Clinical characteristics and outcomes of spontaneous bacterial peritonitis caused by Enterobacter species versus Escherichia coli: a matched case-control study
Bae et al. BMC Infectious Diseases
Clinical characteristics and outcomes of spontaneous bacterial peritonitis caused by Enterobacter species versus Escherichia coli: a matched case-control study
Seongman Bae 0
Taeeun Kim 0
Min-Chul Kim 0
Yong Pil Chong 0
Sung-Han Kim 0
Heungsup Sung 1
Young-Suk Lim 2
Sang-Oh Lee 0
Mi-Na Kim 1
Yang Soo Kim 0
Jun Hee Woo 0
Sang-Ho Choi 0
0 Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
1 Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
Background: Enterobacter species are important nosocomial pathogens, and there is growing concern about their ability to develop resistance during antimicrobial therapy. However, few data are available on the clinical characteristics and outcomes of Enterobacter spontaneous bacterial peritonitis (SBP). Methods: We retrospectively identified all patients with SBP caused by Enterobacter species admitted to a tertiary care hospital between January 1997 and December 2013. Each case was age- and sex-matched with four patients with Escherichia coli SBP. Results: A total of 32 cases with Enterobacter SBP and 128 controls with E. coli SBP were included. Twenty-one (65.6 %) cases and 111 (86.7 %) controls had Child-Pugh class C (P = 0.006). Cases were significantly more likely to have hepatocellular carcinoma (65.6 % vs. 37.5 %, P = 0.004) and upper gastrointestinal bleeding (28.1 % vs. 9.4 %, P = 0.005). The initial response to empirical therapy (81.3 % vs. 81.2 %, P = 0.995) and the 30-day mortality (37.5 % vs. 28.9 %, P = 0.35) were not significantly different between the groups. Drug resistance emerged in one case and in no controls (4.3 % [1/23] vs. 0 % [0/98], P = 0.19). Conclusions: Compared with E. coli SBP, patients with Enterobacter SBP more frequently had hepatocellular carcinoma and upper gastrointestinal bleeding, yet clinical outcomes were comparable. Development of resistance during third-generation cephalosporin therapy was infrequent in patients with Enterobacter SBP.
Enterobacter; Spontaneous bacterial peritonitis; Liver cirrhosis
Enterobacter species are important nosocomial pathogens
that cause a variety of infections, including bacteremia,
pneumonia, surgical site infections, and urinary tract
]. Among Enterobacteriaceae isolated from
hospital-acquired infections, Enterobacter species have
been ranked as the third most frequent isolate following
Escherichia coli and Klebsiella species [
]. For more
than two decades, there has been growing concern about
the induction of β-lactam resistance in Enterobacter
infections mediated by chromosomally encoded AmpC
βlactamase following antibiotic exposure [
]. This type of
inducible resistance is reported to develop at frequencies
of 8.3 to 19.6 % during therapy with broad-spectrum
cephalosporins for bloodstream infections [
Enterobacter species are known to be part of the
microbial etiology for spontaneous bacterial peritonitis
(SBP), being the second to fourth most common
causative organism among gram-negative bacilli [
However, there is a paucity of clinical data about the
prevalence, characteristics, and outcomes of Enterobacter
SBP. Although some small studies included Enterobacter
species as causative organisms of SBP, the number of
included episodes did not exceed five in any study and
Enterobacter SBP has not yet been analyzed separately.
Furthermore, the clinical responses and outcomes of
patients treated with third-generation cephalosporins, the
most widely used antimicrobials for SBP, have not yet been
investigated. Therefore, with a large SBP cohort, we
sought to characterize the frequency, clinical
manifestations, responses to antimicrobial therapy, emergence of
resistance, and outcomes of Enterobacter SBP.
Study design, setting, and population
We performed a retrospective case-matched study in
Asan Medical Center, a 2700-bed tertiary care institution
in Seoul, Republic of Korea. All patients over 17 years
who were admitted for SBP between January 1997 and
December 2013 were identified by searching for the
diagnostic codes “cirrhosis” and “peritonitis” in the
computerized database of our institute. Patients with
secondary peritonitis, defined as peritonitis caused by
perforation or inflammation of intra-abdominal organs,
were excluded [
]. Patients who were receiving peritoneal
dialysis were also excluded. Finally, we confirmed SBP
cases through a detailed review of the medical records. All
patients who had Enterobacter SBP were included in the
study as cases, and they were matched with four-times as
many patients with E. coli SBP with a similar age (±5 years)
and the same sex. If more than four control patients were
available for each case, we chose those patients whose
dates of admission were closest to that of the case. This
study was approved by the institutional review board of
the Asan Medical Center.
