Members & Committees
DNT Subcommittee

VANCOMYCIN RESISTANT ENTEROCOCCI (VRE) AND VR COAGULASE NEGATIVE STAPHYLOCOCCUS (VRCNS): A CONSENSUS STATEMENT FOR RENAL UNITS
January 2000

Dr Katherine Kociuba
Microbiologist and Infectious Diseases Physician
South Western Area Pathology Service
Dr Michael Suranyi,
Director of Dialysis Services,
SWS Renal Services
Liverpool Hospital, Sydney

Produced under the auspices of the Dialysis and Transplantation Subcommittee of the KHA and ANZSN.

EXECUTIVE SUMMARY

1. A patient colonised with VRE heavily contaminates the surrounding environment. VRE may persist on surfaces for weeks or months and is not removed by routine terminal cleaning.
   
2. Rational antiobiotic utilisation plans minimise inappropriate use of Vancomycin and broad spectrum antibiotics such as 3rd generation Cephalosporins, which drive selective pressures promoting the emergence of VRE. Empiric antibiotic protocols should be reviewed to reduce reliance on Vancomycin.
   
3. Each Renal Unit should develop effective policies for screening, identification and isolation of VRE patients. Prompt notification to Infection Control of positive cases is essential.
   
4. Periodic stool, rectal or peri-rectal swabs are required to detect VRE.
   
5. All patients transferring in or out of a Renal Unit, including holiday patients, must be screened prior to transfer.
   
6. There is no effective way to eliminate colonisation with VRE and antibiotic therapy is not indictated. Such patients require isolation and cohorting for the indefinite future.
   
7. Where patients have VRE infection, rather than simple colonisation, the treatment regimen should be designed based on site of infection, organism sensitivities and antiobiotics available, in conjunction with local microbiological/infectious diseases consultation.

PREAMBLE
Enterococci are a normal part of bowel and female genital flora. They have a low intrinsic virulence, however are emerging as important nosocomial pathogens due to escalating antibiotic pressure leading to increasing drug resistances. Some enterococci have acquired resistance to aminoglycosides (high level), erythromycin, tetracycline and more recently vancomycin. In the USA and Europe, since 1989 vancomycin resistant enterococci (VRE) have been increasingly important as significant nosocomial pathogens. VRE was first isolated in Australia in 1994. A steady increase in the number of reports of VRE in Australia has been noted since then, from multiple institutions, and are thought to have arisen locally. Multiple strain types have been identified on testing for vancomycin resistance genes, antibiograms and typing (1,2,3).

In a similar fashion but to a lesser extent vancomycin resistant coagulase negative Staph (VRCNS) have been detected worldwide (4,5). Vancomycin resistant Staph epidermidis (VRSE) has been reported in the setting of prolonged vancomycin usage particularly in the setting of CAPD.

RISK FACTORS FOR VRE
Vancomycin and third generation cephalosporin usage has been identified as a major risk factor for colonisation and infection with VRE (6) Usage of other antimicrobial agents including metronidazole, length of hospital stay and admission to the Intensive Care Unit, severe illness (malignancy, neutropenia, transplant, renal failure etc.), abdominal and cardiothoracic surgery, presence of an indwelling urinary catheter or a venous catheter are also risk factors. Multiple outbreaks have been described with transmission attributed to person to person contact, contact with contaminated hospital environment (7) and contaminated shared medical equipment. A patient colonised with VRE heavily contaminates the surrounding environment. VRE may persist on dry surfaces for weeks to months (8) and may not be adequately removed by routine terminal cleaning. Appropriate terminal cleaning guidelines for VRE are documented (9,10).

PREVENTION AND CONTROL OF VRE
Several published guidelines (9,10,11) agree that in order to prevent or control the spread of VRE a multi-pronged approach is required which includes

1. Review of appropriate vancomycin and other antibiotic usage
   
2. Education programs -for medical and paramedical staff to inform them regarding the epidemiology of VRE, its impact on patient care and the importance of infection control procedures.
   
