Risk factors for relapse or persistence of bacteraemia caused by Enterobacter spp.: a case–control study
Harris et al. Antimicrobial Resistance and Infection Control
Risk factors for relapse or persistence of bacteraemia caused by Enterobacter spp.: a case-control study
Patrick N. A. Harris 0 3 4
Anna M. Peri 2 4
Anita M. Pelecanos 1 4
Carly M. Hughes 4
David L. Paterson 4 7
John K. Ferguson 4 5 6
0 University of Queensland, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Building 71/918 Royal Brisbane & Women's Hospital Campus , 4029 Herston, QLD , Australia
1 QIMR Berghofer Medical Research Institute , Herston, QLD , Australia
2 Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan , Milan , Italy
3 University of Queensland, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Building 71/918 Royal Brisbane & Women's Hospital Campus , 4029 Herston, QLD , Australia
4 Hunter, John Hunter Hospital , Newcastle, NSW , Australia
5 School of Rural Medicine, University of New England , Armidale, NSW , Australia
6 School of Biomedical Sciences and Pharmacy, University of Newcastle , Newcastle, NSW , Australia
7 UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, QLD, Australia & Wesley Medical Research, University of Queensland , Toowong, QLD , Australia
Background: Enterobacter spp. possess chromosomal AmpC beta-lactamases that may be expressed at high levels. Previous studies have demonstrated a risk of relapsed bacteraemia following therapy with third generation cephalosporins (3GCs). What additional factors predict microbiological failure in Enterobacter bacteraemia is unclear. We aimed to determine factors associated with microbiological failure in Enterobacter bacteraemia. Methods: We retrospectively identified cases of bacteraemia caused by Enterobacter spp. occurring in four hospitals. Using a case-control design, we determined clinical risk factors for persistence or relapse defined as repeated positive blood cultures collected between 72 hours and up to 28 days post initial positive blood culture. Results: During the study period a total of 922 bacteraemia events caused by Enterobacter spp. in adults were identified. The overall risk of relapsed or persisting bacteraemia at 28 days was low (31 of 922, 3.4%), with only 2 patients experiencing emergent resistance to 3GCs. A total of 159 patients were included in the case-control study. Using multivariate logistic regression, independent predictors for relapse were a line-associated source of infection (OR 3.87; 95% CI 1.56-9.60, p = 0.004) and the presence of immunosuppression (OR 2.70; 95% CI 1.14-6.44, p = 0.02). On univariate analysis definitive therapy with a broad-spectrum beta-lactam-beta-lactamase inhibitor (BLBLI, e.g. piperacillin-tazobactam) was not associated with relapse (OR 1.83; 95% CI 0.64-5.21, p = 0.26) although the proportion of patients receiving a BLBLI as definitive therapy was relatively small (21/159, 13.2%). Conclusions: The risk of relapsed or persistent Enterobacter bacteraemia appears to be low in Australia. A line-associated source of infection and immunocompromise were significant independent predictors for relapse. Larger, preferably randomized, studies are needed to address whether BLBLIs represent an effective carbapenem-sparing option for Enterobacter bacteraemia.
Enterobacter cloacae; Enterobacter aerogenes; Beta-lactamase; AmpC; Bacteraemia; Outcomes; Relapse; Treatment
Bacteria belonging to the genus Enterobacter spp. are
Gram-negative Proteobacteria of the family
Enterobacteriaceae and currently comprise 22 species . They
represent a diverse group which are widely distributed in
nature  and possess multiple mechanisms to allow
survival in a variety of environmental niches . In humans,
they may cause a wide variety of clinical infections and are
a common cause of bacteraemia , especially within
adult and neonatal intensive care units (ICUs) [4, 5].
