Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization
Transcript of Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization
Enterococcal bacteraemia: factors influencing mortality, length of stay
and costs of hospitalization
A. L. Y. Cheah1,2,3, T. Spelman4,5, D. Liew6, T. Peel7, B. P. Howden3,8,9, D. Spelman2,10,11, M. L. Grayson3,12, R. L. Nation1 and
D. C. M. Kong1
1)Centre forMedicine Use and Safety, Monash University, Parkville, 2)Department of Infectious Diseases, The Alfred, Melbourne, 3) Infectious Diseases Department,
Austin Health, Heidelberg, 4) Centre for Population Health, Burnet Institute, Prahran, 5) School of Public Health and Preventive Medicine, Monash University,
Melbourne, 6)Melbourne EpiCentre, The Royal Melbourne Hospital, Parkville, 7) Department of Surgery, St Vincent’s Health, University of Melbourne, Melbourne,
8)MicrobiologyDepartment, AustinHealth, Heidelberg, 9)Department ofMicrobiology and Immunology, University ofMelbourne,Melbourne,10)Microbiology Unit,
The Alfred, Melbourne, 11) Department of Infectious Diseases and Microbiology, Monash University, Melbourne and 12) Department of Medicine, University of
Melbourne, Melbourne, Victoria, Australia
Abstract
Enterococci are a major cause of nosocomial bacteraemia. The impacts of vanB vancomycin resistance and antibiotic therapy on outcomes in
enterococcal bacteraemia are unclear. Factors that affect length of stay (LOS) and costs of managing patients with enterococcal bacteraemia are
also unknown. This study aimed to identify factors associated with mortality, LOS and hospitalization costs in patients with enterococcal
bacteraemia and the impact of vancomycin resistance and antibiotic therapy on these outcomes.Data from116 patientswith vancomycin-resistant
Enterococci (VRE), matched 1:1 with patients with vancomycin-susceptible Enterococcus (VSE), from two Australian hospitals were reviewed for
clinical and economic outcomes. Univariable andmultivariable logistic and quantile regression analyses identified factors associatedwithmortality,
LOS and costs. Intensive care unit admission (OR, 8.57; 95%CI, 3.99–18.38), a higher burdenof co-morbidities (OR, 4.55; 95%CI, 1.83–11.33) and
longer time to appropriate antibiotics (OR, 1.02; 95%CI, 1.01–1.03)were significantly associatedwithmortality in enterococcal bacteraemia.VanB
vancomycin resistance increased LOS (4.89 days; 95% CI, 0.56–11.52) and hospitalization costs (AU$ 28 872; 95% CI, 734–70 667), after
adjustment for confounders. Notably, linezolid definitive therapy was associated with lower mortality (OR, 0.13; 95% CI, 0.03–0.58) in vanB VRE
bacteraemia patients. In patientswithVSEbacteraemia, time to appropriate antibiotics independently influencedmortality, LOS and hospitalization
costs, and underlying co-morbidities were associated with mortality. The study findings highlight the importance of preventing VRE bacteraemia
and the significance of time to appropriate antibiotics in the management of enterococcal bacteraemia.
Keywords: Enterococci, bacteraemia, health outcomes, length of stay, mortality, cost
Original Submission: 4 July 2012; Revised Submission: 2 October 2012; Accepted: 13 December 2012
Editor: G. Pappas
Article published online: 17 January 2013
Clin Microbiol Infect 2013; 19: E181–E189
10.1111/1469-0691.12132
Corresponding author: D. C. M. Kong, Centre for Medicine Use
and Safety, Monash University, 381 Royal Parade, Parkville, Victoria
3052, Australia
E-mail: [email protected]
Introduction
In recent years,Enterococcihavebecomeoneof themost common
causes of nosocomial bloodstream infections. Coupled with
the rise in enterococcal infections, is the emergence of
vancomycin-resistant Enterococci (VRE) [1]. The predominant
VRE genotype in published studies is vanA [2]. In Australia, the
majority of isolates are vanB (VRE in Australia: results of the
Australian Group on Antimicrobial Resistance (AGAR) surveys
1995–2010, http://www.agargroup.org/files/VRE%20in%20Aus-
tralia.pdf) [3], which are susceptible to teicoplanin [2]. VRE
bacteraemia has been linked to increased mortality, prolonged
length of stay (LOS) and higher costs of hospitalization [4,5].
Importantly, the impact of the time to, and type of, antibiotic
therapy on mortality in enterococcal (i.e. VRE and vancomycin-
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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases
ORIGINAL ARTICLE INFECTIOUS DISEASES
susceptible Enterococci (VSE)) bacteraemia is still unclear. Knowl-
edge regarding factors affecting LOS and costs is also lacking.
Identification of potentially preventable risk factors for
mortality, LOS and costs of hospitalization, and understanding
the impact of antimicrobial therapy on these outcomes, would
improve the management of patients with enterococcal
bacteraemia. Information regarding the LOS and costs of
hospitalization would also facilitate evaluations of various
infection control measures to minimize the spread of VRE.
Thus, the aims of this study are two-fold: (i) to determine the
factors associated with mortality, LOS and costs in patients
with enterococcal (VRE and VSE) bacteraemia, and (ii) to
investigate the impact of vancomycin resistance and antibiotic
therapy on mortality, LOS and costs in patients with entero-
coccal bacteraemia.
