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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
https://doi.org/10.1186/s13756-024-01441-1 Antimicrobial Resistance &
Infection Control
†Zhang Hongchen, Wang Yue and Zhang Xiaochen contributed
equally to this work.
*Correspondence:
Xiaofeng Zhang
moonshadowing@126.com
Full list of author information is available at the end of the article
Abstract
Background Endoscopic retrograde cholangiopancreatography (ERCP) has become a routine endoscopic procedure
that is essential for diagnosing and managing various conditions, including gallstone extraction and the treatment of
bile duct and pancreatic tumors. Despite its ecacy, post-ERCP infections – particularly those caused by carbapenem-
resistant Enterobacterales (CRE) – present signicant risks. These risks highlight the need for accurate predictive
models to enhance postprocedural care, reduce the mortality risk associated with post-ERCP CRE sepsis, and improve
patient outcomes in the context of increasing antibiotic resistance.
Objective This study aimed to examine the risk factors for 30-day mortality in patients with CRE sepsis following
ERCP and to develop a nomogram for accurately predicting 30-day mortality risk.
Methods Data from 195 patients who experienced post-ERCP CRE sepsis between January 2010 and December
2022 were analyzed. Variable selection was optimized via the least absolute shrinkage and selection operator (LASSO)
regression model. Multivariate logistic regression analysis was then employed to develop a predictive model, which
was evaluated in terms of discrimination, calibration, and clinical utility. Internal validation was achieved through
bootstrapping.
Results The nomogram included the following predictors: age > 80 years (hazard ratio [HR] 2.61), intensive care unit
(ICU) admission within 90 days prior to ERCP (HR 2.64), hypoproteinemia (HR 4.55), quick Pitt bacteremia score ≥ 2 (HR
Carbapenem-resistant Enterobacterales
sepsis following endoscopic retrograde
cholangiopancreatography: risk factors for 30-
day all-cause mortality and the development
of a nomogram based on a retrospective
cohort
HongchenZhang1,2,3,4†, YueWang1,3,4†, XiaochenZhang2,3,4†, ChenshanXu2,3,4, DongchaoXu1,2,3,4,
HongzhangShen1,2,3,4, HangbinJin1,2,3,4, JianfengYang1,2,3,4 and XiaofengZhang1,2,3,4*
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Page 2 of 12
Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
Introduction
Endoscopic retrograde cholangiopancreatography
(ERCP), which was rst performed in 1968, has become
a routinely performed endoscopic procedure that has
proven to be eective in diagnosing and treating various
conditions, including gallstone removal and bile duct and
pancreatic tumor treatment [1]. ERCP is the gold-stan-
dard therapeutic modality for treating diseases aect-
ing the biliary and pancreatic ducts. e prevalence of
post-ERCP infections is less than 5% [2]. High hygienic
standards during the procedure, along with proper dis-
infection and storage of endoscopic equipment, have
signicantly reduced infection rates. However, failure to
reestablish drainage after the infusion of contrast media
into obstructed bile ducts during ERCP remains the pri-
mary risk factor for post-ERCP infections [3]. Post-ERCP
infections pose a signicant danger and could potentially
lead to life-threatening sepsis, particularly when these
infections are associated with carbapenem-resistant
Enterobacterales (CRE) [4].
CRE comprises gram-negative bacteria that are resis-
tant to carbapenem antibiotics, which are often consid-
ered the last line of defense against multidrug-resistant
infections [5]. CRE infections are a major concern
because of their resistance to carbapenems and other
antibiotics, thus leading to fewer eective therapeutic
options. Predominant CRE types include Klebsiella pneu-
moniae and Escherichia coli. High antibiotic resistance in
CRE leads to increased treatment failure, extended hos-
pitalizations, increased healthcare costs, and signicantly
elevated mortality rates [6]. A study in a ai tertiary
care institution reported an in-hospital mortality rate of
68.33% among CRE-infected patients [7].
Post-ERCP infections represent a substantial clini-
cal hurdle, with the etiological spectrum encompassing
a diverse array of microbial entities [8]. e connec-
tion between ERCP and subsequent infections is often
attributed to the procedural disturbance of innate infec-
tion barriers in the biliary and pancreatic ductal sys-
tems, thus creating a route for microbial invasion. e
clinical manifestations of post-ERCP infections range
from mild cholangitis to severe sepsis, signicantly
increasing the complexity of patient management and
disease prognostication. e emergence of CRE as a
predominant pathogen in post-ERCP infections heralds
a daunting clinical scenario [9]. Post-ERCP sepsis is an
acute-onset infection that often has a poor prognosis
due to the limited availability of successful antimicro-
bial treatments. e complex relationship between the
post-ERCP anatomical milieu and CRE pathogenic-
ity mandates a thorough exploration of the prognostic
determinants governing the clinical course of post-ERCP
CRE sepsis. Numerous studies have explored prognostic
models for patients with CRE infections or similar con-
ditions with the aim of predicting 30-day mortality [10,
11]. Nonetheless, a notable gap persists in the literature
concerning patient-centered predictive paradigms spe-
cically tailored for post-ERCP CRE sepsis.
is study aimed to identify the risk factors for 30-day
mortality in patients with CRE sepsis following ERCP
and to develop and validate a nomogram that can be used
to accurately predict 30-day mortality risk. By combin-
ing several important prognostic factors into a simple
graphical tool, this nomogram will help clinicians assess
mortality risk quickly.