The annual incidence of bacteraemia caused by
Enterobacter spp. has been reportedly increasing in some
parts of the world . This bacterial genus presents
particular challenges for the selection of optimal therapy
due to the presence of chromosomally encoded AmpC
beta-lactamase enzymes . These enzymes are able to
hydrolyse many beta-lactams, including third generation
cephalosporins and may be induced by beta-lactam
exposure. Furthermore, AmpC gene expression can
become constitutively de-repressed by mutational loss of
regulatory genes, leading to high-levels of AmpC
production and a phenotype that demonstrates in vitro
resistance to most beta-lactams and
beta-lactam/betalactamase inhibitor (BLBLI) combination agents, except
cefepime and carbapenems.  Such variants are usually
present at low levels (e.g. between 10−5 to 10−7 of the
total bacterial population) but may be rapidly selected
during antibiotic therapy . This phenomenon has
been best described with the use of third generation
cephalosporins (3GCs). In a prospective study of
Enterobacter bacteraemia, emergence of resistance developed
during treatment in 6 of 31 (19%) bacteraemia episodes
treated with 3GCs . Similar outcomes were replicated
in a later study , although relapse rates have been
reported as lower in other studies [10–12]. In a large
cohort of patients from South Korea, emergent resistance
during therapy with 3GCs was more likely to occur with a
complex focus of infection (particularly malignant bile
duct obstruction) but was never seen in urinary tract
infections . Development of resistance in Enterobacter
infections has been associated with higher mortality and
healthcare-related costs . As a result, 3GCs are usually
not recommended as first line therapy, even when
susceptible in vitro.
Enterobacter may also acquire other major resistance
determinants such as extended-spectrum beta-lactamase
(ESBL) enzymes or carbapenemases [14, 15].
Carbapenem resistance may also develop from
AmpChyperproduction in association with porin mutations
 and multi-drug resistant (MDR) Enterobacter has
been implicated in nosocomial outbreaks [17–21]. As
such, Enterobacter spp. have become important
‘problem’ pathogens in the healthcare setting . Most
significant Enterobacter infections are treated with agents
such as carbapenems, quinolones or aminoglycosides.
Cefepime may be a useful option given its stability to
AmpC enzymes . Trimethoprim-sulphamethoxazole
may also be effective , but is rarely used in
contemporary practice for serious invasive Enterobacter
infections. BLBLI agents, such as piperacillin-tazobactam,
have an uncertain role in this context.  Although they
are often avoided over concerns relating to the
development of AmpC-mediated resistance, the risk of this
occurring for this antibiotic class has rarely been examined, and
may even be associated with improved outcome when
used as empirical therapy in one study .
The aim of the study was to determine clinical factors
associated with relapsed or persistent infection in patients
with Enterobacter bacteraemia. A specific hypothesis to be
tested was that the use of BLBLI agents as definitive
therapy carried no additional risk of bacteraemia relapse
when compared with alternative established therapies.
The study was undertaken across four hospitals served by
two public microbiology laboratories in Queensland and
New South Wales, Australia. These included the Royal
Brisbane and Women’s Hospital (in Queensland), John
Hunter Hospital in Newcastle, The Mater Hospital in
Newcastle and Belmont Hospital (all in New South Wales).
A case–control design was used to determine risk
factors for bacteraemia relapse or persistence beyond
3 days following initial positive blood culture. Adult
patients (> = 18 years of age) with laboratory confirmed
Enterobacter spp. in at least one blood culture draw
were identified from August 1998 to August 2012 from
Pathology North, and between October 1999 and
November 2015 from Pathology Queensland. ‘Relapsed
or persistent’ cases were defined if there was any
positive blood culture ≥72 hours, and up to 28 days, after
the initial positive blood culture with identification of
an Enterobacter isolate of the same species. Control
patients (at a ratio of approximately 1:4) were randomly
selected from those patients who had no relapsed
bacteraemia during the 28 days following initial positive
blood culture. For the logistic regression, control
patients who died within 28 days were excluded as it
was unknown whether they would have relapsed had
Inclusion / exclusion criteria
Any patient with at least one positive monomicrobial
blood culture with Enterobacter spp. was included.
Clinical data collection
Cases were identified by data extraction from the
Pathology North and Pathology Queensland laboratory
information systems (AUSLAB; PJA, Melbourne). Clinical and
demographic data on all significant bloodstream infections
were prospectively collected as routine surveillance by the
infection control and microbiology services. Relapsed
cases were retrospectively identified from laboratory data.
Outcomes were determined at 28 days post initial positive
blood culture for all cases and controls.
