Clinical characteristics and predictors of mortality in patients with Enterobacter aerogenes bacteremia.

Abstract

Enterobacter aerogenes is increasingly encountered in nosocomial infections. This study aimed to clarify the clinical characteristics and to identify the predictors of mortality in patients with E. aerogenes bacteremia.
From March 2001 to April 2007, all patients with positive blood cultures for E. aerogenes at Taipei Veterans General Hospital, Taipei, Taiwan, were enrolled in this retrospective study. The medical records were reviewed for clinical and laboratory data.
Eighty eight patients were included, 9 (10.2%) of whom died of E. aerogenes bacteremia. Most of the patients had comorbidities. Seventy nine patients (89.8%) had nosocomial infections, and 43 patients (48.9%) had polymicrobial infections. Eighty four patients (95.5%) presented with fever. Empirical antimicrobial therapy was administered for 80 patients (90.9%), but was appropriate for only 55 patients (62.5%). Of the 9 patients who died, 8 had polymicrobial infection, 5 of whom had nosocomial pneumonia, and 6 did not receive appropriate antimicrobial therapy. Multivariate analysis indicated that high Acute Physiology and Chronic Health Evaluation (APACHE) II score (>16) [odds ratio (OR), 16.569; 95% confidence interval (CI), 1.24-221.24; p = 0.034] and strains not susceptible to extended-spectrum cephalosporins (OR, 9.21; 95% CI, 1.02-83.04; p = 0.048) were independent risk factors for mortality.
The severity of E. aerogenes bacteremia, reflected by high APACHE II score and isolation of strains with no susceptibility to extended-spectrum cephalosporins, were independent risk factors for mortality. Patients with severe illness and isolates resistant to extended-spectrum cephalosporins should be treated with more potent antimicrobial agents.

Full text

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329© 2009 Journal of Microbiology, Immunology and Infection
Clinical characteristics and predictors of mortality in patients
with Enterobacter aerogenes bacteremia
En-Pen Chang1, Dung-Hung Chiang2, Mei-Lin Lin2, Te-Li Chen2,3, Fu-Der Wang2, Cheng-Yi Liu2
1Section of Infectious Diseases, Department of Internal Medicine,
Wei Gong Memorial General Hospital, Miaoli; 2Division of Infectious Diseases,
Department of Medicine, Taipei Veterans General Hospital; and 3Institute of Tropical Medicine,
School of Medicine, National Yang-Ming University, Taipei, Taiwan
Received: February 29, 2008 Revised: April 6, 2008 Accepted: May 14, 2008
Corresponding author: Dr. Te-Li Chen, Division of Infectious
Diseases, Department of Medicine, Taipei Veterans General
Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei, Taiwan.
E-mail: tlchen@vghtpe.gov.tw
Background and purpose: Enterobacter aerogenes is increasingly encountered in nosocomial infections.
This study aimed to clarify the clinical characteristics and to identify the predictors of mortality in patients with
E. aerogenes bacteremia.
Methods: From March 2001 to April 2007, all patients with positive blood cultures for E. aerogenes at Taipei
Veterans General Hospital, Taipei, Taiwan, were enrolled in this retrospective study. The medical records were
reviewed for clinical and laboratory data.
Results: Eighty eight patients were included, 9 (10.2%) of whom died of E. aerogenes bacteremia. Most of the
patients had comorbidities. Seventy nine patients (89.8%) had nosocomial infections, and 43 patients (48.9%)
had polymicrobial infections. Eighty four patients (95.5%) presented with fever. Empirical antimicrobial therapy
was administered for 80 patients (90.9%), but was appropriate for only 55 patients (62.5%). Of the 9 patients who
died, 8 had polymicrobial infection, 5 of whom had nosocomial pneumonia, and 6 did not receive appropriate
antimicrobial therapy. Multivariate analysis indicated that high Acute Physiology and Chronic Health Evaluation
(APACHE) II score (>16) [odds ratio (OR), 16.569; 95% confidence interval (CI), 1.24-221.24; p = 0.034] and
strains not susceptible to extended-spectrum cephalosporins (OR, 9.21; 95% CI, 1.02-83.04; p = 0.048) were
independent risk factors for mortality.
Conclusions: The severity of E. aerogenes bacteremia, reflected by high APACHE II score and isolation of
strains with no susceptibility to extended-spectrum cephalosporins, were independent risk factors for mortality.
Patients with severe illness and isolates resistant to extended-spectrum cephalosporins should be treated with
more potent antimicrobial agents.
Key words: Bacteremia; Enterobacter aerogenes; Mortality; Risk factors
Original Article
J Microbiol Immunol Infect.
2009;42:329-335
Introduction
Enterobacter spp. are emerging as important patho-
gens for a wide variety of nosocomial infections [1,2],
including pneumonia, urinary tract infections, men-
ingitis, wound infections, and infections related to
intravascular and prosthetic devices [3]. Outbreaks
of infection have been traced to contaminated ice,
benzalkonium chloride, platelet transfusions, pressure
monitoring devices, and intravenous fluids [4].
Enterobacter spp. isolated from clinical samples in-
clude Enterobacter cloacae, Enterobacter aerogenes,
Enterobacter gergoviae, Enterobacter sakazakii, and
Enterobacter hormaechei [5]. E. aerogenes is respon-
sible for 15% to 25% of all Enterobacter infections [6].
E. aerogenes can cause primary bacteremia in pediatric
patients [7,8], mediastinitis following cardiac surgery
[9], and crepitant cellulitis [10]. Enterobacter bacter-
emia has been reported [11-13] and the mortality rate
for Enterobacter bacteremia was 29% in one study [11].
However, the clinical features and the risk factors for
mortality in patients infected with E. aerogenes has not

