Journal of Antimicrobial Chemotherapy (2002) 50, 1003–1009

DOI: 10.1093/jac/dkf216

Risk factors associated with ampicillin resistance in patients with

bacteraemia caused by Enterococcus faecium

Jesús Fortún1*, Teresa M. Coque2, Pilar Martín-Dávila1, Leonor Moreno1, Rafael Cantón2, Elena Loza2,
Fernando Baquero2 and Santiago Moreno1

Departments of 1Infectious Diseases and 2Microbiology, Ramón y Cajal Hospital, University of Alcalá,
Crtra Colmenar Km 9.1, Madrid 28034, Spain

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Received 5 April 2002; returned 3 July 2002; revised 9 August 2002; accepted 22 August 2002

Epidemiological characteristics of ampicillin-resistant, vancomycin-susceptible Enterococcus

faecium are not well known. Recently, these strains have been proposed as the substratum for
the later appearance of vancomycin-resistant E. faecium. To analyse this problem, the medical
charts of patients with bacteraemia caused by E. faecium diagnosed in our institution during a
6 year period (1994–1999) were reviewed. Demographic data, clinical characteristics, antibiotic
exposure and outcome were compared among patients with ampicillin-resistant (MIC > 16 mg/L,
NCCLS criteria) and ampicillin-susceptible strains. Clonality between different strains was
analysed by pulsed-field gel electrophoresis (PFGE). We evaluated 49 cases of E. faecium
bacteraemia; 29 patients with ampicillin-resistant strains and 20 patients with -susceptible
strains were identified. By logistic regression analysis, only previous administration of
β-lactams (OR: 6.3; 95% CI: 1.12–20.0) and urinary catheterization (OR:4.2; 95% CI: 1.3–30.0)
were identified as predictors of ampicillin resistance in enterococcal bacteraemic patients. An
elevated APACHE II score was the only independent factor associated with mortality in entero-
coccal bacteraemia (OR:13.5; 95% CI: 1.04–175.4). PFGE analysis revealed a strong association
between specific ampicillin-resistant clones and the location of patients during hospitalization,
suggesting nosocomial transmission. Bacteraemia caused by ampicillin-resistant enterococci
was not associated with increased mortality when compared with bacteraemias caused by
ampicillin-susceptible strains.

Introduction alteration of penicillin-binding proteins, mainly PBP5.5,6

PBP5-mediated ampicillin resistance is thought to be intrinsic
Enterococci have become the fourth most common cause of to the enterococci and is usually non-transferable. Recently,
bloodstream infections in Spain, with Enterococcus faecium cotransfer of ampicillin and vancomycin resistance has been
and Enterococcus faecalis the predominant species.1 In recent described, and ampicillin resistance has been proposed as
years, increasing resistance to first line antibiotics has been a risk factor for endemic spread of vancomycin-resistant
observed among enterococcal species worldwide, especially strains.6–9
in E. faecium, thus limiting the already reduced therapeutic Several studies have been published on risk factors
options to treat severe enterococcal infections.2,3 for vancomycin-resistant enterococcal infection or coloniza-
Epidemiology of enterococci resistant to different anti- tion;10–15 however, information about risk factors for acquisi-
biotics (vancomycin, aminoglycosides and ampicillin) is tion of ampicillin-resistant enterococci has focused on
complex and varies among hospitals and countries. Suscept- colonization,16–19 although there are a few studies in relation
ibility of enterococci to ampicillin remained stable until 1982, to cases with bacteraemia.20–22 We recently noted an increased
when the first nosocomial outbreak of ampicillin-resistant number of ampicillin-resistant E. faecium being isolated by
E. faecium was reported.4 This resistance is related to an the clinical microbiology laboratory at our 1200 bed tertiary
..................................................................................................................................................................................................................................................................

*Corresponding author. Tel: +34-91-336-8709; Fax: +34-91-336-8792; E-mail: fortun@mi.madritel.es

...................................................................................................................................................................................................................................................................