Methods
A retrospective matched cohort study was conducted at two
tertiary hospitals, The Alfred and Austin Health, both in
Victoria, Australia. All inpatients for whom VRE was first
isolated from the blood between January 2002 and March 2010
(inclusive) were classified as VRE patients. Identification of
Enterococci was based on VITEK 2 Compact (bio M�erioux,
Durham, NC, USA) at The Alfred or D-Ala-D-Ala ligase
polymerase chain reaction (PCR) at Austin Health. Determina-
tion of resistance genotype was based on van gene PCR at both
institutions, which had VRE active screening programmes that
changed over time. Corresponding patients from the same
institutions who had VSE isolated from blood were matched 1:1
with VRE patients according to date of admission (within
2 years) and unit of admission. Where more than one VSE
patient was eligible for matching, the VSE patient was randomly
chosen (without prior knowledge of patient outcomes) from the
list of eligible patients. Patients with LOS >2 days were eligible
for inclusion in the study. Pregnant patients and those <18 years
of age were excluded; these exclusions were to ensure that the
cohort of patients studied was uniform in terms of their
management and treatment considerations for enterococcal
bacteraemia. Risk factors for the development of enterococcal
bacteraemia are presented in another manuscript (Cheah et al.
Case-case–control study on risk factors for development of
vancomycin-resistant and vancomycin-susceptible enterococcal
bacteraemia, manuscript submitted for review).
Information on patient demographics, antimicrobial use,
medical procedures, treatment of enterococcal bacteraemia
and outcomes of hospitalization was collected via a retro-
spective review of patient medical records by the same
researcher (ALYC). All data for costs of hospitalization were
obtained from the clinical costing units of the respective study
hospitals. Costs were in Australian dollars (AU$) and inflated
to the financial year 2010–2011. Due to the acute nature of
the infection, discounting was not performed. This study was
approved by the Human Research Ethics Committees of The
Alfred Hospital, Austin Health and Monash University.
Definitions
Definitions of enterococcal bacteraemia were based upon the
definitions for nosocomial infections of the Centers for
Disease Control and Prevention (CDC) [6]. Patients with
enterococcal bacteraemia included patients classified as having
healthcare- or community-associated bacteraemia. Enterococ-
cal bacteraemia was considered to be healthcare-associated if
any one of the following criteria applied [7,8]: (i) � 1 positive
blood culture(s) taken more than 48 h after hospital admis-
sion; (ii) patient resided in a nursing home or long-term care
facility, within the last year preceding the positive blood
culture(s); (iii) patient had previous hospital admission for
� 2 days, within the last year preceding the positive blood
culture(s); (iv) patient attended hospital for the haemodialysis
clinic or was receiving haemodialysis; or (v) patient received
intravenous therapy at home. Criteria for community-associ-
ated enterococcal bacteraemia were: (i) patient did not meet
the aforementioned criteria for healthcare-associated entero-
coccal bacteraemia, and (ii) patient had � 1 positive blood
culture(s) taken � 48 h after hospital admission [8].
The Charlson Co-morbidity Index (CCI) was used to
measure co-morbidities [9]. Severity of illness on the day of
positive blood culture was recorded as the Pitt bacteraemia
and Apache II scores [10,11]. Polymicrobial bacteraemia was
the isolation of one or more bacterial or fungal pathogens
within 24 h from the same blood sample that the initial VRE or
VSE was isolated from or a different blood sample. Neutro-
penia days was the number of days neutrophils were <500/
mm3, within 30 days prior to bacteraemia. Exposures to
central lines, mechanical ventilation, urinary catheter and total
parenteral nutrition were defined as exposures within the
30 days prior to bacteraemia. The antibiotic-specific days were
calculated as the total number of days that antibiotic(s) were
administered orally or intravenously, within 30 days prior to
bacteraemia. Definitive therapy referred to antibiotic(s)
administered to the patient upon receipt of final culture and
susceptibility results. ‘Days to appropriate antibiotics’ was
defined as the number of days before antibiotics to which the
Enterococci isolated were susceptible were administered.
Data analyses
Comparisons were performed for matched VRE and VSE
patients (Table 1). Continuous variables were first tested for
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E182 Clinical Microbiology and Infection, Volume 19 Number 4, April 2013 CMI
skew. Depending upon whether data were skewed or normally
distributed, Wilcoxon matched-pairs signed rank or matched-
pairs t-tests were used, respectively. Categorical variables
were compared using the McNemar test [12].
Regression analyses were performed for patients with entero-
coccal (VRE and VSE) bacteraemia, and individual VRE and VSE
bacteraemia groups. Variables previously identified in the litera-
ture, or clinically important or biologically plausible factors, were
included in multivariable models. The variables related to
appropriateness of antibiotic therapy and ‘VRE bacteraemia’
(independent variablesof interest), ‘total numberof intensive care
unit (ICU) admissions’ and/or ‘prior ICU stay’ were included in all
multivariablemodels. All models for LOS and costs were adjusted
for in-patient mortality and duration of hospitalization prior to
bacteraemia. Adjustment for the variables ‘enterococcal species’
and ‘healthcare-associated bacteraemia’ was performed
wherever possible (dependent on assessments of model fit).
The CCI with various cut-offs of 2, 3 or 4 was used to measure
patient co-morbidities. TheCCI variablewith the smallest p-value
was included in the multivariable models.
Logistic regression was used to identify factors associated
with in-hospital mortality in the individual VRE and VSE groups.
