRE

The antimicrobial treatment of serious enterococcal infections usually includes a penicillin in combination with an aminoglycoside. Vancomycin, alone or in combination with an aminoglycoside, has been the mainstay of therapy for isolates that are resistant to $-lactam agents. The treatment options for patients with nosocomial VRE infections are limited to a few unproven combinations of antimicrobials and investigational drugs. Because VRE is new and treatment is difficult, consultation with an expert is essential. VRE are typically resistant to many other antibiotic agents. In published reports of recent VRE outbreaks, the isolates not only had high-level resistance to vancomycin and teicoplanin (unavailable in the U.S.) but also to ampicillin, penicillin, gentamicin, and streptomycin. Based on inconsistent study results it is difficult to select any one option as the therapy of choice.