Recommendations for Preventing the Spread of Vancomycin Resistance Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC) U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Centers for Disease Control and Prevention (CDC) Atlanta, Georgia 30333 Hospital Infection Control Practices Advisory Committee Membership List, November 1994 CHAIRMAN Walter J. Hierholzer, Jr., M.D. Yale-New Haven Hospital New Haven, Connecticut EXECUTIVE SECRETARY Julia S. Garner, R.N., M.N. Centers for Disease Control and Prevention Atlanta, Georgia MEMBERS Audrey B. Adams, R.N. Montefiore Medical Center Bronx, New York Donald E. Craven, M.D. Boston City Hospital Boston, Massachusetts David W. Fleming, M.D. Oregon Health Division Portland, Oregon Susan W. Forlenza, M.D. Nassau County Medical Center East Meadow, New York Mary J. Gilchrist, Ph.D. Veterans Administration Medical Center Cincinnati, Ohio Donald A. Goldmann, M.D. Children's Hospital Boston, Massachusetts Elaine L. Larson, Ph.D. Georgetown University Washington, D.C. C. Glen Mayhall, M.D. University of Texas Medical Branch Galveston, Texas Rita D. McCormick, R.N. University of Wisconsin Hospital and Clinics Madison, Wisconsin Ronald L. Nichols, M.D. Tulane University School of Medicine New Orleans, Louisiana Subcommittee on Prevention and Control of Antimicrobial-Resistant Microorganisms in Hospitals CHAIRMAN Donald A. Goldmann, M.D. Children's Hospital Boston, Massachusetts MEMBERS Mary J. Gilchrist, Ph.D. American Society for Microbiology Veterans Administration Medical Center Cincinnati, Ohio C. Glen Mayhall, M.D. University of Texas Medical Branch Galveston, Texas Rita D. McCormick, R.N. University of Wisconsin Hospital and Clinics Madison, Wisconsin CONSULTANTS Charles E. Edmiston, Jr., M.D. Surgical Infection Society Dennis G. Maki, M.D. Infectious Diseases Society of America Gina Pugliese, R.N. American Hospital Association Barbara J. Russell, R.N. Association for Professionals in Infection Control and Epidemiology Robert A. Weinstein, M.D. American Hospital Association This material was prepared for publication by the Subcommittee in collaboration with: Ofelia C. Tablan, M.D. Fred C. Tenover, Ph.D. William J. Martone, M.D. Robert F. Gaynes, M.D. William R. Jarvis, M.D. Martin F. Favero, Ph.D. SUMMARY Since 1989, a rapid increase in the incidence of infection and colonization with vancomycin-resistant enterococci (VRE) has been reported from U.S. hospitals. This increase poses several problems, including a) the lack of available antimicrobials for therapy of infections caused by VRE, because most VRE are also resistant to multiple other drugs (e.g., aminoglycosides and ampicillin) previously used for the treatment of infections due to these organisms, and b) the possibility that the vancomycin resistance genes present in VRE may be transferred to other gram-positive microorganisms such as Staphylococcus aureus. An increased risk of VRE infection and colonization has been associated with previous vancomycin and/or multi-antimicrobial therapy, severe underlying disease or immunosuppression, and intraabdominal surgery. Because enterococci can be found in the normal gastrointestinal or female genital tract, most enterococcal infections have been attributed to endogenous sources within the individual patient. However, recent reports of outbreaks and endemic infections due to enterococci, including VRE, have shown that patient-to-patient transmission of the microorganisms can occur either via direct contact or indirectly via hands of personnel or contaminated patient-care equipment or environmental surfaces. Prevention and control of the spread of vancomycin resistance will require coordinated, concerted effort from various departments of the hospital and can only be achieved if each of the following elements is addressed: 1) prudent vancomycin use by clinicians, 2) education of hospital staff regarding the problem of vancomycin resistance, 3) early detection and prompt reporting of vancomycin resistance in enterococci and other gram-positive microorganisms by the hospital microbiology laboratory, and 4) immediate implementation of appropriate infection- control measures to prevent person-to-person transmission of VRE. INTRODUCTION From 1989 though 1993, the percentage of nosocomial enterococcal infections reported to the Centers for Disease Control and Prevention (CDC) National Nosocomial Infections Surveillance (NNIS) System that were caused by vancomycin-resistant enterococci (VRE) increased from 0.3% to 7.9%[1]. The increase was due mainly to the 34-fold rise (0.4% to 13.6%) of VRE infections in intensive-care unit (ICU) patients, although a trend towards increased VRE infections was also noted in non-ICU patients[1]. The occurrence of VRE in NNIS hospitals was associated with larger hospital size (>200 beds) and university affiliation[1]. Other hospitals also have reported increased endemic rates and