Subjects and methods
Study design and subjects
is retrospective analysis examined the clinical data of
patients who underwent inpatient ERCP at the Depart-
ment of Gastroenterology, Aliated Hangzhou First
People’s Hospital, School of Medicine, Westlake Uni-
versity, from January 2010 to December 2022. Detailed
records of the demographic and clinical characteristics of
these individuals were kept. e inclusion criteria were
patients who exhibited sepsis and positive CRE blood
culture results within 5 days post ERCP. e exclusion
criteria were as follows: (1) patients for whom essential
information was lacking; (2) individuals displaying any
signs of bacteremia before ERCP, including symptoms or
abnormal laboratory results; (3) patients who were given
antibiotics before ERCP; (4) patients with a conrmed
infection in other areas, such as pneumonia or urinary
tract infection after ERCP; and (5) individuals younger
than 18 years. is study utilized a retrospective cohort
design. e primary outcome was the mortality rate
2.61), post-ERCP pancreatitis (HR 2.52), inappropriate empirical therapy (HR 3.48), delayed denitive therapy (HR 2.64),
and short treatment duration (< 10 days) (HR 5.03). The model demonstrated strong discrimination and calibration.
Conclusions This study identied signicant risk factors associated with 30-day mortality in patients with post-ERCP
CRE sepsis and developed a nomogram to accurately predict this risk. This tool enables healthcare practitioners to
provide personalized risk assessments and promptly administer appropriate therapies against CRE, thereby reducing
mortality rates.
Keywords Endoscopic retrograde cholangiopancreatography, Carbapenem-resistant Enterobacterales, Sepsis,
Mortality, Nomogram
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
within one month after the rst positive blood culture
for CRE. e survivor and nonsurvivor subgroups were
analyzed together to determine the predictors of mortal-
ity. e survival data were analyzed via a Cox regression
model to identify risk factors, which was useful for the
development of a predictive model. is model was then
used to develop a nomogram to assess the 30-day mortal-
ity rate for patients with post-ERCP CRE sepsis.
Approval for the research protocol was obtained from
the Research Ethics Committee (ZN20231106) of the
institution. Due to the retrospective nature of the analy-
sis, the requirement to obtain written informed consent
was waived.
Clinical and epidemiological data
e following data were extracted from medical records:
patient characteristics (age, sex, and Charlson comorbid-
ity index); exposures in the 90-day period before ERCP
(use of antibiotics, hospitalization, invasive procedures,
and intensive care unit [ICU] admission); exposures in
the 30-day period before ERCP (use of immunosuppres-
sive drugs); epidemiological information (time inter-
val from ERCP to the onset of CRE sepsis); presence
of comorbid conditions (previous infection with CRE,
cerebrovascular diseases, malignant tumors, diabe-
tes, cirrhosis, and hypoproteinemia); severity of illness
at the time of CRE sepsis onset (quick Pitt bacteremia
score and Acute Physiology and Chronic Health Evalua-
tion [APACHE] II score); reasons for performing ERCP
(malignant biliary stricture, benign biliary stricture, bile
duct stone, pancreatic duct stone, pancreatic duct stric-
ture, bile leak, and pancreatic stula); details related
to the procedure (placement of biliary stent, cholan-
gioscopy, biliary sphincterotomy, removal of bile duct
stone, bile duct radiofrequency ablation, total duration
exceeding 45min, occurrence of post-ERCP pancreatitis,
post-ERCP perforation, and post-ERCP bleeding); and
management of antibiotic therapy (inappropriate initial
treatment, delayed denitive treatment, and short treat-
ment duration [therapy lasting less than 10 days]). e
main focus of the study was to examine the risk of all-
cause mortality within a period of 30 days.
Denitions
We dened CRE sepsis as a bloodstream infection con-
rmed by the presence of a CRE strain in blood cul-
ture, along with a Sequential Organ Failure Assessment
(SOFA) score of ≥ 2, according to the Sepsis 3.0 guide-
lines [12]. Before a susceptibility report is available,
empirical therapy involves administering antimicrobials.
