Journal of Antimicrobial Chemotherapy (2009) 64, 1029 –1034

doi:10.1093/jac/dkp337
Advance Access publication 22 September 2009

Flucloxacillin, still the empirical choice for putative

Staphylococcus aureus infections in intensive care units
in the Netherlands

M. I. A. Rijnders, R. H. Deurenberg, M. L. L. Boumans, J. A. A. Hoogkamp-Korstanje, P. S. Beisser

and E. E. Stobberingh* on behalf of the Antibiotic Resistance Surveillance Group†

Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands

Received 28 May 2009; returned 26 June 2009; revised 5 August 2009; accepted 19 August 2009

Downloaded from http://jac.oxfordjournals.org/ by guest on February 17, 2016

Objectives: To determine the usefulness of flucloxacillin as empirical therapy for putative
Staphylococcus aureus infections in intensive care unit (ICU) patients in the Netherlands, the antibiotic
resistance of S. aureus isolates from ICUs over a 13 year period was investigated.
Methods: From 1996 to 2008, 1146 consecutive S. aureus isolates from ICU patients in 14 large referral
hospitals were collected. The susceptibility to relevant antibiotics was determined by microbroth
dilution according to CLSI guidelines.
Results: Resistance to flucloxacillin was only found in 12 isolates (1%). The resistance to clarithromycin,
ciprofloxacin and moxifloxacin showed a significant trend over time, from 4.2% to 10.3%, from 1.0% to
10% and from 0.0% to 5.0%, respectively (P<0.05). The resistance to penicillin, clindamycin and doxy-
cycline increased over time, from 74% to 75%, from 3.0% in 1996 to 3.2% in 2008 and from 2.2% in 1996
to 8.2% in 2008, respectively (P >0.05). Resistance to cephalosporins, carbapenems, rifampicin and genta-
micin was sporadically observed. No resistance was found to vancomycin, teicoplanin and linezolid.
Conclusions: The empirical choice of flucloxacillin in the case of putative S. aureus infections in patients
admitted to ICUs in the Netherlands is still justified.

Keywords: antibiotic resistance, S. aureus, critical care, ICUs, empirical therapy

Introduction national levels the resistance patterns of microorganisms isolated

from ICUs, and the outpatient departments of pulmonology and
Between 20% and 30% of intensive care unit (ICU)-acquired urology of 14 hospitals geographically spread over the
infections are caused by Staphylococcus aureus,1,2 which is an Netherlands. The aim of this national surveillance programme is
aetiological agent of bloodstream infections, endocarditis, soft to provide actual antibiotic resistance data to clinicians, in order
tissue infection, osteomyelitis and pneumonia.3 Forty percent of to optimize their empirical antibiotic choice, to control antibiotic
ICU patients receive empirical therapy.4 use and, indirectly, to control the antibiotic resistance problem.6
The choice of empirical antibiotic treatment for ICU patients The results of 13 years of surveillance of the antimicrobial
is challenging, because of the emergence of antibiotic-resistant resistance of S. aureus isolated from ICU patients in the
organisms and the risk of superinfections with circulating resist- Netherlands are described.
ant organisms.4 As early optimal empirical therapy decreases the
mortality and morbidity of ICU patients,5 it is essential to
provide the clinician with resistance data for the local circulating Materials and methods
strains in order to optimize the empirical choice.
A national longitudinal resistance surveillance programme in Population and study design
specific hospital wards, including ICUs, started in 1996 in the From 1 January 1996 until 1 July 2008, unique consecutive isolates
Netherlands. This programme, from the Dutch Antibiotic (a maximum of 100 isolates per ICU per year) from blood, wounds,
Resistance Surveillance Group (SWAB), monitors at local and bronchial aspirate and urine of patients on ICUs from 14 medical

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

*Corresponding author. Tel: þ31-43-3876644; Fax: þ31-43-3876643; E-mail: e.stobberingh@mumc.nl

†Members are listed in the Acknowledgements section.
.....................................................................................................................................................................................................................................................................................................................................................................................................................................