Clinical data collection and analysis
We collected the following clinical data for each case
and control: age, sex, site of acquisition of the infection,
etiology of cirrhosis, comorbid diseases, Child-Pugh
score, model for end-stage liver disease (MELD) score,
invasive procedures performed within 30 days prior to
SBP, antecedent administration of antimicrobials within
30 days, history of past hospital stays before the onset of
SBP, initial clinical manifestations, laboratory findings,
antimicrobial susceptibility, antibiotic therapy, and
In both cases and controls, SBP was subcategorized as
either definite or probable. Definite SBP was defined by
an ascitic polymorphonuclear cell (PMN) count > 250
cells/mm3 and a positive ascitic culture, while probable
SBP was defined by an ascitic PMN count > 250 cells/
mm3 with only a positive blood culture without any
other primary focus [
Ascitic fluid samples were inoculated onto blood agar
plates, MacConkey agar plates, and Brucella agar plates,
and/or the BACTEC system (Becton Dickinson,
Heidelberg, Germany). Identification of Enterobacter
species and antimicrobial susceptibility testing were
performed using the Microscan system (Dade Behring,
Deerfield, IL, USA). Susceptibility to third-generation
cephalosporins was defined according to the revised
2009 guidelines of the Clinical and Laboratory Standards
Institute (susceptible, ≤ 8 μg/ml; intermediate, 16–32 μg/
ml; and resistant, ≥ 64 μg/ml) [
Continuous variables were compared using Student’s
ttest and the Mann-Whitney U-test, while categorical
variables were tested by χ2 or Fisher’s exact test. To
identify clinical factors associated with Enterobacter
rather than E. coli SBP, univariate and multivariate
analyses were conducted using a logistic regression
model. The clinical variables favoring Enterobacter SBP
over E. coli SBP in the univariate analysis (P < 0.1) were
included in the multivariate analysis. All P values are
two-tailed, and P < 0.05 was considered statistically
significant. SPSS Statistics, version 19.0 (IBM, Armonk,
NY, USA), was used for analyses.
Demographic characteristics of SBP patients
During the 17 year period of study, a total of 1,172
episodes of culture-proven SBP were identified.
Enterobacter SBP occurred in 32 patients (2.7 %), including 26
with E. cloacae SBP and six with E. aerogenes SBP.
Enterobacter species was ranked as the fourth most
frequent pathogen among gram-negative bacilli
following E. coli (n = 536), K. pneumoniae (n = 196), and
Aeromonas species (n = 62).
The 32 Enterobacter SBP patients (cases) were
ageand sex-matched with 128 control subjects who had E.
coli SBP. The demographic characteristics of the patients
are summarized in Table 1. In both groups, 81.3 % were
male and the mean age was 55 years. The Enterobacter
SBP patients had a significantly higher percentage of
definite SBP cases (81.2 % vs. 60.9 %, P = 0.03),
hospitalacquired infections (62.5 % vs. 23.4 %, P < 0.001), and
concomitant hepatocellular carcinoma (HCC) (65.6 % vs.
37.5 %, P = 0.004), whereas they had a significantly lower
proportion of cases with Child-Pugh score C (65.6 % vs.
86.7 %, P = 0.006) and median value of MELD score (19
vs. 23, P = 0.03). Antecedent endoscopic interventions
had more frequently been performed in the Enterobacter
SBP group (25.0 % vs. 5.5 %, P = 0.001), and the median
period between endoscopy and the diagnosis of
Enterobacter SBP was 22 days (range, 2 − 30 days). Of the eight
Enterobacter cases involving prior endoscopic
intervention, three occurred within 5 days of the endoscopy
whereas the remaining five developed more than 3 weeks
after the procedure. Anticancer chemotherapy (9.4 % vs.
0 %, P = 0.007) and prior exposure to antimicrobial agents
(59.4 % vs. 28.1 %, P = 0.001) within 30 days were more
common in the cases. Multivariate analysis showed that
hospital acquisition (OR, 3.19; 95 % CI, 1.25-8.14; P =
0.02) and prior endoscopic intervention (OR, 3.57; 95 %
CI, 1.02-12.44; P = 0.046) were independent factors
favoring Enterobacter SBP rather than E. coli SBP. Results
of univariate and multivariate analysis are shown in
Additional file 1: Table S1.
Clinical features and laboratory findings
Table 2 compares the clinical features of SBP and the
laboratory findings between the groups. Abdominal pain
and fever were the most common initial manifestations
in both groups. Upper gastrointestinal bleeding episodes
were significantly more frequent in the Enterobacter SBP
than in the E. coli SBP group (28.1 % vs. 9.4 %, P =
0.005). Concomitant bacteremia was less common in
cases than in controls (34.4 % vs. 68.0 %, P = 0.001). The
laboratory findings in the Enterobacter SBP group vs. the
E. coli group revealed a trend towards higher levels of
systemic inflammatory markers such as serum white
blood cell count (median, 8,050 cells/μL vs. 6,450 cells/
μL, P = 0.12) and serum C-reactive protein (median,
6.41 mg/dL vs. 3.06 mg/dL, P = 0.06), but the differences
were not statistically significant.
