Clinical outcomes and prognostic factors in bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae among patients with malignancy: a meta-analysis

Abstract

Background
The colonization of Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) in bloodstream infections (BSIs) has been increased dramatically worldwide, and it was associated with worse clinical outcomes in patients with malignancy. We performed the meta-analysis to investigate the prognosis and risk factors in BSIs caused by ESBL-PE in oncological patients.

Methods
PubMed, EMBASE, and Cochrane Library were searched for related studies. All-cause mortality was considered as the primary outcome. Subgroup analyses, meta-regression analyses, and sensitivity analysis were used to investigate heterogeneity and reliability in results.

Results
6,729 patients from 25 studies were eligible. Six studies enrolled oncological patients with BSIs caused by ESBL-PE only, while 19 studies both enrolled ESBL-PE and non-ESBL-PE infections. The results showed that BSIs caused by ESBL-PE in patients with malignancy was associated with higher mortality than non-ESBL-PE infections (RR = 2.21, 95% CI: 1.60–3.06, P < 0.001), with a significant between-study heterogeneity (I² =78.3%, P < 0.001). Subgroup analyses showed that children (RR = 2.80, 95% CI: 2.29–3.43, P < 0.001) and hematological malignancy (RR = 3.20, 95% CI: 2.54–4.03, P < 0.001) were associated with a higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality.

Conclusions
Our study identified that BSIs caused by ESBL-PE in patients with malignancy were associated with worse clinical outcomes compared with non-ESBL-PE infections. Furthermore, children and hematological malignancy were associated with higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality.

Full text

Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
https://doi.org/10.1186/s12941-020-00395-7
RESEARCH
Clinical outcomes andprognostic
factors inbloodstream infections due
toextended-spectrum β-lactamase-producing
Enterobacteriaceae amongpatients
withmalignancy: ameta-analysis
Ai‑Min Jiang1†, Na Liu1†, Rui Zhao2, Hao‑Ran Zheng1, Xue Chen1, Chao‑Xin Fan1, Rui Zhang1,
Xiao‑Qiang Zheng1, Xiao Fu1, Yu Yao1* and Tao Tian1*
Abstract
Background: The colonization of Extended‑spectrum β‑lactamase‑producing Enterobacteriaceae (ESBL‑PE) in
bloodstream infections (BSIs) has been increased dramatically worldwide, and it was associated with worse clinical
outcomes in patients with malignancy. We performed the meta‑analysis to investigate the prognosis and risk factors
in BSIs caused by ESBL‑PE in oncological patients.
Methods: PubMed, EMBASE, and Cochrane Library were searched for related studies. All‑cause mortality was con‑
sidered as the primary outcome. Subgroup analyses, meta‑regression analyses, and sensitivity analysis were used to
investigate heterogeneity and reliability in results.
Results: 6,729 patients from 25 studies were eligible. Six studies enrolled oncological patients with BSIs caused by
ESBL‑PE only, while 19 studies both enrolled ESBL‑PE and non‑ESBL‑PE infections. The results showed that BSIs caused
by ESBL‑PE in patients with malignancy was associated with higher mortality than non‑ESBL‑PE infections (RR = 2.21,
95% CI: 1.60–3.06, P < 0.001), with a significant between‑study heterogeneity (I2 =78.3%, P < 0.001). Subgroup analy‑
ses showed that children (RR = 2.80, 95% CI: 2.29–3.43, P < 0.001) and hematological malignancy (RR = 3.20, 95% CI:
2.54–4.03, P < 0.001) were associated with a higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admis‑
sion were the most common predictors of mortality.
Conclusions: Our study identified that BSIs caused by ESBL‑PE in patients with malignancy were associated with
worse clinical outcomes compared with non‑ESBL‑PE infections. Furthermore, children and hematological malignancy
were associated with higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most
common predictors of mortality.
Keywords: Bloodstream infection, Extended‑spectrum β‑lactamase, ESBL‑PE, Malignancy, Mortality, Meta‑analysis
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Background
In recent years, the incidence of bloodstream
infections (BSIs) caused by Extended-spectrum
β-lactamase-producing Enterobacteriaceae (ESBL-
PE) has been increasing over time all over the world
Open Access
Annals of Clinical Microbiology
and Antimicrobials
*Correspondence: 13572101611@163.com; tiantao0607@163.com
†Ai‑Min Jiang and Na Liu contributed equally to this work.