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Enterobacter aerogenes bacteremia mortality
© 2009 Journal of Microbiology, Immunology and Infection
been reported. This study aimed to characterize the
clinical features and identify the predictors of mortal-
ity in patients with E. aerogenes bacteremia.
Methods
Study population
Patients with positive blood culture for E. aerogenes
and who were admitted to the Taipei Veterans General
Hospital (TVGH), Taipei, Taiwan, from March 2001
to April 2007 were included in the study. The patients’
medical records were retrospectively reviewed for
demographic data, clinical characteristics, underlying
diseases, history of recent surgical or other invasive
procedures, clinical presentation, sources of bacter-
emia, laboratory and microbiological data, antimicro-
bial therapy, and outcomes.
Bacterial identification and antimicrobial
susceptibility testing
Blood culture samples were processed by the BACTEC
NR-660 system (Becton Dickinson Diagnostic Instru-
ment Systems, Spark, MD, USA). An automatic iden-
tification system for Gram-negative rods (ID 32 GN;
BioMérieux Vitek, Inc., Marcy l’Etoile, France) was
used for species identification. Antimicrobial susceptibil-
ity was determined by the disk diffusion method, and the
results were interpreted according to the recommenda-
tion of Clinical and Laboratory Standards Institute [14].
Clinical definitions
Nosocomial infection was defined as an infection
that occurred more than 48 h after admission to the
hospital or an infection that occurred less than 48 h
after discharge for patients who had been admitted to
hospital in the previous 2 weeks. Fever was defined
as an oral or tympanic temperature of more than
38.0°C. Septic shock was defined as sepsis associated
with evidence of organ hypoperfusion and a systolic
blood pressure <90 mm Hg or 30 mm Hg less than
baseline or a need for vasopressors to maintain the
blood pressure [15]. Acute renal failure was defined
as hemodialysis requirement or serum creatinine level
50% greater than baseline, resulting in an estimated
creatinine clearance of <40 mL/min (0.67 mL/sec)
following a bacteremic episode [16]. Chronic renal
disease was defined as kidney damage or glomerular
filtration rate <60 mL/min per 1.73 m2 for 3 months
or more [17]. Acute respiratory failure was defined
as new-onset respiratory failure requiring mechanical
ventilator support. Severity of illness was assessed
by Acute Physiology and Chronic Health Evaluation
(APACHE) II score within 72 h of the onset of symp-
toms of bacteremia.
The source of the bacteremia was determined by
concomitant or previous (within the past 7 days) isola-
tion of the same organism from urine, bile, wound, or
abscess aspirate. The source was considered to be an
intravenous catheter when the same organism was iso-
lated from blood and the catheter tip, but not from any
other body sites and there were >15 colony forming
units in the semiquantitative culture of the tip [18], or
when clinical findings of infection over the insertion
site of the catheter were evident without any other
possible sources of bacteremia. Bacteremia was con-
sidered to have originated from the respiratory tract
when clinical or radiological evidence of new-onset or
progressive pneumonia was found with concomitant
isolation of E. aerogenes from blood, or when the
strains with antibiograms identical to those isolated
from blood were discovered from sputum, bronchial
secretion, or other respiratory specimens. Bacteremia
was categorized as polymicrobial if additional micro-
organisms were concomitantly isolated from blood
cultures.
Antimicrobial therapy was considered empiric
when antimicrobial agents were administered for
treating E. aerogenes bacteremia before the results
of in vitro susceptibility tests were available. Anti-
microbial therapy was considered appropriate if the
treatment regimen included 1 antimicrobial agent ac-
tive against E. aerogenes in vitro, and if the dose and
route of administration conformed to current medical
standards. Antimicrobial therapy was considered to be
inappropriate if the drugs used did not have in vitro
activity against the isolated strain or if the patient did
not receive antimicrobial therapy. Non-susceptibility
to extended-spectrum cephalosporins was defined
as non-susceptibility to cefotaxime or ceftazidime
in vitro. Mortality was considered directly related to
bacteremia if it occurred in the active infection phase
without evidence of any other attributable cause [19].
Statistical analysis
Chi-squared or Fisher exact tests were used to com-
pare differences in dichotomous variables, and Mann-
Whitney U test was used for continuous variables.
Multivariate analysis with logistic regression was
performed to identify prognostic factors indepen-
dently associated with mortality due to E. aerogenes