Appropriate empirical therapy was dened as the admin-
istration of in vitro active antimicrobials against the iso-
lates within 24h of infection onset, which continued for
at least 48 h [13]. Treatments that did not meet these
requirements were considered inappropriate. e admin-
istration of antimicrobial treatment after susceptibility
testing results are available is known as denitive therapy
[14]. e timely initiation of eective antimicrobial treat-
ment based on susceptibility testing results within 72h of
infection is considered early denitive therapy, whereas
treatments that do not meet this time requirement are
considered delayed denitive therapy [15]. Combina-
tion therapy refers to the use of multiple in vitro active
antimicrobial treatments. A Short treatment duration
was characterized by the administration of in vitro active
antimicrobial treatment for less than 10 days, whereas a
long treatment duration referred to the administration
of such treatment for 10 days or longer [16]. Post-ERCP
pancreatitis (PEP) was identied when the serum amy-
lase level increased to more than three times the usual
limit, along with prolonged abdominal discomfort last-
ing more than 24h after ERCP [17]. Malignant biliary
strictures were identied when biliary strictures were
induced by malignancies. A biliary leak was recognized
when bile leaked from any of the ducts channeling bile
to the small intestine [18]. Instances of an abnormal con-
nection between the epithelial surface of the pancreatic
duct and another surface were used to dene a pancreatic
stula [19]. Hypoproteinaemia was identied when the
serum albumin level was less than 30g/L on the same day
(or within 24h) that a positive CRE blood culture sample
was obtained.
Tests for identifying bacteria and determining their
sensitivity to drugs
e process of isolating and identifying pathogenic
bacteria was conducted in strict adherence to the stip-
ulations outlined in the National Clinical Laboratory Pro-
cedures. Cultures derived from clinical specimens were
scrutinized for identication and susceptibility via the
automated VITEK2 system (BioMérieux, France). Drug
resistance was determined via both the Kirby–Bauer
(K-B) method (disk diusion method) and broth micro-
dilution (BMD), where the BMD was utilized to deter-
mine the minimum inhibitory concentration (MIC). e
cutos set by the European Committee on Antimicrobial
Susceptibility Testing (EUCAST) were used for the anti-
biotics tigecycline and colistin, whereas the interpreta-
tion of the other antibiotics adhered to the standards
specied in the Clinical and Laboratory Standards Insti-
tute (CLSI) document [20, 21].
Data collection and variable analysis
Our database included 36 clinical variables. Categori-
cal variables are presented as percentages and numeri-
cal values, and comparisons were made via either the
chi-square test or Fisher’s exact test. Continuous vari-
ables were compared via the independent t test or the
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
Mann‒Whitney U test. e signicance threshold was
set at a p value less than 0.05.
Identication of signicant variables
To identify the key characteristics, we used the least
absolute shrinkage and selection operator (LASSO)
regression model, which selects variables with nonzero
coecients. Univariate Cox regression analysis was con-
ducted to analyze the study outcomes, comparing the
survival and nonsurvival cohorts. Hazard ratios (HRs)
and 95% condence intervals (CIs) were calculated for
each variable. Variables that were signicant in the uni-
variate analysis were subsequently included in the mul-
tivariate Cox regression to identify independent risk
factors inuencing the outcome. ese factors are pre-
sented as HRs with 95% CIs and p values.
Development of the nomogram
Based on the multivariate Cox regression analysis, we
developed a nomogram to predict the risk of 30-day mor-
tality. e performance of the nomogram was evaluated
by calibrating the model via bootstrapping with 1,000
samples and by calculating the C-index.
Validation and clinical usability
To validate the nomogram, we compared its performance
with the SOFA score and logistic organ dysfunction score
(LODS) via receiver operating characteristic (ROC) curve
analysis and decision curve analysis (DCA). X-tile soft-
ware was used to determine the optimal threshold for
categorizing patients into low-risk and high-risk groups.
e Kaplan‒Meier method was used to estimate cumula-
tive survival rates over time. A p value of less than 0.05
was considered statistically signicant. All the statistical
analyses were performed via STATA 15.1 (College Sta-
tion, Texas) and R 3.6.2 (Chicago, Illinois) software.
Results
Patient characteristics
During the specied study interval, 417 patients devel-
oped CRE sepsis within 5 days post-ERCP. After apply-
ing the inclusion and exclusion criteria, a total of 195
patients were chosen for the present study. e study
ow chart is shown in Fig.1. e patients were divided
into two groups: (1) the survivor group (n = 103), which
included individuals who survived for more than 30 days
after the onset of post-ERCP CRE sepsis, and (2) the
nonsurvivor group (n = 92), which included individuals
who died within 30 days after the onset of post-ERCP
CRE sepsis. Table1 shows the baseline characteristics of
these groups. Categorical variables were compared via
the chi-square test or Fisher’s exact test. Signicant dif-
ferences between the survivor and nonsurvivor groups
were observed in terms of the percentages of patients
aged > 80 years (10.7% and 27.2%, respectively; p < 0.01),
ICU admission within 90 days prior to ERCP (4.9% and
16.3%, respectively; p < 0.01), hypoproteinemia (51.5%
and 81.5%, respectively; p < 0.01), quick Pitt bacteremia
score ≥ 2 (34.0% and 75.0%, respectively; p < 0.01), chol-
angioscopy (4.9% and 14.1%, respectively; p = 0.03), PEP
(3.9% and 12%, respectively; p = 0.03), post-ERCP per-
foration (2.9% and 13%, respectively; p = 0.01), inappro-
priate empirical therapy (11.7% and 48.9%, respectively;
p = 0.01), delayed denitive therapy (8.7% and 20.7%,
respectively; p = 0.02), and short treatment duration (< 10
days) (24.3% and 41.3%, respectively; p = 0.01).