1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an
Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China
Full list of author information is available at the end of the article
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
[1]. There is a growing body of evidence to show that
BSIs caused by ESBL-PE are more worrisome in clini-
cal practice. Extended-spectrum β-lactamases (ESBLs)
mediates resistance to a wide variety of antibiotics,
including third-generation cephalosporins, amino-
glycosides, and quinolones. Furthermore, most of
empirical antimicrobial regimens can not cover these
pathogens [2, 3]. Therefore, the antimicrobial thera-
peutic regimens are often limited in these infections
[1].
Patients with malignancy are more vulnerable to
developing severe infection, including those caused by
ESBL-PE since they are more likely to be immunocom-
promised due to chemotherapy, radiotherapy, surgery,
invasive procedures, malnutrition, and malignancy
itself [4, 5]. As a result, these infections have become
significant therapeutic challenges for clinicians due to
delayed initiation of chemotherapy, reduced standard
dosage, prolonged hospitalization, increased financial
burden on healthcare, and raised severe morbidity and
mortality [3, 6]. Therefore, rapid initiation of appropri-
ate antibiotic therapy is pivotal for oncological patients
with BSIs caused by ESBL-PE, [4] while inappropriate
empirical antibiotic treatment is associated with worse
outcomes and survival [3].
Previous meta-analyses have investigated the prev-
alence of BSIs caused by ESBL-PE in patients with
malignancy [7, 8]. However, there was no further anal-
ysis of clinical outcomes and risk factors in these pop-
ulations. Therefore, we conducted this study to assess
the prognosis and risk factors of BSIs due to ESBL-PE
in patients with malignancy and provide updated evi-
dence via meta-analysis.
Methods
Search strategy
Our meta-analysis was based on the Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines [9]. We conducted an overall lit-
erature retrieval for PubMed, EMBASE, and Cochrane
Library published up to 10 December 2019. Both
MeSH terms and free words were used to search for
title/ abstract. Our search terms were: “(ESBL OR
(extended-spectrum beta-lactamase) OR (extended-
spectrum β-lactamase)) AND (tumor OR neoplasia OR
malignancy OR cancer OR carcinoma OR sarcoma OR
leukemia OR leukaemia OR lymphoma OR hematolog*
OR haematolog* OR oncolog*)”. We manually screened
other relevant studies andreference lists. The search
was performed independently by two investigators
(AM Jiang and N Liu).
Study selection
Studies were considered as eligible based on the follow-
ing criteria: [1] population: patients with solid or hema-
tological malignancies; [2] intervention (exposure): BSIs
caused by ESBL-PE; [3] comparison: BSIs caused by
non-ESBL-PE; [4] outcome: the mortality of BSIs. Litera-
ture that satisfied the following criteria were excluded: [1]
letters, case reports, editorials, expert opinion or reviews
without original data; [2] overlappingor duplicate data;
[3] incomplete data about outcomes; [4] not English liter-
atures; [5] the sample size of BSIs caused by ESBL-PE in
oncological patients less than 10; [6] studies only focus-
ing on risk factors for ESBL-PE infections.
Data extraction andquality assessment
Two investigators (AM Jiang and N Liu) independently
extracted the data using a standardized approach. Any
disagreement in the study selection and data extrac-
tion phases was resolved through discussion with the
third investigator (R Zhao). e following data informa-
tion was retrieved from each article: first author’s name,
year of publication, country, study population, infection
type of BSIs, the total number of screened subjects, the
total number of ESBL-PE caused BSIs, the total number
of BSIs caused death and ESBL-PE BSIs caused death,
and ESBL detection method. e data was extracted
from texts or tables in articles. Newcastle Ottawa Qual-
ity Assessment Scale (NOS) was used in our research
to assess the quality of selected studies [10]. e scale
included three aspects: selection, comparability, and out-
come. Studies that scored more than five were considered
of high quality.
Denitions andstudy outcomes
Neutropenia was defined as an absolute neutrophil count
of < 500 neutrophils/mm3 [11].
