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Infectious Diseases
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Mortality and length of hospital stay after
bloodstream infections caused by ESBL-producing
compared to non-ESBL-producing E. coli
Nina Handal, Jimmy Whitworth, Magnus Nakrem Lyngbakken, Jan Erik
Berdal, Olav Dalgard & Silje Bakken Jørgensen
To cite this article: Nina Handal, Jimmy Whitworth, Magnus Nakrem Lyngbakken, Jan Erik
Berdal, Olav Dalgard & Silje Bakken Jørgensen (05 Oct 2023): Mortality and length of hospital
stay after bloodstream infections caused by ESBL-producing compared to non-ESBL-producing
E. coli, Infectious Diseases, DOI: 10.1080/23744235.2023.2261538
To link to this article: https://doi.org/10.1080/23744235.2023.2261538
© 2023 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Published online: 05 Oct 2023.
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INFECTIOUS DISEASES,
2023; VOL. 0,
NO. 0, 1–13
https://doi.org/10.1080/23744235.2023.2261538
RESEARCH ARTICLE
Mortality and length of hospital stay after bloodstream infections caused by
ESBL-producing compared to non-ESBL-producing E. coli
Nina Handal
a
, Jimmy Whitworth
b
, Magnus Nakrem Lyngbakken
c,d
, Jan Erik Berdal
c,d
, Olav Dalgard
c,d
and Silje Bakken Jørgensen
a,e
a
Department of Microbiology and Infection Control, Division for Diagnostics and Technology, Akershus University Hospital,
Lørenskog, Norway;
b
Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United
Kingdom;
c
Department of Infectious Diseases, Division of Medicine, Akershus University Hospital, Lørenskog, Norway;
d
Institute
for Clinical Medicine, University of Oslo, Norway;
e
Department for Emergency Medicine, Division for Internal Medicine, Akershus
University Hospital, Lørenskog, Norway
ABSTRACT
Objective: To compare mortality and length of hospital stay between patients with ESBL-producing E. coli bloodstream
infections (BSIs) and patients with non-ESBL E. coli BSIs. We also aimed at describing risk factors for ESBL-producing
E. coli BSIs and time to effective antibiotic treatment for the two groups.
Methods: A retrospective case-control study among adults admitted between 2014 and 2021 to a Norwegian University
Hospital.
Results: A total of 468 E. coli BSI episodes from 441 patients were included (234 BSIs each in the ESBL- and non-ESBL
group). Among the ESBL-producing E. coli BSIs, 10.9% (25/230) deaths occurred within 30 days compared to 9.0%
(21/234) in the non-ESBL group. The adjusted 30-day mortality OR was 1.6 (95% CI 0.7–3.7, p= 0.248). Effective antibiotic
treatment was administered within 24 hours to 55.2% (129/234) in the ESBL-group compared to 86.8% (203/234) in the
non-ESBL group. Among BSIs of urinary tract origin (n=317), the median length of hospital stay increased by two days
in the ESBL group (six versus four days, p<0.001). No significant difference in the length of hospital stay was found for
other sources of infection (n= 151), with a median of seven versus six days (p=0.550) in the ESBL- and non-ESBL groups,
respectively.
Conclusion: There was no statistically significant difference in 30-day mortality in ESBL-producing E. coli compared to
non-ESBL E. coli BSI, despite a delay in the administration of an effective antibiotic in the former group. ESBL-production
was associated with an increased length of stay in BSIs of urinary tract origin.
KEYWORDS
Extended-spectrum beta-lactamases (ESBL)
bloodstream infection
mortality
Enterobacterales
antimicrobial resistance
healthcare associated infection
ARTICLE HISTORY
Received 12 May 2023
Revised 14 September 2023
Accepted 14 September 2023
CONTACT
Nina Handal
nina.handal@ahus.no
Department of Microbiology and Infection
Control, Division for Diagnostics and Technology,
Akershus University Hospital, Lørenskog, Norway
� 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any
way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
Introduction
Escherichia coli is one of the most common pathogens
causing bloodstream infections (BSIs) [1]. E. coli BSIs may
be hospital acquired or healthcare associated, but
are also commonly of community-acquired origin [2–4].
The incidence of E. coli BSIs has increased in the last
decades, as well as the prevalence of third generation
cephalosporin resistance caused by Extended-Spectrum
Beta-Lactamases (ESBL) [5–9]. Third generation cephalo-
sporin resistant E. coli are estimated to be one of the
leading causes of deaths associated with antimicrobial
resistance [10]. Furthermore, the spread of ESBL is asso-
ciated with increased resistance to other important anti-
biotics (e.g. aminoglycosides, fluoroquinolones and
trimethoprim-sulfamethoxazole) as several antibiotic
resistance genes often assemble on the same mobile
genetic elements that transfer between Gram-negative
bacteria [11].