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331© 2009 Journal of Microbiology, Immunology and Infection
Chang et al
bacteremia. Variables entered in the multivariate
analysis were required to have plausible relations with
mortality or a p value of ≤0.05. All analyses were
performed with the Statistical Package for the Social
Sciences (SPSS) for Window (Version 15.0; SPSS
Inc., Chicago, IL, USA). A p value <0.05 was consid-
ered statistically significant.
Results
Bacteremic episodes
During the study period, 98 patients with E. aerogenes
bacteremia were identified. Eighty eight patients with
adequate medical data were included. Nine of 88 pa-
tients died of E. aerogenes bacteremia.
Demographic data, comorbidities, and source of
bacteremia
Most of the patients were adults (mean ± standard
deviation [SD] age, 66.81 ± 16.71; range, 21-93
years). There were 62 men and 26 women. The mean
age ± SD of the patients who recovered was slightly
younger than those who died, but the difference was
not statistically significant (66.15 ± 17.40 years vs
72.56 ± 6.59 years; p = 0.393). Male sex was not as-
sociated with mortality (7/62 vs 2/26; p = 1.000), nor
was nosocomial infection (8/79 vs 1/9; p =1.000). The
associations between underlying diseases or source of
bacteremia and mortality are listed in Table 1. Patients
with non-neoplastic hepatobiliary diseases had a higher
mortality rate. Among the 5 patients who succumbed
to the infection, 3 patients had liver cirrhosis and 2 had
choledocholithiasis. Of the patients with liver cirrhosis,
1 had bacteremia after endoscopic ligation for bleeding
esophageal varices, 1 presented with spontaneous bac-
terial peritonitis, and 1 had pneumonia. Both patients
with choledocholithiasis experienced bile leakage and
poor wound healing after surgical intervention, which
resulted in polymicrobial infection.
Clinical characteristics and laboratory data
The clinical characteristics and laboratory data of the
patients are shown in Table 2. The majority of patients
(n = 84) presented with fever, but this symptom was
Table 1. Underlying diseases, risk factors, and sources of bacteremia associated with mortality in 88 patients with Enterobacter
aerogenes bacteremia.
Variable