Empirical antibiotics treatment was considered inap-
propriate once the antibiotics could not suppress the
activity of the isolated pathogens according to the results
of antimicrobial susceptibility tests during the first 24h
after the blood culture was obtained [11].
e all-cause mortality at the end of the study and the
predictors in BSIs due to ESBL-PE in patients with malig-
nancy were the primary outcomes in the study [12].
Statistical analysis
e RRs and 95% CIs for mortality were calculated to
assess the outcomes of BSIs caused by ESBL-PE in onco-
logical patients. All results were depicted as forest plots.
Heterogeneity was assessed using Cochran’s Q test and
the I2 statistic test. When the heterogeneity was statisti-
cally significant (P < 0.05 and I2 > 50%), a random-effect s
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
model was applied to obtain the pooled RRs; otherwise,
a fixed-effects model was performed. Subgroup analyses
and meta-regression analyses were conducted to explore
the sources of heterogeneity. We also performed a sen-
sitivity analysis to evaluate the quality and stability of
results by omitting one study in each turn. Begg’s test
and Egger’s test were used to assess the publication bias.
Statistical tests were two-tailed at the significance level of
P < 0.05. All analyses were used with STATA V.14.0 (Stata
Corporation, College Station, TX).
Results
Study characteristics andquality assessment
Our literature search identified 1,260 studies. After
excluding repeated records and the initial screening
based on titles and abstracts, 25 articles were eligible
in this study. Of these, six studies enrolled oncologi-
cal patients with BSIs caused by ESBL-PE only, while 19
studies both enrolled ESBL-PE and non-ESBL-PE infec-
tions. Of the 25 studies, there were eight prospective
cohort studies, 14 retrospective cohort studies, and three
case–control studies. All included studies were published
between 2009 and 2019, and there were six studies pub-
lished in 2019, accounting for 24%. ere were 15 studies
conducted in Asia, seven studies conducted in Europe,
and three studies were conducted in North America. e
detailed flow chart of the study selection process was
described in Fig.1. Table1 summarized the characteris-
tics of 25 selected studies. e majority of the included
studies had a NOS score of more than 5 points, and 21
Fig. 1 Flow chart of the eligible studies for meta‑analysis
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
Table 1 Characteristics ofthestudies andtheir populations included inthereview
First author Design Year Country Population Infection type—
bacteria No. ofscreened No. ofESBL-PE
BSIs (%) No. ofBSIs
caused
death
No. ofESBL-PE
BSIs caused
death (%)
ESBL detection
method
ESBL‑PE only
Wang [31] MC retrospective
cohort 2011 Taiwan, China Adults with solid
or hematologi‑
cal malignancy
E. coli and Kleb‑
siella 351 113 (32.2%) 35 35 (31.0%) MicroScan
Wu [15] SC prospective
cohort 2012 Taiwan, China Adults with solid
or hematologi‑
cal malignancy
E. coli 97 39 (40.2%) 10 10 (25.6%) Disk diffusion
Kang [17] MC retrospective
cohort 2013 Korea Adults with solid
malignancy E. coli 92 36 (39.1%) 6 6 (16.7%) Microdilution or
disk diffusion
Gudiol [29] MC retrospective
cohort 2017 Spain Adults with acute
leukemia and
neutropenia
E. coli, Klebsiella,
and Enterobacter
cloacae
NR 425 65 65 (15.3%) Disk diffusion
Cattaneo [23] MC prospective
cohort 2018 Germany Adults with
hematological
malignancy
E. coli, Klebsiella,
and other
Enterobacter spp
137 61 (44.5%) 10 10 (16.4%) Microdilution
Benanti [32] SC retrospective
cohort 2019 USA Adults with
hematological
malignancy
E. coli NR 103 11 11 (10.7%) NR
ESBL‑PE and non‑ESBL‑PE
Trecarichi [13] SC retrospective
cohort 2009 Italy Adults and
children with
hematological
malignancy
