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Outcome of a screening program for vancomycin-resistant enterococci in a hospital in Victoria

Elizabeth A Grabsch, Dianne Olden, Melissa Aberline, H Y Li, Geoffrey Hogg, Marguerite Abbott and Peter G Kerr
Med J Aust 1999; 171 (3): 133-136.
Published online: 2 August 1999
Research

Outcome of a screening program for vancomycin-resistant enterococci in a hospital in Victoria

M Lindsay Grayson, Elizabeth A Grabsch, Paul D R Johnson, Dianne Olden,
Melissa Aberline, H Y Li, Geoffrey Hogg, Marguerite Abbott and Peter G Kerr

MJA 1999; 171: 133-136
See also Ferguson, Robertson et al & Collignon

Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details
- - More articles on Infectious diseases and parasitology


Abstract Objective: To screen for faecal colonisation with vancomycin-resistant enterococci (VRE) among potentially at-risk patients.
Design: Infection control screening program.
Setting: Monash Medical Centre (a tertiary care hospital), Melbourne, Victoria, in the seven months from June 1997.
Patients: Patients in the Renal, Oncology and Intensive Care (ICU) Units.
Main outcome measures: Presence of VRE in a rectal swab or faecal specimen taken at admission and at regular intervals during inpatient stay; presence of vancomycin-resistance genes (vanA, vanB and vanC) assessed by polymerase chain reaction (PCR); genetic clonality of isolates assessed by pulsed-field gel electrophoresis (PFGE).
Results: 574 patients (356 renal, 134 ICU and 84 oncology) were screened; 12 were colonised with VRE -- nine renal inpatients, two having peritoneal dialysis or in-centre haemodialysis, and one ICU patient. Nine isolates were Enterococcus faecalis (seven positive for vanB and two negative for all three resistance genes) and three were Enterococcus faecium (all positive for vanB). Eight were high-level gentamicin resistant. PFGE suggested genetic clonality between the index isolate and five other isolates from renal patients. No specific clinical practice was associated with VRE colonisation. Attempts to clear rectal carriage with oral ampicillin/amoxycillin or bacitracin were of limited success. Although antibiotic prescribing in the Renal Unit was generally consistent with defined protocols, use of vancomycin and third-generation cephalosporins has been further restricted.
Conclusions: Renal inpatients in our institution appear most at risk of VRE colonisation (4.6% overall) and therefore of VRE infection. Routine screening, especially of potentially high-risk patients, should be considered in major Australian hospitals.


Introduction Vancomycin-resistant enterococci (VRE) were first reported in the United Kingdom, Europe and the United States in 1988,1-6 and in Australia in 1994.7 In the United States, VRE have become common and potentially fatal nosocomial pathogens; they account for 14% of enterococcal bacteraemias in intensive care patients, while VRE bacteraemia has an attributable mortality of 30%-46%.4,8 In Australia, cases of VRE infection have now been reported from hospitals in all States and Territories except the Australian Capital Territory and Tasmania.9,10

In May 1997, a patient

receiving renal haemodialysis at Monash Medical Centre, Melbourne, developed a VRE urinary tract infection (see Box 1). This was the first identified case of VRE infection at this institution. As the patient had had close contact with other patients and had suffered diarrhoea, we were concerned about a significant nosocomial outbreak of VRE infection. Clinical infection is almost always associated with faecal colonisation with this organism. We therefore assessed the extent of faecal VRE colonisation among renal and other high-risk patients by active screening, and isolated infected or colonised patients. We describe the results of this screening program and our infection control measures, and highlight some of the clinical issues.


Methods An infection control screening program for faecal colonisation with VRE was implemented in the Renal, Oncology and Intensive Care Units at Monash Medical Centre, Melbourne, Victoria, for the seven months from June 1997. These patients were chosen as experience (local, US and European) suggested they were at greatest risk of VRE infection.4-6,8,10

Patients In the Renal Unit, screening was planned for all patients receiving care in the renal ward and in-centre haemodialysis or continuous ambulatory peritoneal dialysis and, when possible, for dialysis patients managed at home. In the Oncology and Intensive Care Units (ICU), screening was planned for an arbitrary number of 100 consecutive patients admitted to each unit.