3. Early detection of VRE carriage. Each institution's laboratory must be able to identify enterococci, detect vancomycin resistance and characterise the strain.
   
4. Effective isolation of cases.

a) REDUCTION OF VANCOMYCIN AND OTHER ANTIBIOTIC USAGE
Development of rational antibiotic utilisation plans to minimise inappropriate use of Vancomycin and also of broad spectrum antibiotic agents, including third generation cephalosporins, is essential.

The use of broad spectrum antibiotics, such as 3rd generation cephalosporins, increase the prevalence of Multiresistant Staph Aureus infections (MRSA) and are themselves a risk factor for VRE. The consequent prevalence of MRSA infections in renal failure populations has increased the use of Vancomycin, favoured due to its long duration of action and lack of reliance on patient compliance. The widespread use of Vancomycin has then contributed to the emergence of VRE and VRCNS. The main risk of continued antibiotic pressure is the generation of further resistant organisms and the risk of horizontal transmission of vancomycin resistance to unrelated strains.

Methicillin resistant Staph aureus infections, exposed to prior vancomycin, have resulted in the detection of strains with only intermediate susceptibility to vancomycin (12,13,14,15,16) which does not appear to be due to transfer of the vancomycin resistance gene cluster found in VRE. However, there is grave concern regarding the possible emergence of highly virulent Vancomycin resistant Staph aureus (17) which may occur through horizontal transfer of this resistance gene cluster. While there have been no clinical isolates, this possibility has been demonstrated in vitro (18).
Studies in Australian hospitals have reported that up to 65% of vancomycin usage is inapproproate (19.20,21). Empiric antibiotic protocols should be reviewed to reduce reliance on Vancomycin. Appropriate indications are addressed in guidelines (19,20,21).

Coagulase negative Staph infection sensitive only to Vancomycin is common in central line sepsis, but simple removal of the line is usually curative. In haemodialysis related infections cephazolin may be used as a useful alternative (22), as intermittent intravenous therapy post haemodialysis. Peritonitis is commonly caused by coagulase negative Staph resistant to Methicillin. In empiric therapy of peritonitis in CAPD, cephazolin and aminoglycoside may be used intraperitoneally (23,24). If initially using a vancomycin-containing regimen empirically wherever possible conversion to a non vancomycin regimen should be initiated as soon as organism susceptibility becomes available.

In many centres the prevalence of MRSA significantly impacts upon empiric and sensitivity guided vancomycin usage. Therefore control of MRSA carriage is an important potentially modifiable factor. Vancomycin use should be restricted to MRSA infections of clinical significance, wherever possible, and prophylactic use should be avoided. Clinically significant MRSA infections requiring vancomycin use may be reduced by screening for and eliminating MRSA nosocomial colonisation (25). There is evidence that the eradication of MRSA nasal carriage through the use of mupirocin topically can significantly reduce the rate of clinically relevant MRSA infection (26,27).

b) EDUCATION OF STAFF
It is important to educate staff on the epidemiology of VRE and develop effective policies regarding screening, identification and isolation. A single point source can be the focus of an epidemic, which if not contained effectively can lead to endemic VRE. Once endemic, VRE and VRCNS increase the risk of spread to other patients through colonisation pressure (28), and further increase the risk of other resistant organisms emerging.

VRE is spread directly by faecal contamination of the environment, directly via the patient or indirectly via nurses' hands or hospital surfaces. Screening is discussed below. It is essential to ensure prompt notification of appropriate hospital staff when VRE is detected and the appropriate process and outcome measures should be monitored e.g. the incidence of VRE colonisation, rate of compliance with isolation precautions and handwashing. It is also relevant to establish a system for identifying infected or colonised patients on readmission as colonisation persists for prolonged periods.

