The control of hyperendemic glycopeptide-resistant Enterococcus spp. on a haematology unit by changing antibiotic usage

Susan J. Bradleya,b, Angela L. T. Wilsona, Michael C. Allenc, Hilary A. Shera, Anthony H. Goldstoneb and Geoffrey M. Scotta,*

a Department of Clinical Microbiology, University College London Hospitals, London, WC1E 6DB b Department of Haematology, University College London Hospitals, London, WC1E 6DB; c Wyeth UK Ltd, Maidenhead, Berks, SL6 0PH, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The rectal carriage of glycopeptide-resistant Enterococcus spp. (GRE) had been established at approximately 50% in a series of prevalence studies on a busy haematological malignancy unit. The aim of this study was to reduce the chance of patients acquiring GRE. A prospective three-phase sequential study was performed. In Phase 1, the acquisition rate of GRE detectable by rectal swab was measured without any intervention for a period of 4 months. For the following 8 months (Phase 2), the first-line treatment for febrile neutropenic episodes was changed from monotherapy with ceftazidime to piperacillin/tazobactam. In addition, an intense education programme was introduced to improve hygiene to reduce the risk of case-to-case spread. In the final 4 months (Phase 3), ceftazidime was again used as the first-line antimicrobial, while continuing the same level of training in relation to hygiene. The carriage of GRE was measured from rectal swabs done weekly. During the initial 4 months, at any time, 40-50% of patients in the unit were colonized with GRE, and 43 of 75 (57%) new patients initially negative for GRE acquired it within 6 weeks of their admission. In Phase 2, 25 patients out of 129 (19%) acquired GRE, with the acquisition rate falling progressively so that in the last 3 months, only one new patient acquired GRE (logrank comparison of probabilities for cohort 1 vs cohort 2b: P < 0.0001). A return to ceftazidime in Phase 3 was associated with a return of the risk of acquiring detectable GRE colonization, despite continued hygiene teaching and surveillance, with 21 out of 58 patients (36%) acquiring GRE (cohort 1 vs cohort 3: P= 0.08). Glycopeptide usage was not reduced during the period of the study. Clinical cases were seen only in Phases 1 and 3. Although the reduction in the risk of acquiring GRE may have been due in part to hygiene practices as well as to the change in antimicrobial usage, or may have occurred spontaneously for other reasons, the return of the problem with the reintroduction of ceftazidime strongly suggests that this antibiotic was responsible for encouraging the acquisition of detectable GRE.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Enterococci have gradually increased in importance as nosocomial pathogens, accounting for up to 12% of all hospital-acquired infections. 1 In addition to intrinsic tolerance to ß-lactam and aminoglycoside antibiotics, the acquisition of transferable high-level resistance to aminoglycoside, 2ß-lactam 3 and glycopeptide 4,5 antimicrobials has meant that infections with some strains of enterococci are essentially untreatable.

Glycopeptide-resistant Enterococcus spp. (GRE) were first detected on this haematology unit in December 1993, with clinical isolates from three patients during one week and, at that time, eight (38%) of 21 patients were found to be colonized on stool culture. Over the following 18 months, surveillance studies confirmed similarly high colonization rates, and there were 12 cases of GRE bacteraemia. This report is of a study to examine the effect of replacing ceftazidime as first-line treatment for febrile neutropenic episodes with piperacillin/tazobactam on the risk of acquiring GRE.