clusters of VRE infection and colonization[2-8]. The actual increase in the incidence of VRE in U.S. hospitals may be larger than reported because the fully automated methods used in many clinical laboratories cannot consistently detect vancomycin resistance, especially moderate vancomycin resistance (as manifested in the VanB phenotype)[9-11]. Vancomycin resistance in enterococci has emerged amidst the increasing incidence of high-level enterococcal resistance to penicillin and aminoglycosides, thus presenting a serious challenge for physicians treating patients with infections due to these microorganisms[1,4]. Treatment options are often limited to combinations of antimicrobials or experimental compounds with unproven efficacy[12-14]. The epidemiology of VRE has not been elucidated completely; however, certain patient populations have been found to be at increased risk for VRE infection or colonization. These include critically ill patients or those with severe underlying disease or immunosuppression, such as ICU patients or patients in the oncology or transplant wards; those who have had an intraabdominal or cardio-thoracic surgical procedure or an indwelling urinary or central venous catheter; and those who have had prolonged hospital stay or received multiantimicrobial and/or vancomycin therapy[2-8]. Because enterococci are part of the normal flora of the gastrointestinal and female genital tracts, most infections with these microorganisms have been attributed to the patient's endogenous flora[15]. However, recent reports have demonstrated that enterococci, including VRE, can spread by direct patient-to-patient contact or indirectly via transient carriage on hands of personnel[8,16] or contaminated environmental surfaces and patient-care equipment[3,8,17]. In addition to the existing problem with VRE, the potential emergence of vancomycin resistance in clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis is a serious public health concern. The vanA gene, which is frequently plasmid-borne and confers high-level resistance to vancomycin, can be transferred in vitro from enterococci to a variety of gram-positive microorganisms,[18,19] including S. aureus[20]. Although vancomycin resistance in clinical strains of S. epidermidis or S. aureus has not been reported, vancomycin-resistant strains of S. haemolyticus have been isolated[21,22]. On November 14, 1993, and February 18, 1994, in response to the dramatic increase in vancomycin resistance in enterococci, the Subcommittee on the Prevention and Control of Antimicrobial-Resistant Microorganisms in Hospitals of the CDC's Hospital Infection Control Practices Advisory Committee (HICPAC) met with representatives from the American Hospital Association, American Society for Microbiology, Association for Professionals in Infection Control and Epidemiology, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, and Surgical Infection Society. The Subcommittee members and other meeting attendees agreed that prompt implementation of control measures is needed and developed recommendations to prevent the spread of VRE. On May 17, 1994, the draft recommendations were published in the Federal Register and later revised on the basis of public comments. On November 13, 1994, HICPAC ratified the following recommendations for the prevention and control of the spread of vancomycin resistance, with special focus on VRE. HICPAC recognizes that a) data are limited and considerable research will be required to elucidate fully the epidemiology of VRE and determine cost-effective control strategies, and b) many U.S. hospitals have concurrent problems with other antimicrobial-resistant organisms, such as methicillin-resistant S. aureus (MRSA) and beta-lactam and aminoglycoside-resistant gram-negative bacilli, that may have different epidemiologic features and require different control methods. RECOMMENDATIONS Hospitals, through collaboration of their infection control and quality improvement programs, pharmacy and therapeutics committee, microbiology laboratory, clinical departments, and nursing, administrative, and housekeeping services, should develop a comprehensive, institution-specific, strategic plan to detect, prevent, and control infection and colonization with VRE. It is strongly suggested that the following elements be addressed in the plan. I. Prudent Vancomycin Use Vancomycin use has been reported consistently as a risk factor for colonization and infection with VRE[2,4,7,8,17] and may increase the possibility of the emergence of vancomycin-resistant S. aureus (VRSA) and/or vancomycin-resistant S. epidermidis (VRSE). Therefore, all hospitals and other healthcare delivery services, even those where VRE have never been detected, should develop a comprehensive antimicrobial- utilization plan to provide education for their medical staff (including medical students rotating through the institution), oversee