1127
Vancomycin-Resistant and Vancomycin-Susceptible Enterococcal Bacteremia:
Comparison of Clinical Features and Outcomes
Gregory M. Lucas, Noah Lechtzin, D. Wonder Puryear,
Linda L. Yau, Charles W. Flexner,
and Richard D. Moore
From the Department of Medicine, The Johns Hopkins University,
Baltimore, Maryland
Vancomycin-resistant Enterococcus (VRE) is a major nosocomial pathogen. We collected clinical
and laboratory data on 93 hospitalized adults with VRE bacteremia and 101 adults with vancomycinsusceptible enterococcal (VSE) bacteremia. Risk factors for VRE bacteremia included central venous
catheterization, hyperalimentation, and prolonged hospitalization prior to the initial blood culture.
VRE-infected patients were less likely to have undergone recent surgery or have polymicrobial
bacteremia, suggesting a pathogenesis distinct from traditional VSE bacteremia. Prior exposure to
metronidazole was the only significant pharmacologic risk factor for VRE bacteremia. Animal
studies suggest metronidazole potentiates enterococcal overgrowth in the gastrointestinal tract and
translocation into the bloodstream. An increasing APACHE II score was the major risk factor for
death in a multivariate analysis, with VRE status being of only borderline significance.
Vancomycin-resistant Enterococcus (VRE) emerged in the
1990s as a major nosocomial pathogen. The first descriptions of
plasmid-mediated resistance to vancomycin among enterococci
appeared in 1988 [1, 2]. Resistant organisms established endemicity at many centers, particularly large, tertiary-care teaching
hospitals [3 – 8]. From 1989 to 1993 the percentage of nosocomial enterococcal pathogens that were resistant to vancomycin
increased 20-fold according to the National Nosocomial Infections Surveillance system [9]. In 1993, nearly 14% of enterococci isolated in intensive care units were resistant to vancomycin [9]. At one center, point-prevalence studies revealed that
20% of inpatients were colonized with VRE [8].
Enterococci, particularly Enterococcus faecium, have intrinsic resistance to many antibiotics, notably penicillinase-resistant penicillins, cephalosporins, and clindamycin. During the
1970s and 1980s, isolates increasingly emerged with acquired,
high-level resistance to ampicillin and aminoglycosides [10 –
12]. The addition of vancomycin resistance to this profile resulted in a pathogen that is untreatable with most available
antibiotics. Efforts to prevent colonization with universal precautions and restricted vancomycin utilization at centers where
VRE is endemic have been largely unsuccessful [8, 13]. Of
Received 14 October 1997; revised 7 January 1998.
Presented in part at the Infectious Diseases Society of America meeting
(poster session) on 15 September 1997 in San Francisco.
Current addresses: Dr. D. Wonder Puryear, Kirklin Clinic, University of
Alabama at Birmingham, Birmingham, Alabama 35233; Dr. Linda L. Yau,
East Baltimore Medical Center, 1000 East Eager Street, Baltimore, Maryland
21202.
Reprints: Dr. Richard D. Moore, 1830 Building, Room 8059, The Johns
Hopkins Hospital, Baltimore, Maryland 21212.
Correspondence: Dr. Gregory M. Lucas, Carnegie 346, The Johns Hopkins
Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287.
Clinical Infectious Diseases 1998;26:1127–33
q 1998 by The University of Chicago. All rights reserved.
1058–4838/98/2605–0019$03.00
/ 9c4c$$my59
04-10-98 01:30:34
even greater concern is the emergence of vancomycin resistance in more virulent gram-positive organisms.
Previous studies have indicated that VRE bacteremia is associated with extensive comorbid pathology, prolonged hospitalizations, heavy exposure to antimicrobial agents, and high
crude mortality rates [14 – 18]. The pathogenesis of VRE bacteremia is incompletely described, and the role of VRE itself
in producing excess mortality is controversial [14, 18]. We
conducted a case-control study of the clinical characteristics,
antibiotic usage, microbiological factors, and clinical endpoints
for patients with VRE and vancomycin-susceptible enterococcal (VSE) bacteremia in an academic medical center. Our study
is the largest reported series of VRE bacteremia cases from a
single institution.
Methods
A database of the Department of Microbiology of The Johns
Hopkins Hospital (Baltimore) was culled for all inpatient enterococcal blood isolates from August 1991 until September
1996. One-hundred thirty-seven patients with VRE-positive
blood cultures were identified. Patients with VSE bacteremia
were selected such that the distribution of initial culture dates
was the same as for the VRE-infected patients. Specifically, for
each VRE-infected patient, a VSE-infected patient was selected
from the database whose date of onset of initial bacteremia
was most proximal to the initial culture date of the VREinfected counterpart. Patients’ medical charts were then reviewed in a systematic manner for demographic, clinical, and
microbiological data points. A structured data collection form
was used to abstract data in eight categories from patients’
records. Only records from which five or more of these categories were able to be completed were included in subsequent
analysis.
