eMJA: Ferguson, Vancomycin-resistant enterococci: causes and control?

Editorial

Vancomycin-resistant enterococci: causes and control?

The overriding emphasis should be on control of antibiotic use in humans and animals

MJA 1999; 171: 117-118

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This issue of the Journal contains three articles on the emergence and control of vancomycin-resistant enterococci (VRE). Clinical infection with VRE was first noted in England and France in 1986,^1,2 and was first detected in Australia (in Melbourne) in 1994.³ To September 1998, 69 sporadic and outbreak-associated strains had been identified in patients from most Australian States.⁴ The spread of VRE brings us ever closer to the appearance of high-level vancomycin resistance in Staphylococcus aureus, lending urgency to efforts to control VRE.

How is vancomycin resistance selected and amplified?
In all types of antibiotic resistance, bacterial clones that carry the resistance factor are selected and expanded (amplified) by the selective pressure of antibiotic exposure. In the case of VRE, resistance can also be transferred horizontally between animal and human enterococcal strains by transposons⁴ (see Box). Of even greater concern is the experimentally demonstrated ability of these transposons to transfer vancomycin resistance to the major human pathogen, S. aureus.⁶ The specific pressures that have led to vancomycin resistance appear to differ between geographical areas and types of resistance.

VanA resistance: As summarised by Collignon,⁷ use of the glycopeptide avoparcin as a growth promoter in farmed animals in Europe, coupled with the presence of the vanA transposon, has fuelled remarkable selection and amplification of VRE in animals. Vancomycin resistance has spread to human populations (and their enterococci) via the food chain. The strength of evidence for this has been assessed at level III-1 (well designed, non-randomised, controlled trials).⁸ However, a second amplification step through medical use of glycopeptides in humans is necessary for VRE to emerge as a clinical problem, while lowered defence is usually required for enterococci to cause human disease. The low incidence of clinical VRE infections in most European countries appears related to low medical use of glycopeptides and other antibiotics. Alternatively, transferred animal VRE strains may be less able to cause human disease (although outbreaks of vanA VRE disease have occurred in England⁹).

The relatedness of vanA VRE strains across the world has been examined. The coding sequence of the vanA transposon, Tn1546, comprises over 10 000 base-pairs, but, remarkably, only a single nucleotide difference in this sequence has been documented in the many strains examined to date from the United States and Europe.¹⁰ This suggests that the vanA transposon emerged through a complex chain of events that occurred only once, and was then transferred to many strains. While the coding sequences of the vanA transposon are strongly conserved, the non-coding insertion sequences (IS) are more variable. Mapping has shown that some US and European vanA strains have identical IS arrangements, indicating a recent common origin.^9-11 As vanA VRE appeared in New York soon after their appearance in Europe,¹² it is likely they were carried to the US (and later to Australia) from Europe in food, livestock or humans. In the US, avoparcin was never used, and VRE has spread among hospitalised patients, with insignificant community colonisation.¹³

VanB resistance: The epidemiology of vanB vancomycin resistance is largely unknown. In Europe, vanB VRE have been isolated infrequently from humans and never, as yet, from animals or food.⁸ A small study comparing US and European vanB strains found their Tn1547 transposons to be distinct by restriction mapping.¹⁴ More recent data indicate that there are at least three vanB genotypes (Dr Robin Patel, Mayo Clinic, Rochester, Minn, USA, personal communication). This greater diversity implies that vanB emerged earlier than vanA.

What is Australia's position? In Australia, relative use of glycopeptides in humans and animals strongly resembles that in Europe, where avoparcin has been largely responsible for VRE amplification in animals. As yet, there has been very limited study of VRE in local animal populations, and local VRE strains have not been subtyped by transposon mapping nor compared with overseas strains. Nonetheless, given that VRE strains carrying the vanA and vanB transposons have been isolated in Australia,⁴ and that these transposons do not emerge by mutation, they must have been imported. Once here, enterococci carrying these transposons may well have been amplified in animals exposed to avoparcin, and passed through the food chain to humans in a manner similar to that in Europe. Community-acquired VRE carriage has been observed at a low level in Victoria,¹⁵ and at least one study found vanA and vanB VRE in animal populations.¹⁶ The extent of community and animal colonisation in Australia urgently needs quantification.

In Australia, in contrast to Europe, most documented human VRE colonisation and disease has been with polyclonal vanB strains. The diverse range of strains implies that there has been either widespread amplification and transfer of VRE transposons within Australia or importation of multiple strains. However, in some regions, clonal strains of vanA VRE have been responsible for hospital-related outbreaks, similar to the US¹⁷ and UK⁹ situations.

How does cross-infection occur in healthcare settings?
Enterococci are ubiquitous gastrointestinal and genital tract bacteria that readily contaminate and persist in hospital environments. Healthcare workers who comply poorly with handwashing are vectors for patient-to-patient transfer of these bacteria. Equipment and contaminated environments have also been identified as important modes of spread in some acute care settings.^18,19 Patients receiving antibiotics usually lose normal protective flora, increasing their risk of colonisation with nosocomial strains of enterococci and other resistant bacteria. Intensive care, organ transplant, renal, haematology and oncology patients are particularly at risk from VRE disease and require protection from inadvertent colonisation.

How can VRE be controlled?
The overriding emphasis must be on control of antibiotic use. In whatever situation, animal or human, use of glycopeptides will amplify vancomycin resistance, increasing the potential for its eventual transfer to S. aureus.

Avoparcin restriction: Collignon has highlighted viable alternatives to use of avoparcin in animals, and Australia should act urgently as a precautionary measure to eliminate or at least restrict avoparcin use.

Control of human antibiotic use: This should go further than the restrictions on vancomycin recommended by the Hospital Infection Control Practices Advisory Committee.²⁰ Broad-spectrum antibiotics, particularly third-generation cephalosporins, have been identified as independent risk factors for VRE colonisation and also play an important role in amplifying methicillin-resistant S. aureus (MRSA). Use of broad-spectrum antibiotics should be reduced whenever possible.

The incidence of nosocomial disease caused by MRSA, VRE and Clostridium difficile is a valuable "ecological" indicator for hospitals, providing early warning of an adverse antibiotic-created environment. Evidence from the US shows the effectiveness of antibiotic control in reducing the incidence of VRE and C. difficile.²¹

Regular auditing of antibiotic use can assist hospital drug committees to define areas for targeted intervention. Robertson and colleagues examined detailed reasons for vancomycin use in five metropolitan hospitals in Victoria.²² They highlight unnecessarily prolonged use of vancomycin in empirical and prophylactic therapy, both amenable to intervention. Their study should be repeated at other Australian hospitals.

VRE infection control procedures: As VRE are already widespread, albeit uncommon, in many animal and human populations, eradication is not possible. To ensure early detection and containment of VRE, a targeted approach is needed among patients most at risk from VRE disease. Grayson and colleagues describe such an approach.²³ After identification of clinical vanB VRE infection in a renal patient, their hospital took measures to prevent a potential outbreak. Screening of at-risk groups for faecal VRE colonisation, which found nine additional isolates of vanB VRE, and review of antibiotic use appear to have been successful in containing VRE.²²

The temptation to screen for VRE colonisation in low-risk patients should be resisted, as few of those identified will develop disease, but the hospital and patient must carry the considerable respective financial and psychological burdens. In low-risk groups, it is more worthwhile to focus initially on assessment and modification of antibiotic use.

John K Ferguson
Director of Microbiology and Infectious Diseases
John Hunter Hospital, Newcastle, NSW

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