All inpatients were screened on admission and discharge. In the renal ward this was later modified to on admission and a regular day of the week (Tuesday). Patients managed by the in-centre haemodialysis unit were screened every three months, and other outpatients were screened at least once.

Screening Rectal swabs were obtained using standard cotton-alginate-tipped sterile swabs from all patients except neutropenic oncology patients. In these, a perianal swab or faecal specimen was substituted for a rectal swab because of their increased risk of septicaemia after rectal trauma.13 Specimens were plated on media specifically selective for vancomycin-resistant enterococci (bile esculin azide agar with 6 µg/mL vancomycin) and cultured for up to 72 hours. Esculin-positive isolates with possible resistance to vancomycin were identified, and single colonies of each morphology type were assessed to identify Enterococcus faecalis and Enterococcus faecium (the pathogenic enterococcal species most commonly associated with vancomycin resistance). Assessment included Gram stain, tests of motility and pigment production, the pyrrolidonyl arylamidase test (Murex Diagnostics Ltd, Dartford, UK) and streptococcal latex grouping.14

VRE assessment VRE isolates were tested further for antibiotic susceptibility. Minimum inhibitory concentrations (MICs) were determined for vancomycin, teicoplanin and ampicillin and high-level gentamicin (MIC > 500 µg/mL) using the E test (AB Biodisk, Dalvagen, Sweden). Production of β-lactamase was assesssed by nitrocephin disc (Becton Dickinson Microbiology Systems, Cockeysville, MD, USA).

Enterococcal species was confirmed and presence of vancomycin-resistance genes vanA, vanB or vanC was assessed by polymerase chain reaction (PCR) genetic probe using a modification of techniques described previously.10,15 Genetic similarity (ie, potential clonality) of VRE isolates was assessed by pulsed-field gel electrophoresis (PFGE) using a method modified after Miranda et al.16

Factors that were potentially associated with VRE colonisation were assessed retrospectively.6,8 Statistical analyses were by χ2 or t test.


Results

Patients Screening was undertaken on 574 patients -- 356 renal, 134 ICU and 84 oncology patients. Renal patients comprised:

  • 194 of 238 inpatients in the renal ward (82%);
  • 66 of 82 peritoneal dialysis and in-centre haemodialysis patients (80%);
  • 94 outpatients (mostly satellite and home haemodialysis patients); and
  • 2 of 180 renal transplantation patients.

In general, consecutive oncology and ICU patients were screened; none refused screening. In the Oncology Unit, the target number (100 patients) was not attained because of a protocol lapse.

VRE colonisation
Faecal colonisation with VRE was found in 12 patients, including the index patient -- 11 renal patients (3% of renal patients tested) and one ICU patient (0.7% of ICU patients tested). Their characteristics are shown in Box 2. No VRE colonisation was found in oncology patients. The 11 renal patients with VRE colonisation comprised nine inpatients (9/194 [5%]) and two having peritoneal dialysis or in-centre haemodialysis (2/66 [3%]). No non-dialysis renal outpatients were colonised. VRE colonisation was found on the initial rectal swab for seven patients and after a series of negative cultures for the remaining five patients.

Characteristics of VRE isolates
Characteristics of the 12 VRE isolates are shown in Box 2. Nine of the 12 were E. faecalis -- seven testing positive for vanB, including the index isolate (vancomycin MICs, 12-32 µg/mL), and two testing negative for vanA, vanB and vanC (vancomycin MICs, 6 and 8 µg/mL, respectively). The other three isolates were E. faecium -- all testing positive for vanB (vancomycin MICs, 16, 64 and > 256 µg/mL, respectively). All isolates were susceptible to teicoplanin. While all E. faecalis isolates were susceptible to ampicillin, all E. faecium isolates were resistant (MICs > 256 µg/mL). Six of the nine E. faecalis isolates and two of the three E. faecium isolates had high-level resistance to gentamicin. None of the 12 produced detectable β-lactamase.