Data regarding exposure to antimicrobials and other pharmaceuticals prior to the initial episode of bacteremia were obtained
cida
UC: CID
1128
Lucas et al.
for each patient from a computerized billing database. Exposure
to antimicrobials was evaluated from the date of admission to
the hospital through the date of the initial enterococcal blood
culture. The records of 93 VRE-infected (68%) and 101 VSEinfected patients (74%) were sufficiently complete to be used
in the study. This study was approved by The Johns Hopkins
University Institutional Review Board.
Microbiology. Blood cultures were performed by inoculating blood samples from either sterile venipuncture or central
venous catheters into BACTEC 460 6A aerobic or 16T anaerobic bottles (Becton Dickinson, Towson, MD) and subsequently
into BacT/Alert bottles (Organon Teknika, Durham, NC). Enterococci were identified on the basis of the following characteristics: growth on sheep blood agar, growth on bile-esculin
agar as well as 6.5% sodium chloride, growth at 457C, lack of
gas production from glucose, and hydrolysis of pyrrolidonylB-naphthylamide. The species of organisms was identified on
the basis of arginine hydrolysis, motility, and carbohydrate
fermentation [19].
Antibiotic susceptibility testing of blood and nonblood isolates was performed by a standard agar-dilution method and
according to guidelines of the National Committee for Clinical
Laboratory Standards [20]. Ampicillin and vancomycin resistance were defined by MICs of ú16 mg/mL and ú64 mg/mL,
respectively. Testing for high-level gentamicin resistance is not
routinely performed on enterococcal isolates at our institution.
Definitions. VRE-infected and VSE-infected patients were
defined as nonpediatric inpatients of age §18 years who had at
least one blood isolate recovered of VRE or VSE, respectively.
APACHE (acute physiology and chronic health evaluation) II
scores were calculated for each patient on the day of the initial
positive enterococcal blood culture. APACHE II is a validated
severity-of-disease scoring system that uses age, 12 physiological parameters, and chronic health status to generate a score
from 0 to 71 in increasing severity of illness [21]. Polymicrobial
bacteremia was defined by the isolation of a second bacterial
species (excluding coagulase-negative staphylococcus) or fungus on the same day as the initial Enterococcus isolation from
blood. Exposure to immunosuppressive therapy refers to the
use of glucocorticoids, cyclosporin, cyclophosphamide, methotrexate, or azathioprine in the 2 weeks prior to onset of bacteremia for the purpose of treating nonmalignant conditions. All
references to mortality are to crude mortality.
Statistics. We compared the characteristics of VREinfected and VSE-infected patients by means of x2 (continuityadjusted) or Student’s t-tests. A two-tailed Fisher’s exact test
was used for comparisons of pharmacological exposure. All
variables having a P value of £.1 were included in logistic
regression modeling, along with selected variables that have
been noted to be significant in other published reports. Multivariate analysis was done with use of logistic regression, with
significant variables selected by a backward stepwise procedure. Pharmacological exposure data were not included in the
regression analyses because inconsistencies between the billing
/ 9c4c$$my59
04-10-98 01:30:34
CID 1998;26 (May)
Table 1. Clinical features of patients with VRE or VSE bacteremia.
Percentage of patients with
bacteremia due to
Variable
Demographic data
Age (y)*
Male sex
White ethnicity
In ICU at time of bacteremia
Hospitalization days prior
to culture*
Clinical characteristics
APACHE II score*
Diabetes mellitus
Malignancy
Organ transplant recipient
HIV-positive
Recent surgery†
Assisted ventilation
Central venous catheter
Receiving hyperalimentation
Urinary catheter
Fecal incontinence
Decubitus ulcers
Treatments and outcomes
Antibiotic therapy changed in
response to initial bacteremia
Vascular catheter removed
Hospitalization days after
initial culture*
Length of hospitalization*
Any ICU stay
Days in ICU per patient*
Crude mortality
VSE
(n Å 101)
VRE
(n Å 93)
60.4 { 16.3
53
49
39
56.1 { 17.5
56
70
38
.125
.732
.003
.888
16.8 { 23.2
24.4 { 24.1
õ.001
17.8 { 9.1
23
32
4
11
62
33
77
36
60
39
5
20.1 { 8.9
19
31
8
8
41
37
88
53
61
47
10
79
46
56
47
21.8 { 20.8
38.6 { 31.2
61
12.5 { 19.0
27
24.7 { 39.9
49.1 { 48.3
70
17.1 { 20.7
45
P value
.044
.536
.940
.275
.420
.004
.570
.031
.014
.647
.305
.202
õ.001
.879
.682
.050
.166
.028
.007
NOTE. APACHE Å acute physiology and chronic health evaluation; ICU
Å intensive care unit; VRE and VSE Å vancomycin-resistant and vancomycinsusceptible Enterococcus.