1003
© 2002 The British Society for Antimicrobial Chemotherapy
 J. Fortún et al.
care hospital.23 This prompted an investigation to determine
the risk factors for the acquisition of ampicillin-resistant
enterococci in bacteraemic patients as well as its related
mortality.
Material and methods
Setting
Hospital Ramón y Cajal is a university teaching hospital
providing gynaecological, paediatric and adult medical and
surgical care, including liver, lung, kidney and bone marrow
transplantation units. The institution provides health care to a
population of 600 000.
Patients and chart review
All patients who had E. faecium isolated from blood cultures
submitted to the clinical microbiology department at the
Ramón y Cajal Hospital from January 1994 to December
1999 were identified. Patients with bacteraemia caused by
ampicillin-resistant strains of E. faecium were considered as
cases and were compared with patients with bacteraemia
caused by ampicillin-susceptible strains that were considered
as controls.
Patients’ medical charts were reviewed, and demographic,
clinical and microbiological data were collected. Exposure to
antimicrobials was evaluated from the last month to the date
of the initial enterococcal blood culture. Outcome of patients
was analysed until hospital discharge or death occurred.
Microbial identification and susceptibility testing
Blood cultures were obtained at the physician’s discretion
and processed by the BACTEC 9240 blood culture system
(Becton Dickinson Diagnostic Instruments, USA). Only one
isolate per patient was further analysed. Preliminary identi-
fication and susceptibility tests were performed by using the
automated microdilution PASCO (Difco, Detroit, MI, USA)
or WIDER Systems (Fco. Soria Melguizo, Madrid, Spain).
For identification of enterococci to the species level, the bio-
chemical scheme of Facklam & Collins,24 and the criteria for
motility and pigment production were used. Identification at
species level was confirmed by amplification of the aac-6′-Ii
gene, which is specific for E. faecium. Antimicrobial suscept-
ibility to different antibiotics was determined by an agar
dilution method according to the NCCLS guidelines.25
Ampicillin resistance was defined by MICs > 16 mg/L.
β-Lactamase production was tested by placing a heavy
suspension of organisms into a microtitre well containing
nitrocefin (100 µmol/mL) (BBL Microbiology, Cockeysville,
MD, USA).
1004
Detection of genes coding for glycopeptide resistance
E. faecium isolates resistant to glycopeptides were examined
for the presence of the vanA and vanB genes using oligo-
nucleotides and PCR conditions previously described.26 Total
DNA was extracted from E. faecium isolates by InstaGene
(BioRad, La Jolla, CA, USA) following manufacturer’s in-
structions.
Pulsed-field gel electrophoresis (PFGE)
Genomic DNA was prepared and digested with SmaI (Amer-
sham Pharmacia) as previously described.27 After digestion,
DNA fragments were separated by electrophoresis in 1.2%
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agarose gels (Pulsed-Field Agarose Certified; BioRad) and
0.5 × Tris–borate–EDTA buffer using a contour-clamped
homogeneous electric field apparatus (CHEF-DRIII system;
BioRad). Electrophoresis conditions were 12°C at 6 V/cm for
27 h with pulse times ranging from 1 to 27 s. The DNA band-
ing patterns were analysed by visual examination by two
independent investigators. According to the standard criteria
given by Tenover et al.27 to establish clonal relationships,
isolates were considered to be related if they exhibited differ-
ences of up to six bands, if there was good epidemiological ev-
idence to suggest relatedness among isolates, or if they had
been isolated over extended periods of time.
Statistical analysis
Characteristics of cases and controls were compared with
the Student’s t-test for continuous data and χ2 analysis for
categorical data. Yates’ correction and two-tailed Fisher’s
exact test were performed if necessary. All variables having a
P value of <0.1 were included in logistic regression model-
ling. Multivariate analysis was carried out with the use of
logistic regression, with significant variables selected by a
backward stepwise procedure. Statistical analysis of the data
was performed with Epi-Info version 6 (CDC, Atlanta) and
SPSS 7.5 for Windows (SPSS Inc., Chicago, IL, USA).
Results
Demographic data
A total of 691 enterococcal blood isolates were identified
through the period of study, with E. faecalis being isolated
in most episodes (522, 75%). E. faecium was isolated from
104 blood cultures, corresponding to 60 patients, and repre-