The association between ESBL-producing
Enterobacterales and outcomes including mortality,
length of stay and effect of inappropriate empiric ther-
apy have been examined with contradicting results. Two
of the earliest meta-analyses found an increased risk of
mortality associated with third generation resistant
Enterobacterales [12,13], but pointed out that results
might have been influenced by different study designs
and populations, and lack of, or incorrectly adjusted,
effect estimates. Further, several of the included studies
had few participants, and they included other pathogens
than E. coli. Still, more recent meta-analyses support the
initial findings of a higher mortality among third gener-
ation cephalosporin resistant Enterobacterales versus
cephalosporin susceptible isolates, although again, esti-
mates might be influenced by heterogenous study
designs and a lack of adjusting for confounders [14–17].
In contrast, other studies examining E. coli BSIs show no
impact of ESBL-production on mortality [18–21],
although none of these are meta-analyses and they dif-
fer in design, study populations and use of empirical
antibiotics. Besides study size, design and population,
other factors that might influence study outcomes of
ESBL-production on mortality are the prevalence of local
antimicrobial resistance, national guidelines on empirical
antibiotic treatment and sepsis management, hospital
resources, definitions of sepsis, health care seeking
behaviour and access to health care and pathogens
examined.
To inform the local antibiotic stewardship program in
our region with a low prevalence of ESBL, we conducted
a study with the primary aim of comparing 30-day mor-
tality and length of hospital stay in patients with ESBL-
producing E. coli (ESBL-EC) BSIs to patients with non-
ESBL E. coli (non-ESBL-EC) BSIs. The secondary aim was
to describe risk factors for ESBL-producing E. coli BSIs
and time to effective antibiotic treatment for the two
groups.
Material and methods
This was a retrospective case-control study conducted at
Akershus University Hospital, Norway, an emergency
care hospital with 1,000 beds and a catchment area of
594,000 inhabitants (approx. 10% of the Norwegian
population). The national prevalence of ESBL-production
in E. coli blood culture isolates varied from 5.8% in 2014
to 7.1% in 2019 [22], with a higher prevalence of 6% in
2014, 11% in 2019 and 6% in 2021 at Akershus
University Hospital (annual antibiotic resistance reports
published locally by the hospital laboratory). The main
empiric antibiotic therapy followed national guidelines
and did not change during the study period.
Adults (18 years) admitted to the hospital with
growth of class A ESBL-producing E. coli [23] in at least
one blood culture bottle sampled between 1st January
2014 to 31st December 2021 were included as cases,
with a minimum of 8 weeks between each included BSI
episode. Controls were selected randomly among adults
with non-ESBL-producing E. coli BSIs after matching by
year of BSI and place of blood culture requisition
(Emergency department or non-Emergency department).
Data were extracted from patient’s electronic medical
records and the laboratory data systems of the hospital.
All data apply to the time of blood culture sampling,
with the following exceptions: the length of stay was
calculated as time from admission to discharge, and
readmissions were defined as a new hospital admission
within 30 days after discharge alive.
Clinical data
The 30-day mortality, length of stay and readmissions
were recorded for all causes, i.e. not only related to BSIs.
The source of infection was extracted from the dis-
charge notes, and if lacking or uncertain, determined by
examining the clinical records during the hospital stay.
Several sources of infections were possible in any given
BSI. Pyelonephritis, kidney abscesses and prostate gland
infections were registered as urinary tract infections.
Charlson Comorbidity Index was calculated based on
2 N. HANDAL ET AL.
comorbidities at the time of blood culture sampling,
according to updated ICD-10 codes [24]. The quick
Sepsis related Organ Failure Assessment (qSOFA) [25]
was calculated based on the worst variable collected up
to 24 h before obtaining the blood culture and used as
a proxy to measure the severity of infection. Septic
shock was defined as patients with a documented serum
lactate >2 mmol/L and vasopressor treatment [25] and
was assessed up to 24 h before obtaining the blood cul-
ture. Neutropenia was defined as a neutrophil count <
0.5 10
9
/L.
The infection was defined as hospital acquired (HA) if
the blood culture was drawn more than 48 h after
admission. A healthcare-associated (HCA) infection was
recorded if the blood culture was sampled 48 h or less
after admission in patients with one or more of the fol-
lowing criteria: hospital stay for two or more days in the
previous 90 days, transfer from a healthcare institution,
day surgery or an invasive procedure in the previous
30 days, regular dialysis or intravenous chemotherapy. A
community acquired (CA) infection was registered if the
blood culture was sampled less than 48 h after admis-
sion in patients without criteria of a HCA infection [26].