Fatality (n = 9)
No. (%)
Recovered (n = 79)
No. (%)
p
Comorbidities
Malignancy
Hypertension
Diabetes mellitus
History of stroke if bedridden
Chronic renal disease
Congestive heart failure
Non-neoplastic hepatobiliary diseasesa
Autoimmune disease
Chronic obstructive pulmonary disease
Risk factors
Operation within 14 days of bacteremia
Invasive procedure within 2 days of bacteremia
Chemotherapy within 1 month of bacteremia
Immunosuppressive drugs within 1 month of bacteremia
Use of antimicrobial agents in previous month
Appropriateness of antimicrobial therapy
Sources
Respiratory tract
Hepatobiliary tract
Intravenous catheter
Urinary tract
Skin and soft tissue
Bone and joint
Undetermined
6 (66.7)
5 (55.6)
2 (22.2)
1 (11.1)
4 (44.4)
2 (22.2)
5 (55.6)
1 (11.1)
1 (11.1)
30 (38.0)
26 (32.9)
24 (30.4)
15 (19.0)
18 (22.8)
7 (8.9)
18 (22.8)
4 (5.1)
3 (3.8)
0.151
0.269
1.000
1.000
0.219
0.229
0.049
0.425
0.356
0 (0)
8 (88.9)
1 (11.1)
1 (11.1)
8 (88.9)
3 (33.3)
24 (30.4)
53 (67.1)
12 (15.2)
3 (3.8)
43 (54.4)
52 (65.8)
0.107
0.265
1.000
0.356
0.073
0.074
1 (11.1)
3 (33.3)
2 (22.2)
0 (0)
2 (22.2)
1 (11.1)
0 (0)
9 (11.4)
16 (20.3)
18 (22.8)
4 (5.1)
6 (7.6)
0 (0)
26 (32.9)
1.000
0.399
1.000
1.000
0.188
0.102
0.053
aIncluding 8 patients with liver cirrhosis, 3 with acute pancreatitis with biliary tract obstruction, and 12 with choledocholithiasis.

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Enterobacter aerogenes bacteremia mortality
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not significantly associated with mortality (p = 0.356).
The mean systolic blood pressure at the onset of the
bacteremic episodes was significantly lower in patients
who died (87.00 ± 13.28 mm Hg vs 118.95 ± 23.34
mm Hg; p < 0.001). Patients who died of E. aerogenes
bacteremia had significantly higher APACHE II score,
creatinine level, and C-reactive protein concentration
(CRP), and lower serum albumin level than those who
recovered. Patients with an APACHE II score >16 (88.9%
vs 11.1%; p = 0.001), CRP level >10 mg/dL (100% vs
0%; p = <0.001), albumin <2.8 gm/dL (77.8% vs 22.2%;
p = 0.003), or creatinine >2 mg/dL (77.8% vs 22.2%;
p ≤ 0.001) were more likely to die. Patients with poly-
microbial bacteremia also had a higher mortality rate.
Microbiological data and antimicrobial
susceptibility
Microorganisms involved in polymicrobial bacteremic
episodes included oxacillin-resistant Staphylococcus
aureus (n = 7), coagulase-negative staphylococci
(n = 4), Enterococcus spp. (n = 2), Pseudomonas
aeruginosa (n = 5), Acinetobacter baumannii (n = 4),
Escherichia coli (n = 13), E. cloacae (n = 6), Serratia
marcescens (n = 2), Klebsiella pneumoniae (n = 11),
and Streptococcus pneumoniae (n = 1). Four patients
had concurrent candidemia. Among the 8 patients
who died of polymicrobial infection, 7 had more than
2 bacterial species isolated. The susceptibility rate of
isolates to imipenem was 100% and to cefepime was
97.7%. Isolates from patients who died due to bacter-
emia were less susceptible to ampicillin-sulbactam,
piperacillin-tazobactam, cefuroxime, cefoperazone,
ceftazidime, cefotaxime, aztreonam, and tetracycline
than those from patients who recovered (Table 3). In-
terestingly, there were 2 patients in whom E. aerogenes
isolates were initially susceptible to ceftazidime, but
became resistant after treatment with this antimicro-
bial agent for 5 days.
Treatment and outcomes
Empirical antimicrobial therapy was administered for
80 patients (90.9%), but was appropriate for only 55
patients (62.5%). Eight patients did not receive any
antimicrobial therapy, but all 8 patients recovered.
Compared with patients who were treated with inap-
propriate therapy, those given appropriate antimicrobial
therapy had a lower mortality rate, but the difference
was not statistically significant (6/33 vs 3/55 patients;
p = 0.074). Among the 21 patients who had isolates
that were not susceptible to extended-spectrum cepha-
losporins, 14 (66.7%) were treated with inappropriate
antimicrobial agents, 4 (28.6%) of whom died of the
infection. Seven patients (33.3%) were treated with
appropriate antimicrobial agents, 3 (42.9%) of whom
died due to bacteremia. There was no significant dif-
ference for inappropriate antimicrobial agents between
the fatal and non-fatal groups (p = 0.638).
Fourteen patients (15.9%) developed acute de-
terioration of renal function, 25 (28.4%) developed
septic shock, and 15 (17%) received mechanical
ventilation support for respiratory failure after the
onset of E. aerogenes bacteremia. The development of
Table 2. Clinical features and laboratory data associated with mortality for 88 patients with Enterobacter aerogenes
bacteremia.
Variable