Fig. 1 Flowchart delineating the inclusion of patients with CRE sepsis following ERCP. Abbreviations: ERCP, Endoscopic retrograde cholangiopancreatog-
raphy; CRE, Carbapenem-resistant Enterobacterales
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
LASSO regression analysis
Initially, a total of 36 relevant factors were combined into
the LASSO regression model to identify potential predic-
tors. irteen possible factors with coecients greater
than zero were identied, as shown in Fig. 2A. ese
factors included age > 80 years, hospitalization within 90
days prior to ERCP, ICU admission within 90 days prior
to ERCP, CRE sepsis within 2 days after ERCP, diabetes,
hypoproteinemia, quick Pitt bacteremia score ≥ 2, chol-
angioscopy, PEP, post-ERCP perforation, inappropriate
empirical therapy, delayed denitive therapy, and short
treatment duration (< 10 days). Figure1B shows the alter-
ations in the LASSO coecients.
Table 1 Basic clinical characteristics of Post ERCP patients with CRE sepsis
Variables Total Survivor Death Test statistic
OR (95%CI), P value
N = 195 N = 103 N = 92
Patients conditions
Age (years, mean ± standard deviation)
Age > 80 (No.%)
Male sex (No.%)
Charlson comorbidity index > 4 (No.%)
71.1 ± 12.0
36 (18.5)
135 (69.2)
96 (49.2)
68.2 ± 12.8
11 (10.7)
70 (68.0)
50 (48.5)
74.4 ± 10.3
25 (27.2)
65 (70.7)
46 (50.0)
1.1(1.0-1.1), P < 0.01
3.1(1.4–6.8), P < 0.01
1.1(0.6–2.1), P = 0.68
1.1(0.6–1.9), P = 0.84
Exposures within 90 days before ERCP
Antibiotics (No.%)
Prior hospitalization (No.%)
Invasive procedures (No.%)
ICU admission (No.%)
62 (31.8)
29 (14.9)
48 (24.6)
20 (10.3)
33 (32.0)
16 (15.5)
25 (24.3)
5 (4.9)
29 (31.5)
13 (14.1)
23 (25.0)
15 (16.3)
0.9(0.5–1.8), P = 0.94
0.8(0.4–1.9), P = 0.78
1.0(0.5–1.9), P = 0.91
3.8(1.3–10.9), P < 0.01
Exposures within 30 days before ERCP
Immunosuppressive agents (No.%) 19 (9.7) 10 (9.7) 9 (9.8) 0.9(0.3–2.6), P = 0.99
Epidemiology
Time from ERCP to sepsis < 2 days (No.%) 34 (17.4) 13 (12.6) 21 (22.8) 0.4(0.2-1.0), P = 0.06
Comorbidities
Prior CRE infection history (No.%)
Cerebrovascular diseases (No.%)
Malignant tumor (No.%)
Diabetes (No.%)
Cirrhosis (No.%)
Hypoproteinemia (No.%)
67 (34.4)
23 (11.8)
64 (32.8)
28 (14.4)
17 (8.7)
128 (65.6)
35 (34.0)
12 (11.7)
33 (32.0)
15 (14.6)
9 (8.7)
53 (51.5)
32 (34.8)
11 (12.0)
31 (33.7)
13 (14.1)
8 (8.7)
75 (81.5)
0.9(0.5–1.7), P = 0.91
1.0(0.4–2.5), P = 0.95
0.9(0.5–1.7), P = 0.81
0.9(0.4–2.2), P = 0.93
0.9(0.3–2.7), P = 0.99
4.2(2.2–7.9), P < 0.01
Illness severity at time of CRE sepsis
qPitt score ≥ 2 (No.%)
APACHE II score > 20 (No.%)
104 (53.3)
17 (8.7)
35 (34.0)
8 (7.8)
69 (75.0)
9 (9.8)
5.8(3.1–10.8), P < 0.01
1.3(0.5–3.5), P = 0.62
Indication for ERCP
Malignant biliary stricture (No.%)
Benign biliary stricture (No.%)
Bile duct stone (No.%)
Pancreatic duct stone (No.%)
Pancreatic duct stricture (No.%)
Bile leak (No.%)
Pancreatic stula (No.%)
60 (30.8)
31 (15.9)
43 (22.1)
23 (11.8)
167 (85.6)
5 (2.6)
4 (2.1)
31 (30.1)
16 (15.5)
23 (22.3)
12 (11.7)
85 (82.5)
3 (2.9)
2 (1.9)
29 (31.5)
15 (16.3)
20 (21.7)
11 (12.0)
82 (89.1)
2 (2.2)
2 (2.2)
1.1(0.6–1.9), P = 0.83
1.1(0.5–2.3), P = 0.88
0.9(0.5–1.9), P = 0.92
0.9(0.4–2.3), P = 0.95
0.9(0.4–1.9), P = 0.78
0.7(0.1–4.5), P = 0.74
1.1(0.2–8.1), P = 0.91
Procedure-related
Biliary stent placement (No.%)
Cholangioscopy (No.%)