surgical prophylaxis, and develop guidelines for the proper use of vancomycin (as applicable to the institution). Guideline development should be part of the hospital's quality improvement program and involve participation from the hospital's pharmacy and therapeutics committee, hospital epidemiologist, and infection control, infectious diseases, medical, and surgical staffs. The guidelines should include the following considerations: A. Situations in which the use of vancomycin is appropriate or acceptable: 1. For treatment of serious infections due to beta-lactam- resistant gram-positive microorganisms. Clinicians should be aware that vancomycin may be less rapidly bactericidal than are beta-lactam agents for beta-lactam-susceptible staphylococci[23,24]. 2. For treatment of infections due to gram-positive microorganisms in patients with serious allergy to beta-lactam antimicrobials. 3. When antibiotic-associated colitis (AAC) fails to respond to metronidazole therapy or if AAC is severe and potentially life-threatening. 4. Prophylaxis, as recommended by the American Heart Association, for endocarditis following certain procedures in patients at high risk for endocarditis[25]. 5. Prophylaxis for major surgical procedures involving implantation of prosthetic materials or devices, e.g., cardiac and vascular procedures26 and total hip replacement, at institutions with a high rate of infections due to MRSA or methicillin-resistant S. epidermidis. A single dose administered immediately before surgery is sufficient unless the procedure lasts >6 hours, in which case the dose should be repeated. Prophylaxis should be discontinued after a maximum of two doses[27-30]. B. Situations in which the use of vancomycin should be discouraged: 1. Routine surgical prophylaxis other than in a patient with life-threatening allergy to beta-lactam antibiotics[28] 2. Empiric antimicrobial therapy for a febrile neutropenic patient, unless there is strong evidence at the outset that the patient has an infection due to gram-positive microorganisms (e.g., inflamed exit site of Hickman catheter), and the prevalence of infections due to MRSA in the hospital is substantial[31-37]. 3. Treatment in response to a single blood culture positive for coagulase-negative staphylococcus, if other blood cultures drawn in the same time frame are negative, i.e., if contamination of the blood culture is likely. Because contamination of blood cultures with skin flora, e.g., S. epidermidis, may cause vancomycin to be administered inappropriately to patients, phlebotomists and other personnel who obtain blood cultures should be trained to minimize microbial contamination of specimens[38-40]. 4. Continued empiric use for presumed infections in patients whose cultures are negative for beta-lactam- resistant gram-positive microorganisms[41]. 5. Systemic or local (e.g., antibiotic lock) prophylaxis for infection or colonization of indwelling central or peripheral intravascular catheters[42-48]. 6. Selective decontamination of the digestive tract. 7. Eradication of MRSA colonization[49,50]. 8. Primary treatment of AAC[51]. 9. Routine prophylaxis for very low-birth-weight infants[52] 10. Routine prophylaxis for patients on continuous ambulatory peritoneal dialysis or hemodialysis[48,53]. 11. Treatment (chosen for dosing convenience) of infections due to beta-lactam-sensitive gram-positive microorganisms in patients with renal failure[54-57]. 12. Use of vancomycin solution for topical application or irrigation. Although a variety of techniques may be useful, further study is required to determine the most effective methods for influencing the prescribing practices of physicians.58-61 In addition, key parameters of vancomycin use can be monitored through the hospital's quality assurance/improvement process or as part of the drug-utilization review of the pharmacy and therapeutics committee and the medical staff. II. Education Program Continuing education programs for hospital staff (including attending and consulting physicians, medical residents, and students; pharmacy, nursing, and laboratory personnel; and other direct patient-care givers) should include information concerning the epidemiology of VRE and the potential impact of this pathogen on the cost and outcome of patient care. Because detection and containment of VRE require a very aggressive approach and high performance standards for hospital personnel, special awareness and educational sessions may be indicated. III. Role of the Microbiology Laboratory in the Detection, Reporting, and Control of VRE The microbiology laboratory is the first line of defense against the spread of VRE in the hospital. The laboratory's ability to identify enterococci and detect vancomycin resistance promptly and accurately is essential in recognizing VRE colonization and infection and avoiding complex, costly containment efforts that are required when recognition