University of Groningen
Methicillin-resistant Staphylococcus aureus in Europe, 1999-2002
Tiemersma, EW; Bronzwaer, SLAM; Lyytikainen, O; Degener, JE; Schrijnemakers, P;
Bruinsma, N; Monen, J; Witte, W; Grundmann, H; European Anti Resis Sur Sys Part
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Emerging Infectious Diseases
DOI:
10.3201/eid1009.040069
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Tiemersma, EW., Bronzwaer, SLAM., Lyytikainen, O., Degener, JE., Schrijnemakers, P., Bruinsma, N.,
Monen, J., Witte, W., Grundmann, H., & European Anti Resis Sur Sys Part (2004). Methicillin-resistant
Staphylococcus aureus in Europe, 1999-2002.
Emerging Infectious Diseases
,
10
(9), 1627-1634.
https://doi.org/10.3201/eid1009.040069
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We explored the variation in proportions of methicillin-
resistant Staphylococcus aureus (MRSA) between and
within countries participating in the European Antimicrobial
Resistance Surveillance System and temporal trends in its
occurrence. This system collects routine antimicrobial sus-
ceptibility tests for S. aureus. We examined data collected
from January 1999 through December 2002 (50,759 iso-
lates from 495 hospitals in 26 countries). MRSA prevalence
varied almost 100-fold, from <1% in northern Europe to
>40% in southern and western Europe. MRSA proportions
significantly increased in Belgium, Germany, Ireland, the
Netherlands, and the United Kingdom, and decreased in
Slovenia. Within countries, MRSA proportions varied
between hospitals with highest variance in countries with a
prevalence of 5% to 20%. The observed trends should
stimulate initiatives to control MRSA at national, regional,
and hospital levels. The large differences between hospi-
tals indicate that efforts may be most effective at regional
and hospital levels.
S
taphylococcus aureus is an important cause of commu-
nity- and hospital-acquired infections. Infections
caused by methicillin- or oxacillin-resistant S. aureus
(MRSA) are mainly nosocomial and are increasingly
reported from many countries worldwide (1). As MRSA
strains are frequently resistant to many different classes of
antimicrobial drugs, second- and third-line antimicrobial
resistance is a growing concern (2). Surveillance of MRSA
provides relevant information on the extent of the MRSA
epidemic, identifies priorities for infection control and the
need for adjustments in antimicrobial drug policy, and
guides intervention programs (3).
In Europe, several surveillance systems collect data on
MRSA (4,5). Most collect data from specific types of hos-
pitals, for certain periods, or information related to specific
antimicrobial susceptibility patterns. The only ongoing ini-
tiative that continuously monitors antimicrobial resistance
in most European countries is the European Antimicrobial
Surveillance System (EARSS), funded by Directorate
General for Health and Consumer Protection of the
European Commission. This network connects national
surveillance systems and provides comparable and validat-
ed results of routine antimicrobial susceptibility tests (AST)
following standardized protocols from a representative set
of laboratories per country (6). Timely and detailed feed-
back is given through a freely accessible and interactive
Web site (http:\\www.earss.rivm.nl). EARSS was estab-
lished in 1998 and currently connects >600 laboratories in
28 countries, which serve >100 million people. Preliminary
EARSS results showed considerable differences in the pro-
portions of MRSA across Europe (7,8).
We report results of antimicrobial susceptibility testing
of S. aureus blood isolates from 1999 to 2002 in Europe;
Methicillin-resistant
Staphylococcus aureus in Europe,
1999–2002
Edine W. Tiemersma,* Stef L.A.M. Bronzwaer,* Outi Lyytikäinen,† John E. Degener,‡
Paul Schrijnemakers,* Nienke Bruinsma,* Jos Monen,* Wolfgang Witte,§ Hajo Grundmann,*
and European Antimicrobial Resistance Surveillance System Participants
1
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004 1627
*National Institute for Public Health and the Environment,
Bilthoven, the Netherlands; †National Public Health Institute,
Helsinki, Finland; ‡University Hospital Groningen, Groningen, the
Netherlands; and §Robert Koch Institute, Werningerode, Germany
1
European Antimicrobial Resistance Surveillance System national
representatives, 2002: Austria: H. Mittermayer, W. Koller; Belgium:
H. Goossens, E. Hendrickx; Bulgaria: B. Markova; Croatia: S.
Kalenic, A. Tambic-Andrasevic; Czech Republic: P. Urbaskova;
Denmark: D. Monnet; Estonia: P. Naaber; Finland: O. Lyytikäinen,
A. Nissinen; France: H. Aubry-Damon, P. Courvalin; Germany: U.
Buchholz, W. Witte; Greece: N. Legakis, G. Vatopoulos; Hungary:
M. Füzi; Ireland: D. O’Flanagan, O. Murphy; Iceland: K.
Kristinsson; Israel: R. Raz; Italy: G. Cornaglia, P. D’Ancona;
Luxembourg: R. Hemmer; Malta: M. Borg; Netherlands: A. de
Neeling, E. Tiemersma; Norway: A. Hoiby, E. Bjørløw; Poland: W.
Hryniewicz; Portugal: M. Caniça; Romania: I. Codita; Slovenia: M.
Gubina, J. Kolman; Slovakia: L. Langsadl; Spain: F. Baquero, J.
Campos; Sweden: B. Liljequist; United Kingdom: A. Johnson, M.
Whale.
these results show variation in the prevalence of MRSA,
including variation in its proportions at the hospital level.
To assess recent changes in the epidemiology of MRSA
within countries, we also present country-specific tempo-
ral trends in the occurrence of MRSA.
Materials and Methods
Data Collection
Data (identification number of isolate, EARSS labora-
tory code, date and type of specimen, sex and age of
patient, EARSS hospital code, hospital ward to which
patient is admitted, result of mecA gene polymerase chain
reaction [PCR], and susceptibility to several antimicrobial
drugs, including oxacillin and vancomycin) are collected
through national surveillance systems. AST results of
every first S. aureus blood isolate per patient per quarter
are submitted to the EARSS database by national data
managers. After authorization by the national representa-
tives by using standard feedback reports, national data are
included in the EARSS database and become available on
the Web site.
Susceptibility Testing
Antimicrobial susceptibility is tested according to a
standardized protocol (5). Briefly, laboratories report
oxacillin susceptibility, preferably determined by an
oxacillin-screening plate or an oxacillin disk-diffusion test.
To confirm methicillin resistance, the minimum inhibitory
concentration (MIC) for oxacillin or the presence of mecA
gene by PCR is determined. Reporting vancomycin MIC is
recommended for MRSA isolates.
Interpretative AST results (i.e., sensitive [S], intermedi-
ate [I], and resistant [R], in accordance with defined guide-
lines) are accepted. Most (71%) of the laboratories have
adopted the guidelines of the National Committee for
Clinical Laboratory Standards (NCCLS; www.nccls.org).
Most guidelines agree that S. aureus isolates should be
considered nonsusceptible (R) to oxacillin if the MIC is ≥4
mg/L. Lower MIC breakpoints (R if MIC >2 mg/L) are
only suggested by the Deutsche Industrie-Norm (DIN)
(www.din.de) and guidelines of the Swedish Reference
Group for Antibiotics (SRGA) (www.srga.org).
Data Analysis
We rejected observations lacking mandatory informa-
tion (i.e., laboratory code, date of specimen, either patient
identification number or month and year of birth, pathogen
code, antibiotic code, or oxacillin test result [S or R]);
duplicate records and repeat isolates from the same patient
were also rejected. Isolates with an interpretative AST
result of “R” (resistant) to oxacillin or one of its equivalents
(cloxacillin, dicloxacillin, and flucloxacillin) were defined
as MRSA. Isolates with intermediate susceptibility were
not counted as MRSA and were excluded from the analy-
ses. MRSA proportions were calculated as the number of
MRSA isolates divided by the total number of S. aureus
isolates obtained from blood cultures.
For the current analysis, data collected from January
1999 through December 2002 were used. We included
only information from hospitals with data for >
20 isolates
from countries reporting >100 isolates. To calculate time
trends for analyses of variation between hospitals, we
included only those hospitals that had participated in at
least 3 consecutive years.