Eleven isolates were assessed by PFGE. Results are shown in the Figure. Six of the seven vanB E. faecalis isolates, including the index isolate, appeared genetically similar (lanes 4-8 and index isolate in lane 9). Three of these similar isolates, plus one dissimilar vanB E. faecalis isolate (not shown), were isolated from patients who had been nursed together in a four-bed area. One of these patients (with vanB E. faecalis) had been nursed with the index patient six months before screening positive. The three E. faecium isolates and the non-ABC E. faecalis isolate (lanes 1-3 and 10, respectively) showed a variety of electrophoretic patterns on PFGE, suggesting they were genetically dissimilar from each other.

Factors potentially associated with VRE
Among the 12 patients with VRE colonisation, nine had received vancomycin in the previous month, four of whom had also received a third-generation cephalosporin (ceftriaxone). Information on previous antibiotics was not available for patients without VRE colonisation.

Among the six renal patients found to have VRE colonisation on their initial swab (including the index case), five had been inpatients during the previous three months, compared with 127 of the 350 non-colonised patients (36%). Mean duration of preswab inpatient stay for these six colonised patients was 17.5 days (range, 0-62), compared with 2.6 days (range, 0-43) for non-colonised patients (P < 0.001).

VRE control measures
All patients identified with faecal VRE colonisation were nursed in a single room according to infection control guidelines.11 In January 1998, an eight-bed VRE isolation facility was established. Continued, less rigorous screening of renal inpatients identified four new cases of VRE colonisation in the following three months (not described here), but these VRE strains were dissimilar on PFGE to the previous 12 strains.

Antibiotic usage patterns were also reviewed. Most antibiotic use in the Renal Unit was found to be consistent with the unit's protocols. These were amended to further restrict use of third-generation cephalosporins and glycopeptides to specific situations, such as nosocomial pneumonia and serious staphylococcal infections.

In seven patients, an attempt was made to "clear" faecal VRE colonisation with either ampicillin or amoxycillin (variable doses, depending on renal function) or oral bacitracin (25 000 units four times a day for 7-14 days).17,18 In four of these patients, follow-up rectal swabs were taken, and in two (one taking ampicillin and one bacitracin) VRE was no longer detected 18 and 13 days, respectively, after therapy.

At completion of the study, nine of the 12 patients with VRE colonisation had died, although, other than the index patient, none had developed VRE infection.


Discussion A screening program introduced at Monash Medical Centre after identification of VRE infection in a renal patient found faecal VRE colonisation in another 10 renal patients (3% of renal patients overall) and one ICU patient (0.7%). Isolates from six of the renal patients, including the index patient, were genetically similar and probably clonal. No patients except the index patient developed VRE infection.

VRE is now a major nosocomial pathogen in many US and European centres, but until recently relatively few clinical VRE infections had been reported in Australia.6,8-10 To our knowledge, this is the first Australian report of a systematic screening program for VRE among potentially at-risk patients.

Our results were consistent with those of previous studies, which suggested that 10-20 patients are likely to have faecal colonisation for every case of clinical VRE infection.6,8,19,20 Although risk factors for VRE infection have been identified by US and European investigators,6,8the factors associated with VRE colonisation are less clear and may vary depending on the epidemiology of VRE in different countries. Antibiotic prescribing patterns, nosocomial transmission and use of antibiotics (eg, avoparcin) in the veterinary industry appear of varying importance in different regions.8,10

Our study did not allow valid assessment of all factors potentially associated with VRE colonisation in our patients. Nevertheless, the fact that renal patients with VRE colonisation spent significantly more days in hospital in the previous three months than patients without colonisation raises the possibility that the hospital environment or illness-related factors influenced the likelihood of VRE colonisation.

