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-

ª2013 The Authors

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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Clinical Microbiology and Infection ª2013 European Society of Clinical Microbiology and Infectious Diseases, CMI, 19, E181–E189

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.

ª2013 The Authors


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

ª2013 The Authors



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

ª2013 The Authors



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

��

��

��


�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



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


�3 �10.29–4.29 �2357 �40 334–35 620


�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


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


�8 �19.91–3.91 �0.47 �5.95–5.00 �47 409 �68 451 to �26 367 �28 697 �47 930–9 464


�3 �15.06–9.06 �36 782 �56 607 to �16 958


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



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.

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Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization

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