Univariate analyses were performed by using chi-square
or t tests if appropriate. Country-specific trends in the
occurrence of MRSA over time were analyzed by using a
multivariate Poisson regression model adjusting for auto-
correlation in hospitals (e.g., attributable to possible simi-
larity in blood culturing and AST practice). We also
compared countries with respect to variation between hos-
pitals, expressed as the variance in hospital-specific MRSA
proportions. To eliminate the natural dependency between
variance and mean, the MRSA ratio was first transformed
by power (Box-Cox) transformation according to the fol-
lowing formula: T(k/n) = (k/n)
λ
, where T is the transformed
MRSA ratio, k/n is the resistance rate (i.e., the number of
resistant isolates divided by the total number of isolates),
and λ was chosen in such a way that variance was inde-
pendent of the mean, i.e., λ = 0.397. The variance was fur-
ther adjusted by size (in terms of number of isolates
reported) of individual hospitals. Country-specific vari-
ances were then graphically displayed and compared.
Results
From January 1999 through December 2002, EARSS
received AST results of 53,264 S. aureus blood isolates
from 27 countries (Norway does not report S. aureus
data), including 628 laboratories serving 896 hospitals.
Twenty-six countries reported AST results of >100 iso-
lates. The current study included 50,759 isolates from 428
laboratories serving approximately 500 hospitals. Overall,
20% of these isolates were reported as methicillin resist-
ant. A total of 295 hospitals (35,921 isolates, 19 countries)
provided data for at least 3 consecutive years and were
included in the time trend analyses. Table 1 describes the
main characteristics of the data and the proportion of
MRSA by country.
MRSA was more frequently isolated from men (21%)
than from women (18%, p < 0.001). Patients with a blood
culture positive for MRSA were older than patients with
methicillin-susceptible S. aureus (MSSA) (mean age, 65.3
[SD 18.7] versus 58.6 [23.4], p < 0.001). The proportion of
MRSA was highest among patients admitted to intensive
care units (35%).
1628 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004
RESEARCH
Geographic variation is displayed in Figure 1, which
shows a north-south gradient, with the lowest MRSA
prevalence in northern Europe and highest prevalence in
southern Europe, Israel, the United Kingdom, and Ireland.
MRSA proportions varied almost 100-fold, with the lowest
proportion in Iceland (0.5%) and the highest proportion in
Greece (44%, Table 1).
Statistical analyses of country-specific time trends by
Poisson regression (Table 2) showed that increases in
MRSA proportions were significant in Belgium (from 22%
in 1999 to 27% in 2002), Ireland (39%–45%), Germany
(9%–19%), the Netherlands (0.4%–1%) and the United
Kingdom (31%–45%). The proportion of MRSA decreased
significantly in Slovenia only, from 22% in 2000 to 15% in
2002. The model had difficulties in estimating changes in
MRSA proportion in countries with low counts of MRSA
isolates, which is reflected in the very wide confidence
intervals for Iceland and Bulgaria (Table 2). Relatively
large year-to-year fluctuations occurred in some countries
(Bulgaria, Greece, Luxembourg, Malta, and Portugal);
some of these countries (Bulgaria, Luxembourg, and Malta)
had low isolate counts (Table 1). Figure 2 presents signifi-
cant time trends by showing MRSA proportions per coun-
try per year for 1999 through 2002.
Figure 3A shows regional variation in MRSA propor-
tions within countries. Particularly high variation was
identified among hospitals in Belgium, the Czech
Republic, Spain, Greece, Italy, Portugal, and the United
Kingdom. After applying the power transformation, the
remaining variation was highest in Germany (Figure 3B),
with a variance after transform of 17%. Other countries
with relatively high variation in MRSA proportions (vari-
ance after transform >15%) between hospitals were
Poland, the Czech Republic, and Slovakia. The highest rel-
ative variation was found in countries with MRSA propor-
tions from 5% to 20%, with the exception of Hungary and
Slovenia. A relatively high variation between hospitals was
also found in countries with MRSA proportions >25%.