E. coli 107 26 (24.3%) 13 11 (42.3%) Disk diffusion
Gudiol [27] SC prospective
cohort 2010 Spain Adults and chil‑
dren with solid
or hematologi‑
cal malignancy
E. coli 531 17 (3.2%) 29 6 (35.3%) MicroScan
Cornejo‑Juarez
[40]Case–control
study 2012 Mexico Adults and
children with
hematological
malignancy
E. coli 670 100 (14.9%) 102 51 (51%) MicroScan
Kang [14] MC retrospective
cohort 2012 Korea Adults with
hematological
malignancy
E. coli and Kleb‑
siella 142 29 (20.4%) 29 13 (44.8%) Microdilution or
disk diffusion
Ha [16] SC retrospective
cohort 2013 Korea Adults with solid
or hematologi‑
cal malignancy
E. coli 350 95 (27.1%) 52 21 (22.1%) Disk diffusion
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
Table 1 (continued)
First author Design Year Country Population Infection type—
bacteria No. ofscreened No. ofESBL-PE
BSIs (%) No. ofBSIs
caused
death
No. ofESBL-PE
BSIs caused
death (%)
ESBL detection
method
Kim [18] SC retrospective
cohort 2013 Korea Adults with
hematological
malignancy
and FN
E. coli and Kleb‑
siella 96 23 (24.0%) 8 4 (17.4%) MicroScan
Metan [34] SC retrospective
cohort 2013 Turkey Adults and
children with
hematological
malignancy
E. coli, Klebsiella,
and Enterobacter
cloacae
154 40 (26.0%) 30 5 (12.5%) NR
Bodro [19] SC prospective
cohort 2014 Spain Adults with solid
or hematologi‑
cal malignancy
Klebsiella and
other Enterobac-
ter spp
392 19 (4.8%) 18 4 (21.1%) Disk diffusion
Kim [28] SC prospective
cohort 2014 Korea Adults and chil‑
dren with solid
or hematologi‑
cal malignancy
Enterobacter spp 203 31 (15.3%) 34 6 (19.4%) Disk diffusion
Han [20] SC retrospective
cohort 2015 Korea Children with solid
or hematologi‑
cal malignancy
and FN
E. coli and Kleb‑
siella 59 21 (35.6%) 3 1 (4.8%) VITEK®2 automated
system
Cattaneo [21] MC prospective
cohort 2016 Italy Adults with acute
leukaemia Enterobacter spp 433 36 (8.3%) 37 5 (13.9%) Microdilution or
disk diffusion
Ma [22] SC retrospective
cohort 2017 China Adults with
hematological
malignancy
E. coli 168 97 (57.7%) 21 15 (15.5%) Disk diffusion
Çeken [24] SC retrospective
cohort 2018 Turkey Adults with solid
or hematologi‑
cal malignancy
E. coli and Kleb‑
siella 122 70 (57.4%) 31 23 (32.9%) VITEK®2 automated
system
Islas‑Muñoz [25] SC prospective
cohort 2018 Mexico Adults with solid
or hematologi‑
cal malignancy
E. coli, Klebsiella,
and Enterobacter
spp
496 123 (24.8%) 89 37 (30.1%) Disk diffusion
Ben‑Chetrit [42] SC retrospective
cohort 2019 Israel Adults with solid
or hematologi‑
cal malignancy
E. coli and Kleb‑
siella 88 26 (19.5%) 17 6 (7.5%) NR
Isendahl [26] Case–control
study 2019 Sweden Adults and chil‑
dren with solid
or hematologi‑
cal malignancy
E. coli and Kleb‑
siella 945 238 (25.2%) 107 45 (18.9%) NR
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
Table 1 (continued)
First author Design Year Country Population Infection type—
bacteria No. ofscreened No. ofESBL-PE
BSIs (%) No. ofBSIs
caused
death
No. ofESBL-PE
BSIs caused
death (%)
ESBL detection
method
Kim [35] SC prospective
cohort 2019 Korea Adults with solid
or hematologi‑
cal malignancy
and FN
E. coli and Kleb‑
siella 179 23 (12.8%) 51 8 (34.8%) MicroScan
Namikawa [30] Case–control
study 2019 Japan Adults with solid
or hematologi‑
cal malignancy
E. coli, Klebsiella,
and Enterobacter
spp
65 42 (64.6%) 13 9 (21.4%) NR
Zhang [33] SC retrospective
cohort 2019 China Adults with solid
or hematologi‑
cal malignancy
E. coli 324 160 (49.3%) 71 39 (24.4%) VITEK®2 automated
system
ESBL-PE extended-spectrum β-lactamase-producing Enterobacteriaceae, BSI bloodstream infection, SC single-center, MC multicenter, NR not reported, FN febrile neutropenia
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
studies included in this article were high-quality stud-
ies. Additional file1: TableS1 presented the results of the
quality assessment.