In addition to demographic details, clinical variables
recorded included source of infection, hospital location,
co-morbid conditions, admitting clinical service,
acquisition status of infection, initial antibiogram of the blood
culture isolate (AmpC de-repressed phenotype), the
presence of vascular access devices and the neutrophil
count on the day of first positive blood culture. Data on
antibiotic use and SAPS II physiology scores 
(determined on the day of first positive blood culture) were
recorded from clinical chart review. Only antimicrobial
agents with Gram-negative activity were recorded, with
those used within the first 48 h after initial blood culture
defined as empirical use and those prescribed after blood
culture results available defined as definitive use.
Healthcare acquisition and source designation of the
bacteraemia were categorised according to standard definitions
[27–29]. Empirical antibiotic therapy was described as
appropriate if the isolate was susceptible to at least one
agent used. If an agent was used for ≥50% of the
definitive treatment duration, this was listed as the primary
agent. If a second agent was used either concurrently or
sequentially, the patient was described as receiving
combination therapy; if combination therapy was used for
the majority of the definitive treatment duration the
antibiotic choice was determined as ‘other’. For
statistical analysis, if the definitive regimen included a
carbapenem, quinolone, co-trimoxazole, cefepime or an
aminoglycoside to which the isolate was susceptible, the
treatment was classified as ‘standard therapy’, if
piperacillin-tazobactam or ticarcillin-clavulanate was
used and the isolate was susceptible, the treatment was
classified as ‘BLBLI’, otherwise the treatment was defined
as ‘inappropriate’ (e.g. cephalexin, cephazolin,
ceftriaxone, ampicillin/amoxicillin, amoxicillin-clavulanate or no
therapy). Standard dosing regimens at participating
hospitals for piperacillin-tazobactam are 4.5 g 8-hourly and
ticarcillin-clavulanate 3.1 g 6-hourly, with dose
adjustment for renal dysfunction according to the Australian
Therapeutic Guidelines . Patients were classified as
being immunosuppressed if they had the following
conditions: neutropenia (neutrophil count <0.5 x109/L),
haematological / solid organ malignancy or
myelodysplastic syndrome, solid organ transplant or if they
received any other immunosuppressive drug therapy
including prolonged high dose corticosteroids (≥30 mg
prednisolone or equivalent daily).
Bacterial isolates were identified by routine diagnostic
methods employed in the laboratory over the study
period. Bacteraemia was diagnosed using the BD
BACTEC automated system (Becton Dickinson, Sydney,
Australia). Species identification methods used included
the Vitek 2 or API 20E systems (Biomerieux,
MarcyL’Etoile, France), BBL Crystal (Becton Dickinson), as well
as MALDI-TOF (Vitek MS, Biomerieux) and routine
bench testing. Susceptibility testing was performed using
Kirby-Bauer disk diffusion methods or by Vitek2
automated microbroth dilution (Biomerieux), with
interpretative standards as defined by the Clinical and Laboratory
Standards Institute (CLSI) at the time of testing ,
although from 2012 onwards Pathology Queensland
switched to EUCAST methodology .
Data describing patient demographics, microbiology
results, clinical features, bacteraemia source, co-morbidity,
acquisition status and clinical service for all patients
were tabulated for relapse cases and non-relapse cases,
with categorical variables expressed as percentages and
median (interquartile range [IQR]), mean (standard
deviation [SD]) and/or ranges calculated as appropriate for
scale variables. Wilcoxon rank-sum test was used to
explore differences between non-parametric continuous
variables. Potential risk factors for relapse as the
dependent variable were included in a univariate logistic
regression model. Variables with a p-value of <0.2 and/or
with large effect estimates (odds ratios [OR] > 2 or < 0.5)
in the univariate analysis were included in the multivariate
model. Odds ratios with 95% confidence intervals (CI)
were calculated for predictors of relapse. The multivariate
model was optimized using a stepwise approach,
beginning with the univariate model demonstrating the
strongest association with relapse. The goodness-of-fit
of the model before and after each step was compared
by the likelihood-ratio test and the optimal model fit
determined using Akaike’s and Bayesian information
criteria. Variables that did not significantly improve the
model fit were discarded. Statistical analysis was
performed using Stata 13.1 (StataCorp; TX, USA). A p-value
<0.05 was considered significant. Using a ratio of 1:4 cases
to controls, and assuming a 40% exposure to variables in
the control group that may influence outcome, we
calculated that we would need 35 cases and 137 controls,
assuming a two-sided confidence level of 95% to achieve
80% power to detect an odds ratio of at least 3.0.