The lowest variation between hospitals was observed for
Slovenia (variance after transform, 3%), and variation was
also low in France (variance after transform, 5%).
Vancomycin resistance did not occur. Intermediate sus-
ceptibility of S. aureus (VISA) was only reported for five
isolates from France in 2001.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004 1629
Staphylococcus aureus in Europe
Table 1. Characteristics of EARSS database by countries
a,b
Country (EARSS country code) No. of hospitals
c
Total no. of
isolates No. of MRSA isolates (%) Period of participation
Austria (AT) 11 656 58 (8.8) Jan 2000–Dec 2002
Belgium (BE) 36 2,953 696 (23.6) Jul 1999–Dec 2002
Bulgaria (BG) 4 183 62 (33.9) Jan 2000–Dec 2002
Croatia (HR) 6 341 125 (36.7) Jul 2001–Dec 2002
Czech Republic (CZ) 35 2,426 142 (5.9) Apr 2000–Dec 2002
Denmark (DK) 22 2,406 14 (0.6) Jan 1999–Sept 2002
Estonia (EE) 3 112 1 (0.9) Jan 2001–Dec 2002
Finland (FI) 17 1,990 19 (1.0) Jan 1999–Dec 2002
France (FR) 24 3,376 1,117 (33.1) Jan 2001–Dec 2002
Germany (DE) 25 3,757 600 (13.8) Jan 1999–Dec 2002
Greece (GR) 19 1,126 500 (44.4) Jan 1999–Dec 2001;
Jul 2002–Dec 2002
Hungary (HU) 12 435 31 (7.1) Jan 2001–Dec 2002
Iceland (IS) 1 184 1 (0.5) Jan 1999–Dec 2002
Ireland (IE) 19 2,897 1,192 (41.2) Jan 1999–Dec 2002
Israel (IL) 5 849 326 (38.4) Jan 2001–Dec 2002
Italy (IT) 57 3,593 1,470 (40.9) Jan 1999–Jun 2000;
Apr 2001–Dec 2002
Luxemburg (LU) 4 214 41 (19.2) Jan 1999–Dec 2002
Malta (MT) 1 240 105 (43.8) Jan 2000–Dec 2002
Netherlands (NL) 45 5,359 30 (0.6) Jan 1999–Dec 2002
Poland (PL) 8 238 42 (17.7) Jan 2001–Dec 2002
Portugal (PT) 15 1,540 535 (34.7) Jan 1999–Dec 2002
Slovakia (SK) 7 228 24 (10.5) Jul 2001–Dec 2002
Slovenia (SI) 8 657 121 (18.4) Jul 2000–Dec 2002
Spain (ES) 35 2,985 739 (24.8) Jan 2000–Dec 2002
Sweden (SE) 54 6,071 48 (0.8) Jan 1999–Dec 2002
United Kingdom (UK) 27 5,343 2,217 (41.5) Jan 1999–Sept 2002
Total 500 50,759 10,256 (20.2)
a
EARSS, European Antibiotic Resistance Surveillance System; MRSA, methicillin-resistant Staphylococcus aureus.
b
Only hospitals providing data of !20 isolates are included.
c
According to EARSS hospital codes provided by the countries.
Discussion
This is the first EARSS report on the prevalence of
MRSA among blood isolates in 27 countries in the
European region. We found that proportions of MRSA
vary largely across Europe, with the highest proportions in
southern and parts of western Europe and lowest propor-
tions in northern Europe. MRSA proportions seem to be
increasing in many countries. Significant increases were
found for Belgium, Germany, the Netherlands, Ireland, and
the United Kingdom, whereas the proportion of MRSA
decreased in Slovenia. In all countries, variation between
hospitals was observed. The variation between hospitals
was highest in Germany and in most other countries with
an MRSA prevalence of 5% to 20%. The lowest variation
between hospitals was found in Slovenia.
Our results show the European situation with respect to
the occurrence of MRSA in blood isolates and confirm
other observations (9–11) on invasive isolates; they are
also in accordance with findings of other studies with
respect to demographic variables, such as sex, age, and
patient ward (9,12). Although blood isolates represent the
minority of clinically relevant samples, they are indicative
of infection. Studies that report MRSA proportions from
all sources usually include screening samples that are sub-
ject to bias because of differential screening practices.