sented 15% of all enterococcal isolates (Figure 1).
The evolution of resistance to ampicillin was clearly differ-
ent for E. faecalis and E. faecium isolates in our centre in the
last 10 years. No cases of ampicillin resistance were observed
among E. faecalis isolates, whereas a high proportion of
 Risk factors associated with ampicillin resistance in bacteraemia
Figure 1. Number of blood culture isolates of E. faecalis (black bars),
E. faecium (hatched bars) and other enterococci (white bars) during the
period 1994–1999 in Ramón y Cajal Hospital.
Figure 2. Evolution of ampicillin resistance in total numbers of
E. faecium isolated at Ramón y Cajal Hospital, 1991–2000.
ampicillin-resistant strains was detected in E. faecium. A
significant increase was observed from 1991 (18% of total
E. faecium isolates) to 2000 (71%), with a mean of 52%
during this period and reaching 80% in 1998 (Figure 2).
We had access to the clinical records in 49 of the 60 patients
with E. faecium bacteraemia. Of the 49 patients analysed,
bacteraemia was caused by ampicillin-resistant strains in 29
(59%) and by ampicillin-susceptible strains in 20 (41%). Data
for analysis were not available for the other 11 patients (seven
with resistant isolates). In these patients the data included in
their clinical records were too scarce to be analysed. How-
ever, patients who were and were not analysed did not differ
with respect to clinical data and outcome.
The source of bacteraemia was mainly related to a urinary
or venous catheter origin in most cases, but this information
was not available for several patients.
Antimicrobial susceptibility
Most of the ampicillin-resistant isolates (n = 29) were also
resistant to erythromycin (93%), clindamycin (87%), co-
trimoxazole (70%) and ciprofloxacin (70%), and were highly
resistant to streptomycin (74%) and kanamycin (81%). Three
1005
isolates (10%) showed high-level resistance to gentamicin
(HLRGm). Glycopeptide resistance was found in two isolates
(vancomycin MIC >128 mg/L, teicoplanin MIC >64 mg/L),
both of which contained vanA. Production of β-lactamase was
not detected in any ampicillin-resistant isolate.
The occurrence of resistance to other antibiotics was lower
for ampicillin-susceptible isolates (n = 20): erythromycin
(42%), clindamycin (37%), co-trimoxazole (4%), ciprofloxa-
cin (4%), high level of resistance to streptomycin (4%) and
kanamycin (25%). All were vancomycin susceptible and did
not show HLRGm.
Pulsed-field gel electrophoresis (PFGE)
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Analysis of SmaI-digested genomic DNA banding patterns
from 29 ampicillin-resistant isolates revealed 13 clonal types.
Isolates from six different patients obtained during 1995–1997
showed identical DNA banding patterns and were classified
as Type A. Four of them were isolated in patients hospitalized
in Gastroenterology or General Surgery Departments (placed
on the 10th and 11th floor, respectively). Isolates from 12 dif-
ferent patients obtained during 1997–2000 showed a DNA
banding pattern that differed from each other by one to six
bands and from the common pattern by one to six bands. We
considered these as a clonal group (Type B). Type B was
found in 12 patients, nine of whom were included in our
analysis. The other isolates corresponded to 11 clones that
were largely unrelated: six patients were included in our
analysis and all of them were hospitalized in other wards not
on the 10th and 11th floor. The association between clones
and place of hospitalization was statistically significant (P =
0.01).
Risk factors for ampicillin resistance
A comparison of demographic data, clinical characteristics
and microbiological features among patients with ampicillin-
resistant and -susceptible strains is shown in Table 1. In
univariate analysis, urinary catheterization was significantly
more frequent in patients with resistant isolates. In addition, a
trend towards a higher number of central venous catheters
was observed in patients with resistant isolates. The analysis
of drug exposure showed a significant association between
exposure to β-lactams in the last month and the development
of bacteraemia by resistant isolates. No association was
found, however, with any specific β-lactam (penicillins,
cephalosporins and carbapenems). Patients with resistant
isolates were more likely to have received quinolones.
By logistic regression analysis, previous administration
of β-lactams (OR: 6.3; 95% CI: 1.12–20.0) and urinary
catheterization (OR: 4.2; 95% CI: 1.3–30.0) were confirmed
as predictors of ampicillin resistance in enterococcal bacter-
aemic patients.
 J. Fortún et al.

