Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients' environment
Boyer et al. Critical Care
Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients' environment
Alexandre Boyer 0 3 6
Adlade Doussau 1 2 7
Rodolphe Thibault 1 2 7
Anne Galle Venier 5 6
Van Tran 0 3
Hlne Boulestreau 5
Ccile Bbar 4
Frdric Vargas 0 3
Gilles Hilbert 0 3
Didier Gruson 0 3
Anne Marie Rogues 5 6
0 Service de Reanimation Medicale, Hopital Pellegrin-Tripode, place Amelie Raba Leon , 33076 Bordeaux Cedex , France
1 Universite Victor Segalen Bordeaux 2 , Institut de Sante Publique d'Epidemiologie et de Developpement (ISPED) , 146 rue Leo Saignat, 33076 Bordeaux Cedex , France
2 CHU de Bordeaux, Centre d'Investigation Clinique-Epidemiologie Clinique (CIC-EC 7), Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux Cedex , France
3 Service de Reanimation Medicale, Hopital Pellegrin-Tripode, place Amelie Raba Leon , 33076 Bordeaux Cedex , France
4 Service de Bacteriologie, Hopital Pellegrin- Tripode, place Amelie Raba Leon , 33076 Bordeaux Cedex , France
5 Service d'Hygiene Hospitaliere Hopital Pellegrin-Tripode, place Amelie Raba Leon , 33076 Bordeaux Cedex , France
6 INSERM, U657 Pharmaco- Epidemiologie et Evaluation de l'Impact des Produits de Sante sur les Populations , 146 rue Leo Saignat, 33076 Bordeaux Cedex , France
7 INSERM, U897 Epidemiologie et Biostatistiques , 146 rue Leo Saignat, 33076 Bordeaux Cedex , France
Introduction: The purpose of this study was to investigate the relationship among Pseudomonas aeruginosa acquisition on the intensive care unit (ICU), environmental contamination and antibiotic selective pressure against P. aeruginosa. Methods: An open, prospective cohort study was carried out in a 16-bed medical ICU where P. aeruginosa was endemic. Over a six-month period, all patients without P. aeruginosa on admission and with a length of stay >72 h were included. Throat, nasal, rectal, sputum and urine samples were taken on admission and at weekly intervals and screened for P. aeruginosa. All antibiotic treatments were recorded daily. Environmental analysis included weekly tap water specimen culture and the presence of other patients colonized with P. aeruginosa. Results: A total of 126 patients were included, comprising 1,345 patient-days. Antibiotics were given to 106 patients (antibiotic selective pressure for P. aeruginosa in 39). P. aeruginosa was acquired by 20 patients (16%) and was isolated from 164/536 environmental samples (31%). Two conditions were independently associated with P. aeruginosa acquisition by multivariate analysis: (i) patients receiving 3 days of antibiotic selective pressure together with at least one colonized patient on the same ward on the previous day (odds ratio (OR) = 10.3 ((% confidence interval (CI): 1.8 to 57.4); P = 0.01); and (ii) presence of an invasive device (OR = 7.7 (95% CI: 2.3 to 25.7); P = 0.001). Conclusions: Specific interaction between both patient colonization pressure and selective antibiotic pressure is the most relevant factor for P. aeruginosa acquisition on an ICU. This suggests that combined efforts are needed against both factors to decrease colonization with P. aeruginosa.
Pseudomonas aeruginosa infections on the ICU are a
constant concern . Colonization with this organism
often precedes infection  and its prevention is,
therefore, extremely important. P. aeruginosa colonization
has been reported to originate from exogenous sources
such as tap water , fomites and/or patient-to-patient
transmission, or as an endogenous phenomenon related
to antibiotic use. Some studies have highlighted the
importance of exogenous colonization during
hospitalization (50 to 70% of all colonizations) [4-9] whereas
others have questioned its relative importance [10-13].
Molecular epidemiology techniques have given an
insight into P. aeruginosa acquisition by demonstrating
that the same pulsotypes may spread from the
environment to patients [14,15], sometimes in an epidemic
mode. This could explain the discrepancies between
studies with different levels of exogenous acquisition
[14-16]. Although genotyping methods are useful, they
fail in giving a definitive result for the origin of bacteria.