1029
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 Rijnders et al.
centres in the Netherlands were collected. Only one S. aureus
isolate from each patient was included.7
The isolates were identified at local laboratories, stored at 2208C
and then sent to a central microbiological laboratory for quantitative
antimicrobial susceptibility testing. From 1996 until 2002, all strains
were tested in the Department of Medical Microbiology of the
University of Nijmegen and, from 2003 until present, in the
Department of Medical Microbiology of the Maastricht University
Medical Centre (MUMC).
Antimicrobial susceptibility testing
Antimicrobial susceptibilities (as MIC values) were determined
according to CLSI guidelines8 using the microbroth dilution method
with cation-adjusted Mueller –Hinton broth II (Becton, Dickinson
and Company, Sparks, USA), an inoculum of 5105 cfu/L and over-
night incubation at 378C. The MIC plates with freeze-dried anti-
biotics were purchased from MCS Diagnostics BV (Swalmen, the
Netherlands), with a guaranteed shelf-life of 1 year. The antimi-
crobial agents tested were (range, mg/L): cefaclor, 0.06 –128;
cefuroxime, 0.06 –128; clindamycin, 0.03 –64; ciprofloxacin,
0.128–32; clarithromycin, 0.03 –64; gentamicin, 0.06–64; imipe-
nem, 0.03 –64; linezolid, 0.03–64; meropenem, 0.06 –64; moxiflox-
acin, 0.12 –32; flucloxacillin, 0.03 –64; penicillin, 0.004– 8;
rifampicin, 0.008– 16; teicoplanin, 0.06–128; doxycycline,
0.03 –64; and vancomycin, 0.06– 128. S. aureus ATCC 29213 was
used as a reference strain. Multidrug resistance was defined as
resistance to more than two groups of antibiotics.
The oxacillin-resistant isolates were analysed for the presence of
the S. aureus-specific femA gene as well as the methicillin-resistant
S. aureus (MRSA)-specific mecA gene using a real-time PCR assay
as described previously.9
Statistical analysis
Data were analysed using SPSS Version 15.0. Trends over time of
the prevalence of antibiotic resistance were determined by linear
regression analysis; the prevalence data were weighted on the
amount of isolates collected each year. The slopes of the resistance
graphs are represented with the generally used symbol (m) and their
respective 95% confidence intervals are given in parentheses.
A P value of ,0.05 was considered statistically significant.
Results
Bacterial isolates
In total, 1146 of the 9911 (12%) ICU isolates collected during
the study period were S. aureus, comprising 270 isolates from
three centres in the north (24%), 267 isolates from two centres
in the east (23%), 276 isolates from five centres in the west
(24%) and 333 isolates from four centres in the south of the
Netherlands (29%). The number of S. aureus isolates each year
was: 1996, n¼ 90; 1997, n ¼ 76; 1998, n ¼ 77; 1999, n ¼70;
2000, n ¼ 63; 2001, n¼ 68; 2002, n ¼ 55; 2003, n ¼ 92; 2004,
n ¼ 117; 2005, n ¼ 106; 2006, n ¼ 130; 2007, n ¼ 105; and 2008,
n ¼ 97.
Antibiotic resistance over time
The overall resistance to penicillin increased from 74% in 1996
to 75% in 2008 (P ¼0.09). Flucloxacillin-resistant strains were
observed among 12 of the 1146 isolates (1.0%), which were
1030
mecA- and femA-positive and thus characterized as MRSA. Of
the 12 MRSA isolates, 2 were found in 1996 (2% of the isolates
in this year), 2 in 1998 (3%), 3 in 2004 (3%), 2 in 2007 (2%)
and 3 in 2008 (3%). These strains were isolated in three regions
and eight hospitals.
Clindamycin showed an increase in resistance from 3.0% in
1996 to 3.2% in 2008 (P ¼ 0.801; Figure 1c) and doxycycline
also showed an increase from 2.2% in 1996 to 8.2% in 2008,
overall 5.6% (P ¼ 0.69; Figure 1b).
The resistance to clarithromycin showed a significant trend
over time, from 4.2% to 10.3% in 2008 (P, 0.05; Figure 1c).
Resistance to ciprofloxacin was 1%– 3% until 2002, increased
significantly up to 14.1% in 2003 and fluctuated after 2003
around 10.0% (P, 0.05; Figure 1a). Resistance to moxifloxacin
increased significantly from 0% to 7.6% in 2003 and fluctuated
thereafter (Figure 1a).
A change was observed in the shape of the MIC distribution
of ciprofloxacin, being unimodal until 2003, with sporadic iso-
lates with an MIC .8 mg/L, and becoming more bimodal from
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2003, with the emergence of more isolates with an MIC value
of .8 mg/L (Figure 2).
Of the 85 ciprofloxacin-resistant isolates, 46 (54%) were
resistant, 23 (27%) were intermediately susceptible and 16
(19%) were susceptible to moxifloxacin.
Resistance to cephalosporins, carbapenems, rifampicin and
gentamicin was sporadically observed. No resistance was found
to vancomycin, teicoplanin and linezolid. One isolate was inter-
mediately susceptible to vancomycin (MIC ¼ 4 mg/L).
Multidrug resistance
Multidrug resistance was observed in 97 isolates and the preva-
lence increased over time (Figure 3). Most frequent was resist-
ance to the combination of penicillin, clarithromycin,
clindamycin and ciprofloxacin (n ¼12). For the penicillin-
susceptible isolates, the most common combination was resist-
ance to clarithromycin, clindamycin and doxycycline (n ¼ 22).
Six MRSA strains were resistant to five or more antibiotic
groups. None of the isolates was resistant to all antibiotics
tested.
Discussion
The finding of 1% flucloxacillin resistance among the clinical
S. aureus isolates from ICU patients over a 13 year period still
justifies the empirical therapy choice of flucloxacillin in the case
of a putative S. aureus infection in these patients in the
Netherlands. It may be combined with gentamicin in the case of
a life-threatening infection and/or rifampicin in the presence of
a foreign body.
ICU-acquired infections are often caused by antibiotic-
resistant microorganisms. Several factors, such as frequent use
of broad-spectrum antibiotics, invasive procedures, underlying
diseases, crowding of patients and transmission of resistant
bacteria between patients, contribute to the high risk of an
ICU as an area for the emergence and spread of antibiotic
resistance.10 – 12 Therefore, especially in the ICU setting, the
choice of empirical antimicrobial therapy for critically ill
patients is challenging.13 Optimal choice of the empirical anti-
biotic prescription is important to improve the outcome of the
 Staphylococcus aureus population structure from Dutch ICUs (1996–2008)