Mortality
In all the studies, the time of death records was not simi-
lar. e majority of studies used 30-day mortality to eval-
uate the clinical outcomes of BSIs caused by ESBL-PE in
patients with malignancy, [13–29] only one study did not
report a particular time of death [30]. In studies that only
enrolled oncological patients with ESBL-PE infections,
the mortality of BSIs varied from 10.7 to 31.0%. However,
the mortality of BSIs varied from 4.8 to 51.0% in studies
that both enrolled ESBL-PE and non-ESBL-PE infections
oncological patients, respectively. We finally included 19
studies that enrolled both ESBL-PE and non-ESBL-PE
infected oncological patients into analyses to estimate
the mortality of BSIs caused by ESBL-PE in patients with
malignancy. e results showed that in patients with
malignancy, ESBL-PE infections were associated with a
higher mortality risk from BSIs than non-ESBL-PE infec-
tions (RR = 2.21, 95% CI: 1.60–3.06, P < 0.001) (Fig. 2),
with a significant between-study heterogeneity (I2 =
78.3%, P < 0.001).
Subgroup analyses andmeta-regression analyses
Subgroup analyses in all selected studies were conducted
by study design, region, study population, malignancy
type, FN, ESBL detection methods, and NOS score. Most
of the subgroups (study design, region, study population,
malignancy type, and ESBL detection methods) were
consistent with the overall trend and showed statistically
significant increases, except for the subgroup without
FN, and the subgroup with NOS score < 6. e subgroup
analyses suggested that study region was identified as
potential sources of the heterogeneity (test for subgroup
difference: P = 0.014), and the RR of mortality in studies
from Asia (RR = 1.49, 95% CI: 1.22–1.82) was lower com-
pared with Europe and North America, with no evidence
of heterogeneity (I2 = 27.3%, P = 0.177). e detailed
information was in Table2 and Additional file1: Figure
S1.
Sensitivity analysis andpublication bias
We then carried out the sensitivity analysis by omit-
ting each study in turn. As summarized in Additional
file1: Figure S2, the pooled RRs and 95% CIs of mortal-
ity ranged from 2.03 (1.53–2.68) to 2.36 (1.72–3.25). e
results of the sensitivity analysis show that our results are
stable and reliable since there were no individual stud-
ies influenced the overall results. Begg’s test and Egger’s
test showed no evidence of publication bias (P = 0.944 for
Begg’s test; P = 0.538 for Egger’s test, respectively) (Addi-
tional file1: Figure S3).
Predictors ofmortality inBSIs caused byESBL-PE
amongpatients withmalignancy
We then summarized the risk factors for BSIs caused by
ESBL-PE in patients with malignancy. It showed that the
most commonly studied risk factors for BSIs caused by
ESBL-PE in patients with malignancy were age, gender,
ESBL production, neutropenia, inadequate initial antimi-
crobial treatment, ICU admission, intra-abdominal infec-
tion, pneumonia, Pitt bacteremia score, severe sepsis/
septic shock, solid tumor, and concurrent corticosteroid
therapy. However, metastasis and mechanical ventilation
were the least studied variables. We also found that the
most common independent risk factors of mortality were
severe sepsis/ septic shock, pneumonia, ICU admission,
and neutropenia. At the same time, indwelling urinary
catheter, [23] pneumonia, [31] Pitt bacteremia score, [32]
and severe sepsis/ septic shock [31] were the most com-
mon independent risk factors of mortality in studies that
only enrolled patients with BSIs caused by ESBL-PE. In
studies that both included ESBL-PE and non-ESBL-PE
infections, severe sepsis/ septic shock, [14, 16, 18, 19,
22, 24, 28, 33] ICU admission, [14, 19, 27, 33, 34] neu-
tropenia, [13, 14, 24, 35] and pneumonia [14, 16, 21, 28]
were the most commonly investigated independent risk
factors, respectively. Interestingly, there were only three
studies [13, 14, 16] identified that ESBL production was
associated with unfavorable outcomes in these patients.
e detailed information was in Table3.
