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Mw4042 bradley

Journal of Antimicrobial Chemotherapy (1999) 43, 261–266
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*
aDepartments of Clinical Microbiology and bHaematology, University College London Hospitals, London, WC1E 6DB; cWyeth UK Ltd, Maidenhead, Berks, SL6 0PH, UK 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:
< 0.0001). A return to ceftazidime in Phase 3 was associated with a return of the risk of acquir-
ing 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 prac-
tices 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 sug-
gests that this antibiotic was responsible for encouraging the acquisition of detectable GRE.

with clinical isolates from three patients during one weekand, at that time, eight (38%) of 21 patients were found to Enterococci have gradually increased in importance as be colonized on stool culture. Over the following 18 nosocomial pathogens, accounting for up to 12% of all months, surveillance studies confirmed similarly high colo-hospital-acquired infections.1 In addition to intrinsic toler- nization rates, and there were 12 cases of GRE bacter- ance to -lactam and aminoglycoside antibiotics, the aemia. This report is of a study to examine the effect ofacquisition of transferable high-level resistance to amino- replacing ceftazidime as first-line treatment for febrile glycoside,2 -lactam3 and glycopeptide4,5 antimicrobials has neutropenic episodes with piperacillin/tazobactam on the meant that infections with some strains of enterococci are Ceftazidime is active against most coliforms and pseudo- Glycopeptide-resistant Enterococcus spp. (GRE) were monads and perhaps one half of coagulase-negative first detected on this haematology unit in December 1993, staphylococci which cause bacteraemia in neutropenic *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.
1999 The British Society for Antimicrobial Chemotherapy S. J. Bradley et al.
patients. However, cephalosporins are, in practice, inactive lence and acquisition rate of GRE colonization. During the against enterococci and treatment would be expected to subsequent 8 months (Phase 2), ceftazidime was replaced select for an enlarged enteric pool of endogenous entero- by piperacillin/tazobactam monotherapy for the initial cocci. Furthermore, cephalosporins have been suggested as treatment of febrile neutropenia. Throughout the study, a risk factor for the emergence of GRE.4,6 Piperacillin/ ciprofloxacin was used for -lactam-allergic patients.
tazobactam was chosen as a substitute for ceftazidime in Glycopeptides (including teicoplanin) were to be reserved this study because it is more active than cephalosporins for piperacillin/tazobactam-resistant Gram-positive iso-and quinolones such as ciprofloxacin against endogenous lates or unremitting fever after 48 h. Metronidazole was penicillin-sensitive strains of enterococci and would there- preferred to oral vancomycin for presumed antibiotic- fore not tend to select for bowel overgrowth with these associated diarrhoea. The change in antibiotic policy applied to all patients on the unit, including those admittedduring Phase 1 still in hospital or readmitted during Phase2, those declining to participate in the study, and those who Patients and methods
Patients with haematological malignancy who were ad-mitted to the unit between June 1995 and October 1996 Since the main objective was to reduce the risk of patients inclusive and who gave informed consent, were recruited to becoming carriers of GRE, thereby reducing the risk of the study. The adult haematology unit comprises approxi- clinical infection due to this group of organisms, new infec- mately 35 designated beds in three adjacent wards, most tion control measures were also introduced at this time.
patients being nursed in single rooms. The majority of These included the identification of GRE carriers by mark- patients were undergoing marrow or peripheral stem-cell ing their rooms discreetly (not previously done), intensive transplants or receiving induction or consolidation chemo- education of nursing, medical and domestic staff about therapy for haematological malignancy. Ceftazidime alone cross-infection and hand hygiene and, in particular, the had been used for primary treatment of febrile neutropenic introduction of alcoholic chlorhexidine hand-rub or alco- episodes since 1988, apart from clinical trials of cipro- hol gel outside each room. During induction into the study, floxacin performed in 1988 and of meropenem in 1990–91.
patients were also educated about GRE and likely methods Gentamicin was added to initial therapy for septic shock.
of transmission, and were encouraged in their own hand Teicoplanin replaced vancomycin for proven or suspected hygiene in the ward environment, particularly in the toilets Gram-positive infections in 1990. Prophylactic antibiotics and before eating. Alcohol wipes were provided in com- and gut decontamination were not used for neutropenic munal toilets as GRE could be isolated from hard surfaces there. After a review of practices, new guidelines fordomestic staff for ward cleaning were introduced, including(following experiments to demonstrate its efficacy) the decontamination of hard surfaces in rooms vacated by Patients were screened for GRE colonization by weekly GRE carriers with a phenolic disinfectant (Hycolin 2%; rectal swab. Swabs were enriched in brain heart infusion Pearson, Glendale, CA, USA). The use of sterilized food broth (Oxoid, Basingstoke, UK) containing tryptose 10 for neutropenic patients had been discontinued in 1992, g/L, NaCl 5 g/L, nalidixic acid 7.5 mg/L, colistin 5 mg/L and and in this study, there were no changes in catering horse serum 10%, and incubated for 24 h at 42°C. The practice. Surveillance failed to show GRE in the kitchen broth was subcultured to selective medium containing bile aesculin agar (Difco, Detroit, MI, USA), nalidixic acid 15mg/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 After 8 months in Phase 2, the antibiotic policy was to 5% horse blood agar, and enterococci identified to changed back to that in place during the introductory species level by ‘API Strep’ (Bio-Mérieux, Hazelwood, phase, with ceftazidime replacing piperacillin/tazobactam.