of the problem is delayed. In addition, cooperation and communication between the laboratory and the infection control program will facilitate control efforts substantially. A. Identification of enterococci: Presumptively identify colonies on primary isolation plates as enterococci by using the colonial morphology, Gram stain, and PYR test. Although identifying enterococci to the species level can help predict certain resistance patterns (e.g., Enterococcus faecium is more resistant to penicillin than is Enterococcus faecalis) and may help determine the epidemiologic relatedness of enterococcal isolates, such identification is not necessary routinely if antimicrobial susceptibility testing is performed. However, under special circumstances or as laboratory resources permit, biochemical tests may be used to differentiate among the various enterococcal species. Although most commercially available identification systems adequately differentiate E. faecalis from other species of enterococci, additional tests for motility and pigment production are required to distinguish Enterococcus gallinarum (motile and nonpigmented) and Enterococcus casseliflavus (motile and pigmented) from E. faecium (nonmotile and nonpigmented). B. Antimicrobial susceptibility testing: Determine vancomycin resistance and high-level resistance to penicillin (or ampicillin) and aminoglycosides62 for enterococci isolated from blood, sterile body sites (with the possible exception of urine), and other sites as clinically indicated. Laboratories may choose to test routinely wound and urine isolates for resistance to vancomycin and penicillin or ampicillin if resources permit (See III-D and III-D-1 below). 1. Laboratories using disk diffusion should incubate plates for 24 hours and read zones of inhibition by using transmitted light[62,63]. 2. Minimum inhibitory concentrations (MICs) can be determined by agar dilution, agar gradient dilution, broth macrodilution, or manual broth microdilution[62-64]. These test systems should be incubated for 24 hours. 3. The fully automated methods of testing enterococci for resistance to vancomycin currently are unreliable[9-11]. C. When VRE are isolated from a clinical specimen: 1. Confirm vancomycin resistance by repeating antimicrobial susceptibility testing using any of the recommended methods in III-B-1 and III-B-2 above, particularly if VRE isolates are unusual in the hospital, OR streak 1 ul of standard inoculum (0.5 McFarland) from an isolated colony of enterococci onto brain heart infusion agar containing 6 ug/ml of vancomycin, incubate the inoculated plate for 24 hours at 35 degrees C, and consider any growth indicative of vancomycin resistance[62,63,65]. 2. Immediately, while performing confirmatory susceptibility tests, notify the patient's primary caregiver, patient-care personnel on the ward on which the patient is hospitalized, and infection control personnel regarding the presumptive identification of VRE, so that the patient can be placed on appropriate isolation precautions promptly (See Section IV-A-4 below). Follow this preliminary report with the (final) result of the confirmatory test. Additionally, highlight the report regarding the isolate to alert staff that isolation precautions are indicated. D. Screening procedures for detecting VRE in hospitals where VRE have not been detected: In many hospital microbiology laboratories, antimicrobial susceptibility testing of enterococcal isolates from urine or nonsterile body sites such as wounds is not performed routinely; thus, recognition of nosocomial VRE colonization and infection in hospitalized patients may be delayed. Therefore, in hospitals where VRE have not yet been detected, special measures can allow earlier detection of VRE. 1. Antimicrobial susceptibility survey. Perform periodic susceptibility testing on an epidemiologic sample of enterococcal isolates recovered from all types of clinical specimens, especially from high-risk patients, such as those in an ICU or oncology or transplant ward. The optimal frequency of testing and number of isolates to test are unknown and may vary from hospital to hospital, depending on the hospital's patient population and number of cultures performed. Hospitals processing large numbers of culture specimens will need to test only a small fraction (e.g., 10%) of enterococcal isolates every 1-2 months, whereas hospitals processing fewer specimens may need to test all enterococcal isolates during the survey period. The hospital epidemiologist can help design a suitable sampling strategy. 