c) SURVEILLANCE
Surveillance is essential as a single point source can rapidly result in an epidemic with VRE. Renal patients are at high risk of VRE carriage (29,30,31). In institutions where VRE have not yet been detected surveillance studies should be undertaken, initially on renal inpatients. Screening in one renal unit in Australia identified a prevalence of 5% for renal patients (2% for peritoneal dialysis or in centre dialysis patients)(3). Periodic culture surveys of stool or rectal swabs are required to detect the presence of VRE. Rectal or perirectal swabs have equal sensitivity and are both suitable specimens (32). The frequency and intensity of surveillance should be based upon the size of the population at risk at the specific unit involved and the perceived risk. Once colonisation or infection has been detected at the institution/unit more frequent screening is required, and an increased frequency of routine susceptibility testing of all enterococcal isolates is advocated. The screening process should be widened to include screening room-mates of patients newly found to be infected or colonised with VRE and screening of other patients sharing the same toilets.

All holiday patients, overseas visiting patients and inter-hospital patient transfers should be screened prior to acceptance, to reduce the risk of clonal spread between hospitals (33). Currently there are no recommendations to screen hospital staff, as they are generally not colonised (34). Screening might be indicated if epidemiological evidence emerges of a staff member as a focus.

d) ISOLATION PRECAUTIONS
Contact precautions are required: Patients should be placed in a private room or cohorted with other patients with VRE. Staff should wear a gown and gloves when entering the room of a VRE infected or colonised patient: (a) If substantial contact with the patient or environmental surfaces of the room is anticipated; (b) If the patient is incontinent; or (c) If the patient has an ileostomy, colostomy or diarrhoea or has wound drainage not contained by a dressing.

It is important to remove gown and gloves before leaving the patient's room and immediately washing hands with an antiseptic soap or waterless antiseptic agent (e.g. chlorhexidine) (35). Dedicated use of non critical medical equipment to a single patient or cohorted patients is recommended. If such devices are to be used on other patients they must be adequately cleaned and disinfected first.

COLONISATION
Colonisation may be detected most often in hospital inpatients receiving multiple antibiotics on a background of severe disease with multiple background comorbidiities. Once colonised with VRE individual patients tend to be colonised for prolonged periods (36). Where feasible, early discharge to the home setting will reduce the risk of spread to other patients. Home based forms of dialysis therapy are more ideal in colonised patients.

There is no effective way to eliminate colonisation with VRE and antibiotic therapy is not indicated in simple colonisation.

CLINICAL INFECTION
Clinical infection may emerge in a minority of patients with prior colonisation (37), usually under stress of hospital admission for illness or injury. Clinically relevant infections may be most commonly bacteraemia or septicaemia, bacterial endocarditis or urinary tract infections. In some studies, even VRE septicaemia has few clinical sequelae however generally the mortality is high (38). VRCNS has a predilection to causing peritonitis (39,40).

There is no definitive antimicrobial agent recommended for the treatment of VRE. Each case needs to be treated on its own merits and treatment regimens based upon site of infection, severity of illness and the susceptibility pattern of the enterococcal isolate should be designed in consultation with a Microbiologist/Infectious Diseases Consultant. In general, whenever an infected foreign device is present removal of the foreign device is recommended. Surgical debridement and drainage of any collections should be performed if possible (41).

Single agents which show some in-vitro activity against some VRE strains include ampicillin, teicoplanin, tetracycline, chloramphenicol, quinupristin-dalfopristin, fluorquinolones, linezolid, novobiocin, nitrofurantoin and rifampicin. While some may be bacteriocidal for some strains, these agents are mostly bacteriostatic only. In-vitro antibiotic sensitivity to trimethprim-sulfamethoxazole is misleading, as enterococci can use exogenous folic acid to bypass the induced folate synthesis block, and TMP/SMX should not be used alone. Combination antibiotics may be most effective and new antibiotics are emerging.

TRANSPLANTATION OR IMMUNOSUPPRESSION
Patients colonised with VRE often have background medical conditions which may preclude them from consideration for a renal or other transplant. However currently VRE or VRCNS colonisation alone is not a contraindication to organ transplantation, providing a complicated course is not forseen. VRE colonisation does not impact greatly on post-transplant mortality, however VRE infection, which mainly emerges in patients with other infections, may have a very significant impact on patient survival (42,43).

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