MO, USA). High- and low-level vancomycin resistance Educational seminars were held for nursing, medical and was confirmed by growth up to a 5 g and 30 g disc respec- domestic staff to ensure that the heightened infection con- tively on Isosensitest agar (Oxoid).
For 4 months the antibiotic policy was not changed. This The cumulative total time of exposure on the ward, exclud- period (Phase 1) was used to establish the baseline preva- ing periods spent at home, was used to calculate the Effect of piperacillin/tazobactam on VRE carriage
interval between induction into the study on first admission were induction and consolidation chemotherapy and and acquisition of detectable GRE in the rectal swab.
peripheral blood stem-cell transplants. There were minor Kaplan–Meier time-to-event analysis was done to deter- changes in the types of patient treated (for example, there mine the probabilities of remaining free of GRE by cohort, were more with multiple myeloma in Phase 2) and in the and logrank tests performed to ascertain statistical signifi- types of treatment administered (for example, more cance between cohorts.7 A P value of 0.05 was deemed to patients had chemotherapy alone rather than transplant- ation in Phase 2) and, by chance, a decreasing number ofallogeneic bone marrow transplants were done.
Forty-three out of 75 (57%) patients in cohort 1 acquired GRE. The acquisition rate fell progressively for thosepatients admitted during Phase 2, with 20 out of 70 (29%) acquiring GRE in cohort 2a, and five out of 59 (8%) in In total, 293 patients were recruited to the study. Fewer cohort 2b. Only one patient acquired GRE in the last 3 than 5% of new admissions to the wards refused to take part. The likelihood of acquiring GRE was analysed in four The return of ceftazidime in Phase 3 was associated with separate 4 month cohorts: those admitted to the wards a rise in GRE acquisition for those patients in cohort 3 withduring Phase 1 (cohort 1), during the first 4 months of the 21 out of 58 (36%) becoming colonized.
intervention Phase 2 (cohort 2a), during the second 4 Figure 1 shows the Kaplan–Meier plot of the probability months of Phase 2 (cohort 2b) and finally during the period of remaining free of GRE colonization by cohort according of return to ceftazidime usage (Phase 3 and cohort 3). Once to time of exposure on the wards. (Time spent at home in assigned to a cohort, patients were followed up through all between courses of chemotherapy was not included as subsequent admissions as belonging to that cohort, what- exposure.) During the second phase of the study, patients were significantly more likely to remain free of GRE Of the patients screened during the first week of the colonization than during the Phase 1 (cohort 1 vs cohort 2b: study, 58% were already GRE carriers and were excluded 0.0001), and this improved with time during Phase 2 from subsequent analysis. During Phase 1 as a whole, 27 out of 102 patients were positive on first screening and were ceftazidime therapy, GRE acquisition rates increased excluded from Kaplan–Meier analysis. During Phase 2 and to the level observed in Phase 1 (cohort 3 vs cohort 1: Phase 3, two out of 131 and two out of 60 patients respec- tively were positive on first screening and were similarlyexcluded. Overall, this left 262 patients out of the original GRE isolates obtained by screening The characteristics of the 262 patients followed up by Of 544 isolates examined, 476 were Enterococcus faecium.
cohort are shown in the Table. The commonest procedures All but one isolate were resistant to both vancomycin and Table. Patient demographics
Most intensive treatment before acquiring GRE or during surveillance (%) autograft bone marrow/stem-cell transplant S. J. Bradley et al.
Figure 1. Kaplan–Meier analysis to show probability of remaining free of glycopeptide-resisitant Enterococcus spp. (GRE) coloniz-
ation by weeks of exposure on the wards from first date of admission. ——, Phase 1; –– - - ––, Phase 2a; – –– , Phase 2b; - - - -, Phase 3.
teicoplanin (VanA phenotype), while a single isolate patient-days of treatment per month), and paradoxically used at a very high rate (260 patient-days per month during phenotype). There were 49 isolates of Enterococcus fae - Phase 2b) when the risk of GRE acquisition was at its calis, 11 isolates of Enterococcus avium—all VanA pheno- lowest. Very little oral vancomycin was used during the type, and eight isolates of Enterococcus casseliflavus (VanC study period, on average 6 patient-days per month during phenotype, low-level vancomycin resistance).