Biliary sphincterotomy (No.%)
Bile duct stone removal (No.%)
Bilde duct radiofrequency ablation (No.%)
Total duration > 45min (No.%)
Post ERCP pancreatitis (No.%)
Post ERCP perforation (No.%)
Post ERCP bleeding (No.%)
167 (85.6)
18 (9.2)
91 (46.7)
37 (19.0)
31 (15.9)
21 (10.8)
15 (7.7)
15 (7.7)
10 (5.1)
85 (82.5)
5 (4.9)
46 (44.7)
19 (18.4)
16 (15.5)
11 (10.7)
4 (3.9)
3 (2.9)
5 (4.9)
82 (89.1)
13 (14.1)
45 (48.9)
18 (19.6)
15 (16.3)
10 (10.9)
11 (12.0)
12 (13.0)
5 (5.4)
0.6(0.3–1.3), P = 0.19
3.2 (1.1–9.4), P = 0.03
0.8(0.5–1.5), P = 0.55
1.1(0.5–2.2), P = 0.84
1.1(0.5–2.3), P = 0.88
1.0(0.4–2.5), P = 0.97
3.4(1.0-10.9), P = 0.03
5.0(1.3–18.3), P = 0.01
1.1(0.3-4.0), P = 0.85
Antibiotic Antimicrobial treatment
Inappropriate empirical therapy (No.%)
Non-early-appropriate therapy (No.%)
Short-duration < 10 days (No.%)
57 (29.2)
28 (14.4)
66 (33.8)
12 (11.7)
9 (8.7)
25 (24.3)
45 (48.9)
19 (20.7)
38 (41.3)
7.3(3.5–15.0), P < 0.01
2.7(1.2–6.3), P = 0.02
2.2(1.2–4.1), P = 0.01
Note: *P < 0.05 (b old values) was considered s tatistically signi cant
Abbreviations: ERCP, Endoscopic retrograde cholangiopancreatography; CRE, Carbapenem-resistant Enterobacterales; qPitt, A quick version of the Pitt Bacteremia
Score; APACHE II, Acute Physi ology and Chronic Heal th Evaluation II; ICU, intensiv e care unit; OR, Odds Ra tio; CI, Condence Inter val
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
Risk factors for mortality
Table 2 shows the 13 predictors identied via LASSO
regression analysis. ese predictors were then fur-
ther examined via both univariate and multivariate
Cox regression analyses. In the multivariate analysis,
eight factors were identied as signicant predictors of
mortality within a 30-day period following post-ERCP
CRE sepsis: age > 80 years (HR 2.61; 95% CI 1.53–4.47;
p < 0.001), ICU admission within 90 days prior to ERCP
(HR 2.64; 95% CI 1.39–5.04; p = 0.003), hyp oproteinemia
(HR 4.55; 95% CI 2.48–8.34; p < 0.001), quick Pitt bacte-
remia score ≥ 2 (HR 2.61; 95% CI 1.55–4.37; p < 0.001),
PEP (HR 2.52; 95% CI 1.29–4.92; p = 0.007), inappropriate
empirical therapy (HR 3.48; 95% CI 2.19–5.53; p < 0.001),
delayed denitive therapy (HR 2.64; 95% CI 1.52–4.60;
p < 0.001), and short treatment duration (< 10 days) (HR
5.03; 95% CI 2.97–8.52; p < 0.001).
Creation of the nomogram for predicting mortality within
30 days
A clinical chart was subsequently created using the sig-
nicant predictors identied via multivariate Cox regres-
sion analysis, as these predictors were observed to greatly
impact the clinical results (Fig. 3). In the nomogram,
every predictor was visually depicted and assigned a cor-
responding score. Aggregating the scores of each predic-
tor, which correspond to the predicted probability of the
clinical event, enables the calculation of the cumulative
total points indicating a clinical event.
Assessment and validation of the nomogram
e developed nomogram demonstrated excellent per-
formance in predicting the risk of 30-day mortality
among patients suering from post-ERCP CRE sepsis,
as indicated by a C-index of 0.884. e strength of this
model was conrmed by bootstrapping validation, which
Table 2 Univariate and multivariate COX regression analysis of predictors of all-cause 30day mortality patients with CRE sepsis post
ERCP.