* Continuous variables are expressed as means ( {SD).
†
Surgery within 2 weeks prior to onset of bacteremia or during prior hospitalization.
dates and administration dates generated potential treatment
bias. Statistical analysis of the data was performed with use of
Epi-Info, version 6 (Centers for Disease Control and Prevention, Atlanta) and SAS for Windows, version 6.11 (SAS Institute, Cary, NC).
Results
A comparison of demographic and clinical characteristics is
shown in table 1. Patients with VRE bacteremia were significantly more likely to be white, have a central venous catheter,
and be receiving hyperalimentation. In addition, VRE-infected
patients had been hospitalized an average of 7.5 days longer
than VSE-infected patients at the time of onset of initial entero-
cida
UC: CID
CID 1998;26 (May)
VRE Bacteremia: Risk Factors and Outcomes
Table 2. Microbiological comparisons of VRE- and VSE-infected
patients.
Percentage of patients with
bacteremia due to
VSE
(n Å 101)
Variable
Species of Enterococcus
E. faecium
E. faecalis
Other
Initial blood culture specimen
from central line
Patients with ú1 positive
enterococcal blood culture
Days between first and last
positive enterococcal blood
culture (mean { SD)
Polymicrobial bacteremia
Enterococcus isolated from
another body site
Enterococcus isolated from
Urine
Wound
Sputum
Biliary drain
Abdominal fluid
Vascular catheter tip
VRE
(n Å 93)
P value
27
70
3
99
1
0
õ.001
45
53
.380
22
45
.005
1.3 { 5.2
12
3.1 { 6.9
5
õ.001
.109
54
53
.805
25
18
15
12
7
9
32
14
14
8
13
9
.247
.465
.863
.308
.162
.939
NOTE. VRE and VSE Å vancomycin-resistant and vancomycin-susceptible Enterococcus.
coccal bacteremia (P õ .001). VSE-infected patients were more
likely than VRE-infected patients to have undergone recent
surgery.
VRE-infected and VSE-infected patients were similarly
likely to be in the intensive care unit and receiving mechanical
ventilation at the time of initial blood culture. The mean ({SD)
APACHE II scores were 20.1 { 8.9 among VRE-infected patients and 17.8 { 9.1 among VSE-infected patients (P Å .04).
The prevalences of diabetes mellitus, malignancy, HIV infection, immunosuppressive pharmacotherapy, and organ transplantation were similar among VRE- and VSE-infected patients.
Microbiological comparisons are shown in table 2. Ninetytwo of the 93 VRE bacteremias were caused by E. faecium.
Twenty-seven of the 101 VSE bacteremias were caused by
E. faecium and 71 by Enterococcus faecalis (table 2). The
initial blood culture specimen was drawn from a central line
in similar percentages of VRE and VSE patients. All but one
of the VRE isolates and 13% of the VSE isolates were resistant
to ampicillin (data not shown).
VRE-infected patients were more likely than VSE-infected
patients to have multiple blood cultures positive for enterococci
over the ensuing hospitalization (45% vs. 22%; P Å .005).
Moreover, VRE-infected patients had bacteremia longer than
VSE-infected patients; the average times between the first and
/ 9c4c$$my59
04-10-98 01:30:34
1129
last positive enterococcal blood culture were 3.1 days and 1.3
days, respectively (P õ .001). Sixteen of 93 VRE-infected
patients had blood cultures positive for VSE at some point
during the hospitalization (data not shown).
Conversely, VSE-infected patients were more likely than
VRE-infected patients to have polymicrobial bacteremia (12%
vs. 5%; P Å .109). The organisms most frequently isolated
from the blood with the initial enterococcal isolates were Staphylococcus aureus, Enterobacter cloacae, and Candida albicans.
In about half of VRE and VSE bacteremia cases, an enterococcus was isolated from a second site. Urine, wounds, and
sputum were the most common additional sites of isolation
(table 2). There was no significant difference between VREinfected and VSE-infected patients in terms of the incidence
of isolation of an enterococcus from additional body sites.
A comparison of exposure to 12 classes of antimicrobial
agents, gastric acid inhibitors, and sucralfate prior to the initial
positive enterococcal blood culture is shown in table 3. Only
exposures to metronidazole, tetracyclines, and chloramphenicol
were significantly more common in VRE-infected than VSEinfected patients; there was a trend toward more quinolone
exposure in the former group (40% vs. 27%; P Å .07). Prior
exposure to vancomycin, aminoglycosides, and cephalosporins
was similar in the two groups.