(a) 20

15
Resistance (%)

10
y = 0.8616x + 0.5702
R2 = 0.434

5
y = 0.5025x – 1.1295
R2 = 0.4675

0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
ciprofloxacin moxifloxacin trendline ciprofloxacin trendline moxifloxacin

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(b) 100

75
Resistance (%)

50 y = 0.0494x + 73.878
R2 = 0.0009

25 y = 0.0868x + 4.4365
R2 = 0.015

0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
penicillin doxycyline trendline penicillin trendline doxycycline
(c) 20

15
Resistance (%)

y = 0.3512x + 3.8036
R2 = 0.3207
10

y = 0.0372x + 2.7641
R2 = 0.0054
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
clarithromycin clindamycin trendline clarithromycin trendline clindamycin

Figure 1. Trendlines of the changes in resistance over time to: (a) ciprofloxacin, m¼0.8616 (0.210– 1.514), and moxifloxacin, m¼0.5025 (0.146– 0.857); (b)
penicillin, m¼0.0494 (21.039–1.141), and doxycycline, m¼0.0868 (20.380–0.554); and (c) clarithromycin, m¼0.3512 (0.005–0.677), and clindamycin,
m ¼0.0372 (20.293–0.371). The slopes of ciprofloxacin, moxifloxacin and clarithromycin had P values of ,0.05. The other antibiotics showed no significant
increase.