Fatality (n = 9)
No. (%)
Recovered (n = 79)
No. (%)
p
Fever
Shock
Acute respiratory failure
Acute renal failure
Polymicrobial infection
White blood cell count (cells/mm3) [mean ± SD]
Absolute neutrophil count (cells/mm3) [mean ± SD]
Platelet (cells/mm3) [mean ± SD]
C-reactive protein (mg/dL) [mean ± SD]a
Creatinine (mg/dL) [mean ± SD]
Albumin (g/dL) [mean ± SD]b
APACHE II score (mean ± SD)
8 (88.9)
7 (77.8)
5 (55.6)
7 (77.8)
8 (88.9)
76 (96.2)
18 (22.8)
10 (12.7)
7 (8.9)
35 (44.3)
12,010 ± 9237
10,483 ± 8731
197,718 ± 106,336
9.56 ± 8.81
1.72 ± 1.80
3.31 ± 0.58
12.95 ± 6.86
0.356
0.002
0.006
<0.001
0.014
0.342
0.146
0.295
0.001
0.003
<0.001
0.001
14,811 ± 10,065
12,487 ± 8682
157,458 ± 87,854
19.61 ± 4.94
3.13 ± 1.28
2.40 ± 0.53
24.33 ± 4.63
aData not available for 1 patient.
bData not available for 2 patients.
Abbreviations: SD = standard deviation; APACHE II = Acute Physiology and Chronic Health Evaluation II.

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333© 2009 Journal of Microbiology, Immunology and Infection
Chang et al
any of these 3 complications was a significant predic-
tor of mortality in univariate analysis (Table 2). For
the 8 patients who died of polymicrobial bacteremia,
5 had nosocomial pneumonia and 6 did not receive
appropriate antimicrobial therapy. The only fatality
due to monomicrobial infection was a patient with old
pulmonary tuberculosis and diabetes mellitus, who
was admitted to hospital for aspiration pneumonia
complicated with respiratory failure and septic shock.
Factors entered into multivariate analysis included
non-neoplastic hepatobiliary diseases, APACHE II
score >16, albumin level <2.8 gm/dL, CRP >10 mg/dL,
polymicrobial bacteremia, and non-susceptibility to
extended-spectrum cephalosporins. Although ap-
propriateness of antimicrobial treatment was not
significant by univariate analysis (Table 1), this factor
was also included in the multivariate analysis. The
results demonstrated that high APACHE II score (>16)
[odds ratio (OR), 16.569; 95% confidence interval (CI),
1.24-221.24; p = 0.034] and isolation of strains non-
susceptible to extended-spectrum cephalosporins (OR,
9.21; 95% CI, 1.02-83.04; p = 0.048) were independent
risk factors for mortality.
Discussion
Enterobacter spp. are emerging as important pathogens
of nosocomial bacteremia [20]. E. cloacae are the most
common species, and accounted for 1.95% of all bacter-
emic episodes at the TVGH during a 2-year study [21].
The mortality rate was 20.4% [21]. E. aerogenes were
less frequently isolated, and accounted for 0.46% of all
bacteremic episodes in this study. The mortality rate
for patients infected with E. aerogenes was also lower
(10.2%).
This study demonstrated that E. aerogenes might
be a low virulence bacterium. Among the patients
with monomicrobial infection, only 1 patient died.
Most of the patients who died of bacteremia were
immunocompromised and had polymicrobial infec-
tion. According to the univariate analysis, a subgroup
of patients with non-neoplastic hepatobiliary disease
were vulnerable to this infection. However, comorbid
malignant diseases were not associated with a poor
prognosis, despite the patients also being immuno-
compromised.
Little is known about the potential virulence of
E. aerogenes. The capsule may contribute to serum
resistance and resistance to phagocytosis [3]. This
study demonstrated that infection with antimicrobial-
resistant isolates was associated with mortality,
but the study did not demonstrate a contribution of
inappropriate therapy to mortality. In some bacteria,
certain virulent determinants have been found to be
colocalized in the same plasmid harboring the anti-
microbial resistance. These newly formed plasmids
can be selected for by antimicrobial pressure, there-
fore, isolates with antimicrobial resistance might also
be more virulent [22]. Among the 8 patients who died
of polymicrobial infection, the isolates had reduced
susceptibility to extended-spectrum cephalosporins
and 6 patients received inappropriate therapy. Entero-
bacter spp. readily develops resistance to second- and
third-generation cephalosporins owing to an inducible
Table 3. Percent of patients with non-susceptible Enterobacter aerogenes isolates according to antibiotic.
Antimicrobial Fatality (n = 9) Recovered (n = 79)
p
Ampicillin
Ampicillin-sulbactam
Piperacillin-tazobactam
Cefazolin
Cefuroxime
Cefoperazone
Ceftazidime
Cefotaxime
Cefepime
Aztreonam
Ciprofloxacin
Amikacin
Gentamicin
Chloramphenicol
Tetracycline
Trimethoprim-sulfamethoxazole
100
77.8
55.6
100
88.9
55.6
77.8
66.7
11.1
55.6
22.2
0
11.1
22.2
66.7
44.4
92.4
25.3
19.0
79.7
32.9
13.9
17.7
20.3
1.3
17.7
6.3
5.1
11.4
13.9
24.1
16.5
1.000
0.003
0.026
0.202
0.002
0.009
<0.001
0.007
0.195
0.020
0.149
1.000
1.000
0.616
0.014
0.066

