P&T News: October 1998

Vancomycin-Resistant Enterococci

Sarah J. Johnson, Pharm. D. and Dena A Behm-Dillon, Pharm. D.
Peer Review Status: Internally Peer Reviewed by Loreen Herwaldt, MD and Ronald N. Jones, MD

Enterococci
Enterococci are Gram-positive cocci that occur in short chains or pairs and are a component of normal human flora in gastrointestinal and genitourinary tracts. 2 The species that are most common and cause most infections are E. faecalis and E. faecium, which account for 80 to 90% and 5 to 10% of clinical isolates, respectively (Table 1).3,4 Enterococci cause infections in the urinary tract, blood, abdomen, and surgical wounds and are among the top four most frequent causes of hospital- acquired infections. 2,4 Patients can become infected with strains from their own flora. In addition, patients can acquire new strains because these organisms are spread mainly from person to person on the hands of healthcare workers or on contaminated hospital equipment.

Table 1. Enterococcal Species3

E. avium E. casseliflavus E. durans E. faecalis* E. faecium* E. gallinarum E. hivae E. malodoratus E. mundtil E. pseudoarium E. raffinosus E. solitarius

*most clinically significant

Enterococci are intrinsically resistant to low concentrations of numerous antimicrobial agents including B-lactams, clindamycin, and aminoglycosides. More recently, these organisms gained high-level resistance to B-lactams, including ampicillin aminoglycosides and vancomycin. Thus, for serious infections caused by these strains there is no therapy that is reliable bactericidal. Consequently, mortality from these infections can be high. A study by Edmond et al documented an attributable mortality rate of 37% for VRE bacteremia .5

Although the precise incidence of VRE is unknown, according to the Centers for Disease Control and Prevention's (CDC) National Nosocomial Infections Surveillance (NNIS) system, the percentage of VRE causing nosocomial infections increased from 0.3% in 1989 to 14.2% in 1996. 2 In 35 hospitals in the San Francisco Bay Area, the percentage of laboratories isolating 2 VRE increased from approximately 19% in 1995 to 91% in 1996 . In our institution, 44% of the E. faecium isolated from January to June 1998 was resistant to vancomycin, compared with 4% during the same period in 1994.7,8 Furthermore, the actual increase in the incidence of VRE in U.S. hospitals might be greater than reported because commercial susceptibility testing methods used in many clinical laboratories cannot detect vancomycin resistance consistently, especially in strains that are moderately resistant to vancomycin. In addition, VRE has been reportable in only one state (Connecticut); however, it will be reportable in Iowa as of January 1, 1999.

Vancomycin Resistance 2,3,6,9
Vancomycin is a glycopeptide that is effective against a broad spectrum of Gram-positive organisms. Vancomycin inhibits the synthesis of the bacterial cell wall by binding to specific subunits containing free D-alanyl-D-alanine, preventing cross-linking, and thus facilitating cell wall lysis. Vancomycin-resistant enterococci make cell wall precursors with a different terminal end so that vancomycin cannot bind at its required site. Teicoplanin is an investigational glycopeptide similar to vancomycin that has been used to treat some VRE, specifically vanB and C; however, use of teicoplanin is limited due to resistance by the same mechanisms that inactivate vancomycin, most commonly vanA, and the drug is not currently available in the U.S.

Enterococci that carry the vanA gene are characterized by high-level resistance to vancomycin (MIC, less than 256 mcg/ml) and to teicoplanin (MIC, less than 8 mcg/ml). Genes for vanA resistance can be transferred from one bacteria to another and are activated in the presence of vancomycin. Enterococci that carry the vanB, gene are characterized by moderate-level resistance to vancomycin (MIC, 32 to 256 mcg/ml), but are not resistant to teicoplanin (MIC, 1 or less mcg/ml). This gene is transferable, and use of vancomycin can induce resistance to teicoplanin. E. faecium and E. faecalis, the two most clinically significant enterococcal isolates with acquired resistance to vancomycin, can have either the vanA or vanB phenotype. Because these organisms can exchange genetic information with other enterococci and with more virulent staphylococci and streptococci, there has recently been increased concern about reports of intermediate resistance to vancomycin in S. aureus. In fact, vancomycin-intermediate S. aureus (VISA) have been identified in Japan, Michigan, New York and New Jersey. 10 However, this vancomycin resistance in staphylococcus is devoid of the vanA, B or C genes found in enterococci. The mechanism for vancomycin intermediate resistance in staphylococci remains unknown. The vanC gene confers low-level resistance to vancomycin (MIC, 8 to 16 mcg/ml). Isolates with the vanC gene are susceptible to teicoplanin. VanC type resistance is an intrinsic characteristic in E. gallinarum and E. casseliflaus, species that are not significant pathogens for humans.

Transmission2
VRE can be transmitted from person to person on hands of health care workers, or on contaminated equipment. Contaminated environmental surfaces may also transmit VRE. VRE remains viable on dry surfaces for days to weeks and may persist even after topical disaffection. Objects such as rectal thermometers, bed rails, ECG monitors, blood pressure cuffs, and stethoscopes are common sites for contamination. Additionally, patients in both the inpatient and outpatient setting who are colonized with VRE can serve as an unrecognized reservoir for these organisms. It is important to remember that colonization is ten times more frequent than infection, and once colonized, most patients carry VRE for over 3 months.