The results of our logistic regression analysis to identify risk
factors associated with VRE bacteremia in hospitalized patients
are shown in table 4. Significant risk factors for VRE bacteremia
included white ethnicity, prolonged hospitalization, a central ve-
Table 3. Comparison of pharmacological exposure in VRE- and
VSE-infected patients.
Percentage of patients
with bacteremia due to
Pharmacological agent(s)
Immunosuppressive therapy
Recent chemotherapy†
Cephalosporins
Vancomycin (intravenous)
Aminoglycosides
Penicillins
Metronidazole
Quinolones
Clindamycin
Sulfonamides
Tetracyclines
Vancomycin (oral)
Chloramphenicol
Gastric acid inhibitors
Sucralfate
VSE
(n Å 101)
VRE
(n Å 93)
P value*
21
7
62
59
55
42
35
27
22
17
3
9
1
45
38
25
13
66
64
58
37
55
40
26
14
30
9
8
54
49
.553
.16
.551
.553
.772
.555
.006
.066
.612
.692
õ.001
1.00
.029
.248
.146
NOTE. VRE and VSE Å vancomycin-resistant and vancomycin-susceptible Enterococcus.
* Calculated with the two-tailed Fisher’s exact test.
†
Chemotherapy within the 30 days prior to onset of bacteremia.
cida
UC: CID
1130
Lucas et al.
Table 4. Multivariate analysis of risk factors for VRE bacteremia
and death.
Variable
OR (95% CI)
Risk of VRE bacteremia
Days in hospital prior
to onset of bacteremia*
Hyperalimentation
Central venous catheter
White ethnicity
Recent surgery
Risk of in-hospital death
APACHE II score†
VRE bacteremia
1.02
3.65
2.68
1.88
.12
P value
(1.01 – 1.04)
(1.45 – 9.26)
(.92 – 7.87)
(1.0 – 3.55)
(.05 – .31)
.004
.006
.072
.052
õ.001
1.14 (1.08 – 1.20)
2.07 (.96 – 4.42)
õ.001
.063
NOTE. Pharmacological exposures were not included in analysis. VRE Å
vancomycin-resistant Enterococcus.
* OR expressed per additional hospital day.
†
OR expressed per additional point on the APACHE (acute physiology and
chronic health evaluation) II scale.
CID 1998;26 (May)
found that length of hospitalization was the strongest clinical
risk factor for VRE bacteremia in comparison with VSE bacteremia [14]. Several series have reported average hospitalizations
of ú2 weeks prior to the development of enterococcal bacteremia [14, 15, 22, 23].
Central venous catheters may serve as the actual conduit
through which the bacteremia is established or may simply be
markers of debilitation and prolonged hospitalization, with
other sources of bloodstream infection predominating. Our data
suggest the latter, as VRE- and VSE-infected patients were
similar in both the percentage of initial blood culture specimens
drawn from a central line (53% and 45%; P Å .38) as well as
the percentage whose catheter tips yielded an enterococcus (9%
for each). The higher prevalence of hyperalimentation indicates
more gastrointestinal dysfunction among the VRE-infected pa-
Table 5. Factors associated with mortality among patients with VRE
and VSE bacteremia.
nous catheter, and hyperalimentation. Recent surgery was statistically more likely in VSE-infected patients. APACHE II scores
and location in an intensive care unit (ICU) were not associated
with VRE bacteremia in this model.
VRE bacteremia was associated with higher crude mortality
than was VSE bacteremia (45% vs. 27%; P Å .007; table 1).
In addition, VRE-infected patients had longer ICU stays and
were less likely to have antimicrobial agents changed in response to the initial episode of bacteremia (table 1). Other
microbiological endpoints, such as multiple positive enterococcal blood cultures, isolation of an enterococcus from more than
one site, and polymicrobial bacteremia, were not associated
with mortality (table 5).
Correlates of in-hospital mortality are listed in table 5. Elevated APACHE II scores, location in an ICU at the time of
culture positivity, and mechanical ventilation were strongly
associated with mortality. Other clinical variables associated
with mortality included fecal incontinence, decubitus ulcers,
presence of a urinary catheter, and presence of a femoral vascular catheter. Patients who died had significantly longer hospital
stays prior to the initial blood culture positivity than patients
who lived. The total length of hospitalization was not significantly different between these two groups.
In a logistic regression model, only APACHE II scores were
strongly associated with mortality. VRE bacteremia retained
a trend toward higher mortality that did not reach statistical
significance (P Å .06) (table 4).