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gene encoding AmpC type β-lactamase that is control-
led by both positive and negative regulators [23-25],
and this is associated with previous use of extended-
spectrum cephalosporins [26-29], as seen in 2 of these
patients. Furthermore, mutants that constitutively pro-
duce a high level of β-lactamase resulting from muta-
tions in the regulatory loci can also confer resistance to
third-generation cephalosporins. Therefore, clinicians
must be aware that emergence of resistant mutants
may lead to treatment failure when third-generation
cephalosporins are selected, even if the isolates appear
to be susceptible at initial testing [26]. As a result,
fourth-generation cephalosporins or carbapenems may
be better choices for the treatment of serious infections
involving large numbers of bacteria [3].
APACHE II is a classification system for disease
severity that uses basic physiologic principles to
stratify acutely ill patients prognostically by risk of
death. In this study, APACHE II score was also an
independent factor for mortality. CRP is a marker of
inflammation that has been used to monitor the course
of infection and inflammatory diseases [30]. Increased
CRP concentrations have been associated with organ
failure, prolonged intensive care unit stay, and high
infection and mortality rates [31]. In this study patients
with bacteremia who died had higher CRP levels in the
univariate analysis than those who recovered. Previous
studies have demonstrated that serum albumin concen-
tration is inversely related to poor clinical outcomes
[32,33]. Several mechanisms might explain the appar-
ent protective effects of serum albumin. Clearly, serum
albumin plays diverse, complex, and important roles
in maintaining physiologic homeostasis. At reduced
albumin levels these homeostatic functions may be im-
paired, resulting in the development and/or progression
of pathologic processes underlying poor outcome [33].
There are some limitations to this study. The use of
the ID 32 GN system for identification of E. aerogenes
has not been validated. This study included patients
with polymicrobial infection, which contributed to most
of the deaths. This result may overestimate the patho-
genicity of E. aerogenes. This was a retrospective study,
in which the confounding factors related to mortality
cannot be perfectly matched. The small number of
patients might mask the effect of inappropriate therapy,
which might be a plausible cause of mortality for pa-
tients with extended-spectrum cephalosporin–resistant
strains.
In conclusion, this study showed that E. aerogenes
is a nosocomial pathogen that is often associated with
polymicrobial infection. The severity of the illness, as
reflected by higher APACHE II score, and isolation of
strains with non-susceptibility to extended-spectrum
cephalosporins were independent risk factors for
mortality. More potent antimicrobial agents should be
provided to patients at increased risk for severe infec-
tion to improve their outcomes.
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