Univariable Multivariable
Characteristic HR 95% CI p-value HR 95% CI p-value
Age > 80 1.88 1.19–2.98 0.007 2.61 1.53–4.47 < 0.001
Prior hospitalization within 90 days 0.93 0.52–1.67 0.800 0.69 0.36–1.30 0.246
ICU admission within 90 days 2.45 1.40–4.26 0.002 2.64 1.39–5.04 0.003
Time from ERCP to Sepsis < 2 days 1.63 1.00-2.65 0.050 1.50 0.87–2.56 0.143
Diabetes 0.90 0.50–1.62 0.732 0.70 0.37–1.32 0.272
Hypoproteinemia 2.86 1.69–4.86 < 0.001 4.55 2.48–8.34 < 0.001
Quick Pitt Bacteremia Score ≥ 2 3.53 2.20–5.67 < 0.001 2.61 1.55–4.37 < 0.001
Cholangioscope 2.11 1.17–3.80 0.013 1.48 0.80–2.75 0.211
Post ERCP pancreatitis 2.19 1.16–4.12 0.015 2.52 1.29–4.92 0.007
Post ERCP perforation 2.98 1.62–5.48 < 0.001 1.24 0.60–2.55 0.563
Inappropriate Empirical therapy 3.60 2.38–5.45 < 0.001 3.48 2.19–5.53 < 0.001
Non-early-appropriate therapy 1.89 1.14–3.13 0.014 2.64 1.52–4.60 < 0.001
Short Duration < 10 days 2.49 1.64–3.78 < 0.001 5.03 2.97–8.52 < 0.001
Note: *P < 0.05 (b old values) was considered s tatistically signi cant.
Abbreviations: HR = Haz ard Ratio; CI = Condence Interval; CRE, Carbapenem-resistant Enterobacterales; ERCP, Endoscopic retrograde cholangiopancreatography
Fig. 2 LASSO regression variable selection. (A) The variation attributes of the variable coecients; (B) the selection procedure for the optimal value of the
parameter λ within the LASSO regression model
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
revealed a C-index of 0.902 for the cohort (Fig.4A-B).
When the nomogram was compared with the SOFA and
LODS metrics, the area under the ROC curve (AUC) was
signicantly better. e calibration ecacy of the model
was then thoroughly assessed via a calibration curve,
which demonstrated excellent calibration performance
(Fig.4C). e clinical utility of the model (Fig.4D) was
assessed through DCA, which demonstrated that the
nomogram model provided net benets across a broad
spectrum of threshold probabilities. Using X-tile soft-
ware, the point of separation that oers the highest level
of sensitivity and specicity in dierentiating patients at
low risk and high risk was determined. e 30-day mor-
tality rate among post-ERCP CRE sepsis patients in the
high-risk group was signicantly greater than that in the
low-risk group (all patients 79.2% vs. 20.8%, p < 0.001; HR
6.55, 95% CI 4.04–10.64) (Fig.4E).
Eects of dierent antimicrobial regimens
Dierent antimicrobial treatments have a wide range of
clinical eectiveness, but the best antimicrobial therapy
for post-ERCP CRE sepsis is still unknown. Accord-
ing to the Kaplan‒Meier analysis, there was no notable
dierence in the 30-day mortality rate among patients
regardless of whether they received empirical carbape-
nem therapy (p = 0.06) (Fig. 5A). According to our data-
set, empirical tigecycline treatment was associated with
unfavorable outcomes (p = 0.005) (Fig. 5B), whereas
empirical polymyxin B treatment was associated with
favorable outcomes (p = 0.003) (Fig . 5C). Further exami-
nation was performed to assess the inuence of the com-
bined treatment. ere was no noticeable variation in
the 30-day mortality rate among patients regardless of
whether they received carbapenem combination therapy
(p = 0.542) (Fig. 5D). Notably, tigecycline combination
treatment markedly increased 30-day mortality (p = 0.04)
(Fig. 5E), whereas combination therapy involving poly-
myxin B substantially increased survival within a 30-day
period (p = 0.005) (Fig.5F).
Discussion
Our study identied several key factors contributing to
30-day mortality in patients with post-ERCP CRE sep-
sis. e signicant independent risk factors included
age > 80 years, ICU admission within 90 days prior to
ERCP, hypoproteinemia, quick Pitt bacteremia score ≥ 2,
post-ERCP pancreatitis (PEP), inappropriate empiri-
cal therapy, delayed denitive therapy, and short treat-
ment duration (< 10 days). ese variables were used to
develop a nomogram for predicting the risk of 30-day
mortality. is nomogram demonstrated strong dier-
entiation, strong calibration, and a high C-index. Our
investigation reported a 30-day all-cause mortality rate of
47.1% for post-ERCP CRE sepsis patients, with those in
Fig. 3 Estimating the likelihood of 30-day mortality in patients with CRE sepsis post-ERCP: a model utilizing nomogram predictions. Abbreviations: ERCP,
Endoscopic retrograde cholangiopancreatography; CRE, Carbapenem-resistant Enterobacterales
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
the high-risk group having a signicantly higher mortal-
ity rate (HR 6.55).