Discussion
Over the past ten years, the colonization and prevalence
of ESBL-PE infections have continued to increase rap-
idly all over the world,[36] and these infections gener-
ally associated with worse clinical outcomes, prolonged
hospitalization, extra healthcare burden, and delayed
initiation of treatment for malignancy [3]. Patients with
malignancy are more easily to develop BSIs caused by
ESBL-PE since oncological patients are easily immu-
nocompromised due to a series of mechanisms as men-
tioned before [5]. erefore, timely and appropriate
empirical antimicrobial therapeutic regimen is pivotal for
patients with malignancy who developed BSIs caused by
ESBL-PE [5].
In this meta-analysis, we included 19 studies that
both enrolled oncological patients with ESBL-PE and
non-ESBL-PE infections, and the results showed that
the mortality in BSIs caused by ESBL-PE among patients
with malignancy was higher compared with non-ESBL-
PE infections (RR = 2.21, 95% CI: 1.60–3.06, P < 0.001).
Consistent with our findings, Trecarichi EM et al.
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
reported that ESBL-PE caused BSIs in patients with
malignancy was associated with high mortality compared
with non-ESBL-PE infections [13, 14, 16]. is result sug-
gests that we should think highly of BSIs caused by ESBL-
PE in patients with malignancy during hospitalization,
and the rapid initiation of antibiotics treatment should be
considered as early as possible once it was recognized.
e results of the subgroup analyses showed that the
mortality of ESBL-PE BSIs varies from different regions.
We found that the mortality in North America and
Europe was higher than in Asia. It could be explained
by the fact that the majority of studies were conducted
in Asia, and the study region was confirmed as a source
of heterogeneity after further meta-regression analyses.
Alevizakos M etal. reported that ESBL-PE are the causa-
tive agents of approximately 10.0% BSIs among patients
with malignancy in Southeast Asia, and it has been
associated with increased mortality in these subjects
compared with Europe and America [37]. erefore,
more relevant studies need to be included in the future
to draw a more reliable conclusion. We also found that
children and hematological malignancy were also associ-
ated with worse prognosis in BSIs caused by ESBL-PE. It
may be attributed to the fact that the included children
population were mainly diagnosed with hematological
malignancies, which were more vulnerable to develop
immunosuppression, prolonged neutropenia, and sep-
tic shock [38, 39]. Interestingly, we observed that FN
was not associated with higher mortality in oncologi-
cal patients with BSIs caused by ESBL-PE. is can be
explained by the fact that only three studies included
patients with FN. Besides, some studies only enrolled
a subset of FN patients, but the data were not accessi-
ble to analyze [13, 14, 16, 21, 24, 25, 30, 34, 40]. Among
these studies, Kang CI etal. reported that FN/ neutrope-
nia was not the risk factor for mortality in BSIs caused
Fig. 2 Forest plot of mortality in BSIs due to ESBL‑PE among patients with malignancy. RR relative risk, CI confidence interval, BSIs bloodstream
infections, Weights are from random‑effects analysis. The size of the squares is analogous to the study’s weight. Diamonds represent the pooled RRs
and their confidence interval
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Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
Table 2 Subgroup analysis formeta-analysis ofmortality