Ceftazidime is active against most coliforms and pseudomonads and perhaps one half of coagulase-negative staphylococci which cause bacteraemia in neutropenic patients. However, cephalosporins are, in practice, inactive against enterococci and treatment would be expected to select for an enlarged enteric pool of endogenous enterococci. Furthermore, cephalosporins have been suggested as a risk factor for the emergence of GRE. 4,6 Piperacillin/ tazobactam was chosen as a substitute for ceftazidime in this study because it is more active than cephalosporins and quinolones such as ciprofloxacin against endogenous penicillin-sensitive strains of enterococci and would therefore not tend to select for bowel overgrowth with these organisms.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients

Patients with haematological malignancy who were admitted to the unit between June 1995 and October 1996 inclusive and who gave informed consent, were recruited to the study. The adult haematology unit comprises approximately 35 designated beds in three adjacent wards, most patients being nursed in single rooms. The majority of patients were undergoing marrow or peripheral stem-cell transplants or receiving induction or consolidation chemotherapy for haematological malignancy. Ceftazidime alone had been used for primary treatment of febrile neutropenic episodes since 1988, apart from clinical trials of ciprofloxacin performed in 1988 and of meropenem in 1990-91. Gentamicin was added to initial therapy for septic shock. Teicoplanin replaced vancomycin for proven or suspected Gram-positive infections in 1990. Prophylactic antibiotics and gut decontamination were not used for neutropenic patients.

Microbiology

Patients were screened for GRE colonization by weekly rectal swab. Swabs were enriched in brain heart infusion broth (Oxoid, Basingstoke, UK) containing tryptose 10 g/L, NaCl 5 g/L, nalidixic acid 7.5 mg/L, colistin 5 mg/L and horse serum 10%, and incubated for 24 h at 42°C. The broth was subcultured to selective medium containing bile aesculin agar (Difco, Detroit, MI, USA), nalidixic acid 15 mg/L, colistin 10 mg/L, vancomycin 8 mg/L and horse serum 10%, and incubated aerobically at 42°C for 24 h. Aesculin-positive colonies were subcultured overnight on to 5% horse blood agar, and enterococci identified to species level by `API Strep' (Bio-Mérieux, Hazelwood, MO, USA). High- and low-level vancomycin resistance was confirmed by growth up to a 5 µg and 30 µg disc respectively on Isosensitest agar (Oxoid).

Antibiotic policy

For 4 months the antibiotic policy was not changed. This period (Phase 1) was used to establish the baseline prevalence and acquisition rate of GRE colonization. During the subsequent 8 months (Phase 2), ceftazidime was replaced by piperacillin/tazobactam monotherapy for the initial treatment of febrile neutropenia. Throughout the study, ciprofloxacin was used for ß-lactam-allergic patients. Glycopeptides (including teicoplanin) were to be reserved for piperacillin/tazobactam-resistant Gram-positive isolates or unremitting fever after 48 h. Metronidazole was preferred to oral vancomycin for presumed antibiotic- associated diarrhoea. The change in antibiotic policy applied to all patients on the unit, including those admitted during Phase 1 still in hospital or readmitted during Phase 2, those declining to participate in the study, and those who were GRE carriers on admission.

Infection control measures

Since the main objective was to reduce the risk of patients becoming carriers of GRE, thereby reducing the risk of clinical infection due to this group of organisms, new infection control measures were also introduced at this time. These included the identification of GRE carriers by marking their rooms discreetly (not previously done), intensive education of nursing, medical and domestic staff about cross-infection and hand hygiene and, in particular, the introduction of alcoholic chlorhexidine hand-rub or alcohol gel outside each room. During induction into the study, patients were also educated about GRE and likely methods of transmission, and were encouraged in their own hand hygiene in the ward environment, particularly in the toilets and before eating. Alcohol wipes were provided in communal toilets as GRE could be isolated from hard surfaces there. After a review of practices, new guidelines for domestic staff for ward cleaning were introduced, including (following experiments to demonstrate its efficacy) the decontamination of hard surfaces in rooms vacated by GRE carriers with a phenolic disinfectant (Hycolin 2%; Pearson, Glendale, CA, USA). The use of sterilized food for neutropenic patients had been discontinued in 1992, and in this study, there were no changes in catering practice. Surveillance failed to show GRE in the kitchen environment or food.