Hospital admission abroad within the last 12 months
were only recorded for non-Nordic countries, as these
patients require contact precautions upon admission
according to national guidelines for control of multi-
drug-resistant microbes, and were therefore registered
in the patient file. Antibiotic therapy was recorded for
the previous six months from the patient’s hospital med-
ical journal and information upon admission, regardless
of length of treatment, with the exception of pre-
operative antibiotic prophylaxis.
The time to first effective dose of antibiotic was
defined as the time between the blood culture was
obtained until the first antibiotic towards which the
microbe showed in vitro susceptibility was administered.
Oral administrations of amoxicillin-clavulanate, cefalexin,
pivmecillinam, trimethoprim and nitrofurantoin were not
counted as effective therapy because breakpoints
according to the European Committee on Antimicrobial
Susceptibility Testing (EUCAST) only apply to uncompli-
cated urinary tract infections [27].
Microbiological data
Blood cultures were incubated in the BACTEC auto-
mated blood culture system (Becton Dickinson, USA)
and pathogens were identified by MALDI-TOF mass
spectometry (Bruker Daltonics, Germany). Antimicrobial
susceptibility testing was performed using disc diffu-
sion (BBL Sensi-Disc, Becton Dickinson, USA and Oxoid
susceptibility discs, Thermo Fisher Scientific, USA) in
accordance with EUCAST recommendations [28], or in
cases of ambiguous results, with gradient tests (Etest,
BioM�
erieux, France and MTS, Liofilchem, Italy) accord-
ing to the manufacturer’s instructions. Susceptibility
results were categorised using the EUCAST breakpoint
tables at the time of reporting [27]. The presence of
class A ESBL-production was confirmed in isolates with
resistance to at least one third generation cephalo-
sporin by a positive synergy disc test between amoxi-
cillin-clavulanate and one or more third or fourth
generation cephalosporins. A polymicrobial blood cul-
ture was recorded if there was growth of other patho-
gens except E. coli. The time between blood culture
sampling until registration of growth (time to positivity)
was measured in hours and only included monomicro-
bial blood cultures.
Statistics
Baseline data are reported as absolute numbers with
proportions or medians with interquartile ranges (IQR)
unless otherwise stated. Continuous variables were ana-
lysed using the Mann Whitney U test and categorical
variables with the Chi square or Fisher exact test as
appropriate. We used logistic regression to assess the
association of ESBL status with 30-day mortality and
adjusted for age, sex, Charlson Comorbidity Index, type
of infection (health associated, hospital or community
acquired), urinary source of infection and septic shock. A
Kaplan-Meier survival plot was generated to illustrate
the unadjusted association between ESBL status and 30-
day mortality with comparison of groups by the log-
rank test. A subgroup analysis of length of stay was per-
formed for BSIs of urinary tract origin, as we expected
the majority of cases to stem from a urinary tract origin
and these may have shorter lengths of stay than BSIs of
other origins [29]. A box plot was created for the
unadjusted association of ESBL with the length of hos-
pital stay. Study data were collected using REDCap and
analysed in Microsoft Excel (version 2016) and STATA
(version 17). A two-sided p-value of <0.05 was consid-
ered significant. All eligible ESBL-producing E. coli BSIs
isolated in our hospital during the study period were
included. The included sample size supports a detection
of 9% difference in 30day mortality with 80% power
and a confidence level of 95%.
INFECTIOUS DISEASES 3
Results
A total of 468 BSI episodes (234 BSIs each in the ESBL-
and non-ESBL group) from 441 patients were included
(210 with ESBL-EC and 231 with non-ESBL-EC, one patient
was included once in both groups). The main demo-
graphic and clinical characteristics are presented in Table
1, with additional characteristics included in Appendix A.
Mortality
Forty-six deaths (46/468, 9.9%) occurred within 30 days
after obtaining a positive E. coli blood culture (Table 2).
Among these, 14 deaths (30.4%) occurred within 26 h. In
the ESBL group, 25 deaths occurred among 230 BSIs
(10.9%; data missing for four BSIs) compared to 21/234
(9%) in the non-ESBL group during the first 30 days
(unadjusted OR 1.2, 95%CI 0.7 −2.3, p¼0.495). After
adjustment for sex, age, type of infection (healthcare or
Table 1. Demographic and clinical characteristics of patients with E. coli blood stream infections.