First, a strain shared by a patient and his/her
environment has not necessarily been transmitted from the
environment to the patient. Furthermore, acquisition of
a strain not isolated from the environment does not
necessarily mean that it is part of the patients flora (the
classical endogenous definition [17,18]). It could also
have been acquired through previous healthcare
procedures from undiscovered environmental sources
(misdiagnosed exogenous acquisition). Whatever the mode
of acquisition, the determinants of colonization remain
unclear. In particular, the role of antibiotic selective
pressure on P. aeruginosa colonization is an important
In a previous study , we carried out a genotypic
analysis on our medical ICU. This analysis eliminated
an exogenous epidemic spread but showed that P.
aeruginosa colonization was associated with tap water
contamination over several weeks. It suggested, together
with an overall incidence of 11.3 colonized/infected
cases per 100 patients, an endemic P. aeruginosa context
. However, this study had several limitations. Only
genotyping from one colony of each culture was
performed so that only one-third of the strains were
analysed. Thus, it was not possible to ascertain which
acquisition mechanism predominated. More
importantly, the potential role of antibiotic selective pressure
on acquisition was not studied. Based on the same study
population, the aim of the current study was to explore
the respective roles of environment and antibiotic
selective pressure on P. aeruginosa colonization during
healthcare delivery in these endemic conditions.
Materials and methods
The study was performed on a 16-bed medical ICU in a
1,624-bed university teaching hospital between April
and November 2003 (29 weeks). Patients were treated in
single rooms distributed on four wards of four rooms
each. Other rooms such as a rest area, sterilization
room (a room dedicated to sterilization of medical
devices), toilet, equipment storage room, office and
night duty bedroom were shared (Figure 1). Each room
had its own water tap. The nurse:patient ratio was 1:4.
The antibiotic policy and hygiene protocols were not
modified during the study period. No digestive
decontamination was used on the ICU. Twice monthly chlorine
tap water disinfection was started in July (Week 11).
Hygiene protocols consisted of contact barrier
precautions for medical and nursing staff caring for patients
colonized or infected with multi-resistant
microorganisms (not including P. aeruginosa). These precautions
were applied systematically on admission of previously
hospitalized patients from other medical or surgical
units for more than 48 h and for known carriers.
P. aeruginosa carriers were identified on admission from
rectal and oropharyngeal swabs. No screening was
performed at discharge. Hand hygiene procedures were
All patients admitted during the study period were
systematically included in a prospective cohort. Secondary
exclusion criteria included: length of ICU stay <72 h
and carriage of P. aeruginosa on admission. These
patients were, however, considered as potential P.
aeruginosa environmental sources as they were present in
the ICU. Data were recorded prospectively each day
until P. aeruginosa colonization/infection, death,
discharge to another unit, or end of the study period. The
variables examined for all patients included
demographic data (age, gender), underlying conditions
(immunosuppression as defined by cancer, AIDS with
CD4 T-lymphocytes <100, haemopathy, or
corticotherapy >0.5 mg/kg/day, diabetes mellitus, end-stage renal
disease, chronic liver disease, chronic heart or
respiratory failure) and severity evaluated by the Simplified
Acute Physiology Score (SAPS II) . Data regarding
the use of intravascular catheters, nasogastric or
endotracheal tubes were also collected daily.
This study was approved by our local ethics
committee (Comit de Protection des Personnes Sud-Ouest et
Outre Mer III, reference number: DC2010/38). The
need to obtain informed consent was waived because no
change was done to our ICUs usual practices (the
endemic context of the ICU justified an intense surveillance
procedure), but patients and/or their proxies were
informed of the studys purpose.
As a routine surveillance procedure, throat, nasal and
rectal swabs as well as sputum and urine samples were
collected on admission and weekly thereafter on
predefined days. Other specimens were taken when clinically
indicated. Environmental screening included weekly tap
water samples from the patients rooms and tap water
samples from shared rooms every three weeks. The
methods of specimen collection and culture have been
described previously .
Definition of acquired P. aeruginosa colonization/infection
Acquired colonization/infection was defined as the
isolation of P. aeruginosa from at least one surveillance or
clinical culture from patients not colonized or infected
at ICU admission. P. aeruginosa infection was defined as
a positive culture with clinical and biological
manifestations of infection. In cases of lower respiratory tract
infection, quantitative cultures were positive if a
threshold of 107 colony-forming units (CFU)/ml for tracheal
Figure 1 Schematic representation of the 16-bed medical ICU.