Resistance to vancomycin among enterococci is generally due to presence of one of four resistance genes -- vanA, vanB, vanC and vanD. These genes result in synthesis of abnormal precursors in the peptidoglycan layer of the bacterial cell wall, thereby reducing the affinity with which vancomycin binds to this target site.8VanA is associated phenotypically with resistance to vancomycin (MIC > 64 µg/mL) and teicoplanin (MIC > 16 µg/mL), and is the most common genotype found in Europe and some centres in the US.8VanB is associated with medium-level resistance to vancomycin (MIC > 4 µg/mL) but susceptibility to teicoplanin. Consistent with our findings, it is the predominant genotype noted in Australia.9,10VanC is associated with naturally occurring low-level resistance to vancomycin and susceptibility to teicoplanin among less pathogenic enterococcal species, while vanD, which is phenotypically similar, has been occasionally noted in some E. faecium isolates.8,21,22 It is possible that our two non-ABC E. faecalis isolates contain vanD, but we are currently unable to test for this gene.

Presence of faecal VRE colonisation among 5% of renal inpatients at our institution (3% of renal patients overall) was higher than expected, but suggested that nosocomial transmission of VRE was not yet a widespread problem. Nevertheless, our PFGE data suggested that six of the seven vanB E. faecalis strains were clonal, raising infection control issues for the Renal Unit. As reported previously,17,18 we found attempts to clear faecal VRE carriage with antibiotic therapy were unsuccessful and not worthwhile. The screening program and establishment of VRE isolation facilities to readily cohort and barrier-nurse patients with VRE colonisation appeared to assist in limiting nosocomial VRE transmission, while continuing to provide medical care for patients in a compassionate manner.

The incidence of faecal VRE colonisation that we found among high-risk patients at our institution suggests that routine screening for faecal VRE colonisation should now be considered by other similar Australian hospitals.



Acknowledgements
We wish to acknowledge the contribution of the nursing staff of the Renal, Oncology and Intensive Care Units and the Outpatient Department in obtaining rectal cultures.


References
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  2. Uttley AHC, Collins CH, Naidoo J, George RC. Vancomycin-resistant enterococci. Lancet 1988; 1: 57-58.
  3. Clark NC, Cooksey RC, Hill BC, et al. Characterization of glycopeptide-resistant enterococci from U.S. hospitals. Antimicrob Agents Chemother 1993; 37: 2311-2317.
  4. Centers for Disease Control. Nosocomial enterococci resistant to vancomycin -- United States, 1989-1993. MMWR Morb Mortal Wkly Rep 1993; 42: 597-599.
  5. Frieden TR, Munsiff SS, Low DE, et al. Emergence of vancomycin-resistant enterococci in New York City. Lancet 1993; 342: 76-79.
  6. Boyce JM. Vancomycin-resistant enterococcus. Detection, epidemiology, and control measures. Infect Dis Clin North Am 1997; 11: 367-384.
  7. Kamarulzaman A, Tosolini FA, Boquest AL, et al. Vancomycin resistant Enterococcus faecium infection in a liver transplant recipient [abstract]. Aust N Z J Med 1995; 25: 560.
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  9. Bell J, Turnidge J, Coombs G, O'Brien F. Emergence and epidemiology of vancomycin-resistant enterococci in Australia. Commun Dis Intell 1998; 22: 249-252.
  10. Bell JM, Paton JC, Turnidge J. Emergence of vancomycin-resistant enterococci in Australia: phenotypic and genotypic characteristics of isolates. J Clin Microbiol 1998; 36: 2187-2190.
  11. Standing Committee on Infection Control (SCIC), Department of Human Services, Victoria. Guidelines for the management of patients with confirmed vancomycin-resistant enterococci (VRE) infection/colonisation. Melbourne: Department of Human Services, 1996.
  12. Moellering RC Jr. The Garrod lecture. The enterococcus: a classic example of the impact of antimicrobial resistance on therapeutic options. J Antimicrob Chemother 1991; 28: 1-12.
  13. Weinstein JW, Tallapragada S, Farrel P, Dembry L-M. Comparison of rectal and perirectal swabs for detection of colonisation with vancomycin-resistant enterococci. J Clin Microbiol 1996; 34: 210-212.
  14. Facklam RR, Sahm DF. Enterococcus. In: Murray PR, Baron EJ, Pfaller MA, et al, editors. Manual of clinical microbiology. 6th ed. Washington: ASM Press, 1995: 308-314.
  15. Dutka-Malen A, Evers S, Courvalin P. Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR. J Clin Microbiol 1995; 33: 24-27.
  16. Miranda AG, Singh KV, Murray BE. A fingerprinting of Enterococcus faecium by pulsed-field gel electrophoresis may be a useful epidemiologic tool. J Clin Microbiol 1991; 29: 2752-2757.
  17. O'Donovan CA, Fan-Havard P, Tecson-Tumang FT, et al. Enteric eradication of vancomycin-resistant Enterococcus faecium with oral bacitracin. Diagn Microbiol Infect Dis 1994; 18: 105-109.
  18. Chia JKS, Nakata MM, Park SS, et al. Use of bacitracin therapy for infection due to vancomycin-resistant Enterococcus faecium. Clin Infect Dis 1995; 21: 1520.
  19. Jordens JZ, Bates J, Griffith DT. Faecal carriage and nosocomial spread of vancomycin-resistant Enterococcus faecium. J Antmicrob Chemother 1994; 34: 515-528.
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(Received 15 Dec 1998, accepted 23 Apr 1999)