Age > 80 years was an independent risk factor for mor-
tality. Elderly patients often have multiple comorbidi-
ties, such as a weakened immune system and reduced
organ function, which make them more susceptible to
severe outcomes from CRE sepsis [22–24]. is nding
underscores the importance of tailored infection pre-
vention strategies for elderly patients, especially in the
context of increasing antibiotic resistance. ICU admis-
sion within the prior 90 days also emerged as a signi-
cant risk factor. ICU patients are often critically ill and
may have compromised immune responses, increasing
their susceptibility to severe infections [25]. Moreover,
Fig. 4 Assessment and verication of the nomogram. (A) ROC curve representation of the nomogram, SOFA score, and LODS score in the training set
and (B) internal validation set. (C) Construction of calibration curves in the training set. (D) DCA curve depicting medical intervention ecacy in patients
as evaluated by the nomogram, SOFA score, and LODS. (E) Kaplan‒Meier survival curves for patients with CRE sepsis post-ERCP grouped according to
the nomogram. The p value (< 0.001) was ascertained via the log-rank test. The information within the table shows the number at risk at particular time
instances. Abbreviations: Sequential Organ Failure Assessment score (SOFA), Logistic Organ Dysfunction Score (LODS)
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
ICU environments are hotspots for multidrug-resistant
pathogens because of the frequent use of broad-spec-
trum antibiotics and invasive procedures [26]. is high-
lights the need for stringent infection control measures
during ERCP for patients recently discharged from ICUs.
Hypoproteinaemia is another independent risk factor,
reecting its role in indicating malnutrition and compro-
mised immune function [27]. Low serum albumin levels
can impair vascular integrity and promote bacterial inva-
sion, exacerbating infection severity [28]. ese ndings
underscore the multifaceted role of albumin in patient
outcomes during severe infections, such as post-ERCP
CRE sepsis.
A quick Pitt bacteremia score ≥ 2 was a signicant pre-
dictor of poor outcomes. is score, which is designed to
assess the severity of bloodstream infections, indicates
substantial systemic infection and the need for intensive
medical interventions [29]. Higher scores correlate with
an increased risk of complications such as septic shock
and organ dysfunction, which aligns with our ndings.
Fig. 5 Visual representation of the consequences of dierent antimicrobial therapies shown through Kaplan‒Meier curves. (A) There was no dierence
in 30-day mortality among patients who were given empirical carbapenems. (B-C) Patients who received empirical tigecycline had a negative prognosis
within 30 days, whereas those who received empirical polymyxin B had a survival benet within the same time frame. (D) There was no variation in the
30-day mortality rate among patients who received combination therapy with carbapenem. (E) Individuals who received combination therapy involving
tigecycline experienced an unfavorable prognosis within a 30-day period. (F) On the other hand, individuals who received combination therapy involving
polymyxin B experienced a survival advantage for a period of 30 days
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Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
Our ndings are consistent with previous research
showing that the quick Pitt bacteremia score eectively
predicts 30-day mortality, not only in patients with bac-
teremia but also in those with K. pneumoniae infections
[30]. Clinicians should accurately calculate and inter-
pret these scores to identify at-risk patients promptly.
Early recognition allows for more intensive treatment,
increased vigilance, and the potential for more aggres-
sive or personalized therapeutic interventions. PEP was
also identied as a risk factor for mortality, highlighting
the importance of preventative measures during ERCP
[31]. e inamed pancreatic environment can facili-
tate bacterial translocation, leading to systemic infec-
tion. Patients with PEP are more susceptible to severe
outcomes, emphasizing the need for careful patient
management post-ERCP [32]. On the basis of our nd-
ings, clinicians should be especially vigilant in managing
post-ERCP patients who develop pancreatitis, as these
patients are more susceptible to severe outcomes from
CRE sepsis.
Our study revealed that delayed denitive therapy and a
treatment duration of less than 10 days were independent
factors negatively aecting 30-day survival rates. Timely
administration of appropriate antimicrobial treatment
is crucial. Delayed antibiotic therapy increases mortal-
ity risk with each hour of delay [33]. Starting appropri-
ate treatment within the rst 24h after blood culture is
most benecial, whereas delays beyond 24h signicantly
increase mortality [34, 35]. Timely empirical treatment is
therefore essential. Patients receiving appropriate empiri-
cal treatment had better outcomes, which is consistent
with the ndings of previous studies. However, the opti-
mal treatment for CRE sepsis remains unclear. Our study
revealed higher mortality with empirical tigecycline use,
likely due to its bacteriostatic nature and limited ecacy
against Pseudomonas aeruginosa [36]. Conversely, poly-
myxin B has shown survival benets, demonstrating e-
cacy against multidrug-resistant gram-negative bacteria
[37], favorable pharmacokinetics, and a reduced risk of
kidney damage [38]. A Japanese multicenter study also
supported the eectiveness of polymyxin B in reducing
mortality in sepsis patients [39]. Combination therapy,
particularly polymyxin B, provides a 30-day survival
advantage [40, 41]. A short treatment duration (< 10
days) was a risk factor for 30-day mortality, likely due to
inadequate bacterial eradication, leading to persistent
infections. Prolonged therapy (≥ 14 days) results in bet-
ter outcomes [42]. e rapid onset of CRE sepsis within
5 days post-ERCP indicates a complex etiology, possibly
involving contaminated duodenoscopes and endogenous
bacteria entering the bloodstream during the procedure.