Discussion
We found three major risk factors for VRE vs. VSE bacteremia: prolonged stay in the hospital prior to the initial culture
positivity, central venous access with hyperalimentation, and
exposure to metronidazole. Linden and colleagues similarly
/ 9c4c$$my59
04-10-98 01:30:34
Variable
present
Variable
Categorical variables*
Male sex
White ethnicity
In ICU at time of onset of
bacteremia
Malignancy
Organ transplant recipient
HIV-positive
Fecal incontinence
Decubitus ulcer(s)
Recent surgery†
Assisted ventilation
Femoral vascular catheter
Receiving hyperalimentation
Urinary catheter
ú1 Positive enterococcal
blood culture
Polymicrobial bacteremia
Enterococcus isolated from
another site
Variable
absent
P value
42/106 (40)
37/111 (33)
27/88 (31)
31/77 (40)
.195
.331
39/74 (53)
14/61 (23)
5/11 (45)
3/18 (17)
41/82 (50)
9/14 (64)
33/100 (33)
38/67 (57)
21/43 (49)
36/85 (42)
49/117 (42)
30/120 (25)
55/133 (41)
64/182 (35)
66/176 (38)
27/109 (25)
58/176 (33)
36/94 (38)
31/127 (24)
46/148 (31)
33/108 (31)
20/75 (27)
õ.001
.013
.498
.079
õ.001
.018
.441
õ.001
.032
.090
.032
27/64 (42)
7/24 (29)
42/130 (32)
62/170 (36)
.177
.484
39/104 (38)
30/90 (33)
.545
Died
(n Å 69)
Continuous variables‡
Age (y)
LOS prior to initial positive
culture
APACHE II score
Lived
(n Å 125)
61 { 16.6
56.9 { 17.1
.103
26.2 { 28.5
24.6 { 8.6
17.2 { 20.4
15.7 { 7.8
.007
õ.001
NOTE. APACHE Å acute physiology and chronic health evaluation; ICU
Å intensive care unit; LOS Å length of stay; VRE and VSE Å vancomycinresistant and vancomycin-susceptible Enterococcus.
* Categorical variables are expressed as proportion (%) of patients with and
without the variable who died.
†
Surgery within 2 weeks prior to onset of bacteremia or during prior hospitalization.
‡
Continuous variables are expressed as means with standard deviations.
cida
UC: CID
CID 1998;26 (May)
VRE Bacteremia: Risk Factors and Outcomes
tients. Gut pathology may predispose to translocation of colonizing VRE into the bloodstream.
The VRE and VSE bacteremic cohorts were similar in many
important clinical variables. Ninety-one percent of the VRE
bacteremia cases and 80% of the VSE bacteremia cases involved hospitalization at least 3 days prior to culture, making
nosocomial acquisition the overwhelmingly predominant mode
of transmission in both groups. Location in an ICU, assisted
ventilation, APACHE II score on day of onset of bacteremia,
diabetes, malignancy, and immunocompromised status were all
similar in the VRE and VSE bacteremic cohorts. A study by
Shay and colleagues found that a higher APACHE II score,
hematologic malignancy, and a bone marrow transplant were
statistically more common among patients with nosocomial
VRE bacteremias than among those with VSE bacteremias
[18]. Their study was conducted over the initial 18 months of
an institutional outbreak. Our study covered a 5-year period
and analyzed data from twice as many patients. Therefore, it
is possible that the similar clinical characteristics of VRE and
VSE bacteremic patients in our study represent the features of
a more stable VRE endemic at our institution.
It is interesting that the finding of polymicrobial bacteremia
at the time of the initial blood culture and recent surgery were
less common among VRE- than VSE-infected patients. Furthermore, the rate of polymicrobial bacteremia in the VRE
bacteremia patients in our study (5%) is significantly less than
the rate reported in past series of patients with VSE bacteremia
(range, 24% – 50%) [22 – 27]. Linden and colleagues noted a
similar trend, with only 9% of VRE-infected patients but 41%
of VSE-infected patients having polymicrobial bacteremia [14].
Traditionally, enterococcal bacteremia has been associated
with microbiologically complex abdominal or genitourinary
infections, often producing polymicrobial bacteremia and necessitating surgical intervention. However, our finding that
VRE bacteremia occurs less commonly in postoperative patients and tends to be monomicrobial implies a pathogenesis
distinct from traditional VSE bacteremia. Other studies have
shown gastrointestinal tract colonization with VRE to be universally present in patients developing bacteremia [4, 17].
Thus, VRE bacteremia may emerge in the setting of prolonged
gastrointestinal colonization as an isolated breakthrough event
in antimicrobial coverage.
With respect to pharmacological exposure, we found that
prior exposures to metronidazole, tetracycline, and chloramphenicol were statistically associated with VRE bacteremia.