Who Is At Risk?2
Patients at highest risk for VRE are hospitalized persons with severe underlying immunosuppressive conditions, nursing home residents, transplant patients, persons with frequent exposure to vancomycin (such as patients on dialysis), and patients with prior MRSA or Clostridium difficile infection. Table 2 summarizes some risk factors for acquisition of VRE.

Prevention and Control2
Due to the lack of adequate antimicrobial therapy for VRE, prevention and control are key factors in managing VRE. Education of health care providers is of the utmost importance. Also, health care workers must strictly adhere to isolation precautions for all patients colonized or infected with VRE to prevent its spread (Table 3).

Table 2. Risk Factors for VRE*

Hospitalization in an ICU Prior exposure to vancomycin Prior exposure to third generation cephalosporins Prior exposure to agents with antianaerobic spectrum of activity Prior nosocomial infections Severe underlying disease Immunosuppressive therapy Exposure to specific health care workers

* Adapted from CDC guidelines [ MMWR 1995; 44 (RR- 12):1-13.]

Prudent Use of Vancomycin Prudent Use of Vancomycin
Because use of antibiotics selects resistant enterococci, use of vancomycin has had an enormous impact on the incidence of VRE.9 According to the CDC, vancomycin usage has increased 15% since 1994, and utilization continues to increase. One study that assessed vancomycin use in 7,147 patients in 131 hospitals showed that 63% of vancomycin orders did not follow CDC guidelines." A study done in our hospital found that only 33% of the patients who received vancomycin had infections requiring this drug. 12 Other studies have shown similar results.9 Vancomycin use has been reported consistently as a risk factor for colonization and infection with VRE. Because vancomycin resistance is transferable, use of this drug may increase the possibility of the emergence of vancomycin-resistant S. aureus (VRSA) and/or vancomycin-resistant coagulase negative staphylococci (VR-CoNS). Therefore, the CDC has developed guidelines regarding appropriate use of vancomycin (Table 4) and has described situations in which vancomycin should not be used (Table 5).

Table. 3. Isolation Precautions*

1. All aspects of standard precautions apply. 2. The patient is placed in a private room. When necessary, patients with the same organism may share a room after unit staff consult with Hospital Epidemiology. 3. One-to-one nursing is preferred. 4. A Special Organism Isolation sign describing the protective attire required will be placed outside the patient's room. 5. All persons entering the room (including visitors) must implement Special Organism precautions strictly, as follows: Gloves Gloves must be worn by all persons on entrance to the room and must be used for all patient contact, as well as contact with the patient's immediate environment (bed, bedside equipment). Health care workers may need to change gloves while caring for the patient (e.g., if gloves become soiled, they should be changed before handling bedside equipment). Gloves must be removed before leaving the room. Hands must be washed before and after leaving the room. Gowns Gowns must be worn by all persons entering the room of the infected or colonized patient. The gown must be removed before leaving the room. Masks and Safety Glasses Mask and safety glasses are not necessary. Shoe and Head Covers Shoe covers are not needed routinely unless the patient has large volumes of diarrhea. Head covers are not necessary. 6. All persons must wash their hands after they remove their gloves and gowns. The handwashing agent must be 4% chlorhexidine gluconate (CHG) or 60% isopropyl alcohol. 7. Dedicate equipment to one person if possible. 8. If equipment must be shared, wipe the items with a hospital approved disinfectant (Virex[R]) and allow a 10-minute contact time. 9. The clean-reclean method will be used for terminal cleaning; a minimum of 10 minutes contact time is required. For further information, please contact Housekeeping.

*Adapted from CDC guidelines [MMWR. 1995; 44(RR-12): 1-13.]

Table 4. Situations in Which Use of Vancomycin Is Appropriate or Acceptable*

Treatment of serious infections due to beta-lactam-resistant Gram-positive microorganisms (documented MRSA or MRCoNS) Treatment of Gram-positive infections in patients with a serious allergy to beta-lactam antimicrobials Antibiotic-associated colitis (AAC) that has failed metronidazole therapy or severe and potentially life-threatening AAC Prophylaxis for endocarditis for certain procedures in patients at high risk for endocarditis, as recommended by the American Heart Association Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices

*Adapted from CDC guidelines2 [MMWR; 44(RR-12): 1-13.]