Phase 3

After 8 months in Phase 2, the antibiotic policy was changed back to that in place during the introductory phase, with ceftazidime replacing piperacillin/tazobactam. Educational seminars were held for nursing, medical and domestic staff to ensure that the heightened infection control measures were maintained.

Analysis

The cumulative total time of exposure on the ward, excluding periods spent at home, was used to calculate the interval between induction into the study on first admission and acquisition of detectable GRE in the rectal swab. Kaplan-Meier time-to-event analysis was done to determine the probabilities of remaining free of GRE by cohort, and logrank tests performed to ascertain statistical significance between cohorts. 7 A P value of <0.05 was deemed to be significant.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
GRE carriage

In total, 293 patients were recruited to the study. Fewer than 5% of new admissions to the wards refused to take part. The likelihood of acquiring GRE was analysed in four separate 4 month cohorts: those admitted to the wards during Phase 1 (cohort 1), during the first 4 months of the intervention Phase 2 (cohort 2a), during the second 4 months of Phase 2 (cohort 2b) and finally during the period of return to ceftazidime usage (Phase 3 and cohort 3). Once assigned to a cohort, patients were followed up through all subsequent admissions as belonging to that cohort, whatever treatment they received.

Of the patients screened during the first week of the study, 58% were already GRE carriers and were excluded from subsequent analysis. During Phase 1 as a whole, 27 out of 102 patients were positive on first screening and were excluded from Kaplan-Meier analysis. During Phase 2 and Phase 3, two out of 131 and two out of 60 patients respectively were positive on first screening and were similarly excluded. Overall, this left 262 patients out of the original 293 to follow up.

The characteristics of the 262 patients followed up by cohort are shown in the Table. The commonest procedures were induction and consolidation chemotherapy and peripheral blood stem-cell transplants. There were minor changes in the types of patient treated (for example, there were more with multiple myeloma in Phase 2) and in the types of treatment administered (for example, more patients had chemotherapy alone rather than transplantation in Phase 2) and, by chance, a decreasing number of allogeneic bone marrow transplants were done.


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Table. Patient demographics
 
Forty-three out of 75 (57%) patients in cohort 1 acquired GRE. The acquisition rate fell progressively for those patients admitted during Phase 2, with 20 out of 70 (29%) acquiring GRE in cohort 2a, and five out of 59 (8%) in cohort 2b. Only one patient acquired GRE in the last 3 months of Phase 2.

The return of ceftazidime in Phase 3 was associated with a rise in GRE acquisition for those patients in cohort 3 with 21 out of 58 (36%) becoming colonized.

Figure 1 shows the Kaplan-Meier plot of the probability of remaining free of GRE colonization by cohort according to time of exposure on the wards. (Time spent at home in between courses of chemotherapy was not included as exposure.) During the second phase of the study, patients were significantly more likely to remain free of GRE colonization than during the Phase 1 (cohort 1 vscohort 2b: P < 0.0001), and this improved with time during Phase 2 (cohort 2a vs cohort 2b: P = 0.02). With the return to ceftazidime therapy, GRE acquisition rates increased to the level observed in Phase 1 (cohort 3 vs cohort 1: P = 0.08).



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Figure 1. Kaplan-Meier analysis to show probability of remaining free of glycopeptide-resisitant Enterococcus spp. (GRE) colonization by weeks of exposure on the wards from first date of admission. ——, Phase 1; — – – — , Phase 2a; — — — , Phase 2b; – – – – , Phase 3.

 
GRE isolates obtained by screening

Of 544 isolates examined, 476 were Enterococcus faecium. All but one isolate were resistant to both vancomycin and teicoplanin (VanA phenotype), while a single isolate remained sensitive to teicoplanin (MIC = 0.5 mg/L, VanB phenotype). There were 49 isolates of Enterococcus faecalis, 11 isolates of Enterococcus avium— all VanA phenotype, and eight isolates of Enterococcus casseliflavus (VanC phenotype, low-level vancomycin resistance).