Tetracyclines and chloramphenicol are rarely given to hospitalized patients at our institution (3% and 1%, respectively, of the
VSE-infected patients), and their use likely represents treatment
bias. The billing database employed to acquire the pharmacological data has an imperfect correlation between billing dates
and administration dates. Therefore, agents used following the
initial enterococcal bacteremia were sometimes recorded on
billing dates prior to the onset of the bacteremia. Because
tetracyclines and chloramphenicol were frequently used in at-
/ 9c4c$$my59
04-10-98 01:30:34
1131
tempt to treat VRE infection, we believe their use represents
a treatment bias and not a genuine risk factor. Metronidazole,
in contradistinction, was not used in the attempted treatment
of VRE infections.
Smaller studies have noted a correlation between total antimicrobial exposure and VRE infection [4, 5, 17]. Other studies
have identified vancomycin, ciprofloxacin, metronidazole, and
cephalosporin exposure as risk factors for VRE infection [3,
6, 8, 13, 17, 18].
The unique association of metronidazole exposure and VRE
bacteremia in our study is intriguing. Edmond and colleagues
hypothesized, on the basis of their findings, that agents with
significant anaerobic activity such as metronidazole increase
the likelihood of VRE colonization in the lower gastrointestinal
tract [17]. In addition, animal models suggest that disruption
of the anaerobic flora by metronidazole may promote overgrowth of enterococcal species in the gastrointestinal tract as
well as increase the frequency of translocation into mesenteric
lymph nodes [28 – 30]. Thus, patients developing gastrointestinal tract colonization with VRE during prolonged hospitalizations may be placed at further risk for bacteremia if metronidazole is concurrently administered.
An unexpected finding in our study was that white ethnicity
was statistically associated with VRE bacteremia. White patients had longer hospitalizations than black patients prior to
the initial onset of bacteremia (23 days vs. 16 days; P Å .04).
As our institution serves as the primary care hospital for an
inner city area whose population is predominantly black, it is
possible that white patients are a subset more likely to be
referred for tertiary care and thus are predisposed to longer
hospitalizations and increased risk for VRE colonization and
infection. Indeed, 78% of the white patients in our study had
a home address outside of Baltimore, whereas only 17% of
black patients were from out of town (data not shown). Thus,
this difference is unlikely to reflect an important biological
phenomenon, as similar trends have not been reported by other
investigators.
In terms of clinical outcomes, VRE bacteremic patients had
longer total hospitalizations than did VSE bacteremic patients
(49 vs. 39 days; P Å .05). This difference was accounted for
entirely by a longer time in the hospital prior to the initial
onset of bacteremia (24 vs. 16 days; P Å .003) rather than
length of stay following onset of bacteremia (25 vs. 22 days;
P Å .7). However, the higher crude mortality rate among VREinfected patients may substantially reduce the average time
hospitalized following onset of bacteremia. While a similar
majority of both VRE- and VSE-infected patients spent some
time in an ICU, VRE-infected patients had longer lengths of
stay (13 vs. 17 days; P Å .03).
In the univariate analysis there were several strong predictors
of mortality, including VRE bacteremia (mortality, 45% vs.
27% in VRE and VSE bacteremic patients, respectively;
P Å .007). In the multivariate analysis, VRE status retained
only a trend toward increased mortality (table 4). Neither the
cida
UC: CID
1132
Lucas et al.
presence of VRE at a second site nor persistent VRE bacteremia
were associated with increased mortality, suggesting a minor
pathogenic role for VRE itself.
Similarly, two other studies comparing VRE and VSE bacteremia noted higher mortality among VRE cases in the univariate analysis that lost significance in logistic regression modeling [16, 18]. However, Linden and colleagues reported
increased mortality among VRE bacteremic patients in a multivariate analysis [14]. A validated severity of disease scoring
system, such as APACHE II, was not used in that study, possibly allowing underlying differences in comorbid factors between VRE-infected and VSE-infected patients to remain
masked. In addition, all of the patients in that series had liver
disease and 81% had undergone liver transplantation, making
the results difficult to extrapolate to a more diverse hospital
population.
Prior to the emergence of VRE, enterococcal bacteremia was
noted in many series to be associated with high mortality rates
(range, 19% – 54%) [22 – 27]. With the exception of causing
endocarditis and meningitis, the actual pathological role of the
enterococcus in this high mortality has been questioned by
several groups [11, 16, 18, 23, 24]. The relative avirulence of
enterococci is supported by a rat model of peritoneal polymicrobial infection. When enterococcus was injected alone, it had
a very low virulence, as measured by the LD50 and intraperitoneal abscess formation [31]. Combination with aerobic gramnegative bacilli or anaerobic organisms potentiated the virulence. Moreover, antibiotic regimens with minimal efficacy
against enterococci but good coverage of gram-negative and
anaerobic organisms were highly effective in treating mixed
enterococcal infections [32].