Table 1. Demographic, clinical data and antibiotic exposure in patients with bacteraemia caused by ampicillin-resistant
(AREF) and ampicillin-susceptible (ASEF) E. faecium

Variable AREF (%) (29 cases) ASEF (%) (20 cases) OR (95% CI) P value

Univariate analysis
Demographic and clinical data
age, mean (years ± S.E.M.) 54.8 ± 5.78 56.0 ± 5.69 – 0.73
male sex 55 60 0.8 (0.22–3.03) 0.96
nosocomial acquisition 76 55 2.6 (0.64–10.53) 0.22
days of hospitalization (±S.E.M.) 16.4 ± 3.0 10.9 ± 3.5 – 0.23
APACHE II score (±S.E.M.) 9.1 ± 1.1 6.3 ± 1.3 – 0.11
diabetes mellitus 23 17 1.5 (0.27–8.85) 0.72
recent surgery 31 20 1.8 (0.40–8.62) 0.59
assisted ventilation 17 10 1.9 (0.27–15.94) 0.68

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central venous catheter 60 27 3.7 (0.90–15.73) 0.07
hyperalimentation 17 15 1.2 (0.20–7.36) 1.0
urinary catheterization 58 17 5.7 (1.30–26.70) 0.012
creatinine > 2 mg/dL 24 5 3.5 (0.60–142.8) 0.12
liver and/or biliary disease 39 20 2.4 (0.55–11.45) 0.30
crude mortality 34 21 2.1 (0.47–9.95) 0.43
related mortality 21 15 1.5 (0.27–8.85) 0.72
Antibiotic exposure
vancomycin (parenteral) 7 16 0.4 (0.04–3.58) 0.39
vancomycin (oral) 10 0 – 0.26
teicoplanin 3 0 – 1.0
metronidazole 17 5 3.9 (0.38–97.4) 0.38
clindamycin 14 5 3.0 (0.28–77.6) 0.63
β-lactams 78 45 4.7 (1.14–20.31) 0.03
sulphonamides 4 0 – 1.0
quinolones 19 0 – 0.07
aminoglycosides 34 30 1.2 (0.30–4.98) 0.91
tetracyclines 14 0 – 0.13
Multivariate analysis
urinary catheterization 6.3 (1.12–20.0) 0.02
β-lactams 4.2 (1.3–30.0) 0.04

S.E.M., standard error of the mean.

Outcome and mortality statistically significant. By logistic regression analysis, only a

There were no significant differences in the outcome of
patients with ampicillin-resistant and -susceptible strains.
We did not find significant differences in mortality
between the two groups. Overall mortality in patients with
bacteraemia caused by ampicillin-resistant and -susceptible
E. faecium was 34% and 21%, respectively (OR: 2.1; 95%
CI: 0.47–9.95). Mortality attributed to bacteraemia was 21%
and 15%, respectively (OR: 1.5; 95% CI: 0.27–8.85).
An elevated APACHE II score and urinary catheteriza-
tion were significantly associated with a higher mortality in
univariate analysis (Table 2). A trend was observed among
patients receiving parenteral nutrition and renal failure
(expressed as a creatinine serum level higher than 2 mg/L).
Although mortality was higher in patients with ampicillin-
resistant E. faecium bacteraemia, the difference was not
high APACHE score (OR: 13.5; 95% CI: 1.04–175.4) was
independently associated with mortality.
Discussion
Enterococci were the third most common cause of blood-
stream infections in our hospital during the study period. The
prevalence of bacteraemia caused by Enterococcus spp. has
remained stable for the last 5 years, and most enterococcal
blood isolates were E. faecalis or E. faecium, which is com-
parable with the distribution of species in previous stud-
ies.1,17,19,21 Ampicillin resistance has developed during the last
decade in E. faecium, being present in 70% of the isolates
during 2000. The prevalence of vancomycin resistance
among blood isolates of E. faecalis and E. faecium in our

