The effect of antibiotic use on prevalence of nosocomial vancomycin-resistant enterococci- an ecologic study
Remschmidt et al. Antimicrobial Resistance and Infection Control
The effect of antibiotic use on prevalence of nosocomial vancomycin-resistant enterococci- an ecologic study
Cornelius Remschmidt 0
Michael Behnke 0
Axel Kola 0
Luis A. Peña Diaz 0
Anna M. Rohde 0
Petra Gastmeier 0
Frank Schwab 0
0 Institute of Hygiene and Environmental Medicine, Charité-Universitätsmedizin Berlin , Hindenburgdamm 27, 12203 Berlin , Germany
Background: Vancomycin-resistant enterococci (VRE) are among the most common antimicrobial-resistant pathogens causing nosocomial infections. Although antibiotic use has been identified as a risk factor for VRE, it remains unclear which antimicrobial agents particularly facilitate VRE selection. Here, we assessed whether use of specific antimicrobial agents is independently associated with healthcare-associated (HA) VRE rates in a university hospital setting in Berlin, Germany. Methods: We conducted the study between January 2014 and December 2015 at the Charité-university hospital of Berlin, Germany. From the hospital pharmacy, we extracted data for all antibacterials for systemic use (anatomical therapeutic chemical (ATC)-classification J01) and calculated ward specific antibiotic consumption in defined daily doses (DDDs) per 100 patient-days (PD). We used the microbiology laboratory database to identify all patients with isolation of invasive or non-invasive VRE and calculated HA-VRE incidence as nosocomial VREcases per 100 patients and HA-VRE incidence density as nosocomial VRE-cases per 1000 PD. We defined VRE isolates as hospital-acquired if they were identified three days or later after hospital admission and otherwise as community-acquired (CA-VRE). We performed univariable and multivariable regression analyses to estimate the association of the frequency of HA-VRE per month with antibiotic use and other parameters such as length of stay, type of ward or presence of at least one CA-VRE on ward. In a second analysis, we considered only patients with VRE infections. Results: We included data from 204,054 patients with 948,380 PD from 61 wards. Overall, 1430 VRE-cases were identified of which 409 (28.6%) were considered hospital-acquired (HA). We found that carbapenem use in the current month and prior-month use of glycopeptides increased the risk for HA-VRE by 1% per 1 DDD/100 PD and 3% per 1 DDD/100 PD, respectively. However, when only VRE from clinical samples were considered, only glycopeptide use showed a statistically significant association. In both models, detection of at least one patient with CA-VRE on a ward in the current month significantly increased the risk of HA-VRE, thereby indicating nosocomial spread of VRE. Conclusions: Our findings suggest that the risk of HA-VRE is associated with specific antimicrobial agents. Prudent use of these antimicrobial agents might reduce nosocomial VRE rates. That appearance of at least one CA-VRE case on the ward increased the risk of HA-VRE detection highlights the importance of strict hand hygiene practices to interrupt person-to-person transmission of VRE.
Vancomycin-resistant enterococcus; Transmission; Antibiotic use; Carbapenems; Glycopeptides
Vancomycin-resistant enterococci (VRE) are emerging
worldwide and are among the most common
antimicrobialresistant pathogens causing nosocomial infections [
Since infections with VRE are associated with prolonged
inhospital stay and excess mortality [
], increasing VRE
rates pose a serious threat to global health. In fact, the
World Health Organization (WHO) judged VRE to be of
high importance in the “Global Priority list of
antibioticresistant bacteria to guide research, discovery and
development of new antibiotics” [
So far, several risk factors for VRE colonization or
infection have been identified, such as long periods of
hospitalization, immunosuppression, serious comorbid
conditions, close proximity to patients infected or
colonized with VRE as well as antibiotic use [
Although antibiotic use has been advocated as a
major modifiable risk factor [
remain regarding the impact of specific antimicrobial
agents or antimicrobial groups on the selection
process of VRE [
Therefore, the primary objective of the study was to
investigate whether use of specific antimicrobial agents
is independently associated with nosocomial VRE rates
in a university hospital setting in Berlin, Germany.
Secondary objective was to identify other risk factors
that are associated with nosocomial VRE rates.
This study was conducted at the Charité-university
hospital of Berlin, between January 2014 and December
2015. The Charité is a tertiary care center with more
than 3000 beds and more than 140,000 inpatient cases
From the microbiology laboratory database of Charité
we prospectively identified patients with
vancomycinresistant Enterococcus (E.) faecium- or E.
faecalis-isolates from intensive care units (ICUs) and surgical,
medical and hemato-oncological wards. In case of
screening samples, selective chromogenic medium (chromID®
VRE, bioMérieux) and VITEK 2 system (bioMérieux) were
used, while clinical samples were processed following
standard procedures dependent on specimen type. Results
were interpreted according to European Committee on
Antimicrobial Susceptibility Testing definitions (EUCAST,
http://www.eucast.org). A molecular characterization of
the VRE isolates was not performed.