In the analysis involving enterococcal bacteraemia patients,
matching was accounted for via the cluster option. As LOS and
cost outcomes were highly skewed, resistant to transforma-
tion and had heteroskedastic residuals with linear regression,
quantile (median) regression was used. Censored least abso-
lute deviations estimator quantile regression (CLAD)
TABLE 1. Comparison of demographics, clinical characteristics and outcomes of patients with enterococcal bacteraemia
CharacteristicsVRE bacteraemia,n = 116
VSE bacteraemia,n = 116 p-values
Age, median (IQR), years 60 (47–68) 63.5 (51–76) 0.095Female 47 (41) 44 (38) 0.691Transfer from another hospital 28 (24) 21 (18) 0.237Reason for admissionMedical 89 (77) 87 (75) ReferenceSurgical 27 (23) 29 (25) 0.670
Charlson Co-morbidity Index, median (IQR) 4 (2–5) 3 (1–5) 0.507Charlson Co-morbidity Index � 2 92 (79) 84 (72) 0.194Charlson Co-morbidity Index � 3 84 (72) 70 (60) 0.048Charlson Co-morbidity Index � 4 73 (63) 57 (49) 0.024ICU admission in prior 30 days 39 (34) 29 (25) 0.423Total number of ICU admissions, median (IQR) 0 (0–1) 0 (0–1) 0.228Neutropenia days, median (IQR), days 1 (0–10) 0 <0.001Liver disease 16 (14) 13 (11) 0.467Central line use 94 (81) 59 (51) <0.001Mechanical ventilation 29 (25) 17 (15) 0.034Urinary catheter 57 (49) 46 (40) 0.138Parenteral nutrition 28 (24) 16 (14) 0.040Prior antibiotic therapy 110 (95) 80 (69) <0.001Third generation cephalosporin (cefotaxime, ceftriaxone and ceftazidime), mean (SD), days 1.4 (3.2) 1.4 (2.9) 0.950Fluoroquinolone (moxifloxacin, norfloxacin and ciprofloxacin), mean (SD), days 4.7 (6.7) 1.9 (4.1) <0.001Metronidazole, mean (SD), days 2.1 (4.4) 1.9 (4.5) 0.754Ticarcillin-clavulanic acid, mean (SD), days 7.2 (68.9) 0.7 (2.7) 0.901Piperacillin-tazobactam, mean (SD), days 1.6 (3.2) 0.5 (2.1) <0.001Meropenem, mean (SD), days 3.9 (6.3) 1.4 (4.0) <0.001Vancomycin, mean (SD), days 5.0 (6.2) 2.0 (4.2) <0.001Any infection (other than enterococcal bacteraemia) 61 (53) 43 (37) 0.537Number of sets of positive cultures, median (IQR) 1 (1–3) 1 (1–2) 0.008Sets of positive cultures � 2 56 (48) 43 (37) 0.096Pitt bacteraemia score, median (IQR) 1 (0–3) 1 (0–2) 0.364APACHE II score, median (IQR) 17 (13–21) 15 (11–20) 0.005Enterococci speciesE. faecalis 9 (8) 71 (61) ReferenceE. faecium 107 (92) 39 (34) <0.001E. casseliflavus, E. galinarum or E. durans – 4 (3) –Both E. faecalis and E. faecium – 1 (1) –Unknown species – 1 (1) –
Polymicrobial bacteraemia 33 (28) 53 (46) 0.024Admission days till bacteraemia, median (IQR), days 16 (7–24) 7.5 (1–18.5) 0.003Admission days after initial culture, median (IQR), days 18 (8–29.5) 15 (10–24.5) 0.599In-hospital mortality 42 (36) 30 (26) 0.077Total length of stay, median (IQR), days 35 (22.5–50.5) 25 (16–45.5) 0.103Total costs, median (IQR), AU$ 86 540 (47 436–170 706) 43 178 (27 578–100 177) 0.002Allied health 2263 (1396–3650) 1205 (545–2809)Emergency 0 (0–682) 550 (0–1293)ICU 0 (0–38 946) 0 (0–10 596)Medical surgical 0 (0–3193) 0 (0–507)Medical non-surgical 4909 (1476–10 539) 4353 (1842–8798)Nursing 19 005 (7066–30 157) 11 854 (5037–20 543)Pathology 6935 (2426–10 767) 2966 (1497–7258)Imaging 4175 (2099–6810) 2027 (786–3951)Pharmacy 20 607 (5676–54 881) 3813 (1136–14 023)Theatre operating room 373 (0–5253) 143 (0–3115)Theatre non-operating room 236 (99–1469) 131 (0–909)
Data are number (%) of patients unless indicated otherwise.Percentages were rounded to the nearest whole number.
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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E181–E189
CMI Cheah et al. Outcomes of enterococcal bacteraemia E183
accounted for matching (in the analysis for enterococcal
bacteraemia patients) and heteroscedasticity [13]. The fits of
the multivariable logistic regression models were assessed
using the Hosmer-Lemeshow Goodness-of-Fit test. The link-
test [14] was utilized to assess model specification error in the
multivariable quantile regression and CLAD models.
Statistical tests were two-tailed and a p <0.05 was
considered significant. All analyses were performed with Stata
version 12.0 (Stata Corporation, College Station, TX, USA).
Results
From January 2002 to March 2010, of 724 patients with
enterococcal bacteraemia across the two clinical sites, there
were 121 (17%) and 603 (83%) patientswith positive VRE andVSE
blood isolates, respectively. A final number of 116 VRE bacter-
aemia patients were included in the analysis as four patients had
missing medical records and one patient was pregnant; 116
matching VSE bacteraemia patients were randomly selected from
the 603 above. As the majority of VRE patients were admitted
from 2008 to 2010, matching VRE and VSE patients for date of
admission minimized any impact of variations in infection control
and medical management over the study period.
All VRE isolates were vanB genotype. Vancomycin mini-
mum inhibitory concentrations were determined for only
approximately 37% of isolates; thus, data have not been
included. Demographics, clinical characteristics and out-
comes of patients with enterococcal bacteraemia are shown
in Table 1. For the studied admission, the reasons for
admission and co-morbidities were similar across the VRE
and VSE groups of patients.
In the VRE patients, 54 (47%), 22 (19%) and 14 (12%) were
treated with teicoplanin monotherapy, linezolid monotherapy
or nil antibiotics, respectively. For patients treated with
teicoplanin, loading doses of 400–800 mg (6–12 mg/kg)
12-hourly for three doses, then maintenance doses of 400–
800 mg daily were administered intravenously, with adjust-
ments for renal impairment. Teicoplanin doses of 800 mg daily
without loading doses were administered to three (0.06%)
patients. The linezolid dose was 600 mg twice daily via
intravenous (IV) injection or orally. A combination (concurrent
or in sequence) of teicoplanin, linezolid, quinupristin-dalfopri-
stin or benzylpenicillin as definitive therapy was administered
to 26 (22%) patients with VRE.