1031
 Rijnders et al.

100.0
1996
80.0
1998
Isolates (%)

60.0 2000
2002 Year
40.0
2004
20.0 2006

0.0 2008
0.12 0.25 0.5 1 2 4 >8

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MIC values (mg/L)

Figure 2. MIC distributions of ciprofloxacin in the Netherlands over a 13 year period.

25

20
Number of isolates

15

10

0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year

more than 3 antibiotic classes 3 antibiotic classes

Figure 3. Multidrug resistance in ICU isolates in the Netherlands over time.

infections, to reduce the patients’ morbidity and mortality, and
to contribute to the control of the emergence of antibiotic
resistance.14 As adequate therapy without delay is crucial for the
outcome and because the microbiological laboratory cannot
support the clinician within the timeframe provided with anti-
biotic resistance data of the causative microorganism(s), the
physicians have to rely on epidemiological data. Surveillance
studies can provide clinicians with actual epidemiological data
and thus support the optimal antibiotic choice for empirical
therapy.13 – 15
In 1996, the SWAB surveillance programme started in the
Netherlands, which is different from other surveillance pro-
grammes. First, the participating hospitals are distributed over
the country, covering 25% of the total Dutch population.
Second, all susceptibility testing methods are quantitatively per-
formed in one reference laboratory. Third, the data of several
years are available, which allows us to follow the development
of resistance over time.6
Recently, the CARE-ICU surveillance project started in eight
European countries. The aim of this project was, among others,
to control the emergence of microbial resistance by judicious
use of antibiotics. The first report after 1 year of surveillance
mentioned a variation in the prevalence of resistance and anti-
biotic consumption between countries.15 Resistance to methicil-
lin among S. aureus isolates ranged per country from 0% to
100%, with a median of 11.6%. One of the limitations of this