We defined VRE isolates as hospital-acquired
(HAVRE) if they were identified three days or later after
hospital admission and otherwise as community-acquired
(CA-VRE). In patients with multiple VRE isolates during
the same hospital stay, only the first identified isolate was
considered. We included isolates irrespective whether they
were obtained for infection control surveillance or
recovered from clinical specimen and irrespective whether
they were associated with colonization or infection.
Performance of screening
At the Charité, a targeted risk adjusted screening policy
is implemented: in patients in whom a VRE has been
isolated within the previous three years, a rectal swab is
obtained at admission. However, during the study period
eight (non-ICU) wards performed an intensified
admission screening that involved all patients irrespective of
underlying risk factors. In this ecologic study, we did not
collect data on compliance with the screening policy or
compliance with hand hygiene or cleaning procedures
on the respective wards.
Systemic antibiotic use
Antimicrobial agents were classified according to the
anatomical therapeutic chemical (ATC) system (34).
From the pharmacy of Charité, ward specific data on
antibiotic consumption were converted into defined
daily doses (DDDs) and reported as DDD/100
patientdays (PD) at monthly intervals. We collected data for all
antibacterials for systemic use (ATC-code J01). Data on
antifungal or antiviral medication were not considered.
Ethics and data protection
For this ecologic study, we analyzed aggregated and
anonymous data that were collected by the hospital in
accordance with the German “Protection against Infection
Act”, §23. Therefore, ethical approval and informed
consent were not required and institutional review boards
were not consulted.
We calculated median and interquartile range (IQR) for
the total study period (24 months) for the following
variables: number of patients, patient-days (PD), average
length of stay (LOS), number of beds per ward, bed
occupancy rate, month of VRE-detection, HA-VRE rates
and antibiotic use. HA-VRE incidence was calculated as
nosocomial VRE-cases per 100 patients and HA-VRE
incidence density as nosocomial VRE-cases per 1000 PD.
We reported data for all wards as well as stratified by
type of ward (i.e. surgical, medical, ICU,
hematooncological). Differences in baseline characteristics
between different types of wards were compared by using
the Kruskal-Wallis test. Univariable and multivariable
regression using generalized linear models was
performed to estimate the association of the frequency of
HA-VRE per month with different antimicrobial groups
in the current month and the month before the current
month and further confounding parameters such as
length of stay (LOS), bed occupancy (patient days/bed
places on ward available), type of ward and at least one
patient with community-acquired VRE on ward in the
current month. In addition, we added a variable that
took the different screening policies (screening of all
patients on admission irrespective of underlying risk
factors on eight wards) into account. Since observations
within a ward are not statistically independent due to
the diagnostic and management policies (particularly the
frequency of microbiological tests and screening),
adjusted incidence rate ratios (IRR) with 95% confidence
intervals (CI) were estimated. They were based on
generalized estimating equation (GEE) models which
account for this clustering effect by using an exchangeable
correlation structure (35).
We used negative-binomial distribution instead of
Poisson distribution because the variance exceeds the
mean and overdispersion was observed. The Lagrange
multiplier test was used to test whether the negative
binomial model significantly differs from the Poisson
model. The log number of patient days during each
month was used as an offset in the model. All parameter
with p < 0.2 in the univariable regression model were
included in a full model and then non-significant
parameters were excluded stepwise. The selection criterion was
the smallest Chi-square value and p ≥ 0.05 in the type
III score statistic. The quasi-likelihood information
criterion (QIC) as a modification of the Akaike information
criterion (AIC) was used as goodness-of-fit measure in
the GEE model. We calculated two models. The first
model considered all identified HA-VRE isolates (clinical
and screening samples) the second model considered
only clinical specimen. Antimicrobial agents that are
relevant for the treatment of VRE, such as daptomycin,
linezolid and tigecyclin were excluded from the analysis.
Additionally, spearman correlation coefficients were
calculated between the antibiotic use and the incidence
density of HA-VRE for the entire study period
(24 months). P-values less than 0.05 were considered
significant. All analyses were performed using SPSS
[IBM SPSS statistics, Somer, NY, USA] and SAS 9.4
[SAS Institute, Cary, NC, USA].
From 61 wards (20 surgical, 18 medical, 14 ICUs, 9
hemato-oncological) we included data from 204,054
patients with 948,380 patient-days. Median length of stay
was 4.7 days (IQR, 3.9–5.8) and was statistically
significant higher in ICUs and hemato-oncological wards as
compared to surgical wards (see Table 1).