Susceptibilities of 31 and 125 clinical isolates of
Enterobacter species and E. coli, respectively, to a range of
antimicrobials are shown in Table 3. Enterobacter species
from 22 patients (71.0 %) and E. coli from 106 patients
(84.8 %) were susceptible to third-generation
cephalosporins and susceptibility of Enterobacter SBP group tended
to be lower than E. coli SBP group (P = 0.07). Rates of
susceptibility to ciprofloxacin (80.6 % vs. 60.8 %, P =
0.038) and trimethoprim-sulfamethoxazole (87.1 % vs.
59.2 %, P = 0.003) were higher in the case group, whereas
piperacillin/tazobactam susceptibility was lower in the
case group (74.2 % vs. 92.8 %, P = 0.003). Of the 31
Enterobacter SBP patients for whom there were antimicrobial
susceptibility test results, 19 (61.3 %) had been exposed to
antecedent antimicrobials. Of those 19 patients, 16 had
histories of exposure to 3rd-generation cephalosporins.
The frequency of resistance to 3rd-generation
cephalosporins of the Enterobacter isolates from patients with prior
antimicrobial exposure was twice as high as that in the
unexposed group, but the difference was not statistically
significant (36.8 % [7/19] vs. 16.7 % [2/12], P = 0.42).
Empirical treatment, outcomes
Antimicrobial treatments and outcomes are summarized
in Table 4. The majority of patients in both groups were
treated empirically with cefotaxime (84.4 and 90.6 %,
respectively). The percentages of appropriateness of the
initial therapy were similar between the groups (87.1 %
vs. 87.2 %, P = 1.00). Treatment outcomes including
response to initial therapy (81.3 % vs. 81.2 %, P = 0.995)
and 30-day mortality (37.5 % vs. 28.9 %, P = 0.35) were
not significantly different between groups. The lengths
of hospital stay were similar between the case group
(median, 20 days; IQR, 11 − 31 days) and control group
(16 days; IQR, 10 − 26 days, P = 0.28). The duration of
antimicrobial use was significantly longer in the cases
(median, 15 days; IQR, 11 − 25 days) than in the controls
(median, 13 days; IQR, 8 − 16 days, P = 0.02). There were
2 cases of recurrent SBP in Enterobacter SBP group.
Among 2 Enterobacter isolates from recurrent episode,
one was susceptible and the other was resistant to
3rdgeneration cephalosporins. Antimicrobial susceptibility
pattern from those 2 Enterobacter isolates were not
changed at recurrent episodes.
Emergence of resistance
A large subgroup of patients was initially treated with
third-generation cephalosporins: 27 cases received
cefotaxime, and 117 controls received either cefotaxime or
ceftazidime. Of these, 23 patients in the Enterobacter
SBP group and 98 in the E. coli SBP group were
susceptible to empirical antimicrobial treatment. Emergence of
resistance during antimicrobial therapy was identified in
one case (4.3 %; 1 of 23) and in no controls (P = 0.19).
In this retrospective, case-matched study, we investigated
the characteristics and outcomes of the Enterobacter SBP.
Compared with E. coli SBP, patients in the Enterobacter
SBP group had less severe liver diseases and more
commonly had concomitant HCC; they were more likely
to have had prior endoscopic interventions and to present
with upper gastrointestinal bleeding. However, response
to empirical therapy and 30-day mortality rate were not
significantly different between the groups. Emergence of
resistance to third-generation cephalosporins was
infrequent in both groups.