ESBL-E. coli (N*5234) Non-ESBL-E. coli (N*5234)
N % N % p
Median age (IQR), years 72 (60-80) 72 (64-80) 0.251
Sex, female 112 47.9% 108 46.2% 0.711
Type of infection
Community acquired 72 30.8% 112 48.5% <0.001
Healthcare-associated 126 53.9% 88 38.1% 0.001
Hospital acquired 36 15.4% 31 13.4% 0.546
Admitted from
Home 186 79.5% 215 91.9% <0.001
Healthcare institutions 37 15.8% 17 7.3% 0.004
Other hospitals 11 4.7% 2 0.9% 0.021
Department requesting the blood culture
Emergency department 173 73.9% 172 73.5%
ICU 15 6.4% 11 4.7% 0.420
Other wards 46 19.7% 51 21.8%
Charlson Comorbidity Index
2 120 51.3% 128 54.7% 0.459
>2 114 48.7% 106 45.3%
Source of infection**
Urinary tract 171 73.1% 146 62.4% 0.013
Biliary tract 24 10.3% 32 13.7% 0.255
Intra-abdominal 13 5.6% 18 7.7% 0.353
Neutropenic fever 5 2.1% 12 5.1% 0.084
Other 13 5.6% 21 9% 0.154
Unknown/Not determined 17 7.3% 18 7.7% 0.861
qSOFA N¼217 N ¼212
0-1 148 68.2% 148 69.8% 0.719
2-3 69 31.8% 64 30.2%
Septic shock N¼217 N ¼215
Yes 8 3.7% 7 3.3% 0.807
Neutropenia N¼233 N ¼232
Yes 5 2.2% 13 5.6% 0.053
Presence of an invasive device >24 hours N¼232 N ¼230
Yes 65 28 % 45 19.6% 0.033
Type of invasive device** N¼232 N ¼230
Urinary catheter 52 22.4% 32 13.9% 0.018
Central venous catheter 15 6.5% 14 6.1% 0.867
Other 6 2.6% 4 1.7% 0.751
Antibiotic therapy previous six months N¼220 N ¼231
Yes 137 62.3% 78 33.8% <0.001
Hospital admission abroad N¼222 N ¼233
Yes 13 5.9% 1 0.4% 0.001
History of ESBL-producing microbe
Yes 93 39.7% 2 0.9% <0.001
Readmission within 30 days of discharge N¼205 N ¼219
Yes 61 29.8% 60 27.4% 0.591
Total N¼234 for all variables unless otherwise indicated.
More than one possible option.
Includes pulmonary, gynaecological, skin and soft tissue and other origins.
Table 2. All-cause mortality for patients with ESBL-producing E.
coli compared to non-ESBL-producing E. coli bloodstream
infections.
ESBL-E. coli
(N¼230)
Non-ESBL-E. coli
(N¼234)
N % N % p
0-26 hours 7 3 % 7 3 % 0.974
30 days 25 10.9% 21 9 % 0.495
60 days 37 16.1% 32 13.7% 0.466
90 days 45 19.6% 38 16.2% 0.351
1 year (only 2014-2020) N ¼202 N ¼206
1 year mortality 58 28.7% 55 26.7% 0.650
4 N. HANDAL ET AL.
hospital versus community acquired), urinary tract as
source of infection and septic shock before obtaining
the blood culture, the 30-day mortality OR was 1.6
(95%CI 0.7 −3.7, p¼0.248). Thirty-day survival according
to ESBL status is presented in Figure 1. Variables associ-
ated with 30-day mortality are presented in Appendix B.
Time to effective therapy
Effective antibiotic treatment was administered within
24 h to 55.2% (129/234) in the ESBL-group compared to
86.8% (203/234) in the non-ESBL group (Figure 2). A his-
tory of ESBL-colonisation-/infection reduced the time to
administration of the first effective antibiotic, but it was
still delayed compared to the non-ESBL group (Appendix
C). There were missing data for 26 (5.6%) BSIs in which
effective antibiotics were administered, but in which we
could not ascertain the time to administration of the first
effective antibiotic (9 (3.8%) among the ESBL-group and
17 (7.3%) among the non-ESBL group (p¼0.099)). Only
two patients did not receive any antibiotics at all (one in
each group). In the 45 BSIs in whom death occured
within 30 days an effective antibiotic had been adminis-
tered within 3 h and 24 h of obtaining a blood culture in
26 (57.8%) and 35 (77.8%) BSIs, respectively (missing data
for one deceased). Antibiotics administered in relation to
ordering blood cultures are summarised in Appendix D.