Rates of HA-VRE
Overall, 1430 VRE-cases were identified of which 409
(28.6%) were considered hospital-acquired. Of those, 238
(58.2%) HA-VRE were identified in 2015. The median
HA-VRE incidence and HA-VRE incidence density in all
61 wards was 0.11 (IQR, 0.03–0.32) and 0.24 (0.07–
0.54), respectively (Table 1); however, rates of HA-VRE
differed significantly between types of ward. Highest
HA-VRE rates were observed on ICUs (incidence
density: 1.17 (0.71–1.75)) and lowest HA-VRE rates
on medical wards (incidence density: 0.07 (0–0.22)).
Systemic antibiotic use
Between 2014 and 2015 median antibiotic use among
all wards was 76.8 (IQR, 61.6–131.9) DDD/100 PD.
Antibiotic use ranged from 64.1 DDD/100 PD on
medical wards to 163.2 DDD/100 PD on ICUs (see
Table 1). Particularly, the use of broad-spectrum
antibiotics such as third-generation cephalosporins,
glycopeptides and carbapenems was 3 to 13-fold higher on
ICUs as compared to medical or surgical wards. For
example, median carbapenem use on medical wards
was 3.2 (1.5–8.4) DDD/100 PD, whereas it was 42.3
(22.5–49.4) DDD/100 PD on ICUs.
Associations between HA-VRE and antibiotic use
According to Spearmans correlation, several antimicrobial
groups were associated with HA-VRE incidence density.
For example, carbapenem use (r = 0.801, p < 0.001, ATC
code J01DH), glycopeptide use (r = 0.76, p < 0.001, ATC
code J01XA) and use of third-generation cephalosporines
(r = 0.57, p < 0.001, ATC code J01DD) showed a strong
correlation with HA-VRE incidence density (see Fig. 1).
The first multivariable regression model (screening
and clinical specimen) indicated that carbapenem use in
the current month independently increased the risk for
HA-VRE by 1% per 1 DDD/100 patient-days (incidence
rate ratio (IRR), 1.01; 95% confidence interval (CI) 1.00–
1.02, p < 0.01), see Table 2. Glycopeptide use in the
previous month but not in the current month was also
associated with an increased risk of HA-VRE (IRR 1.03;
95% CI, 1.01–1.05, p < 0.01). In addition, type of hospital
ward (ICU and hemato-oncological ward vs. surgical
ward), detection of at least one patient with CA-VRE in
the current month, an intensified screening policy and
the year 2015 were independently associated with higher
The second multivariable regression model
considering only VRE from clinical specimen showed that
glycopeptide use in the previous month (IRR 1.03, 95% CI
1.01–1.05, p < 0.01) were the only antimicrobial agent
that was statistically significant associated with HA-VRE
(see Table 3). Furthermore, being hospitalized on an
ICU, detection of at least one patient with CA-VRE in
the current month and the year 2015 increased the risk
In both multivariable models, size of ward, length of
stay and bed occupancy rate were no independent risk
factors for HA-VRE in the final models.
Antibiotic use is one of the most important risk factors
for VRE occurrence within the hospital setting [
Although specific antimicrobial agents such as
] or ceftriaxone [
] or antimicrobial
groups such as glycopeptides, third-generation
cephalosporines and fluoroquinolones [
] have been found
to be associated with increasing VRE prevalence,
controversies remain. For example, although a large
prospective study found that vancomycin was strongly associated
with increased prevalence of VRE [
], a systematic
review that assessed the impact of reducing vancomycin
use on the prevalence and incidence of VRE colonization
in the US did not find a positive effect of such
]. Interestingly, Kritsotakis et al. found
that the effect of antibiotic use might influence VRE
rates with a time lag, ranging from 2 month for
vancomycin to 6 months for third-generation cephalosporins.
Studies that did not account statistically for such a time
delay might therefore miss a possible association.
It is unclear, why among antimicrobial groups only
glycopeptides but not carbapenems were associated in
both models with HA-VRE rates. A possible explanation
is that glycopeptide use constitutes only a first step in
the selection process of VRE: Although glycopeptide
exposure does not promote emergence of VRE through
genetic mutations in individual patients, it might
facilitate selection of intestinal VRE [
]. In a second step,
use of specific antimicrobial agents further influences
the microbial balance leading to high-density colonization
with VRE at detectable levels [
2, 8, 20
In fact, Donskey et al. showed that in patients
colonized with VRE exposure to antimicrobial agents with
activity against Gram-negative bacteria or with
antianaerobic activity leads to a rapid increase of intestinal
VRE density, whereas discontinuation of these
antibiotics decreased VRE density [
]. Since fecal density of
VRE directly affects the sensitivity of screening results,
active surveillance (i.e. rectal screening) for VRE at
hospital admission might lead to false-negative results in
patients with low VRE densities [
]. In case that
VRE-related precaution measures are not implemented,
this may contribute to increased spread of VRE within
hospitals, particularly if antibiotic therapy is initiated
. However, for clinical infections other factors such
as immunosuppression or hygiene practices might be
more important, factors that were only indirect (ward
type ICU; presence of at least one CA-VRE on ward)
assessed in our study.