Further research is necessary to understand these factors
and develop eective preventive measures.
We developed a validated tool to predict the 30-day
mortality risk for patients with post-ERCP CRE sepsis.
is tool helps healthcare professionals identify high-
risk patients early, facilitating initial risk categorization
and personalized treatment. Fundamentally, this nomo-
gram has the potential to improve patient outcomes and
enhance clinical decision-making in managing post-
ERCP CRE sepsis.
Limitations
We acknowledge several limitations within our study.
e generalizability of our ndings is limited, as the
data were collected exclusively from a patient cohort in
a tertiary hospital in Zhejiang Province, which may not
represent the wider range of Chinese patients. Further-
more, our examination did not cover every possible vari-
able aecting the 30-day mortality rate. We were unable
to thoroughly examine numerous potential factors that
could aect the risk of 30-day mortality, such as specic
strains of CRE and variations in enzyme types, owing to
the inherent limitations of our research environment.
Despite our thorough examination of the strength of the
nomogram via bootstrapping, the lack of external valida-
tion raises doubts about the generalizability of the results
to dierent populations in various regions and countries.
is underscores the necessity for subsequent external
validation within a more expansive patient population
to further ascertain the applicability and validity of the
nomogram in dierent clinical settings and geographic
locations.
Conclusions
In this study, risk factors for 30-day mortality in patients
with CRE sepsis following ERCP were successfully iden-
tied, and a validated nomogram was developed to
accurately predict this risk. Nomograms are tools that
clinicians can use to quickly identify patients at high risk,
thus facilitating timely and appropriate interventions
against CRE sepsis. Further research is needed to conrm
whether the nomogram developed herein can be used to
guide personalized treatments can decrease mortality
rates and improve outcomes in these patients. External
validation of the nomogram is also essential to ensure its
eectiveness across dierent healthcare settings.
Acknowledgements
The information used for this study was provided by the Department of
Gastroenterology, Hangzhou First People’s Hospital.
Author contributions
Conceptualization: H.Z. and X.Z.; Methodology: H.Z., Y.W., and C.X.Z.; Software:
Y.W., D.X., C.X., and H.S.; Validation: H.J. and J.Y.; Formal Analysis: D.X., C.X., and
Y.W.; Investigation: Y.W.; Resources: H.Z., D.X., and X.Z.; Data Curation: H.Z. and
H.S.; Writing—Original Draft Preparation: H.Z., Y.W., and C.X.Z.; Writing—Review
and Editing: C.X.Z., H.J. and J.Y.; Supervision: X.Z.; Funding Acquisition: H.Z., D.X.,
J.Y., and X.Z. All the authors have read and agreed with the published version
of the manuscript.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 11 of 12
Zhang et al. Antimicrobial Resistance & Infection Control (2024) 13:84
Funding
Support for this project was provided by multiple prestigious organizations,
including the Zhejiang Provincial Traditional Chinese Medicine Science and
Technology Project (2022ZB271),the National Natural Science Foundation
of China (NSFC No. 82000516), the Westlake University School of Medicine
Junior Physician-Scientist Cultivation Program, the Key R&D Program of
Zhejiang Province (No. 2023C03054, No. 2024C03048), the Hangzhou Medical
and Health Science and Technology Plan (A20200737), and the Construction
Fund of Medical Key Disciplines of Hangzhou (OO20190001). Importantly,
the sponsors of this research were not involved in any aspect of the study’s
design, data collection, data analysis, data interpretation, or writing of the
manuscript.
Data availability
The datasets used in this study can be obtained from the corresponding
author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study protocol was approved by the Institutional Review Board of
Hangzhou First People’s Hospital (reference number ZN20231106). All
procedures followed the ethical standards of the responsible committee
on human experimentation (institutional and national) and the Helsinki
Declaration. The requirement for informed consent was waived by the
Institutional Review Board of Hangzhou First People’s Hospital because of the
retrospective nature of the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1The Department of Gastroenterology, Aliated Hangzhou First People’s
Hospital, School of Medicine, Westlake University, No. 261 HuanSha Road,
Zhejiang, China
2The Fourth School of Clinical Medicine, Zhejiang Chinese Medical
University, Hangzhou First People’s Hospital, Hangzhou 310003, China
3Key Laboratory of Integrated Traditional Chinese and Western Medicine
for Biliary and Pancreatic Diseases of Zhejiang Province, Zhejiang, China
4Hangzhou Institute of Digestive Disease, Zhejiang, China
Received: 10 November 2023 / Accepted: 25 July 2024
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