Length of hospital stay
The overall unadjusted median length of stay was seven
(IQR 4-10) days in the ESBL-group compared to five (IQR
3-8) days in the non-ESBL group (p¼0.001). In a suba-
nalysis among BSIs of urinary tract origin (n¼317), the
median length of stay increased by two days in the
ESBL group, with a median of six (IQR 4-9) versus four
(IQR 3-7) days in the non-ESBL group (p<0.001). No sig-
nificant difference was observed in the patients with
other sources of infection (n¼151), with a median
length of stay of seven (IQR 3-15) days in the ESBL-
group compared to six (IQR 3.5-14) days in the non-
ESBL-group (p¼0.550) (Figure 3).
Risk factors for ESBL-producing E. coli BSIs
Variables univariatly associated with ESBL-producing BSIs
were healthcare-associated infections, admissions from
other healthcare institutions and hospitals, BSIs of urin-
ary tract origin, indwelling urinary catheters, antibiotic
Figure 1. Thirty-day survival in ESBL-producing E. coli compared to
non-ESBL-producing E. coli blood stream infections.
Figure 2. Time to administration of the first dose of effective antibiotic in ESBL-producing E. coli compared to non-ESBL-producing E. coli
blood stream infections.
INFECTIOUS DISEASES 5
therapy in the previous six months, hospital admission
outside a Nordic country in the previous twelve months
and a history of infection or colonisation with an ESBL-
producing microbe (Table 1). A previous history of ESBL
colonisation/- infection was recorded in 93/234 (39.7%)
ESBL-EC BSIs compared to only 2/234 (0.9%) non-ESBL-
EC BSIs. Among the ESBL-EC BSIs with a documented
history of ESBL-producing microbes, the median time
between the first and the most recent detection of an
ESBL-producing microbe (in any samples) and the cur-
rent BSI was 197 days and 61 days, respectively.
Microbiological findings
Among 468 BSIs, 422 (90.2%) were monomicrobial.
There was no significant difference in the prevalence of
polymicrobial infections between the ESBL and non-
ESBL group (p¼0.280). E. coli was isolated from urinary
tract samples in 242/317 (76.3%) BSIs diagnosed as origi-
nating in the urinary tract.
The median time to blood culture positivity for mono-
microbial BSIs with recorded laboratory data (n¼408)
was 11.8 h (IQR 10.6 −13.8 h, range 4.4 −105.1 h), with
no significant difference between the ESBL- and non-
ESBL groups (p¼0.522).
Antimicrobial resistance results are shown in
Appendix E. Co-resistance with antibiotics outside the
beta-lactam group was higher among the ESBL-EC
isolates, especially for ciprofloxacin, gentamicin and tri-
methoprim-sulfamethoxazole.
Discussion
The main finding of this single centre retrospective case-
control study was the lack of a significant difference in
30-day mortality between ESBL-EC and non-ESBL-EC
BSIs. This occurred even though treatment with an
effective antibiotic often was delayed in the ESBL-EC
BSIs. Furthermore, ESBL-production increased the length
of hospital stay in E. coli BSIs of urinary tract origin.
The observed 30-day mortality of 9.9% was among the
lower rates compared to previous studies [19,20,30–34],
including a review of E. coli BSIs in adults in high-income
countries that reported a pooled case-fatality rate of
12.4% [2]. Mortality rates might vary depending on
numerous factors, including whether studies are restricted
to community- or hospital acquired infections, certain
patient groups as well as the infectious origins of BSIs. In
our study, a large proportion of the BSIs were of urinary
tract origin and community acquired, both factors shown
to be associated with a reduced mortality [19,20,34–36].
After adjusting for confounders, there was an increased
30-day mortality OR of 1.6 in the ESBL-group, but this did
not reach statistical significance. This finding is in accord-
ance with other studies which did not observe any
impact of ESBL-production on mortality in E. coli BSIs
Figure 3. Length of stay of ESBL-producing E. coli compared to non-ESBL-producing E. coli blood stream infections according to source of
infection.
6 N. HANDAL ET AL.
[18–21]. However, several meta-analyses have found an
increased risk of mortality associated with third gener-
ation resistant Enterobacterales, reporting pooled, mostly
unadjusted OR of 1.5 −2, albeit with important limitations
[13–16]. As our study was powered according to the ear-
liest meta-analyses with an estimated risk ratio of
approximately two [12,37], and the 30-day mortality in
the ESBL-EC BSIs was low compared to other estimates, a
type two error cannot be ruled out.