Risk factors for P. aeruginosa colonization/infection
Antibiotic treatment was recorded daily and classified
according to P. aeruginosa susceptibility (no antibiotic
treatment, inactive or active against P. aeruginosa
including ureido and carboxypenicillins,
antipseudomonal cephalosporins, carbapenems, fluoroquinolones,
aminoglycosides, colimycin, fosfomycin). If a patient was
treated simultaneously with both active and non-active
antibiotics, the patient was considered to have been
treated with active antibiotics.
Systematic environmental screening included other
patients from the ward on which the patient was
hospitalized, other patients on the ICU, tap water from the
same ward, tap water from the ICU and tap water from
shared rooms. Daily indices of environmental pressure
were calculated as assessed in other studies of
patientinduced colonization pressure . Briefly, for each
study day, the number of patients and tap water samples
colonized with P. aeruginosa on the ward/ICU where
the patient was hospitalized was estimated. Two
variables were then described: (i) the colonization of
patients or tap water samples on the previous day
(called previous patient/tap water colonization pressure);
and (ii) the number of patients or tap water samples
colonized since the patients admission (called
cumulative patient/tap water colonization pressure).
Environmental exposure was assumed to be constant between
two screenings. Hence, patients who acquired P.
aeruginosa had several environmental pressure profiles
(including patient colonization pressure and tap water
colonization pressure) allowing a comparison with
patients who did not acquire P. aeruginosa.
Quantitative variables were compared using the
Students t-test or Wilcoxon test according to the
distribution of data. Qualitative variables were compared using
the Chi2 or Fishers exact test. A marginal logistic
regression model accounting for repeated measurements 
was used to assess the relationship between environment,
antibiotic pressure and P. aeruginosa acquisition each
day, and the results were expressed as odds ratios (OR)
and 95% confidence intervals (CI). Univariate analysis of
P. aeruginosa acquisition included: (i) fixed variables for
patient characteristics at admission; (ii) longitudinal data
on patient/tap water colonization pressures, as described
above, on the cumulative number of days since admission
with a nasogastric tube (which was selected to represent
invasive devices as it is strongly associated with the use
of other invasive devices in our clinical practice) or with
antibiotics classified as active or inactive against P.
aeruginosa. Selection of the environmental exposure index
(previous or cumulated colonization pressure) was based
on Akaike criteria : patient/tap water colonization
pressure on the previous day was finally introduced in
the multivariate analysis. Quantitative data were analyzed
as categorical variables when the log-linearity assumption
was not followed. All factors with a P-value < 0.20 in
univariate analysis were selected for multivariate analysis. In
multivariate analysis, the factors related to patient/tap
water colonization pressures, that is, patients on the
same ward, tap water from the ICU, tap water from
the shared rooms or antibiotics were first introduced
together and forced in the model. Because wards are
included in the ICU, only the most significant index
among colonization pressure onto the ward or the ICU
was selected for analysis purpose. Other factors were
then introduced in a stepwise manner to control for
confounding. According to our main objective, the final
model looked for interactions between each of the three
patient/tap water colonization pressures and antibiotic
variables. A P-value of <0.05 was considered significant.
Data were recorded prospectively with Epidata (3.1;
Odense, Denmark). The model was fitted using the
GENMOD procedure on SAS software (SAS Institute, Inc.,
Cary, NC, USA).
Of the 415 patients admitted to the ICU during the
29week study period, 262 were excluded because their
length of stay was <72 h and 27 were excluded because
screening at admission revealed P. aeruginosa. Finally,
126 patients were included, comprising 1,345
patientdays. The demographic and clinical characteristics of
these patients are shown in Table 1.
Table 1 Demographic and clinical characteristics of the
study population (n = 126)
Values are shown as mean SD, n (%), or median (1st to 3rd quartile).
SAPS II: Simplified Acute Physiology Score; ICU: intensive care unit.
urine and 55 miscellaneous cultures. Cultures were not
available for 15 patients, accounting for 94 patient-days.
Each patient had a median of five cultures (range: two
to nine) during their ICU stay. Acquired P. aeruginosa
was present in 27 cultures (3.4%): 11 respiratory, 7
rectal, 4 throat and 3 nasal cultures, 1 stool and 1
Twenty patients (16%) acquired P. aeruginosa during
their ICU stay. P. aeruginosa colonization was present in
11 patients: rectal culture (n = 5), sputum culture (n =
2), rectal and throat or nasal culture (n = 2), sputum
culture associated with rectal, nasal and throat colonization
(n = 1) and stool culture (n = 1). P. aeruginosa infection
was observed in nine other patients (nosocomial
pneumonia (n = 8) and nosocomial peritonitis (n = 1)). P.
aeruginosa isolation occurred a median of 11 days (range: 8
to 16) after admission.