RR relative risk, CI condence interval, FN febrile neutropenia, ESBL extended-spectrum β-lactamase; NOS Newcastle–Ottawa scale
a p for heterogeneity within each subgroup
b p for heterogeneity between subgroups with meta-regression analyses
Variables No RR (95% CI) I2PaPb
Design Retrospective cohort 10 1.72 (1.38–2.14) 62.2% 0.005 0.395
Prospective cohort 6 2.02 (1.57–2.60) 75.7% 0.001
Case–control study 3 3.11(2.47–3.92) 90.2% < 0.001
Region Europe 5 2.79(2.10–3.69) 78.2% 0.001 0.014
Asia 12 1.49(1.22–1.82) 27.3% 0.177
North America 2 3.47 (2.73–4.41) 93.5% < 0.001
Population Adults and children 7 2.80 (2.29–3.43) 88.3% < 0.001 0.303
Adults 12 1.80 (1.50–2.15) 28.4% 0.167
Malignancy type Hematological 7 3.20 (2.54–4.03) 83.0% < 0.001 0.355
Solid or hematological 12 1.81 (1.54–2.14) 60.9% 0.003
FN Yes 3 1.48 (0.87–2.53) 0.0% 0.418 0.530
No 16 2.21 (1.92–2.54) 80.8% < 0.001
ESBL detection methods Disk diffusion 6 2.21 (1.72–2.83) 64.6% 0.015 0.554
MicroScan 4 3.99 (3.10–5.15) 85.9% < 0.001
NOS < 6 2 0.76 (0.39–1.49) 16.5% 0.274 0.065
≥ 6 17 2.30 (2.00–2.64) 77.3% < 0.001
Table 3 The most commonly studied characteristics aspredictors ofmortality inthereviewed studies
ESBL-PE extended-spectrum β-lactamase-producing Enterobacteriaceae, CCI Charlson Index Score, ICU intensive care unit
Refers to the variables for which data were reported in the individual studies
Risk factor ESBL-PE
onlystudies n/N
(%)
ESBL-PE vs non-
ESBL-PE studies n/N (%) Total n/N (%) Identied asindependent
predictor formortality
Age 5/6 (83.3) 13/19 (68.4) 18/25 (72.0) 0 + 0
Gender 4/6 (66.7) 11/19 (57.9) 15/25 (60.0) 0 + 1 (22)
CCI 1/6 (16.7) 4/19 (21.1) 5/25 (20.0) 0 + 2 (16,42)
ESBL production 1/6 (16.7) 12/19 (63.2) 13/25 (52.0) 0 + 3 (13,14,16)
Neutropenia 2/6 (33.3) 11/19 (57.9) 13/25 (52.0) 0 + 4 (13,14,24,35)
Inadequate initial antimicrobial treatment 3/6 (50.0) 13/19 (68.4) 16/25 (64.0) 0 + 3 (13,19,25)
ICU admission 2/6 (33.3) 6/19 (31.6) 8/25 (32.0) 0 + 5 (14,19,27,33,34)
Immunosuppressant use 0 3/19 (15.8) 3/25 (12.0) 0 + 1 (14)
Indwelling urinary catheter 2/6 (33.3) 1/19 (5.3) 3/25 (12.0) 1 (23) + 1 (14)
Infecting organism, Klebsiella pneumoniae 0 5/19 (26.3) 5/25 (20.0) 0 + 1 (18)
Intra‑abdominal infection 4/6 (66.7) 3/19 (15.8) 7/25 (28.0) 0 + 1 (28)
Mechanical ventilation 0 2/19 (10.5) 2/25 (8.0) 0 + 1 (16)
Metastasis 0 1/19 (5.3) 1/25 (4.0) 0 + 1 (33)
Organ failure 1/6 (16.7) 2/19 (10.5) 3/25 (12.0) 0 + 1 (33)
Pneumonia 1/6 (16.7) 5/19 (26.3) 6/25 (24.0) 1 (31) + 4 (14,16,21,28)
Pitt bacteremia score 4/6 (66.7) 4/19 (21.1) 8/25 (32.0) 1 (32) + 2 (14,42)
Severe sepsis/ septic shock 3/6 (50.0) 11/19 (57.9) 14/25 (56.0) 1 (31) + 8 (14,16,18,19,22,24,28,33)
Solid tumor 3/6 (50.0) 8/19 (42.1) 11/25 (44.0) 0 + 1 (27)
Simultaneous corticosteroid therapy 0 8/19 (42.1) 8/25 (32.0) 0 + 2 (19,27)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 10 of 12
Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
by ESBL-PE among patients with malignancy [14, 16,
21, 24]. Hence, the accuracy of the conclusion needs to
be further confirmed. e combined RR of sensitivity
analysis further confirmed the stability of the results.
Besides, the meta-regression analyses also suggested that
the study region might be the source of heterogeneity in
this meta-analysis, despite other relevant factors such as
age, comorbidities, and antimicrobial treatment regimens
cannot be analyzed due to lack of relevant data. However,
Begg’s test and Egger’s test showed there was no evidence
of publication bias in our study.