Authors' details Infectious Disease and Clinical Epidemiology Department, Monash Medical Centre, Melbourne, VIC.
M Lindsay Grayson, MD, FRACP, Director, and Professor of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC;
Elizabeth A Grabsch, BSc, GradDipClinEpid, Infection Control Scientist;
Paul D R Johnson, PhD, FRACP, Infectious Disease Physician, and Senior Lecturer, Microbiology Department, Monash University, Melbourne, VIC;
Dianne Olden, PhD, Research Scientist.

Infection Control Unit, Monash Medical Centre, Melbourne, VIC.
Melissa Aberline, RN, BSc, Infection Control Nurse.

Microbiological Diagnostic Unit, Melbourne University, Melbourne, VIC.
H Y Li, MMed, Scientist;
Geoffrey Hogg, FRACP, FRCPA, Director.

Nephrology Department, Monash Medical Centre, Melbourne, VIC.
Marguerite Abbott, RN, BAppSci, Nurse Director;
Peter G Kerr, PhD, FRACP, Deputy Director.

Reprints will not be available from the authors.
Correspondence: Professor M L Grayson, Infectious Diseases and Clinical Epidemiology Department, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168.
Email: Lindsay.GraysonATmed.monash.edu.au






Pulsed-field gel electrophoresis of vancomycin-resistant enterococcal isolates.
Lanes 1-3: E. faecium (vanB) isolates from renal patients.
Lanes 4-9: E. faecalis (vanB) isolates from renal patients, including index isolate (lane 9).
Lane M: Molecular weight markers.
Lane 10: E. faecalis (non-ABC) isolate from renal patient.
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1: Case history of the index patient

In May 1997, a 26-year-old woman presented to Monash Medical Centre with a fever and urinary tract infection caused by vancomycin-resistant enterococci (VRE). She had faecal colonisation with the same VRE strain. She had endstage renal failure requiring in-centre haemodialysis three times a week.

Ten days later, the patient presented in status epilepticus with faecal incontinence that led to substantial faecal contamination of the Emergency Department and the in-centre Haemodialysis Unit. Appropriate cleaning protocols11 were implemented in each area, and limited environmental cultures suggested no contamination.

Five months later, the patient developed symptomatic VRE bacteraemia after surgical insertion of a femoral Goretex arteriovenous fistula. The VRE isolate was phenotypically identical to the initial urinary isolate. As it had high-level gentamicin resistance, she was treated with continuous-infusion ampicillin, continuing for 10 weeks because of the possibility of graft sepsis.12 The patient continued to show faecal VRE colonisation until her death (not related to VRE) in September 1998.

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Received 19 November 2018, accepted 19 November 2018

  • Elizabeth A Grabsch
  • Dianne Olden
  • Melissa Aberline
  • H Y Li
  • Geoffrey Hogg
  • Marguerite Abbott
  • Peter G Kerr


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