2. Culture survey of stools or rectal swabs. In tertiary medical centers and other hospitals with many critically ill (e.g., ICU, oncology, transplant) patients at high risk for VRE infection or colonization, periodic culture surveys of stools or rectal swabs of such patients can detect the presence of VRE. Because most patients colonized with VRE will have intestinal colonization with this organism, fecal screening is recommended before VRE infections have been identified clinically [2,4,16]. The frequency and intensity of surveillance should be based on the size of the population at risk and the specific hospital unit(s) involved. If VRE have been detected in other institutions in a hospital's area and/or if a hospital wishes to determine whether VRE are present in the hospital despite the absence of recognized clinical cases, stool or rectal-swab culture surveys are useful. The cost of screening can be reduced greatly by inoculating specimens onto selective media containing vancomycin [2,17,66] and restricting screening to those patients who have been in the hospital long enough (e.g., 5-7 days) to have a substantial risk of colonization, or who have been admitted from a facility, such as a tertiary-care hospital or a chronic-care facility, where VRE are known to be present. After colonization with VRE has been detected, it would be appropriate to begin to screen routinely all of the enterococcal isolates (including those from urine and wounds) from patients in the hospital for vancomycin resistance and to intensify efforts to contain VRE spread, i.e., by strict adherence to handwashing and compliance with isolation precautions (See Section IV-A-4 below). Intensified fecal screening for VRE may facilitate earlier identification of colonized patients, leading to more efficient containment of the microorganism. IV. Prevention and Control of Nosocomial Transmission of VRE Eradication of VRE from the hospital is most likely to succeed when VRE infection or colonization is confined to a few patients on a single ward. After VRE have become endemic on a ward or have spread to multiple wards or to the community, eradication becomes extremely difficult and costly. Aggressive infection control measures and strict compliance by hospital personnel are required to limit nosocomial spread of VRE. Control of VRE requires a collaborative institution-wide multidisciplinary effort. Therefore, the hospital's quality assurance/improvement department should be involved at the outset in order to identify specific problems in hospital operations and patient-care systems and to design, implement, and evaluate appropriate changes in these systems. A. For all hospitals, including those where VRE have been isolated infrequently or not at all: 1. Notify appropriate hospital staff promptly when VRE are detected. (See Section III-C-2 above). 2. Make clinical staff aware of the hospital's policies regarding VRE-infected or colonized patients. Because the slightest delay can lead to further spread of VRE and complicate control efforts, implement the required procedures as soon as VRE are detected. Clinical staff play a pivotal role in limiting the spread of VRE in patient-care areas. Accordingly, continuing education regarding the appropriate response to the detection of VRE is critical (See Section II above). 3. Establish system(s) for monitoring appropriate process and outcome measures, such as cumulative incidence or incidence density of VRE colonization, rate of compliance with VRE isolation precautions and handwashing, interval between VRE identification in the laboratory and implementation of isolation precautions on the wards, and the percentage of previously colonized patients admitted to the ward who are recognized promptly and placed on isolation precautions. Relay these data to the clinical, administrative, laboratory, and support staff as reinforcement to ongoing education and control efforts[67]. 4. Isolation precautions to prevent patient-to-patient transmission of VRE: a. Place VRE-infected or colonized patients in single rooms or in the same room as other patients with VRE[8]. b. Wear gloves (clean, nonsterile gloves are adequate) when entering the room of a VRE-infected or colonized patient; extensive environmental contamination with VRE has been noted in some studies [3,8,16,68]. During the course of caring for a patient, a change of gloves may be necessary after contact with material that may contain high concentrations of VRE (e.g., stool). c. Wear a gown (a clean, nonsterile gown is adequate) when entering the room of a VRE-infected or colonized patient if substantial contact with the patient or environmental surfaces in the patient's room is anticipated, or if the patient is incontinent, or has diarrhea, an ileostomy, a colostomy, or a wound drainage not contained by a dressing[8]. d. i. Remove gloves and gown before leaving the patient's room and wash hands immediately with an antiseptic soap or use a waterless antiseptic agent [69-72]. Hands can be contaminated via glove leaks [73-77] or during glove removal and bland soap has been shown to be relatively ineffective in removing VRE from the hands [78]. ii. Ensure that after glove and gown removal and handwashing, clothing and hands do not contact environmental surfaces in the patient's room that are potentially contaminated with VRE (e.g., door knob or curtain) [3,8]. 