In the VSE patients, definitive therapy with IV glycopeptides
(12-hourly vancomycin 1 g or teicoplanin 400–800 mg), peni-
cillins (ampicillin 1–2 g 4- to 6-hourly, benzylpenicillin 1.8 g 4-
hourly, ticarcillin-clavulanic acid 3 g/0.1 g 4 to 6-hourly or
piperacillin-tazobactam 4/0.5 g 8-hourly), meropenem 500 mg
8-hourly and no antibiotics were given to 46 (40%), 21 (18%),
one (1%) and nine (8%) patients, respectively. A combination
(concurrent or in sequence) of vancomycin, teicoplanin, linezo-
lid, ampicillin, benzylpenicillin or meropenem was administered
to 30 (26%) of the VSE patients. Intravenous gentamicin 90–
240 mg daily was administered in combination with ampicillin in
six (5%) patients with VSE. In two (2%) patients with VSE, oral
linezolid 600 mg twice daily was administered.
Factors associated with mortality in patients with entero-
coccal (i.e. both VRE and VSE), VRE-only and VSE-only
TABLE 2. Factors associated with in-hospital mortality among patients with enterococcal bacteraemia (clustered logistic
regression)
VariablePatients whodied, n = 72
Patients whosurvived, n = 160
Univariable Multivariable
OR 95% CI OR 95% CI
Age, median (IQR), years 61 (51.5–69.5) 62 (47–73) 1.00 0.98–1.02Female 25 (35) 66 (41) 0.76 0.42–1.37Healthcare-associated bacteraemia 40 (56) 88 (55) 1.02 0.59–1.77 0.96 0.46–2.01Prior ICU stay 51 (71) 47 (29) 5.84 3.13–10.91 8.57 3.99–18.38Charlson Co-morbidity Index � 2 57 (79) 119 (74) 1.31 0.66–2.60Charlson Co-morbidity Index � 3 54 (75) 100 (62.5) 1.80 0.94–3.44 4.55 1.83–11.33Charlson Co-morbidity Index � 4 46 (64) 84 (52.5) 1.60 0.94–2.72Pitt bacteraemia score, median (IQR) 2 (1–3) 1 (0–2) 1.48 1.21–1.81Apache II score, median (IQR) 18 (15–23) 15 (11–19) 1.10 1.05–1.16Neutropenia days 0 (0–5) 0 (0–6.5) 1.00 0.97–1.03Any infection (other than enterococcal bacteraemia) 61 (85) 117 (73) 2.04 1.02–4.06 1.31 0.49–3.49VRE bacteraemia 42 (58) 74 (46) 1.63 0.95–2.79 1.21 0.53–2.79Polymicrobial bacteraemia 24 (33) 59 (37) 0.86 0.47–1.54Number of sets of positive culture, median (IQR) 1 (1–3) 1 (1–2) 1.15 1.03–1.28Enterococci speciesE. faecalis 17 (24) 63 (39) Reference ReferenceE. faecium 52 (72) 94 (59) 2.05 1.12–3.75 1.12 0.42–3.01E. casseliflavus, E. galinarum or E. durans 1 (1) 3 (2) 1.24 0.12–13.13 1.79 0.32–9.96Both E. faecalis and E. faecium 1 (1) 0 – – – –Unknown 1 (1) 0 – – – –Days to appropriate antibiotic, median (IQR), days 1.5 (0.7–2.6) 1.6 (0.8–2.9) 1.01 1.00–1.02 1.02 1.01–1.03Appropriate antibiotics in 24 h 15 (21) 26 (16) 1.68 0.79–3.55Appropriate antibiotics in 48 h 37 (51) 86 (54) 1.35 0.70–2.61
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E184 Clinical Microbiology and Infection, Volume 19 Number 4, April 2013 CMI
bacteraemia are presented in Tables 2 and 3. Tables 4 and 5
list the factors associated with LOS and costs.
Notably, VRE bacteraemia was not associated with increased
mortality in patients with enterococcal bacteraemia (Table 2),
but VRE bacteraemia was independently associated with
prolonged LOS and higher hospitalization costs (Table 4).
For patients with VRE bacteraemia (Table 3), prior ICU
admission, CCI � 4 and nil definitive antibiotic therapy were
associated with mortality. Linezolid therapy in patients with
VRE bacteraemia was associated with reduced mortality. LOS
and costs in patients with VRE bacteraemia were not
influenced by type of antibiotic therapy (Table 5).
In patients with VSE bacteraemia, an increase in the number
of days to appropriate antibiotics was associated with higher
odds of mortality (Table 3), longer LOS and higher costs
(Table 5).
Discussion
To our knowledge, this is the first study to investigate the
outcomes of vanB VRE bacteraemia patients treated with teicopl-
anin. It is also the first to estimate the LOS and costs of
hospitalization for enterococcal bacteraemia in the Australian
hospital setting. The strength of this study is that corresponding
mortality, LOS and costs data for patients with enterococcal
bacteraemia were compared. As such, the impact of vanB
vancomycin resistanceonmortality, LOSand costswas elucidated.