1032
 Staphylococcus aureus population structure from Dutch ICUs (1996–2008)
surveillance is the low number of participating ICUs per
country, mostly four or less.
Several studies described a higher prevalence of antimicro-
bial resistance in ICU patients compared with patients from
other hospital wards and the community,12,16,17 due to high anti-
biotic use in ICU settings and critically ill patients.4,18 However,
we found no significant differences in resistance to vancomycin,
linezolid, teicoplanin, cephalosporins, carbapenems and fluclox-
acillin between ICU isolates and the isolates from other wards
of the hospitals or the community.6 Significant differences
(P, 0.05) in resistance between the isolates from the community
and the ICU patients were observed for penicillin (71% versus
75%), tetracycline (4% versus 6%), clarithromycin (4% versus
8%) and ciprofloxacin (1% versus 12%), respectively.6 A signifi-
cant difference in resistance to ciprofloxacin was also observed
between hospital and ICU patients (7% versus 12%).6 No differ-
ences in resistance to clarithromycin and penicillin were
observed between hospitals and ICU patients.6
Low antibiotic resistance percentages of S. aureus from ICU
patients, for example flucloxacillin resistance ,2%, were also
observed in Swedish ICUs over a 5 year period.19 – 21 A recent
systematic review and meta-analysis by Tacconelli et al. 22
showed clear associations between exposure to fluoroquinolones,
glycopeptides and b-lactam antibiotics and the prevalence of
MRSA. Antibiotic use in both Sweden and the Netherlands is
relatively low compared with other European countries.19 This,
in combination with the search-and-destroy policy as applied for
MRSA in the Netherlands, is very likely the main reason for the
low prevalence of MRSA in this country.20
According to the European Antibiotic Resistance
Surveillance Study (EARSS) data, the prevalence of MRSA in
the Netherlands increased from 0.3% in 1999 to 1.4% in 2007,
whereas in the present study no increase was observed.21 The
difference in prevalence might be due to differences in the
source of the isolates. Although one might expect a higher
MRSA percentage in ICU patients, this hypothesis was not con-
firmed by the data from this study. There are several reasons that
could lead to differences in results between our study and the
EARSS study: (i) our study includes all intensive care isolates,
while the EARSS study only includes invasive isolates (blood
culture and CSF isolates); (ii) we only include one isolate per
patient, while the EARSS study includes invasive isolates—this
can lead to a selection bias when more than one isolate per
patient is included; and (iii) both studies include different hospi-
tals and differences in the prevalence of MRSA between hospi-
tals in the same country do exist.21
Although the percentage resistance to most antibiotics
remained ,10% over the years of study (except for penicillin),
a significant increase in resistance was observed for clarithro-
mycin, moxifloxacin and ciprofloxacin. Overall, the increase in
resistance to moxifloxacin was lower than for ciprofloxacin
and started later, because moxifloxacin was available from
199823 and ciprofloxacin was obtainable 10 years earlier.
Between both compounds, a partial cross-resistance has been
described—a double mutation in grlA and gyrA is required for
moxifloxacin resistance compared with a single mutation for
ciprofloxacin resistance.24,25 This was confirmed by the data
from the present study for the ciprofloxacin-resistant isolates,
which showed that 19% of the ciprofloxacin isolates were still
susceptible to moxifloxacin and .50% of the strains were
resistant to both agents.
1033
Ciprofloxacin has a low intrinsic activity against S. aureus
(MIC90 0.5– 1 mg/L) and, therefore, it was never the drug of
first choice for S. aureus infections in the Netherlands.5 Since
the resistance percentage is .10%, it cannot be used as empiri-
cal therapy in these infections.
The emergence of multidrug resistance needs consideration.
Resistance to three or more antimicrobial groups was found in
8% of the isolates and increased over time. This phenomenon
was sporadically found in the northern part of the Netherlands,
which may be explained by the absence of a participating uni-
versity hospital.
In conclusion, based on the antibiotic susceptibility data of
ICU isolates collected over more than a decade, the empirical
therapy for putative S. aureus infections in ICU patients in the
Netherlands is still flucloxacillin, with or without gentamicin.
Acknowledgements
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We wish to thank P. Terporten for his advice with the statistical
analysis. Furthermore, we would like to thank our colleagues
from the research laboratory of the Department of Medical
Microbiology of the MUMC for their excellent laboratory
support.
The members of the Antibiotic Resistance Surveillance Group
were: Dr H. van Dessel, MUMC; Dr P. Bloembergen,
Laboratory Zwolle; Dr M. G. R. Hendrix, Laboratory of
Microbiology Twente Achterhoek; Dr W. H. M. Vogels, Martini
Hospital Groningen; Dr W. D. H. Hendriks, Medical Centre
Rotterdam location Clara; Dr P. J. G. M. Rietra, Onze Lieve
Vrouwe Gasthuis Amsterdam; Dr B. M. Dejongh, Sint Antonius
Hospital Nieuwegein; Dr A. G. M. Buiting, St Elisabeth
Hospital Tilburg; Dr A. J. Beunders, Public Health Laboratory
Kennemerland Haarlem; Dr K. Waar, Regional Public Health
Laboratory Leeuwarden; Dr L. J. M. Sabbe, Regional
Laboratory Zeeland Goes; Dr P. Sturm, University Medical
Centre Nijmegen; Dr T. A. M. Trienekens, VieCuri Medical
Centre Venlo; and Dr H. A. Bijlmer, Bronovo Hospital the
Hague (collection of isolates).
Funding
The project was supported by a grant of Bayer BV from 1996
until 2000 and thereafter by the Dutch Working Party on
Antibiotic Policy (SWAB).
Transparency declarations
None to declare.
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