It is also unclear, why carbapenem use in the
current but not in the prior month was associated
1 = reference
with HA-VRE-rates when screening and clinical
specimen were considered. However, given the available
evidence it seems unlikely that a single antimicrobial
agent is responsible for the multifactorial process of
VRE selection. It is rather an interaction of different
antimicrobial agents with the competing intestinal
microbiota and might differ from individual to
Regarding antibiotics, the use of broad-spectrum
antibiotics such as glycopeptides and carbapenems was 3 to
13-fold higher on ICUs as compared to medical or
surgical wards. Although interpreting these results without
individual patient data is challenging, this rates might
indicate inappropriate use of these antibiotics on ICUs.
Antibiotic stewardship could limit unnecessary or
inappropriate use of antibiotics, thereby improving the
quality of antibiotic use in hospitals [
In addition to glycopeptides and carbapenems, we
found that hospitalization on an ICU as well as detection
of CA-VRE increased the risk of HA-VRE acquisition.
These results are in line with other studies that found
that hospitalization on ICUs or severe underlying
comorbidities and immunosuppression are risk factors for
VRE colonization or infection [
2, 12, 25
appearance of at least one CA-VRE case on the ward almost
doubled the risk of HA-VRE detection highlights the
importance of strict hand hygiene practices for health
care workers to interrupt person-to-person
The fact that HA-VRE cases increased from 2014 to
2015 might indicate an epidemiological trend that has
been already observed in other studies [
16, 17, 29, 30
however, the situation regarding spread of VRE in
Europe is diverse . Since data in our study were
collected for only two years, these results have to be
interpreted with caution.
Our study has several limitations. First, we used an
ecological study design, which can give valuable insights
in understanding the association between antibiotic use
and VRE selection; however, causality cannot be proven.
Second, we analyzed aggregated data on ward level and
had no data on individual patients. Therefore,
controlling for important confounders, such as duration of
antibiotic therapy, history of antibiotic exposure or severity
of underlying illness was not possible. Since it has been
shown that group-level and individual-patient-level
analyses might yield different results when the association
between antibiotic exposure and resistance is assessed
], our results have to be interpreted with caution.
Third, routine screening for VRE at hospital admission
was implemented only on some wards at Charité.
Patients from other wards may have been colonized on
admission or may have acquired VRE in outside
hospitals. Therefore, the proportion of HA-VRE might be
]. Fourth, the DDD is the assumed
average maintenance dose per day for a drug used for its
main indication in adults and does not necessarily reflect
the recommended or prescribed daily dose [
]. Fifth, a
molecular characterization of the identified VRE was not
performed and we could not exclude clonal
dissemination on the respective wards; however, since we did not
identify VRE cluster on ward level during the study
period, large outbreaks seems unlikely. Finally, data on
compliance with hand hygiene and cleaning procedures
were not measured, therefore confounding effects of
these factors on our results are unknown.
In conclusion, we found a positive correlation between
prior-month use of glycopeptides and current use of
carbapenems and the incidence of HA-VRE on ward level
when invasive and non-invasive VRE were considered. In
addition, detection of at least one patient with CA-VRE
in the current month significantly increased the risk of
nosocomial acquisition of VRE, thereby indicating the
risk of person-to-person transmission of VRE. To this
end, a multifaceted approach to lower HA-VRE rates is
required including prudent use of antimicrobial agents
as well as implementation of and strict compliance to
infection control measures to prevent VRE transmission.
95% CI: 95% confidence interval; ATC: Anatomical therapeutic chemical
(classification system); CA: Community-acquired; DDD: Defined daily dose;
HA: Hospital-acquired; ICU: Intensive care unit; IQR: Interquartile range;
IRR: Incidence rate ratio; LOS: Length of stay; PD: Patient-days; VRE:
No external funding was received for this study.
Availability of data and materials
The datasets used and/or analysed during the current study are available
from the corresponding author on reasonable request.
CR, PG and FS were responsible for the study design. PG supervised the study.
MB, LPD and AR were responsible for data collection and data cleaning. AK
analyzed the microbiological isolates and/or interpreted the results on
antimicrobial susceptibility testing. FS conducted the statistical analysis.
All authors interpreted the data, gave important intellectual content and revised
the manuscript critically. All authors read and approved the final manuscript.
Ethics approval and consent to participate
For this ecologic study, we analyzed aggregated and anonymous data that
were collected by the hospital in accordance with the German “Protection
against Infection Act”, §23. Therefore, ethical approval and informed consent
were not required and institutional review boards were not consulted.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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