In contrast to results of previous studies on factors
associated with mortality in vanA VRE bacteraemia (summa-
rized in a meta-analysis) [15], our study findings suggest that
vanB VRE bacteraemia was not associated with mortality after
adjusting for co-morbidities, prior ICU admission and days to
appropriate antibiotic therapy. The meta-analysis revealed that
vanA vancomycin resistance (i.e. VRE infections) more than
doubled the odds of death in enterococcal infections [15]. It is
possible that the effect of vancomycin resistance may have been
confounded in the meta-analysis by inappropriate or inadequate
antimicrobial therapy. Earlier studies predominantly included
vanA isolates and involved only a small proportion of patients
treated with antibiotics that were active against VRE (e.g. under
compassionate-use programmes) or older agents such as
chloramphenicol and quinupristin-dalfopristin [16–18]. A
recent study that could not adjust for appropriate antibiotic
therapy found that VRE bacteraemia was linked to higher
mortality 1 year after haematopoietic stem cell transplantation
[19]. In contrast, in the present study, adjustment was made for
time to appropriate antibiotic therapy in the analysis. Thus, the
impact of vancomycin resistance on mortality is probably less
profound and may partially explain our findings.TABLE
3.Factors
associatedwithin-hosp
italmortality
amongpatients
withVREandVSEbacteraemia
(logisticregression)
Variables
VREbacteraemia
VSEbacteraemia
Patients
who
died,n=42
Patients
who
survived,n=74
Univariable
Multivariable
Patients
who
died,n=30
Patients
who
survived,n=86
Univariable
Multivariable
OR
95%
CI
OR
95%
CI
OR
95%
CI
OR
95%
CI
Age,median(IQR),years
59(45–68)
60(48–69)
0.99
0.97–1.02
63.5
(56–75)
63.5
(47–76)
1.01
0.98–1.04
Female
13(31)
34(46)
0.53
0.24–1.17
12(40)
32(37)
1.13
0.48–2.64
Healthcare-associatedbacteraemia
21(50)
52(70)
0.42
0.19–0.93
19(63)
36(42)
2.40
1.02–5.65
PriorICU
stay
33(79)
19(26)
10.61
4.30–26.18
27.76
8.12–94.84
18(60)
28(33)
3.11
1.32–7.33
4.65
1.78–12.17
CharlsonCo-m
orbidityIndex�2
32(76)
60(81)
0.75
0.30–1.87
25(83)
59(69)
2.29
0.79–6.62
CharlsonCo-m
orbidityIndex�3
31(74)
53(72)
1.12
0.48–2.62
23(77)
47(55)
2.73
1.06–7.03
4.89
1.66–14.43
CharlsonCo-m
orbidityIndex�4
29(69)
44(59)
1.52
0.68–3.39
6.13
1.82–20.66
17(57)
40(47)
1.50
0.65–3.47
Pittbacteraemiascore,median(IQR)
2.5
(1–4)
1(0–1)
1.57
1.23–2.00
2(0–3)
1(0–2)
1.34
1.00–1.79
ApacheIIscore,median(IQR)
20(15–26)
16(13–19)
1.10
1.03– 1.17
17(15–20)
14(10–18)
1.10
1.02–1.18
Anyinfection(otherthan
enterococcal
bacteraemia)
35(83)
56(76)
1.61
0.61–4.24
26(87)
61(71)
2.66
0.84–8.42
Polymicrobialbacteraemia
10(24)
23(31)
0.69
0.29–1.64
14(47)
36(42)
1.22
0.53–2.80
Numberofsets
ofpositive
culture,median(IQR)
2(1–5)
1(1–2)
1.15
1.02–1.31
1(1–2)
1(1–2)
1.06
0.83–1.37
Daysto
appropriateantibiotic,median(IQR)
2.1
(1.5–3.5)
2.6
(1.6–3.4)
0.89
0.67–1.18
1.0
(0.3–1.4)
1.0
(0.3–1.8)
1.01
0.97–1.06
1.02
1.01–1.03
Appropriateantibiotics
in48h
14(33)
23(31)
1.11
0.49–2.49
23(77)
63(73)
1.55
0.47–5.10
Typeofdefinitivetherapy
Teicoplanin
16(38)
38(51)
Reference
Reference
Linezolid
3(7)
19(26)
0.38
0.10–1.45
0.13
0.03–0.58
Other
12(29)
14(19)
2.04
0.77–5.36
0.79
0.21–3.04
Nilantibiotics
11(26)
3(4)
8.71
2.14–35.45
6.85
1.42–33.09
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CMI Cheah et al. Outcomes of enterococcal bacteraemia E185
An increase in the time to appropriate antibiotic therapy
was independently associated with higher odds of in-hospital
mortality in patients with enterococcal bacteraemia. This
finding was supported by results from another study, wherein
appropriate antibiotics within 48 h of positive blood culture
were found to independently reduce the odds of death in
enterococcal bacteraemia [16]. Importantly, the results from
the current study suggest that compared with teicoplanin,
linezolid therapy for vanB VRE bacteraemia was associated
with lower odds of in-hospital mortality. Comparison with
findings from earlier studies is difficult given that the vanA
genotype was predominant in the earlier studies, and findings
from those studies are varied [17, 20–24]. For example,
Camins et al. found that appropriate administration of antibi-
otics (chloramphenicol and quinupristin-dalfopristin) was
linked to lower mortality in VRE bacteraemia [17]. In another
study, daptomycin trended towards higher mortality when
compared with linezolid [24]. Conversely, other studies
reported that linezolid vs. quinupristin-dalfopristin [20,21], or
linezolid vs. daptomycin [22, 23, 25], did not have an impact on
mortality in VRE bacteraemia. In the present study, the type of
antibiotic (for VRE only) and time to appropriate antibiotic (for
VSE only) independently influenced mortality. The latter
observation was supported by a recent study which found
that inappropriate antibiotic therapy in VSE bacteraemia
independently increased the odds of mortality [26].
Patient co-morbidities significantly influenced mortality in
enterococcal bacteraemia. Prior ICU stay (which may repre-
sent severity of bacteraemia) was also strongly associated with
odds of death in enterococcal and VRE bacteraemia. Published
data suggest that patient co-morbidities and illness severity
were linked to higher mortality in patients with enterococcal
bacteraemia [27–29] and VRE bacteraemia [20,21], respec-
tively. Similar to another study [17], VRE bacteraemia patients
with a CCI � 4 had higher odds of death in the present study.
Interestingly, in the current study a higher CCI cut-off was
significantly associated with increased odds of death in patients
with VRE compared with VSE bacteraemia.
VanB VRE bacteraemia was found to be independently
associated with longer LOS and higher costs of hospitalization.
This finding was consistent with a study involving vanA VRE
bacteraemia, which adjusted LOS and costs for illness severity
and ICU admission [4]. Differences in LOS and cost estimates
between the aforementioned [4] and the current study may be
due to differences in VRE genotype, approaches to costing and
healthcare systems, and adjustment for appropriateness of
antibiotic therapy in the analysis of the present study.