The lack of association between ESBL-production and
mortality despite the delayed administration of effective
antibiotics in a significant proportion of the ESBL-EC BSIs
may be explained by several factors. First, most deaths
within 30 days occurred in patients who did receive
effective antibiotics early. Second, almost one third of the
30-day mortality occurred within 26 h after the blood cul-
tures had been obtained, similar to findings in an English
national study of E. coli BSIs [20]. This suggests that some
deaths might not be preventable even with effective anti-
biotic treatment [38]. Third, a high proportion of the BSIs
in this study were of urinary tract origin. Since several
antibiotics accumulate in the urinary tract, some antibiot-
ics declared resistant in vitro might actually have been
effective in vivo and active treatment achieved earlier
than recorded. Finally, the study registered all-cause mor-
tality, so not all deaths were necessarily caused by E. coli
infection. Similarly, other studies have reported a lack of
association between initially delayed effective antibiotic
treatment and mortality in antimicrobial resistant E. coli
[19,29,39–41]. Nevertheless, this is still a controversial
topic and likely impacted by a number of confounding
factors, as other studies have found a clear association
between delayed antibiotic therapy and risk of death
[42,43]. The Surviving Sepsis Campaign has concluded
that antibiotic treatment should be administered within
one hour in adults with septic shock or a high likelihood
of sepsis, but may be delayed in order to ascertain the
diagnosis in adults with possible sepsis without shock
(preferably no more than three hours) [44].
The median length of stay increased by two days in
ESBL-EC BSIs originating from the urinary tract compared
to non-ESBL-EC BSIs. This is consistent with other studies
which have demonstrated an increased length of stay in
patients with bacteraemia caused by third generation
cephalosporin-resistant E. coli [14,15,19,29,45]. Patients with
BSIs of urinary tract origin had a shorter length of stay
compared to BSIs of other origins, presumably because
these patients often are discharged with oral antibiotics
after only a few days of intravenous therapy. The delayed
treatment with an effective parenteral antibiotic thus
prolongs the stay in the ESBL-EC group more than the
non-ESBL-EC. In addition, ESBL-producing microbes are
often co-resistant to oral antibiotics, sometimes leaving
parenteral therapy the only treatment option. Considering
the rising antimicrobial resistance, alternative solutions for
parenteral administration of antibiotics outside hospitals
such as in outpatient clinics, home nursing care or nursing
homes are important to mitigate the effect of ESBL-pro-
duction on the length of hospital stay.
Compared to non-ESBL-EC BSIs, patients with ESBL-EC
BSIs were more often admitted from other healthcare
institutions and hospitals, had healthcare-associated
infections, previous antibiotic exposure, hospital admis-
sion abroad, an indwelling urinary catheter or BSIs of a
urinary tract origin. These have been identified as risk
factors of infections with ESBL-producing pathogens in
other studies [29,30,46–48]. Notably, 39.7% of the ESBL-
EC BSIs had a recent history of ESBL-colonisation/-
infection compared to almost none in the non-ESBL-EC
BSIs. This supports data from a Swedish population-
based study which found that colonisation is a substan-
tial risk factor for subsequent BSIs with ESBL-producing
Enterobacterales, and that this risk declines rapidly dur-
ing the first year after detection [49].
The median time between blood culture sampling until
registration of growth in this study was 11.8h. Depending
upon laboratory opening hours, current diagnostics may
provide susceptibility results of E. coli within 18-24 h after
blood culture sampling in a substantial proportion of BSIs
[50]. Developing rapid, culture-independent diagnostics
could further optimise patient treatment and prevent
unnecessary use of broad-spectrum antibiotics [51].
There are several limitations to this study. First, the
retrospective design means that information bias was
most likely present, especially since some variables were
easier to collect from the most recent period when the
electronic medication records had been introduced at our
hospital. Second, there has been a national campaign to
secure rapid treatment of sepsis during the end of the
study period. In an effort to reduce these biases alike in
the ESBL- and non-ESBL-groups, the controls were
matched by year of blood culture sampling. Third, both
mortality and length of stay were recorded for all causes,
meaning that not all associations were necessarily caused
by E. coli blood stream infections. Fourth, only a small
proportion of patients presented with septic shock at the
time of obtaining the blood culture, reflecting the strict
criteria we used for recording septic shock in the study
and was thus likely underreported. Fifth, further analysis
of mortality and the source of infection was hampered by
INFECTIOUS DISEASES 7
the large number of deaths occurring with an unknown
source of infection. The proportion of unkown origin of
infections was similar in the ESBL-EC and non-ESBL-EC
BSIs. Sixth, information on limitations of life-sustaining
treatment was not collected systematically, thus any influ-
ence on the results cannot be assessed. Finally, as a sin-
gle centre study from a university hospital, our data may
not be transferable to other settings, especially consider-
ing the many factors involved in diagnosing and treating
sepsis that may affect outcomes.