During the study periods for each location, a total of 922
positive blood cultures growing Enterobacter spp. were
identified, after excluding polymicrobial infections,
individuals aged <18 years and repeatedly positive cultures
within the first 72 h after initial bacteraemia. A total of
31 (3.4%) patients were classified as having persistent or
relapsed Enterobacter bacteraemia, occurring between 3
and 28 days post initial positive blood culture. A total of
159 patients (all 31 cases and 128 randomly-selected
controls) were included in the case–control study to
identify risk factors for bacteraemia relapse or
persistence (see Fig. 1). The proportions of different species
identified and their antimicrobial susceptibilities are
shown in Table 1. The most common species identified
was Enterobacter cloacae (76.7%). A proportion of
isolates had an initial antibiogram suggesting AmpC
derepression (61/159, 38.4%), but of these only 9 relapsed.
Furthermore, in only 3 of the relapsed cases did 3GC
resistance develop during treatment (1.9% of the total
cohort) (see Additional file 1: Table S1 for detail).
Empirical combination therapy was common (73/159,
45.9%), most frequently employing ampicillin plus
gentamicin (10/73, 13.7%). Excluding patients treated
with combination therapy, the most commonly
prescribed agents for empirical treatment, with in vitro
activity against Enterobacter spp., were aminoglycosides
(31/86, 36%) or a broad-spectrum BLBLI
(ticarcillin-clavulanate or piperacillin-tazobactam) (12/86, 13.9%)
followed by carbapenems (11/86, 12.8%). For definitive
treatment, a carbapenem was most commonly used (45/
159, 28.3%), followed by a fluoroquinolone (39/159,
24.5%), BLBLIs (21/159, 13.2%) and aminoglycosides
(11/159, 6.9%) (Table 2). The median duration of
treatment was 10 days (range 0 to 328 days; IQR 2–40 days)
and did not differ significantly between cases and
controls (p = 0.13, Wilcoxon rank-sum test). The mean
SAPSII score was 34.7 (range 6–89; SD 13.6), which
corresponds to a risk of in-hospital mortality of
Results for the univariate and multivariate logistic
regression are summarised in Table 3. In the final
model, the strongest predictors of relapsed or persistent
bacteraemia were the presence of immunosuppression
(OR 2.70; 95% CI 1.14-6.44 p = 0.02) or a
lineassociated source of bacteraemia (OR 3.87; 95% CI
1.56-9.60, p = 0.004), whereas choice of definitive
antibiotic therapy did not show a significant effect on the
Fig. 1 Inclusion flowchart for case–control study
Table 1 Antibiotic susceptibility of Enterobacter species causing bacteraemia
Other Enterobacter spp.
CRO ceftriaxone, GENT gentamicin, TZP piperacillin-tazobactam, TIM ticarcillin-clavulanate, CAZ ceftazidime, FEP cefepime, CIP ciprofloxacin, MER meropenem, IMI
imipenem, SXT trimethoprim-sulphamethoxazole
aLimited number of isolates as not routinely tested in all labs until 2010
In this case–control study, 3.4% of patients with
Enterobacter bacteraemia were found to have relapsed by
28 days. The most striking finding is the effect of
bacteraemia source on the risk of this outcome; 74% of all
relapsed cases had a line-associated source for the
bacteraemia, and this variable had the greatest effect size in
the multivariate logistic regression model (OR 3.87).
Although data were not available to reliably determine
the precise date of line-removal in the majority of cases,
we would hypothesise delayed line removal as a likely
reason for this association.
Given the well-described association with 3GC
treatment and AmpC-mediated relapse when used for
Enterobacter infections, this study also aimed to assess
the effect of antibiotic choice on the risk of relapse.
When compared with alternative effective therapies
(such as carbapenems, cefepime, quinolones or
aminoglycosides) BLBLIs were not significantly associated with
bacteraemia relapse when used as definitive therapy.
However, BLBLIs were used relatively infrequently for
definitive therapy. Overall antibiotic use was
heterogeneous and often included combination therapy, meaning
that effects for individual agents were diluted. We defined
BLBLI therapy as including ticarcillin-clavulanate and
piperacillin-tazobactam. However, these agents have some
important differences with respect to AmpC-enzymes.