Considering hospital-acquired MRSA only seems to pro-
vide insight into the European MRSA epidemic, as the
prevalence of community-acquired MRSA in Europe
remains very low (0.03%–1.5%), even in countries with a
high MRSA prevalence in hospitals (13–17). EARSS pro-
vides comparable data, annually validated through external
quality assurance exercises, which have repeatedly con-
firmed a good-to-excellent concordance for identifying
MRSA (18).
EARSS accepts susceptibility data according to clinical
breakpoints (S, I, R) in agreement with international guide-
lines. Methicillin resistance is usually defined as having an
MIC of >
4 mg/L. Because of lower breakpoints (MIC >2
mg/L) defined by SRGA and DIN, this definition may
1630 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004
RESEARCH
Figure 1. Geographic variation in proportions of methicillin-resist-
ant Staphylococcus aureus (MRSA) (1999–2002).
Table 2. Relative change in MRSA proportion per country per year and 95% confidence intervals as calculated from Poisson
regression models
a,b,c
Country
Reported %
MRSA at start
Reported %
MRSA in 2002
Relative change per
year, ratio
95% CI of estimated change
p value
Austria 7.0
d
7.6 0.80 0.48 – 1.34 0.39
Belgium 22.1 27.2 1.25 1.12 – 1.41
0.01
Bulgaria 35.1
d
37.7 1.11 0.59 – 2.09 0.76
Czech Republic 4.5
d
6.2 1.15 0.89 – 1.50 0.29
Denmark 0.3 1.0 1.64 0.97 – 2.75 0.06
Finland 1.5 0.8 0.69 0.43 – 1.11 0.13
Germany 9.4 19.2 1.72 1.54 – 1.93
0.01
Greece 37.0 48.6 1.23 0.89 – 1.71 0.21
Iceland 0.0 0.0 0.52 0.07 – 3.67 0.51
Ireland 39.4 45.0 1.36 1.17 – 1.58
0.01
Italy 35.2 40.0 1.11 0.94 – 1.30 0.23
Luxembourg 15.0 18.3 1.09 0.71 – 1.67 0.70
Malta 34.7
d
42.5 1.58 0.92 – 2.74 0.10
Netherlands 0.4 1.0 1.62 1.01 – 2.58 0.04
Portugal 39.7 38.9 0.91 0.75 – 1.09 0.32
Slovenia 22.3
d
14.7 0.69 0.51 – 0.93 0.02
Spain 28.4
d
23.5 1.03 0.87 – 1.21 0.74
Sweden 1.1 0.7 0.95 0.73 – 1.23 0.68
United Kingdom 30.5 44.5 1.48 1.31 – 1.66
0.01
a
CI, confidence interval; MRSA, methicillin-resistant Staphylococcus aureus.
b
Adjusted for autocorrelation within hospitals and for variation in the number of isolates per quarter, including only the hospitals participating for at least 3
consecutive years and reporting data of > 20 isolates.
c
The change estimated by the model does not necessarily correspond to the overall change that can be calculated from the second and third column, this
is because some trends first show an increase, followed by a decrease, or vice versa.
d
Data from year 2000 onwards.
![Figure 3. A) Variation in methicillin-resistant Staphylococcus aureus (MRSA) proportions between hospitals with AST results of >20 blood isolates, displayed by ranking of MRSA proportion (from lowest to highest). Only countries with more than one hospital are displayed. Hospital-specific proportions (open diamonds) are grouped per country. The solid vertical bars represent the mean MRSA proportion per country. B) Local variation, showing the power-transformed variance being independent of the mean MRSA proportion per country, displayed by ranking of MRSA proportion (from lowest to highest). Only hospitals reporting >20 isolates are included. Countries with less than five reporting hospitals are not shown (Iceland and Malta [1], Estonia [3], Bulgaria and Luxembourg [4]).](/figures/figure-3-a-variation-in-methicillin-resistant-staphylococcus-cwmpmzxz.webp)