Conclusion
Even though effective antibiotic administration often was
delayed in the ESBL-EC BSIs, the difference in 30-day mor-
tality between the ESBL-EC and non-ESBL-EC BSIs did not
reach a level of statistical significance. In a setting with a
low ESBL-prevalence, our findings support the continued
use of empiric carbapenem-sparing antibotic regimens in
patients with E. coli bloodstream infections, although indi-
vidual assessments of risk factors of invasive ESBL-produc-
tion as well as the severity of illness must be taken into
account when choosing the empiric regimen.
Disclosure statement
The authors report no conflict of interest.
Ethical approval
Ethical approval was granted by the Norwegian Regional
Committee for Medical and Health Research Ethics (REK reference
2019/918) with a waiver of informed consent and from the
Akershus University Hospital’s Data Protection Official (19/07915).
Funding
Preliminary work received funding from the research network
Turning the Tide of Antimicrobial Resistance and the Norwegian
Society for Medical Microbiology. The main study received fund-
ing from Helse Sør-Øst Regional Health Authority (grant 2020012).
ORCID
Nina Handal http://orcid.org/0000-0001-6129-3036
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10 N. HANDAL ET AL.
Appendix A: Additional clinical data of patients with E. coli blood stream infections
Appendix B: Variables associated with 30-day mortality
ESBL-E. coli (N*5234) Non-ESBL-E. coli (N*5234)
N % N % p
Comorbidities**
Myocardial infarction 36 15.4% 33 14.1% 0.696
Congestive heart failure 20 8.6% 17 7.3% 0.607
Peripheral vascular disease 23 9.8% 20 8.6% 0.631
Cerebrovascular disease 37 15.8% 34 14.5% 0.699
Dementia 11 4.7% 10 4.3% 0.823
Chronic pulmonary disease 48 20.5% 43 18.4% 0.559
Connective tissue disease 21 9 % 11 4.7% 0.067
Ulcer disease 7 3 % 13 5.6% 0.170
Mild liver disease 16 6.8% 5 2.1% 0.014
Moderate/severe liver disease 7 3 % 3 1.3% 0.338
Diabetes mellitus without complications 59 25.2% 44 18.8% 0.094
Diabetes mellitus with complications 18 7.7% 10 4.3% 0.119
Hemi-/Paraplegia 10 4.3% 5 2.1% 0.189
Chronic renal disease 45 19.2% 43 18.4% 0.813
Non-metastatic cancer 48 20.5% 51 21.8% 0.734
Metastatic cancer 19 8.1% 29 12.4% 0.128
Leukaemia 6 2.6% 9 3.9% 0.431
Lymphoma 8 3.4% 10 4.3% 0.631
HIV/AIDS 0 – 0 –
Immunosuppressive therapy N¼231 N ¼230
Yes 62 26.8% 63 27.4% 0.894
Organ or haematopoietic stem cell transplantation
Yes 18 7.7% 14 6% 0.464
Dialysis previous 12 months N¼232 N ¼234
Yes 10 4.3% 4 1.7% 0.112
Surgery or invasive procedure previous 30 days N¼230 N ¼229
Yes 71 30.9% 58 25.3% 0.187
Total N¼234 for all variables unless otherwise indicated.
More than one possible option.
Deceased (N*546) Alive (N*5418) Unadjusted OR
N % N % (95% CI) p
Median age (IQR), years 75 (64-81) 72 (61-80) -0.140
Sex, female 26 56.5% 190 45.5% 1.6 (0.8 −2.9) 0.154
ESBL-producing E. coli BSI 25 54.4% 205 49 % 1.2 (0.7 −2.3) 0.495
Charlson Comorbidity Index 210 21.7% 234 56 % Base
Charlson Comorbidity Index >236 78.3% 184 44 % 4.6 (2.2 −9.6) <0.001
Type of infection N¼46 N ¼415
Community acquired 6 13 % 175 42.2% Base
Health care associated 26 56.5% 188 45.3% 4 (1.6 - 10) 0.003
Hospital acquired 14 30.4% 52 12.5% 7.9 (2.9 −21.5) <0.001
Source of infection
Urinary tract 15 32.6% 299 71.5% 0.2 (0.1 −0.4) <0.001