Clavulanate is a potent inducer of AmpC and a poor
inhibitor, whereas piperacillin and tazobactam are only
weak inducers of AmpC .
Many laboratories suppress susceptibility results for
AmpC-producers (such as Enterobacter spp.) in favour
of carbapenems or quinolones due to concerns of
selecting for AmpC de-repressed variants. According to the
findings of this study, this may not be justified as a
routine policy, especially in cases where source control has
been addressed or in the absence of significant
immunosuppression. If BLBLIs are used against susceptible
Table 2 Frequency of bacteraemia relapse by definitive treatment category
No antibiotic treatment
aIncludes combination therapy
15 (48.4%) 30 (23.4%)
6 (19.4%) 16 (12.5%)
6 (19.4%) 15 (11.7%)
6 (19.4%) 27 (21.4%)
29 (93.5%) 99 (77.3%)
16 (51.6%) 55 (43.0%)
9 (29.0%) 52 (40.6%)
37.9 (15.9) 33.9 (12.9)
Table 3 Univariate and multivariate logistic regression of the effects of clinical variables on relapsed Enterobacter bacteraemia
SAPS II score, mean (SD)
*significant p < 0.05
16 (51.6%) 49 (38.3%) female as reference
15 (48.4%) 79 (61.7%)
10 (32.3%) 82 (64.1%) general medical / surgical as reference
23 (74.2%) 105 (82.0%) carbapenem, quinolone, cefepime, aminoglycoside or co-trimoxazole
8 (25.8%) 80 (62.5%) non-line source as reference
23 (74.2%) 48 (37.5%)
12 (38.7%) 83 (64.8%) no immunosuppression as reference
19 (61.3%) 45 (35.2%)
25 (80.6%) 99 (78.6%) non-ICU admitted as reference
29 (22.7%) community-associated infection as reference
15 (48.4%) 73 (57.0%)
New South Wales region as reference
De-repressed AmpC phenotype Absent
22 (71.0%) 76 (59.4%) no de-repressed AmpC as reference
Other Enterobacter spp. 6 (19.4%) 31 (24.2%) other Enterobacter spp. as reference
25 (80.6%) 97 (75.8%)
Enterobacter isolates there does not appear to be any
clear association with microbiological failure; and failure
with the emergence of AmpC-mediated resistance
appears to be rare. However, given the small number of
patients treated with BLBLIs in this study, the possibility
of a type II error exists, and this needs further
investigation in larger cohorts. The proportion of patients treated
with BLBLIs was lower than expected, which
compromised the power of the study to address the effect of
antibiotic choice on outcome.
In this current era of emerging carbapenem-resistance,
it is critical that alternatives to carbapenems are sought
for common infections. Infectious disease practitioners
in our region most frequently recommend carbapenems
for AmpC beta-lactamase producing Enterobacteriaceae
. As such, it may be a significant driver of
carbapenem use. Our findings would suggest that using a
BLBLI when susceptibility is demonstrated, especially in
immunocompetent patients in whom adequate source
control has been achieved, is not clearly associated with
microbiological failure. Further work would help to
delineate patients for whom carbapenems may still be a
Not only was the risk of relapsed Enterobacter
bacteraemia low (3.4%) in this study, but in only 3 cases did
resistance to 3GCs (a marker for AmpC de-repression)
emerge during treatment. This figure is lower than
described in some previous studies [8, 9]. There may be
several reasons for this observed difference. Firstly,
clinicians are more aware of this clinical phenomenon and
3GCs are currently rarely used as definitive treatment
for Enterobacter bacteraemia. In this study only 3 of 159
(1.9%) bacteraemia events received either ceftriaxone or
ceftazidime as definitive therapy, and in 2 of these 3GCs
were given in combination with another agent. This may
also reflect local laboratory practice for withholding
susceptibility reporting for 3GCs against Enterobacter.
Secondly, low rates of relapse may also result from
better recognition of source control and the availability
of other effective antibiotics, especially carbapenems,
cefepime and fluoroquinolones. Other variables that
may have influenced the low rate of relapse in this
study might include the clinical characteristics of our
patient population as well as long-standing infection
control and antimicrobial stewardship programs.