Our data suggest that advancing age reduced hospitalization
costs. This may be due to the preference for less aggressive
and possibly less expensive therapy in the elderly. OlderTABLE4.Factors
associatedwithlength
ofstayandcostsofhosp
italizationamongpatients
withentero
coccalbacteraemia
(CLAD)
Variables
Length
ofstay,days
Costsofhosp
italization,AU$
Univariable
Multivariable
Univariable
Multivariable
Coefficient
95%
CI
Coefficient
95%
CI
Coefficient
95%
CI
Coefficient
95%
CI
Age
�0.27
�0.60to
�0.04
�0.03
�0.26–0.09
�1410
�2042to
�613
�948
�2600to
�150
Female
�1�6
–80.92
�2.63–5.25
�8155
�34004–16336
Healthcare-associatedbacteraemia
18
11–25
�0.15
�5.65–5.50
50495
37254–65506
�19385
�48707–160
ICU
stay
7�3
–18
42602
18333–66871
�43630
�152328–60951
TotalnumberofICU
admissions
10.5
2.33–22.8
7.97
5.35–19.56
60948
34341–87367
73363
�8196–158504
CharlsonCo-m
orbidityIndex
�2
�5�1
7–5
2.81
�4.21–7.87
� 22833
�71880–1996
CharlsonCo-m
orbidityIndex
�3
�3�8
–9�9
628
�29798–20379
2672
�15968–46211
CharlsonCo-m
orbidityIndex
�4
�1�1
1–8
�3600
�26684–27406
Anyinfection(otherthan
enterococcalbacteraemia)
12
6–19
3.63
0.41–9.73
33404
7634–55466
12155
�57356–34501
Neutropeniadays
0.9
0.3–1.4
1507
�1566–2921
�1779
�6724to
�113
VREbacteraemia
10
3–17
4.89
0.56–11.52
21538
285–53418
28872
734–70667
Enterococcispecies
E.faecalis
Reference
Reference
Reference
E.faecium
12
9–18
30197
3390–53942
�3187
�28336–25571
E.casseliflavus,E.galinarum
orE.durans
––
––
––
Both
E.faecalisandE.faecium
––
––
––
Unknown
��
��
��
Polymicrobialbacteraemia
�5�1
1–3
2110
�28165–22208
Sets
ofpositive
cultures�2
94–16
29349
9747–59939
Daysto
appropriateantibiotic
0.09
�2.00–2.19
0.07
�0.79–1.20
913
�6685–8442
358
�383–8518
Appropriateantibiotics
in48h
�3�1
1–4
�4749
�36718–17580
Daysfrom
admissionuntilbacteraem
ia1.08
0.90–1.49
1.03
0.74–1.23
3145
1843–4800
2421
1172–4660
In-patientmortality
�5�1
3–2
�12.33
�18.49to
�6.72
17929
�7346–66447
1256
�45139–43385
ª2013 The Authors
Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E181–E189
E186 Clinical Microbiology and Infection, Volume 19 Number 4, April 2013 CMI
TABLE 5. Factors associated with length of stay and costs of hospitalization among patients with VRE and VSE bacteraemia
(quantile regression)
Variables
Length of stay, days Costs of hospitalization, AU$
Univariable Multivariable Univariable Multivariable
Coefficient 95% CI Coefficient 95% CI Coefficient 95% CI Coefficient 95% CI
VRE bacteraemia
Age �0.13 �0.37–0.11 �1508 �2152 to �863 �751 �1684–183Female �1 �8.77–6.77 �11 488 �46 295–23 318Healthcare-associatedbacteraemia
18 9.31–26.69 68 771 30 905–106 637
ICU stay 0 �6.47–6.47 �44.46 �56.57 to �32.34 64 242 18 893–109 591 �136 584 �180 095to �93 072
Total number of ICUadmissions
10 4.30–15.70 44.40 38.70–50.09 99 953 79 942–119 963 154 176 140 038–168 314
Charlson Co-morbidityIndex � 2
�7 �14.83–0.83 1.03 �8.42–10.49 �21 322 �71 864–27 220 �21 770 �56 898–13 358
Charlson Co-morbidityIndex � 3
�3 �10.29–4.29 �2357 �40 334–35 620
Charlson Co-morbidityIndex � 4
�3 �9.75–3.75 �2 357 �34 898–30 184
Any infection(other thanenterococcalbacteraemia)
9 �2.57–20.57 4.41 �3.62–12.43 51 456 15 597–87 316 30 779 �1475–63 033
E. faecium comparedwith E.faecalis bacteraemia
12 �1.70–25.70 5.47 �7.87–18.80 51 323 �5260–107 905
Polymicrobialbacteraemia
0 �6.96–6.96 �651 �37 899–36 597
Sets of positivecultures � 2
10 3.54–16.46 51 725 19 341–84 109
Pitt bacteraemiascore � 4
�5 �15.20–5.20 39 246 �18 044–96 536
Days to appropriateantibiotic
�0.87 �3.29–1.56 �0.64 �2.42–1.14 �7505 �22 743–7732 974 �7674–9622
Appropriate antibioticsin 48 h
1 �6.93–8.93 �9432 �53 112–34 249
Days from admissionuntilbacteraemia
1.04 0.83–1.24 1.02 0.84–1.20 3470 2869–4070 1662 921–2402
In-patient mortality �4 �10.60–2.60 �15.85 �24.70 to �7.01 24 499 �20 637–69 636 �9095 �46 549–28 358Type of definitivetherapyTeicoplanin Reference ReferenceLinezolid �4 �13.58–5.58 �6.88 �15.80–2.05 �51 302 �95 641 to �6964 �31 120 �65 056–2815Other 4 �5.31–13.31 3.64 �5.03–12.31 15 359 �26 981–57 699 �3217 �36 937–30 504Nil antibiotics �10 �21.08–1.08 �33 448 �83 622–16 727
VSE bacteraemia
Age �0.31 �0.55 to �0.07 0.05 �0.08–0.19 �1294 �1956 to �633 �551 �1013 to �89Female �2 �13.05–9.05 �9250 �37 157–18 657Healthcare-associatedbacteraemia
17 9.95–24.05 28 824 8162–49 486
Prior ICU stay 9 0.17–17.83 �3.24 �9.72–3.24 55 759 42 925–68 593 18 370 748–35 991Total number of ICUadmissions
13 9.23–16.77 7.70 4.08–11.32 48 843 43 040–54 645
Charlson Co-morbidityIndex � 2
�8 �19.91–3.91 �0.47 �5.95–5.00 �47 409 �68 451 to �26 367 �28 697 �47 930–9 464
Charlson Co-morbidityIndex � 3
�3 �15.06–9.06 �36 782 �56 607 to �16 958
Charlson Co-morbidityIndex � 4
2 �7.74–11.74 �24 501 �46 972–2031
Any infection (other thanenterococcal
bacteraemia)
11 0.82–21.18 2.76 �2.50–8.01 17 960 9703–45 624 504 �18 072–19 081