5. Dedicate the use of noncritical items, such as stethoscope, sphygmomanometer, or rectal thermometer, to a single patient or cohort of patients infected or colonized with VRE [17]. If such devices are to be used on other patients, adequately clean and disinfect the devices first [79]. 6. Obtain culture of stools or rectal swabs of roommates of patients newly found to be infected or colonized with VRE to determine their colonization status, and apply isolation precautions as necessary. Perform additional screening of patients on the ward at the discretion of the infection control staff. 7. Adopt a policy for deciding when patients infected or colonized with VRE can be removed from isolation precautions. The optimal requirements remain unknown; however, because VRE colonization may persist indefinitely [4], stringent criteria may be appropriate, e.g., VRE-negative results on at least three consecutive occasions, one or more weeks apart, for all cultures from multiple body sites (including stool or rectal swab, perineal area, axilla or umbilicus, and wound, Foley catheter, and/or colostomy sites if present). 8. Because patients with VRE may remain colonized for long periods after discharge from the hospital, establish a system for highlighting the records of infected or colonized patients so that they can be recognized and placed on isolation precautions promptly upon readmission to the hospital . Ideally, this information should be computerized so that placement of colonized patients on isolation precautions will not be delayed because of unavailability of the patients' medical records. 9. Discharging VRE-infected or colonized patients: Consult local and state health departments in developing a plan regarding the discharge of VRE-infected or colonized patients to nursing homes, other hospitals, or home health care, as part of a larger strategy for handling patients with resolving infections and patients colonized with antimicrobial-resistant microorganisms. B. In hospitals with endemic VRE or continued VRE transmission despite implementation of measures described in IV-A-1 through IV-A-9: 1. Focus control efforts initially on ICUs and other areas where the VRE transmission rate is highest [4]. Such units may serve as a reservoir of VRE, from where VRE can spread to other wards when patients are well enough to be transferred. 2. Where feasible, cohort staff who provide regular ongoing care to patients to minimize the movement/contact of health-care givers between VRE-positive and VRE-negative patients [4,8]. 3. Carriers of enterococci on the hospital staff have been implicated rarely in the transmission of this organism [8,16]. Nonetheless, in conjunction with careful epidemiologic studies and upon the direction of the infection control staff, examine personnel for chronic skin and nail problems and perform hand and rectal-swab cultures of these workers. Remove VRE-positive personnel epidemiologically linked to VRE transmission from the care of VRE-negative patients until their carrier state has been eradicated. 4. Because the results of several enterococcal outbreak investigations suggest a potential role for the environment in the transmission of enterococci [3,8,16,17,68,80], institutions experiencing ongoing VRE transmission should verify that the hospital has adequate procedures for the routine care, cleaning, and disinfection of environmental surfaces (e.g., bedrails, charts, carts, doorknobs, faucet handles, bedside commodes) and that these procedures are being followed by housekeeping personnel. Some hospitals may elect to perform focused environmental cultures before and after cleaning of rooms housing patients with VRE to verify the efficacy of hospital policies and procedures. All environmental culturing should be approved and supervised by the infection control program in collaboration with the clinical laboratory (3,8,16,17,68,80). 5. Consider sending representative VRE isolates to reference laboratories for strain typing by pulsed field gel electrophoresis or other suitable techniques to aid in defining reservoirs and patterns of transmission. V. Detection and Reporting of VRSA and VRSE The microbiology laboratory has the primary responsibility for detecting and reporting the occurrence of VRSA or VRSE in the hospital. A. Antimicrobial susceptibility testing Routinely test all clinical isolates of S. aureus and S. epidermidis for susceptibility to vancomycin by using standard methods [62]. B. When VRSA or VRSE is identified in a clinical specimen: 1. Confirm vancomycin resistance in S. aureus or S. epidermidis by repeating antimicrobial susceptibility testing using standard methods [62]. It is advisable to restreak the colony to ensure that the culture is pure. 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