Bureau of Epidemiology August 1997 Utah Department of Health
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Emerging Pathogens: Vancomycin Resistant Enterococci
Michael Barton, Pharm. D., Pharmacoepidemiology Program, Steven Hutchings, Pharm. D., Pharmacy Services, Karen Carroll, M.D., Interim Hospital Epidemiologist; University of Utah Hospital

n September 1995, the national Hospital Infection Control Practices Advisory Committee (HICPAC), in conjunction with the Centers for Disease Control and Prevention (CDC) published guidelines for preventing the spread of vancomycin resistance among gram-positive organisms. These guidelines were developed in response to a rapid increase in the rates of nosocomial infections due to vancomycin resistant enterococci (VRE) as detected by the National Nosocomial Infections Surveillance (NNIS) system. From 1989 to 1993, nosocomial VRE infections reported to the CDC increased from 0.3% to 7.9% of all nosocomial infections. The most dramatic change was the 34 fold increase in nosocomial VRE infection rates in intensive care units (0.4% to 13.6%) that was noted primarily in larger hospitals and university affiliated hospitals.

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

For treatment of serious infections caused by $-lactam resistant gram-positive microorganisms including MRSA.
For treatment of infections caused by gram-positive microorganisms in patients who have serious allergies to $-lactam antimicrobials.
When antibiotic associated colitis fails to respond to metronidazole therapy or is severe and potentially life threatening, oral vancomycin therapy is appropriate.
Prophylaxis, as recommended by the American Heart Association, for endocarditis following certain procedures in patients at high risk for endocarditis.
Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices as in the case of total hip replacement, cardiovascular, and major vascular operations at institutions that have a high rate of infections caused by MRSA or methicillin resistant SE.

Situations in which the use of vancomycin should be discouraged

Routine surgical prophylaxis other than in a patient who has a life threatening allergy to $-lactam antibiotics.
Empiric antimicrobial therapy for a febrile neutropenic patient, unless initial evidence indicates that the patient has an infection caused by gram-positive microorganisms and the prevalence of infections caused by MRSA in the hospital is substantial.
Treatment in response to a single blood culture positive for coagulase-negative staphylococcus, if other blood cultures taken during the same time frame are negative (i.e., if contamination of the blood culture is likely). Because contamination of blood cultures with skin flora could result in inappropriate administration of vancomycin, phlebotomists and other personnel who obtain blood cultures should be trained to minimize microbial contamination of specimens.
Continued empiric use for presumed infections in patients whose cultures are negative for $-lactam resistant gram-positive microorganisms.
Systemic or local prophylaxis for infection or colonization of indwelling central or peripheral intravascular catheters.
Selective decontamination of the digestive tract.
Eradication of MRSA colonization.
Primary treatment of antibiotic associated colitis.
Routine prophylaxis for very low-birth weight infants (i.e., infants who weigh < 1,500 g).
Routine prophylaxis for patients on continuous ambulatory peritoneal dialysis or hemodialysis.
Treatment of infections caused by $-lactam sensitive gram-positive microorganisms in patients who have renal failure.
Use of vancomycin solution for topical application or irrigation.

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.

Notify appropriate staff promptly when VRE are detected. This includes all individuals involved in direct contact care for the patient.
Place VRE patients in private rooms or in the same room as other patients who have VRE.
Wear gloves (clean, non-sterile gloves are adequate) when entering the room of a VRE patient. VRE can extensively contaminate the room environment.
Wear a gown (clean, non-sterile gown is adequate) when entering the room of a VRE patient.
Remove gloves and gown before leaving the patient’s room and immediately wash hands with an antiseptic soap. Hands can be contaminated via glove leaks or during glove removal, and bland soap does not always completely remove VRE from the hands.
Ensure that after glove and gown removal and hand washing, clothing and hands do not contact environmental surfaces in the patient’s room that are potentially contaminated with VRE (e.g., door knob or curtains).
Dedicate the use of noncritical items (e.g., stethoscope, sphygmomanometer, etc.) to a single patient or cohort of patients infected or colonized with VRE.

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.

Synercid®, which is a fixed 70/30 combination of two water soluble, and thus injectable, streptogramin compounds (quinupristin/dalfopristin), is an investigational drug that demonstrates the most promise. Synercid® has been shown to be very effective against vancomycin and multidrug resistant gram-positive bacteria including E. faecium, and other enterococcal strains. However, it has no effect against resistant E. faecalis. Synercid® can be obtained from Rhône-Poulenc Rorer by satisfying an emergency use protocol. Call the drug company at (610) 454-3071. Based only on in vitro tests, a triple combination of ampicillin, gentamicin, and vancomycin appears to be the best choice for empiric therapy of VRE. The ability to pick a specific empiric therapy or treatment is difficult given the varying susceptibilities and different species of enterococci. The microbiology laboratory’s ability to promptly and accurately detect vancomycin resistance and identify enterococcal species is critical. In addition, the laboratory’s ability to determine antimicrobial susceptibilities may be the most important step in selecting optimal drug therapy. The infectious disease specialist has a pivotal role in interpreting the MIC results for the organism and aiding in the selection of the most appropriate course of treatment.

This article is adapted from Barton M, Hutchings S, Carrol K. Emerging Pathogens: Vancomycin Resistant Enterococci. Trends in Drug Therapeutics, University of Utah Hospital, March 1997, 11:1-8. Reprinted by permission. Copyright 1997, Department of Pharmacy Services, University of Utah Hospital, Salt Lake City, Utah. We would like to thank the authors and the University of Utah Hospital for the use of this article. Reprints of the original article with complete reference list are available from the Communicable Disease Control Program, Bureau of Epidemiology, Utah Department of Health, (801) 538-6191.