Table: 5. Situations in Which Vancomycin Use Is:Discouraged*

Routine surgical prophylaxis Empirical antimicrobial therapy for febrile neutropenia In response to a single blood culture positive for coagulase-negative staphylococcus, if other blood cultures drawn at the same time are negative Treatment in response to a single blood culture positive for coagulase-negative staphylococcus, if contamination is likely Continued empirical use for presumed infections in patients whose cultures are negative for beta-lactam-resistant Gram-positive microorganisms Systemic or local prophylaxis for infection or colonization of indwelling central or peripheral intravascular catheters Decontamination of the digestive tract Eradication of MRSA colonization Primary treatment of antibiotic-associated colitis (i.e., C. difficile) Routine prophylaxis for very low-birth-weight infants Routine prophylaxis for patients on continuous ambulatory peritoneal dialysis or hemodialysis Treatment of infections due to beta-lactam-susceptible Gram-positive microorganisms in patients with renal failure Use of vancomycin solution for topical application or irrigation

*Adapted for UIHC from CDC guidelines [MMWR. 1995;44(RR-12): 1-13.]

Treatment Considerations
Currently, no definitive therapy is available for VRE infections. Few data exist to guide therapy for a patient infected with VRE because there are no published comparative clinical trials. If a strain of E. faecium is resistant to both the penicillins and vancomycin, susceptibility testing to determine the MIC of ampicillin may still be useful. In addition, susceptibility testing to all antimicrobial possibilities should be obtained to guide drug therapy. Unfortunately the most common Enterococcus species exhibiting vancomycin resistance is E. faecium, which is inherent inherently more resistant to penicillins than E. faecalis; therefore, the majority of VRE in the U.S. are completely resistant to penicillins.6 Furthermore, even if the strain appears to be susceptible, the drug is usually at best bacteriostatic, not bactericidal .6 If the organism can be inhibited by 32 mcg/ml of ampicillin or less, doses of ampicillin high enough to exceed that MIC may be worthwhile. 6 If the VRE isolate is highly resistant to ampicillin (MIC, less than 32 mcg/ml), susceptibility testing should be performed to test various other antimicrobials such as tetracyclines (usually doxycycline), erythromycin, chloramphenicol, aminoglycosides (for high levels of resistance), rifampin, and some fluoroquinolones. If the patient has a urinary tract infection, nitrofurantoin may be useful . Very little data are available from in vivo studies on the appropriate therapy for VRE; however, data from in vitro studies and from case reports have suggested that combinations of various antimicrobials to which the enterococcal strain is susceptible should be used. Combination therapy may also prevent emergence of further resistance. However, urinary tract infections may be treated with monotherapy because many compounds will concentrate in the urine.

Quinupristin-dalfopristin (Synercid[R]), an agent that is still investigational, belongs to a new class of drugs called the streptogramins. It has been evaluated for VRE infections in non-comparative trials .4 Quinupristin-dalf6pristin has been shown to be somewhat effective for E. faecium; however, it exhibits essentially no activity (MICs, less than 2 mcg/ml) against E. faecalis. Teicoplanin is an investigational glycopeptide that is similar to vancomycin; it is active against vanB and vanC strains of enterococci. Use of teicoplanin is limited because most VRE have the vanA gene. In addition, teicoplanin resistance has been reported in an isolate of E. faecium with the vanB phenotype and this drug will not be available in the United States. 6 Figure I (page 24) provides a summary of the treatment considerations.

Conclusion
The emergence of vancomycin resistance among enterococci and S. aureus has very serious consequences. Currently, there is no definitive therapy for treatment of serious VRE infections. Therefore, prevention is very important. Control of VRE can be accomplished by prudent use of vancomycin and other antimicrobial agents and by aggressive implementation of infection control practices.

Furthermore, the genes coding for vancomycin resistance could be transferred to S. aureus, S. epidermis, penicillin-resistant viridans group streptococci, penicillin-resistant pneumococci, or C. difficile. Such organisms could cause severe, life-threatening infections that are not treatable; this would be a medical crisis.

Susceptibility testing of VRE isolates to numerous therapeutic agents may help guide appropriate therapy. Data from in vitro studies and from some in vivo studies suggest that combinations of antimicrobials to which VRE is susceptible should be used. There are no good clinical trials to support this approach. New drugs (new fluoroquinolones, linezobid, SCH27899, LY333328, etc.) are needed to treat VRE now and to treat VRSA when it occurs.

For assistance in treating patients infected with VRE, the Infectious Diseases Division and Medical Microbiology Division (Department of Pathology) may be consulted. For questions about isolation precautions and methods for preventing spread of VRE, contact staff in the Program of Hospital Epidemiology.  

References

1. Lancet 1997;349:1901-6.
2. MMWR 1995;44(RR-12):1-13.
3. Pharmacotherapy 1996;16:819-29.
4. Pharmacotherapy 1996;16:584-92.
5. Clin Infect Dis 1996;23:1234-9.
6. Am J Med 1997;102:284-93.
7. "Guide to Choice of Antibiotic Therapy" 1994
8. "Guide to Choice of Antibiotic Therapy" Sept 1998
9. Rybak MJ. Multidrug-Resistant Enterococci. Presented at 32nd Annual ASHP Midyear Clinical Meeting. Atlanta, GA: 1997 Dec. 7.
10. MMWR 1997;46:724-66.
11. The Wall Street Journal Sept. 4, 1997:B1.
12. JAMA 1993;269:598-602.
13. Diagn Microbiol Infect Dis 1994;18:105-9.

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