Our study had three main limitations. First, VRE- and VSEinfected patients were selected on the basis of a single positive
blood culture that may have been drawn from an indwelling
vascular catheter. This raises the concern that many of the cases
may have represented contamination and not true bloodstream
infection. The guidelines of the Centers for Disease Control and
Prevention for nosocomial infections indicate that a primary
bloodstream infection may be diagnosed when a recognized
pathogen that is not a common part of the skin flora is isolated
in a single blood culture [33]. However, other investigators
often use more selective criteria such as multiple blood cultures
or administration of antibiotics by the treating physician.
Only a small percentage of the patients in our study were
selected on the basis of results of a single culture of blood
from an indwelling catheter, without subsequently having the
catheter removed or antibiotic treatment redirected (4% of VSE
and 6% of VRE bacteremic patients; data not shown). To further explore the issue, we compared 67 VRE bacteremic patients who had multiple positive blood cultures or whose antibiotics were changed in response to the bacteremia with the
remaining 26 VRE-infected patients not meeting these criteria.
The two groups had a similar mean number of hospital days
prior to onset of bacteremia (22 vs. 25); mean APACHE II
/ 9c4c$$my59
04-10-98 01:30:34
CID 1998;26 (May)
scores (20 in each group); and crude mortality (50% vs. 43%)
(data not shown). This subset analysis lends support to the
contention that VRE bacteremia is primarily a marker for severe illness rather than a major determinant of it.
A second limitation of the study was that while virtually all
VRE bacteremia cases were caused by E. faecium, only 30%
of the VSE bacteremia cases were caused by this species; the
remainder were due to E. faecalis. E. faecium has greater intrinsic resistance to penicillinase-susceptible penicillins, penicillinase-resistant penicillins, and aminoglycosides than does
E. faecalis [11]. One study suggested that E. faecium itself
may be associated with greater morbidity than E. faecalis [22].
Therefore, the species difference may be a confounding variable in our attempt to discriminate between clinical differences
associated with vancomycin resistance. However, we found no
difference in the mortality among VSE-infected patients with
E. faecium bacteremia and those with E. faecalis bacteremia
(22% vs. 27%; P Å .645).
A third limitation was that our pharmacological-exposure
data likely include drugs used following the initial enterococcal
bacteremia, as discussed previously. This predisposes to potential treatment bias, as we believe to be the case for tetracycline
and chloramphenicol. In addition, it is possible that other antimicrobials were not identified as risk factors for VRE bacteremia, because their usage was artifactually increased in VSEinfected patients as a result of treatment initiated following
onset of bacteremia.
In conclusion, prolonged hospital stay, central venous access,
and gastrointestinal tract dysfunction requiring hyperalimentation were the major clinical risk factors for VRE bacteremia
in our study. Previous studies have shown universal VRE gut
colonization in patients subsequently developing infection [4,
17]. In our study, VRE-infected patients were less likely than
VSE-infected patients to have polymicrobial bacteremia, a
finding suggesting that bloodstream infection in VRE bacteremia occurs as an isolated breakthrough in broad-spectrum
antimicrobial coverage. Metronidazole may uniquely predispose to bacteremia in patients with VRE colonization in the
gastrointestinal tract by eliminating anaerobic competition and
augmenting enterococcal translocation into the bloodstream.
Further study is needed of measures that can break the cycle
of VRE gut colonization and susceptibility to invasive infection
in hospitalized patients.
References
1. Uttley AH, Collins CH, Naidoo J, George RC. Vancomycin-resistant enterococci [letter]. Lancet 1988; 1:57 – 8.
2. Leclercq R, Derlot E, Duval J, Courvalin P. Plasmid-mediated resistance
to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med
1988; 319:157 – 61.
3. Frieden TR, Munsiff SS, Low DE, et al. Emergence of vancomycinresistant enterococci in New York City. Lancet 1993; 342:76 – 9.
4. Montecalvo MA, Horowitz H, Gedris C, et al. Outbreak of vancomycin-,
ampicillin-, and aminoglycoside-resistant Enterococcus faecium bacter-
cida
UC: CID
CID 1998;26 (May)
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
VRE Bacteremia: Risk Factors and Outcomes
emia in an adult oncology unit. Antimicrob Agents Chemother 1994;
38:1363 – 7.
Jordens JZ, Bates J, Griffiths DT. Faecal carriage and nosocomial spread of
vancomycin-resistant Enterococcus faecium. J Antimicrob Chemother
1994; 34:515 – 28.
Livornese LL, Dias S, Samel C, et al. Hospital-acquired infection with
vancomycin-resistant Enterococcus faecium transmitted by electronic
thermometers. Ann Intern Med 1992; 117:112 – 6.
Weinstein JW, Roe M, Town M, et al. Resistant enterococci: a prospective
study of prevalence, incidence, and factors associated with colonization
in a university hospital. Infect Control Hosp Epidemiol 1996; 17:36 –
41.