1006
 Risk factors associated with ampicillin resistance in bacteraemia
Table 2. Risk factors associated with mortality in patients with enterococcal bacteraemia
Variable Variable present (%)
Univariate analysis
APACHE II score (>8) 67
parenteral nutrition 38
creatinine > 2 mg/dL 38
urinary catheterization 71
malignancy 28
AREF bacteraemia 71
Multivariate analysis
APACHE II score (>8)
AREF, ampicillin-resistant E. faecium.
hospital during the study period was <3%; all were classified
as vanA-type.
We found that previous exposure to β-lactams and urinary
catheterization were two major risk factors for ampicillin
resistance in patients with bacteraemia caused by E. faecium.
Since the early studies of Boyce et al.,18 which related
ampicillin-resistant enterococci to the use of imipenem,
different authors have demonstrated the association of
ampicillin-resistant enterococci with β-lactams,16,18,20 quino-
lones,17,19 aminoglycosides21 and co-trimoxazole.21 Anti-
biotics may facilitate colonization and infection by depleting
the gastrointestinal tract of its normal anaerobic flora and
by selecting enterococci due to limited bactericidal activity
against these organisms. Exposure to multiple antimicro-
bial agents is favoured by prolonged hospitalization, a
circumstance that has been associated with the selection of
ampicillin-resistant enterococci,20,21,28 as well as of entero-
cocci with high-level resistance to aminoglycosides.28–30
The second factor identified as independently associated
with the development of ampicillin-resistant E. faecium
bacteraemia in our study was urinary catheterization. Gross
et al.31 demonstrated that nosocomial enterococcal urinary
pathogens come from the gastrointestinal tract. Bladder
catheterization has been shown to increase urinary entero-
coccal colonization in patients with ampicillin-resistant
enterococcal bacteraemia, and a gastrointestinal origin of
urinary colonization has been indicated by plasmid analysis.32
Positive clinical specimens in the absence of rectal carriage
provide evidence for exogenous acquisition. E. faecium, in-
cluding multiply resistant strains, has been isolated from the
hands of hospital staff during some outbreaks.33,34 Patterns of
environmental contamination compatible with staff hand
carriage35 and the ability of E. faecium to survive on fingertips
and gloves indicate that nosocomial transmission via staff
hands is feasible.36 Nosocomial transmission was suggested
for most isolates in our study. Two-thirds of the strains ana-
lysed belonged to two of 13 clonal types. The strains were
1007
Variable absent (%) OR (95% CI) P value
24 5.7 (1.38–25.13) 0.01
9 3.5 (0.93–42.01) 0.06
9 3.5 (0.93–42.01) 0.06
27 5.2 (1.29–21.98) 0.017
15 2.2 (0.42–12.30) 0.48
54 2.15 (0.55–8.50) 0.34
13.5 (1.04–175.4) 0.01
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grouped by time and hospital location: clone A was observed
during 1995 and 1997 and accounted for 66% of strains from
the Gastroenterology and General Surgery Departments; and
clone B, observed from 1997 to 1999, accounted for 50% of
the strains obtained in these departments. These departments
account for <10% of hospital beds.
Based on similar data, some authors have recommended
infection control precautions. By containing the nosocomial
spread of ampicillin-resistant enterococci, the need for vanco-
mycin use is reduced and may therefore delay the occurrence
of vancomycin-resistant enterococci in those institutions
where such organisms are not yet a problem. Recently, four
cases of infection caused by a vancomycin-resistant (vanB-
type) strain occurred during a clonal outbreak caused by
genomically related ampicillin-resistant E. faecium, and in
association with an increase in vancomycin use.37
The spread of ampicillin-resistant enterococci in our hospi-
tal was not associated with a higher mortality in bacteraemic
patients. Other authors have found an increased intrahospital
death rate for patients infected by ampicillin-resistant entero-
cocci. However, mortality has been ultimately related to the
underlying disease of the patients or to inappropiate anti-
microbial therapy in these studies.21 Our data support these
findings; although mortality was higher in patients with
ampicillin-resistant enterococcal bacteraemia, the only factor
independently associated with mortality was a high APACHE
score.
In conclusion, we have observed a rise in ampicillin-
resistant enterococci among bacteraemic patients. This in-
crease has been favoured by different factors. Prolonged anti-
biotic use during hospitalization, and urinary catheterization
in patients with perianal colonization, may have contributed
to the selection of these strains and the later development
of bacteraemia. Nosocomial transmission may account for
the increase of ampicillin-resistant enterococci observed, but
fortunately, bacteraemia caused by these bacteria was not
associated with increased mortality.
 J. Fortún et al.
Acknowledgements
Presented in part at the Fortieth Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC), Toronto,
Canada, September 2000.
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