Clinical isolates of GRE

There were five patients with clinical isolates of GRE during the initial phase of the study: two with isolates from urine (one E. faecalis, one E. faecium), two from blood (both E. faecium) and one with post-mortem isolates from the spleen and tunnelled intravenous line tip (E. faecium). There were no clinical isolates during Phase 2. However, in Phase 3, there were three further patients with clinical isolates: two from blood (both E. faecium) and one from urine cultures (E. faecalis), coincident with increased incidence of detectable rectal carriage.

Antibiotic usage

The monthly prescriptions of ceftazidime, piperacillin/ tazobactam, ciprofloxacin and teicoplanin over the study period are shown in Figure 2. Average ceftazidime usage was 186 patient-days per month during Phase 1, and 200 patients-days per month for Phase 3. Piperacillin/tazobactam usage was similar during Phase 2, at 197 patient-days per month on average. The use of ciprofloxacin was fairly constant throughout the study period at an average of 57 patient-days per month. Although it was intended that the new antibiotic guidelines and surveillance would reduce glycopeptide usage, teicoplanin was used intensively throughout the study (average 218 (range 126-365) patient-days of treatment per month), and paradoxically used at a very high rate (260 patient-days per month during Phase 2b) when the risk of GRE acquisition was at its lowest. Very little oral vancomycin was used during the study period, on average 6 patient-days per month during Phase 1, 3 during Phase 2 and 8 during Phase 3.



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Figure2. The usage of the principal intravenous antibiotics (——, ceftazidime; — — — , teicoplanin; ···· , piperacillin/tazobactam; — – — , ciprofloxacin) by month. Phase 1, mid-month 1 to month 4; Phase 2, month 5 to mid month 14; Phase 3, to the end of month 17.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study suggests that colonization with GRE can be controlled despite very high endemicity. Replacing ceftazidime with piperacillin/tazobactam for broad-spectrum antibacterial treatment of febrile neutropenic episodes and the introduction of improved hygiene were associated with a profound reduction in the risk of acquiring detectable GRE. However, the effect was delayed suggesting that the impact of the intervention was complex, and may not have been detected if patients had simply been randomized to the two antibiotics of interest. The reintroduction of ceftazidime resulted in a significant rise in the risk of GRE acquisition despite maintaining heightened infection control measures. The change in incidence of GRE carriage was clearly not influenced by teicoplanin usage. Clinical cases of GRE infection were only seen when the prevalence of carriage was high and not at all during the piperacillin/tazobactam phase of the study.

Numerous outbreaks of GRE infection and colonization have now been documented. Smaller outbreaks have been successfully controlled by enforcing strict infection control measures, 8,9,10 but the control of larger outbreaks where endemicity has become well established has proved more elusive. 11,12 In 1995, the Hospital Infection Control Practices Advisory Committee (HICPAC) from the Centers for Disease Control, Atlanta issued comprehensive guidelines aimed at reducing the spread of vancomycin resistance. 13 These address `prudent' use of vancomycin, education programmes and the role of the microbiology laboratory in the detection and identification of GRE, and outline measures to prevent and control nosocomial transmission of GRE. However, these recommendations do not address broad-spectrum antibiotic usage. A study by Morris et al. 11 showed that reducing oral vancomycin use by 85% and intravenous vancomycin by 59%, together with the implementation of strict infection control practices as outlined by HICPAC, failed to reduce the prevalence of GRE. Quale and co-workers, 14 however, showed that restricting antimicrobials including cefotaxime, ceftazidime and clindamycin as well as vancomycin could result in a reduction of GRE colonization and infection when the prevalence rate was high, and where infection control measures alone had failed. A similar effect on a different organism was observed in a study by Impallomeni et al. 15 where a sudden increase in the incidence of Clostridium difficile diarrhoea was observed following a 20-fold increase in the use of cefotaxime. Infection control measures did not prevent new cases, but restriction of the use of cefotaxime did. The effect of restricting the use of an antibiotic on the susceptibility of an organism to that agent has been demonstrated recently in a report by Seppala and co-workers. 16 Restricting the use of macrolide antibiotics for the out-patient treatment of group A streptococcal infections in Finland was associated with a reduction in resistance to this agent from 16.5% to 8.6% over 4 years. A number of other studies have shown that exerting control over antibiotic usage can prevent the spread of antibiotic resistance, and that relaxing these controls will result in the re-emergence of resistant organisms. 17