Morris JG, Shay DK, Hebden JN, et al. Enterococci resistant to multiple
antimicrobial agents, including vancomycin: establishment of endemicity in a university medical center. Ann Intern Med 1995; 123:250 – 9.
Nosocomial enterococci resistant to vancomycin — United States, 1989 –
1993. MMWR Morb Mortal Wkly Rep 1993; 42:597 – 9.
Spera RV, Farber BF. Multidrug-resistant Enterococcu faecium: an untreatable nosocomial pathogen. Drugs 1994; 48:678 – 88.
Murray BE. The life and times of the enterococcus. Clin Microbiol Rev
1990; 3:46 – 65.
Murray BE. Vancomycin-resistant enterococci. Am J Med 1997; 101:284 –
93.
Slaughter S, Hayden MK, Nathan C, et al. A comparison of the effect of
universal use of gloves and gowns with that of glove use alone on the
acquisition of vancomycin-resistant enterococci in a medical intensive
care unit. Ann Intern Med 1996; 125:448 – 56.
Linden PK, Pasculle AW, Manez R, et al. Differences in outcomes for
patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium. Clin Infect Dis 1996; 22:
663 – 70.
Montecalvo MA, Shay DK, Patel P, et al. Bloodstream infections with
vancomycin-resistant enterococci. Arch Intern Med 1996; 156:1458 –
62.
Stroud L, Edwards J, Danzig L, Culver D, Gaynes R. Risk factors for
mortality associated with enterococcal bloodstream infections. Infect
Control Hosp Epidemiol 1996; 17:576 – 80.
Edmond MB, Ober JF, Weinbaum DL, et al. Vancomycin-resistant Enterococcus faecium bacteremia: risk factors for infection. Clin Infect Dis
1995; 20:1126 – 33.
Shay DK, Maloney SA, Montecalvo M, et al. Epidemiology and mortality
risk of vancomycin-resistant enterococcal bloodstream infections. J Infect Dis 1995; 172:993 – 1000.
Facklam RR, Sahm DF. Enterococcus. In: Murray PR, Baron EJ, Phaler
MA, Tenover FC, Yolken RH, eds. Manual of clinical microbiology.
/ 9c4c$$my59
04-10-98 01:30:34
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
1133
6th ed. Washington, DC: American Society for Microbiology 1995:
308 – 14.
National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically.
3rd ed. NCCLS document M7-A3. Villanova, Pennsylvania: National
Committee for Clinical Laboratory Standards, 1994.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a
severity of disease classification system. Crit Care Med 1985; 13:818 –
28.
Barrall DT, Kenney PR, Slotman GJ, Burchard KW. Enterococcal bacteremia in surgical patients. Arch Surg 1985; 120:57 – 63.
Maki DG, Agger WA. Enterococcal bacteremia: clinical features, the risk
of endocarditis, and management. Medicine (Baltimore) 1988; 67:248 –
69.
Noskin GA, Peterson LR, Warren JR. Enterococcus faecium and Enterococcus faecalis bacteremia: acquisition and outcome. Clin Infect Dis
1995; 20:296 – 301.
Shlaes DM, Levy J, Wolinski E. Enterococcal bacteremia without endocarditis. Arch Intern Med 1981; 141:578 – 81.
Malone DA, Wagner RA, Myers JP, Watanakunakorn C. Enterococcal
bacteremia in two large community teaching hospitals. Am J Med 1986;
81:601 – 6.
Garrison NR, Fry DE, Berberich S, Polk HC. Enterococcal bacteremia:
clinical implications and determinants of death. Ann Surg 1982; 196:
43 – 7.
Wells CL, Maddaus MA, Jechorek RP, Simmons RL. Role of intestinal
anaerobic bacteria in colonization resistance. Eur J Clin Microbiol Infect
Dis 1988; 7:107 – 13.
Wells CL, Maddaus MA, Reynolds CM, Jechorek RP, Simmons RL. Role
of anaerobic flora in the translocation of aerobic and facultatively anaerobic intestinal bacteria. Infect Immun 1987; 55:2689 – 94.
Wells CL, Jechorek RP, Maddaus MA, Simmons RL. Effects of clindamycin and metronidazole on the intestinal colonization and translocation
of enterococci in mice. Antimicrob Agents Chemother 1988; 32:1769 –
75.
Onderdonk AB, Bartlett JG, Louie T, Sullivan-Seigler N, Gorbach SL.
Microbial synergy in experimental intra-abdominal abcess. Infect Immun 1976; 13:22 – 6.
Bartlett JG, Louie TJ, Gorbach SL, Onderdonk AB. Therapeutic efficacy
of 29 antimicrobial regimens in experimental intraabdominal sepsis.
Rev Infect Dis 1981; 3:535 – 41.
Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:
128 – 40.
cida
UC: CID