Enterococci speciesE. faecalis Reference Reference ReferenceE. faecium 5 �6.68–16.68 10 132 �17 467–37 730 �6385 �24 025–11 254E. casseliflavus,E. galinarum or
E. durans
�10 �35.61–15.61 �17 763 �77 437–41 911 �7607 �37 618–22 403
Both E. faecalis andE. faecium
�2 �8.81–4.81 69 824 53 733–85 916 �6191 �33 286–20 904
Unknown � � � � � �Polymicrobial bacteraemia 0 �9.82–9.82 7053 �24 505–38 612Sets of positive cultures� 2
7 �3.21–17.21 5.36 0.77–9.95 5806 �22 124–33 737
Pitt bacteraemia score � 4 1 �15.85–17.85 88 194 55 833–120 554Days to appropriate
antibiotic0.11 0.10–0.13 0.06 0.03–0.08 442 395–489 753 655–851
Appropriate antibiotics in48 h
4 �8.90–16.90 11 697 �22 974–46 367
Days from admissionuntil bacteraemia
1.12 1.01–1.22 0.98 0.83–1.13 2652 2345–2960 1967 1494–2440
In-patient mortality 2 �7.70–11.70 �7.57 �12.99 to �2.15 16 418 �8335–41 171 3067 �17 060–23 194
ª2013 The Authors
Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E181–E189
CMI Cheah et al. Outcomes of enterococcal bacteraemia E187
patients are likely to be sicker and may not be able to tolerate
aggressive treatments such as surgery [30]. We have also
noted that infections other than enterococcal bacteraemia
were independently associated with prolonged LOS. An
increase in the number of ICU admissions per patient was
associated with prolonged LOS, which may be due to a higher
severity of illness. Hence, future studies of this type should
control for other types of infections via adjustment in the
multivariable analysis. In patients with enterococcal bacter-
aemia, a higher burden of patient co-morbidities did not
significantly affect LOS and costs of hospitalization, in contrast
to their effect on mortality. The reasons for this are currently
unknown. Future studies could explore the impact and validity
of various measures of co-morbidities on the outcomes of LOS
and costs.
Retrospective data collection and pooling of data may be
subject to variability. To ensure precision in data interpreta-
tion, criteria for the exposure and outcome measures were
standardized prior to study commencement. As the majority
of VRE patients were admitted from 2008 to 2010, matching
VRE and VSE patients for date of admission minimized any
impact of variations in infection control and medical manage-
ment over the study period. Furthermore, standardized data
on costs of hospitalization submitted to the Australian
government for the purpose of hospital funding reimburse-
ment were utilized.
In summary, vanB VRE bacteraemia was independently
associated with increased LOS and costs of hospitalization.
Thus, it is crucial to prevent the spread of VRE, from both
patient care and resource management perspectives. Impor-
tantly, we reveal for the first time that linezolid definitive
therapy, compared with teicoplanin, was associated with lower
odds of mortality. Further investigation via randomized
controlled trials comparing the effectiveness of existing
antibiotics in managing vanB VRE bacteraemia is warranted.
Acknowledgements
We thank Graham Bushnell, Christopher Jackson, Marco
Luthe, Fiona Webster and Joanne Siviloglou from the clinical
costing departments of The Alfred and Austin Health. We also
thank Kathleen Collins, Natasha Holmes, John Coutsouvelis,
Donna Cameron and Peter Ward, for the insightful discus-
sions. We acknowledge the microbiology departments and
Kerrie Watson from the Infectious Diseases Unit at The
Alfred, Elizabeth Grabsch from the Microbiology Department
at Austin Health, and Ray Robbins and Peter Davey from the
Clinical Information, Analysis and Reporting Department at
Austin Health for providing the list of patients eligible for
matching. Preliminary data for this study were presented at the
Interscience Conference on Antimicrobial Agents and Che-
motherapy (ICAAC) 2011 in Chicago, abstract K-1480.
Transparency Declaration
There was no external financial support or grant for this study.
DCMK has sat on advisory boards for Pfizer and received
financial support (not related to the current work) from Pfizer,
Merck and Gilead Sciences. DL has sat on advisory boards for
and received honoraria from Pfizer that are not related to the
current work. BPH is supported by an NHMRC Career
Development Fellowship. An Australian Postgraduate Award
scholarship was provided to ALYC to undertake the study. All
other authors: nothing to declare.
References
1. Hidron Alicia I, Edwards Jonathan R, Patel J et al. NHSN annual update:
antimicrobial-resistant pathogens associated with healthcare-associated
infections: annual summary of data reported to the National Healthcare
Safety Network at the Centers for Disease Control and Prevention,
2006–2007. Infect Control Hosp Epidemiol 2008; 29: 996–1011.
2. Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci.
Clin Microbiol Rev 2000; 13: 686–707.