The overall risk of Enterobacter bacteraemia with a
de-repressed AmpC phenotype in our region was also
relatively low over the study period, with only 38.4% of
isolates being resistant to 3GCs (either ceftriaxone or
ceftazidime). Very few isolates showed resistance to
carbapenems, although MIC breakpoints were lowered
during the study period. Both current and older clinical
breakpoints may fail to detect the presence of
carbapenemase in Enterobacteriaceae [35, 36]. Our findings may
not be generalizable to populations encountering higher
rates of baseline 3GC resistance, or frequent ESBL /
carbapenemase acquisition in Enterobacter species.
Limitations of the study are acknowledged. Although
the bacteraemia database was collected prospectively as
part of routine surveillance, clinical and microbiological
data extraction for Enterobacter cases was retrospective.
Although a laboratory servicing several hospitals was
used to identify cases, these occurred within a limited
area in Australia and may not represent the diversity of
infections and patient populations found in other states
and countries. Whether all repeat bacteraemia episodes
were true relapsed events or new infections is also not
known, as isolates were not available for molecular
typing. Equally, the presence of co-existing ESBLs was not
sought systematically for isolates demonstrating
resistance to 3GCs; inferring Amp-C de-repression based on
the antibiogram alone may be unreliable. This study only
examined relapsed bacteraemia, since such an endpoint
is easily defined. However, the risk of relapsed infection
and emergent resistance from other clinical sites infected
with Enterobacter may be different and care should be
taken when extrapolating from bacteraemia data alone.
Given the inherent limitations of retrospective studies, it
is hoped that the efficacy of BLBLIs or other
carbapenemsparing options for Enterobacter infections could be
addressed in large prospective observational studies or
even randomised controlled trials (RCTs). A pilot RCT
comparing piperacillin-tazobactam with meropenem for
bloodstream infections caused AmpC-producers is
currently recruiting (MERINO-2 Trial; ClinicalTrials.gov
In a cohort of patients with bacteraemia caused by
Enterobacter species, the overall risk of relapsed
bacteraemia was low. Patient factors, such as a line-source for
the bacteraemia or the presence of immunosuppression,
were the strongest predictors of relapse. Use of a BLBLI
agent as definitive therapy was not associated with
treatment failure, but the total number of patients treated
with a BLBLI was relatively low. Although this would
suggest that susceptibility in vitro should translate into
in vivo efficacy for BLBLI agents, especially if the patient
has adequate source control, further studies are
warranted to determine if BLBLIs are a safe and effective
carbapenem-sparing option, especially for patients with
severe disease, a complex focus of infection or immune
compromise. Our data also reinforce the importance of
line removal when suspected as the source for
bacteraemia, especially for isolates with the genetic capacity to
respond rapidly to antimicrobial exposure.
Additional file 1: Table S1. Clinical details of relapsed Enterobacter
bacteraemia cases with emergence of antibiotic resistance. (DOCX 17 kb)
3GC: Third generation cephalosporin; BLBLI: Beta-lactam/beta-lactamase
inhibitor; CLSI: Clinical and laboratory standards institute; ESBL:
Extendedspectrum beta-lactamase; EUCAST: The European committee on antimicrobial
susceptibility testing; ICU: Intensive care unit; MALDI-TOF: Matrix assisted laser
desorption/ionization time of flight; MDR: Multi-drug resistant; MIC: Mimimum
inhibitory concentration; OR: Odds ratio; RCT: Randomised controlled trial
We would also like to acknowledge the contribution of Dr Stuart Paynter.
No external funding was required for this study. PH is supported by an
Australian Postgraduate Award from the University of Queensland.
Availability of data and materials
The dataset generated during the current study are available at Harvard
PH, DP and JF conceived and designed the study. PH, JF, and CH were
responsible for data collection, PH and AP performed the statistical analysis.
All authors contributed to the writing of the manuscript and approved the
DP has received research grants from AstraZeneca and has attended Advisory
Boards, acted as a consultant to, or given lectures with honoraria from Cubist
Pharmaceuticals, Merck, AstraZeneca, SanofiAventis, Pfizer, Johnson & Johnson
and Leo Pharmaceuticals. All other authors declare no conflicts of interest.
Consent for publication
Ethics approval and consent to participate
Ethical approval for the study, with a waiver for consent, was provided by
the Royal Brisbane & Women’s Hospital Human Research Ethics Committee.
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