Biliary tract 1 2.2% 54 12.9% 0.1 (0 −1.1) 0.033
Intra-abdominal 8 17.4% 23 5.5% 3.6 (1.5 −8.7) 0.002
Neutropenic fever 4 8.7% 13 3.1% 3 (0.9−9.6) 0.056
Other 7 15.2% 27 6.5% 2.6 (1.1 −6.4) 0.031
Unknown/Not determined 15 32.6% 20 4.8% 9.6 (4.3 −21.5) <0.001
qSOFA N¼40 N ¼385
0-1 16 40 % 276 71.7% Base
2-3 24 60 % 109 28.3% 3.8 (1.9 −7.5) <0.001
Septic shock N¼34 N ¼394
Yes 7 20.6% 8 2% 12.5 (4 −38.8) <0.001
Neutropenia N¼44 N ¼417
Yes 4 9.1% 14 3.4% 2.9 (0.9 −9.2) 0.062
Immunosuppressive therapy N¼44 N ¼413
Yes 15 34.1% 110 26.6% 1.4 (0.7 to 2.8) 0.292
Surgery/invasive procedure previous 30 days N¼45 N¼410
Yes 17 37.8% 112 27.3% 1.6 (0.8 to 3.1) 0.140
Time to administration of first effective antibiotic N¼45 N¼393
0−3 hours 26 57.8% 213 54.2% Base
>3 - 12 hours 3 6.7% 44 11.2% 0.6 (0.2 −1.9) 0.357
>12 - 24 hours 6 13.3% 37 9.4% 1.3 (0.5 −3.4) 0.559
>24 - 48 hours 0 – 71 18.1% –
>48 −72 hours 3 6.7% 13 3.3% 1.9 (0.5 - 7) 0.344
>72 hours 1 2.2% 8 2 % 1 (0.1−8.5) 0.982
No effective treatment 6 13.3% 7 1.8% 7 (2.2 −22.5) 0.001
¼Total N unless otherwise indicated.
More than one possible option.
INFECTIOUS DISEASES 11
Appendix C: Time to administration of the first in vitro susceptible antibiotic
Appendix D: Antibiotics administered in relation to ordering blood cultures
The figure shows the first antibiotic treatment prescribed in the hospital in relation to ordering blood cultures, irrespective of in vitro
susceptibility results. For patients in which blood cultures were ordered by the Emergency department, the antibiotic is the first admin-
istered upon arrival at the hospital. For inpatients, the antibiotic prescribed in relation to obtaining the blood culture is recorded (e.g. if
an antibiotic treatment was changed to a new treatment). For BSIs treated with combination therapy (e.g. aminoglycosides and penicil-
lins), only the antibiotic with the broadest gram-negative coverage is included in the figure.
ESBL-E. coli (N ¼234) Non-ESBL - E. coli (N ¼234)
All BSIs N % of N Cum. %N% of N Cum. %
0-3 hours 80 34.2% 34.2% 162 69.2% 69.2%
>3-12 hours 21 9 % 43.2% 26 11.1% 80.3%
>12-24 hours 28 12 % 55.2% 15 6.4% 86.7%
>24 −48 hours 63 26.9% 82.1% 9 3.9% 90.6%
>48 −72 hours 16 6.8% 88.9% 0 – 90.6%
>72 hours 8 3.4% 92.3% 1 0.4% 91 %
No effective antibiotic 9 3.9% 96.2% 4 1.7% 92.7%
History of ESBL (N 5 93) No history of ESBL (N 5 141)
Only ESBL-EC BSIs N % of N Cum. %N% of N Cum. %
0-3 hours 39 41.9% 41.9% 41 29.1% 29.1%
>3-12 hours 11 11.8% 53.7% 10 7.1% 36.2%
>12-24 hours 15 16.1% 69.8% 13 9.2% 45.4%
>24 −48 hours 16 17.2% 87 % 47 33.3% 78.7%
>48 −72 hours 4 4.3% 91.3% 12 8.5% 87.2%
>72 hours 3 3.2% 94.5% 5 3.6% 90.8%
No effective antibiotic 4 4.3% 98.8% 5 3.6% 94.4%
12 N. HANDAL ET AL.
Appendix E: Number and proportion of E. coli isolates resistant to antibiotics
ESBL - E. coli (N5234) Non-ESBL- E. coli (N5234)
Antibiotic N % resistant N % resistant
Trimethoprim-sulfamethoxazole 165 70.5% 43 18.4%
Ciprofloxacin 174 74.4% 19 8.1%
Ampicillin iv 234 100 % 76 32.5%
Cefuroxime iv 234 100 % 5 2.1%
Cefotaxime 234 100 % 0 –
Ceftazidime 205 87.6% 0 –
Gentamicin 114 48.7% 6 2.6%
Meropenem 0 – 0 –
Piperacillin-tazobactam 11 4.7% 2 0.9%
Aztreonam 198 84.6% 0 –
Resistance determined according to EUCAST breakpoint tables at the time of reporting.
INFECTIOUS DISEASES 13