At the start of this study, the probability of new patients acquiring detectable rectal carriage of GRE in this unit was very high and had been so for at least 18 months according to a series of prevalence studies and one 3 month incidence study. Although the turn-down in the rate of acquisition of GRE could be ascribed to factors other than the change of ceftazidime to piperacillin/tazobactam, such as improved hygiene, the return of the problem with the reintroduction of ceftazidime, at a time when the prevalence was the lowest it had been for 30 months while maintaining heightened infection control measures, is most persuasive evidence that ceftazidime alone was responsible.


    Acknowledgments
 
Dr Bradley and Ms Wilson were generously supported by a grant from Wyeth Pharmaceuticals. We are grateful to Ms C. Beer, pharmacist to the leukaemia unit, for invaluable help, to Alison Newberry and Andrew Nunn for statistical advice and to Professors David Speller, Patrice Courvalin and Roland Leclerq for their encouragement and advice.


    Notes
 
* Correspondence address. Department of Clinical Microbiology, University College London Hospitals, Grafton Way, London WC1E 6DB. Tel:+44-171-380-9914; Fax:+44-171-388-8514. Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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6 . Frieden, T. R., Munsiff, S. S., Low, D. E., Willey, B. M., Williams, G., Faur, Y. et al . (1993). Emergence of vancomycin-resistant enterococci in New York City. Lancet 342, 76–69.[ISI][Medline]

7 . Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V. et al . (1977). Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II: analysis and examples. British Journal of Cancer 35, 1–39.[ISI][Medline]

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9 . Livornese, L. L., Dias, S., Samel, C., Romanowski, B., Taylor, S., May, P. et al. (1992). Hospital-acquired infection with vancomycin-resistant Enterococcus faecium transmitted by electronic thermometers. Annals of Internal Medicine 117, 112–6.[ISI][Medline]

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11 . Morris, J. G., Shay, D. K., Hebden, J. N., McCarter, R. J., Perdue, B. E., Jarvis, W. et al. (1995). Enterococci resistant to multiple antimicrobial agents, including vancomycin. Establishment of endemicity in a university medical centre. Annals of Internal Medicine 123, 250–9.[Abstract/Free Full Text]

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13 . Hospital Infection Control Practices Advisory Committee (HICPAC). (1995). Recommendations for preventing the spread of vancomycin resistance. Infection Control and Hospital Epidemiology 16, 105–13.[ISI][Medline]

14 . Quale, J., Landman, D., Saurina, G., Atwood, E., DiTore, V. & Patel, K. (1996). Manipulation of a hospital antimicrobial formulary to control an outbreak of vancomycin-resistant enterococci. Clinical Infectious Diseases 23, 1020–5.[ISI][Medline]

15 . Impallomeni, M., Galletly, N. P., Wort, S. J., Starr, J. M. & Rogers, T. R. (1995). Increased risk of diarrhoea caused by Clostridium difficile in elderly patients receiving cefotaxime. British Medical Journal 311, 1345–6.[Free Full Text]

16 . Seppala, H., Klaukka, T., Voupio-Varkila, J., Muotiala, A., Helenius, H., Lager, K. et al . (1997). The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. New England Journal of Medicine 337, 441–6.[Abstract/Free Full Text]

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Received 4 February 1998; returned 9 June 1998; revised 31 July 1998; accepted 11 September 1998