In our study, approximately 72.0% of studies analyzed
the relationship between age and mortality of BSIs caused
by ESBL-PE in patients with malignancy. However, there
were no studies that identified age as independent pre-
dictor. Furthermore, more than 50.0% of studies con-
cluded that severe sepsis/ septic shock, pneumonia, and
ICU admission were the most common independent risk
factors in mortality. Besides, fewer studies confirmed
that neutropenia was more common in patients who
died. According to a study conducted by Vardakas KZ
etal., they reported that underlying diseases and sever-
ity scores were the most commonly identified prognos-
tic factors of mortality in patients with infections due to
multi-drug resistant Gram-negative bacteria (MDRGNB)
[12]. Similar to the previous study, [12] we also found
that severe sepsis/ septic shock was the most common
risk factor in mortality. However, only fewer studies
concluded that the Pitt bacteremia score and Charlson
Index Score (CCI) were more common in patients who
died. An interesting finding of our study is that only three
studies confirmed ESBL production was an independent
risk factor in mortality. Rottier WC etal. reported that
ESBL production was associated with higher mortality
compared with bacteremia with non-ESBL-PE [41]. is
could be due to the small sample size of some studies we
included in this study. erefore, more prospective mul-
ticenter studies and clinical trials were urgently needed in
the future to provide sufficient evidence.
To our knowledge, this is the first study that evaluated
the clinical outcomes and risk factors in BSIs caused by
ESBL-PE among patients with malignancy using Meta-
analysis. However, our study has several limitations. First,
all of the included articles were observational studies and
published in English. Besides, high-estimated heteroge-
neity was observed, which is probably related to different
design, study region, and study population. Moreover,
some studies included oncological patients with FN, but
the data was not available for subgroup analysis. ere-
fore, the clinical outcomes of BSIs caused by ESBL-PE
in these patients should be further validated since these
patients are more vulnerable to severe infections. To
sum up, clinical conclusions need to be comprehensive
assessment in combination with other indicators, and
more sample sizes and studies need to be added to verify
our results.
Conclusions
In summary, our study provided a systematic analysis
for the prognosis and risk factors of BSIs due to ESBL-
PE in oncological patients. Our findings suggested that
BSIs caused by ESBL-PE in patients with malignancy
were associated with worse clinical outcomes compared
with non-ESBL-PE infections. Furthermore, children and
hematological malignancy were associated with higher
mortality. We also identified that severe sepsis/ septic
shock, pneumonia, and ICU admission were the most
common predictors of mortality. Large-scale and pro-
spective studies are warranted to verify the results of our
study.
Supplementary information
Supplementary information accompanies this paper at https ://doi.
org/10.1186/s1294 1‑020‑00395 ‑7.
Additional le1: TableS1. Quality assessment conducted according to
the NOS for all included studies. Figure S1. Forest plots of mortality in BSIs
due to ESBL‑PE among patients with malignancy by different subgroups.
(a) study design; (b) region; (c) population; (d) malignancy type (e) FN; (f)
ESBL detection methods; (g) NOS score. Figure S2. Sensitivity analysis of
mortality in BSIs due to ESBL‑PE among patients with malignancy. Figure
S3. Tests for publication bias. a Begg’s funnel plot with pseudo 95% confi‑
dence limits; b Egger’s publication bias plot.
Abbreviations
ESBL‑PE: Extended‑spectrum β‑lactamase‑producing Enterobacteriaceae; BSI:
Bloodstream infection; SC: Single‑center; MC: Multicenter; NR: Not reported;
FN: Febrile neutropenia; RR: Relative risk; CI: Confidence interval; NOS: Newcas‑
tle–Ottawa scale; CCI: Charlson Index Score; ICU: Intensive care unit.
Acknowledgements
Not applicable.
Authors’ contributions
TT and YY conceived the study. AMJ, NL, and RZ performed the search,
extracted the data and performed the analyses. HRZ, XC, CXF, and RZ partici‑
pated in the study design and helped with the data analyses. XQZ and XF par‑
ticipated in the study design and manuscript revision. All authors interpreted
the data, and AMJ and NL wrote the paper. All authors read and approved the
final manuscript.
Funding
This research did not receive any specific grant from funding agencies in the
public, commercial, or not‑for‑profit sectors.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or
analyzed during the current study.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 11 of 12
Jiangetal. Ann Clin Microbiol Antimicrob (2020) 19:53
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiao‑
tong University, Xi’an, Shaanxi 710061, People’s Republic of China. 2 Depart‑
ment of Nutrition and Food Hygiene, School of Public Health, Tongji Medical
College, Huazhong University of Science and Technology, Wuhan, China.
Received: 21 February 2020 Accepted: 7 November 2020
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