Enterobacter species are usually regarded as
nosocomial pathogens [
]. According to different studies,
56 − 100 % of Enterobacter infections were acquired
]. Among the 32 Enterobacter
SBP patients in our study, 20 cases (62.5 %) had
hospital-acquired infections; this proportion is within
the range of prior reports. Prior antimicrobial usage was
also more common in the Enterobacter SBP group than
in the E. coli group. This finding is consistent with
previous studies in which prior use of antimicrobial
agents was a crucial risk factor for Enterobacter infection
1, 10, 24–26
]. Interestingly, about two-thirds of the
Enterobacter SBP group had concomitant HCC; this
proportion is significantly higher than in the E. coli
group, whereas the patients in the Enterobacter SBP
group had less severe hepatic impairment than the case
group. We presume that the treatment of HCC, or HCC
per se, may contribute to the development of SBP by
increasing the probability of hospitalization or
We found that prior endoscopic interventions were
more frequently performed in the Enterobacter group than
in the E. coli group. The rate of transient bacteremia after
endoscopic intervention has been reported to be
substantial, within the range of 6 − 53 % [
could lead to subsequent SBP in patients with cirrhotic
ascites. A few studies showed that endoscopic
interventions for varix control, including endoscopic variceal
ligation and endoscopic sclerotherapy, could be
complicated by SBP in 0.5 − 3.0 % of cases [
]. The interval
between the endoscopic intervention and a diagnosis of
SBP in those studies was about 2 − 4 days. Of the eight
Enterobacter SBP patients in our study who received prior
endoscopic intervention, three cases were diagnosed with
SBP within 5 days and the remaining five cases developed
more than 3 weeks after the procedure. Therefore, only
the three cases with a short interval between endoscopy
and SBP development seem to be directly related to the
endoscopic procedure. Intriguingly, we found that upper
gastrointestinal bleeding occurred more frequently in the
Enterobacter group, despite the higher frequency of severe
liver disease in the E. coli group. Of the nine Enterobacter
SBP patients with bleeding, seven had HCC, all in an
unresectable state. Three of these HCC cases were
complicated by portal vein tumor thrombosis and one
case by direct duodenal wall invasion of the cancer. Portal
vein thrombosis has been considered a risk factor for
variceal bleeding [
]. We conjecture that more
frequent bleeding episodes in the Enterobacter group
could be explained in part by complications of advanced
Although susceptibility to third-generation
cephalosporins tended to be lower in the Enterobacter group,
the percentages of appropriateness of antimicrobial
therapy, the initial responses to empirical therapy, and the
30-day mortality rates were comparable between groups.
The development of resistance during third-generation
cephalosporin therapy has been a great concern to
clinicians. However, the frequency of resistance arising
during third-generation cephalosporin therapy in our
study (4.3 %, 1/23) was much lower than those in
previous studies regarding Enterobacter bloodstream
infections (8.3 − 19.6 %) [
]. Cefotaxime, the most
widely used initial empiric therapy for SBP in cirrhosis,
can penetrate into ascites rapidly and achieve a higher
drug concentration in ascites than in blood [
This pharmacokinetic distinctiveness of the
antimicrobial agent could explain the lower rate of emergence of
resistance in our study population. Since Enterobacter
SBP accounted for only 2.7 % of the whole SBP cohort
and the treatment outcomes of the Enterobacter SBP
patients were comparable to those of the E. coli SBP, it
seems likely that a change of treatment strategy to target
Enterobacter species is unnecessary.
There are several limitations of this study. First, we
conducted a retrospective, case-matched study in a single
tertiary center with a limited sample size, which does not
permit generalization of our results. Although age and sex
were matched in the control group, unexpected
confounding factors may have been overlooked. Second, since the
isolates were not available, the emergence of resistance
during therapy could not be confirmed by molecular
methods such as pulsed-field gel electrophoresis. Finally,
E. cloacae and E. aerogenes were analyzed together as a
group. The possible differences of antimicrobial resistance
pattern and mortality between the two species may have
affected antimicrobial susceptibility profile and outcomes
in our study [
Our study shows clinical features and treatment outcomes
of spontaneous bacterial peritonitis caused by
Enterobacter species. Compared with E. coli SBP, Enterobacter SBP
was more commonly associated with underlying
hepatocellular carcinoma and upper gastrointestinal bleeding.
Clinical outcomes associated with SBP were comparable
between the groups. Development of resistance during
third-generation cephalosporin therapy was infrequently
Additional file 1: Table S1 Univariate and multivariate factors
associated with Enterobacter spontaneous bacterial peritonitis vs. E.
coli spontaneous bacterial peritonitis. (DOCX 21 kb)
SBP, spontaneous bacterial peritonitis; MELD, model for end-stage liver
disease; PMN, polymorphonuclear cell; HCC, hepatocellular carcinoma; IQR,
interquartile range; ERCP, endoscopic retrograde cholangiopancreatography;
WBC, white blood cells; ICU, intensive care unit
This study was supported by a grant from the Asan Institute of Life Sciences
Availability of data and materials
All the data supporting our findings are contained within this work.
SHC, SOL and SHK conceived, initiated and designed the study and
coordinated drafting the manuscript. SB and SHC carried out data analysis,
and wrote the manuscript. MCK, TK and YPJ were responsible for the data
collection, reviewing medical charts and assisted in performing statistical
analyses. YSL participated in interpretation and evaluation of treatment
responses and assisted in data analysis. YSK and JHW supervised the
study design, reviewed and commented the manuscript, and approved
the final draft. MNK and SH supervised and check the issues of
microbiologic and laboratory data. All authors read and approved the
The authors declare that they have no competing interest.
Ethics approval and consent to participate
The institutional review board of the Asan Medical Center gave approval to
conduct this research with a waiver of informed consent.
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