Phase 1, 3 during Phase 2 and 8 during Phase 3.
There were five patients with clinical isolates of GRE dur-ing the initial phase of the study: two with isolates from This study suggests that colonization with GRE can be urine (one E. faecalis, one E. faecium), two from blood controlled despite very high endemicity. Replacing cefta- (both E. faecium) and one with post-mortem isolates from zidime with piperacillin/tazobactam for broad-spectrum the spleen and tunnelled intravenous line tip (E. faecium).
antibacterial treatment of febrile neutropenic episodes and There were no clinical isolates during Phase 2. However, the introduction of improved hygiene were associated within Phase 3, there were three further patients with clinical a profound reduction in the risk of acquiring detectable isolates: two from blood (both E. faecium ) and one from GRE. However, the effect was delayed suggesting that the urine cultures (E. faecalis), coincident with increased impact of the intervention was complex, and may not haveincidence of detectable rectal carriage.
been detected if patients had simply been randomized to the two antibiotics of interest. The reintroduction ofceftazidime resulted in a significant rise in the risk of GRE acquisition despite maintaining heightened infection con- The monthly prescriptions of ceftazidime, piperacillin/ trol measures. The change in incidence of GRE carriage tazobactam, ciprofloxacin and teicoplanin over the study was clearly not influenced by teicoplanin usage. Clinical period are shown in Figure 2. Average ceftazidime usage cases of GRE infection were only seen when the preva- was 186 patient-days per month during Phase 1, and 200 lence of carriage was high and not at all during the patients-days per month for Phase 3. Piperacillin/tazo- piperacillin/tazobactam phase of the study.
bactam usage was similar during Phase 2, at 197 patient- Numerous outbreaks of GRE infection and colonization days per month on average. The use of ciprofloxacin was have now been documented. Smaller outbreaks have been fairly constant throughout the study period at an average of successfully controlled by enforcing strict infection control 57 patient-days per month. Although it was intended that measures,8–10 but the control of larger outbreaks where the new antibiotic guidelines and surveillance would endemicity has become well established has proved more reduce glycopeptide usage, teicoplanin was used inten- elusive.11,12 In 1995, the Hospital Infection Control Prac- sively throughout the study (average 218 (range 126–365) tices Advisory Committee (HICPAC) from the Centers for Effect of piperacillin/tazobactam on VRE carriage
Figure 2. 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.
Disease Control, Atlanta issued comprehensive guidelines At the start of this study, the probability of new patients aimed at reducing the spread of vancomycin resistance.13 acquiring detectable rectal carriage of GRE in this unit was These address ‘prudent’ use of vancomycin, education pro- very high and had been so for at least 18 months according grammes and the role of the microbiology laboratory in the to a series of prevalence studies and one 3 month incidence detection and identification of GRE, and outline measures study. Although the turn-down in the rate of acquisition of to prevent and control nosocomial transmission of GRE.
GRE could be ascribed to factors other than the change of However, these recommendations do not address broad- ceftazidime to piperacillin/tazobactam, such as improved spectrum antibiotic usage. A study by Morris et al.11 hygiene, the return of the problem with the reintroduction showed that reducing oral vancomycin use by 85% and of ceftazidime, at a time when the prevalence was the low- intravenous vancomycin by 59%, together with the imple- est it had been for 30 months while maintaining heightened mentation of strict infection control practices as outlined infection control measures, is most persuasive evidence by HICPAC, failed to reduce the prevalence of GRE.
that ceftazidime alone was responsible.
Quale and co-workers,14 however, showed that restrictingantimicrobials including cefotaxime, ceftazidime and clin-damycin as well as vancomycin could result in a reduction Acknowledgements
of GRE colonization and infection when the prevalencerate was high, and where infection control measures alone Dr Bradley and Ms Wilson were generously supported by a had failed. A similar effect on a different organism was grant from Wyeth Pharmaceuticals. We are grateful to Ms observed in a study by Impallomeni et al.15 where a sudden C. Beer, pharmacist to the leukaemia unit, for invaluable increase in the incidence of Clostridium difficile diarrhoea help, to Alison Newberry and Andrew Nunn for statistical was observed following a 20-fold increase in the use of cefo- advice and to Professors David Speller, Patrice Courvalin taxime. Infection control measures did not prevent new and Roland Leclerq for their encouragement and advice.
cases, but restriction of the use of cefotaxime did. Theeffect of restricting the use of an antibiotic on the suscepti-bility of an organism to that agent has been demonstrated References
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