3. 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.
4. Butler AM, Olsen Margaret A, Merz Liana R et al. Attributable costs of
enterococcal bloodstream infections in a nonsurgical hospital cohort.
Infect Control Hosp Epidemiol 2011; 31: 28–35.
5. Song X, Srinivasan A, Plaut D, Perl T. Effect of nosocomial vancomycin-
resistant enterococcal bacteremia on mortality, length of stay, and
costs. Infect Control Hosp Epidemiol 2003; 24: 251–256.
6. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC
definitions for nosocomial infections. Am J Infect Control 1988; 16:
128–140.
7. Klevens RM, Morrison MA, Nadle J et al. Invasive methicillin-resistant
Staphylococcus aureus infections in the united states. J Am Med Assoc
2007; 298: 1763–1771.
8. Klevens RM, Morrison MA, Fridkin SK et al. Community-associated
methicillin-resistant Staphylococcus aureus and healthcare risk factors.
Emerg Infect Dis 2006; 12: 1991–1993.
9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of
classifying prognostic comorbidity in longitudinal studies: development
and validation. J Chronic Dis 1987; 40: 373–383.
10. Chow JW, Yu VL. Combination antibiotic therapy versus monotherapy
for gram-negative bacteraemia: a commentary. Int J Antimicrob Agents
1999; 11: 7–12.
11. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a
severity of disease classification system. Crit Care Med 1985; 13:
818–829.
12. Durkalski VL, Palesch YY, Lipsitz SR, Rust PF. Analysis of clustered
matched-pair data. Stat Med 2003; 22: 2417–2428.
13. Powell JL. Least absolute deviations estimation for the censored
regression model. J Econometrics 1984; 25: 303–325.
ª2013 The Authors
Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E181–E189
E188 Clinical Microbiology and Infection, Volume 19 Number 4, April 2013 CMI
14. Pregibon D. Goodness of link tests for generalized linear models. J Roy
Stat Soc C Appl Stat 1980; 29: 15–14.
15. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of
mortality associated with vancomycin-resistant and vancomycin-sus-
ceptible enterococcal bloodstream infections: a meta-analysis. Clin
Infect Dis 2005; 41: 327–333.
16. Vergis EN, Hayden MK, Chow JW et al. Determinants of vancomycin
resistance and mortality rates in enterococcal bacteremia. A prospec-
tive multicenter study. Ann Intern Med 2001; 135: 484–492.
17. Camins BC, Farley MM, Jernigan JJ, Ray SM, Steinberg JP, Blumberg
HM. A population-based investigation of invasive vancomycin-resistant
enterococcus infection in metropolitan atlanta, georgia, and predictors
of mortality. Infect Control Hosp Epidemiol 2007; 28: 983–991.
18. Stosor V, Peterson LR, Postelnick M, Noskin GA. Enterococcus faecium
bacteremia: does vancomycin resistance make a difference? Arch Intern
Med 1998; 158: 522–527.
19. Vydra J, Shanley RM, George I et al. Enterococcal bacteremia is
associated with increased risk of mortality in recipients of allogeneic
hematopoietic stem cell transplantation.Clin Infect Dis 2012; 55: 764–770.
20. Han SH, Chin BS, Lee HS et al. Vancomycin-resistant enterococci
bacteremia: risk factors for mortality and influence of antimicrobial
therapy on clinical outcome. J Infect 2009; 58: 182–190.
21. Erlandson K, Sun J, Iwen P, Rupp M. Impact of the more-potent
antibiotics quinupristin-dalfopristin and linezolid on outcome measure
of patients with vancomycin-resistant enterococcus bacteremia. Clin
Infect Dis 2008; 46: 30–36.
22. McKinnell JA, Patel M, Shirley RM, Kunz DF, Moser SA, Baddley JW.
Observational study of the epidemiology and outcomes of vancomycin-
resistant enterococcus bacteraemia treated with newer antimicrobial
agents. Epidemiol Infect 2011; 139: 1342–1350.
23. Crank CW, Scheetz MH, Brielmaier B et al. Comparison of outcomes
from daptomycin or linezolid treatment for vancomycin-resistant
enterococcal bloodstream infection: a retrospective, multicenter,
cohort study. Clin Ther 2010; 32: 1713–1719.
24. Mave V, Garcia-Diaz J, Islam T, Hasbun R. Vancomycin-resistant
enterococcal bacteraemia: is daptomycin as effective as linezolid? J
Antimicrob Chemother 2009; 64: 175–180.
25. Twilla JD, Finch CK, Usery JB, Gelfand MS, Hudson JQ, Broyles JE.
Vancomycin-resistant enterococcus bacteremia: an evaluation of
treatment with linezolid or daptomycin. J Hosp Med 2012; 7:
243–248.
26. Suppli M, Aabenhus R, Harboe ZB, Andersen LP, Tvede M, Jensen JU.
Mortality in enterococcal bloodstream infections increases with
inappropriate antimicrobial therapy. Clin Microbiol Infect 2011; 17:
1078–1083.
27. Shay DK, Maloney SA, Montecalvo M et al. Epidemiology and mortality
risk of vancomycin-resistant enterococcal bloodstream infections. J
Infect Dis 1995; 172: 993–1000.
28. Lucas GM, Lechtzin N, Puryear DW, Yau LL, Flexner CW, Moore RD.
Vancomycin-resistant and vancomycin-susceptible enterococcal bac-
teremia: comparison of clinical features and outcomes. Clin Infect Dis
1998; 26: 1127–1133.
29. Lautenbach E, Bilker WB, Brennan PJ. Enterococcal bacteremia: risk
factors for vancomycin resistance and predictors of mortality. Infect
Control Hosp Epidemiol 1999; 20: 318–323.
30. Hamel MB, Phillips RS, Teno JM et al. Seriously ill hospitalized
adults: do we spend less on older patients? J Am Geriatr Soc 1996; 44:
1043–1048.
ª2013 The Authors
Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E181–E189
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