During the study, microbiological screening yielded 807
samples: 166 sputum or bronchoalveolar cultures, 144
blood cultures, 114 nasal, 111 rectal, 109 throat, 108
During their ICU stay, 106 patients (84%) received a
total of 970 antibiotic days with a median of two
antibiotics (range: one to three) for a median duration of
seven days (range: 3 to 11) per patient. The antibiotics
used are described in Table 2. All patients who acquired
P. aeruginosa (except one) had received antibiotics
before acquisition (median of two antibiotics (two to
four) vs. median of two antibiotics (two to three) in the
other group; P = 0.09). Among the 106 patients treated
with antibiotics, two-thirds (n = 67) received at least
one day of antibiotics active against P. aeruginosa
whereas one-third (n = 39) did not.
Environmental screening results
The results of environmental screening are shown in
Table 3. In addition to the 20 patients who acquired P.
aeruginosa during the study, 27 patients were colonized
and/or infected with P. aeruginosa at ICU admission.
Thus, 47 patients potentially contributed to the patient
colonization pressure. Tap water screening from the
patients rooms yielded 152/464 positive samples (33%).
Surveillance of tap water from shared rooms yielded 72
samples, of which 12 were positive for P. aeruginosa
(17%). Contaminated tap water was observed four times
in the shared toilet, three times in the sterilization
room, twice in the night duty bedroom and once in the
rest area, office or equipment storage room. The
implementation of tap water disinfection at Week 11 of the
study should have decreased the patients environmental
pressure. However, no significant interaction was found
between tap water colonization and time period (before
or after Week 11) (P = 0.69).
Risk factors for P. aeruginosa acquisition
By univariate analysis, the presence of an invasive device
(nasogastric tube), previous patient colonization pressure
on the same ward and previous tap water colonization
pressure from the ICU and shared rooms were
significantly associated with P. aeruginosa acquisition (Table 4).
Multivariate analysis revealed that the presence of a
nasogastric device was independently associated with P.
aeruginosa acquisition (OR = 7.72 (95% CI: 2.32 to 25.70); P =
0.001). In addition, the interaction between antibiotics
inactive against P. aeruginosa and the patient
colonization pressure was also significant (P < 0.03). It means
Table 2 Distribution of antibiotic treatment according to acquisition group*
* The data represent the number of patients who received at least one day of antibiotic of each class (percentage of patients in each group).
Table 3 Summarization of environmental screening data according to acquisition group
No P. aeruginosa
acquisition (n = 106)
Total (n = 126)
Values shown are: median (1st to 3rd quartile), or n.
*Cumulative patient/tap water-induced environmental pressure represents the number of contaminated patients/tap water samples since admission.
**Patient/tap water-induced environmental pressure represents the number of patient that were exposed to a contaminated patient/tap water at least one time
during their ICU stay.
Excluding tap water in shared rooms.
that, in patients receiving equal to or more than three
days of antibiotics inactive against P. aeruginosa, the
presence of at least one colonized patient on the same ward
on the previous day increased the risk of P. aeruginosa
acquisition on a given day (OR = 10.26 (95% CI: 1.83 to
57.43); P = 0.01) compared to patients without colonized
patient in the same ward. This association was not
observed in patients with less than three days of
antibiotics inactive against P. aeruginosa.
This study suggests two main conclusions. First, P.
aeruginosa acquisition should be related to the proximity of
a patient colonized with P. aeruginosa in the area (same
room) with a chronological component (the previous
day) along with selective antibiotic pressure. Antibiotic
selective pressure alone did not influence P. aeruginosa
acquisition. The hypothesis of a complex mechanism
involving antibiotic selective pressure and patient
colonization pressure should be relevant for P. aeruginosa
acquisition in an ICU with endemic context. If the
interaction of both pressures overriding each pressure
taken separately is reviewed, there could be some
practical implications. Developing strategies for either
decreased antibiotic use for endogenous-like
acquisition or hygiene improvement in response to
environmental contamination in exogenous-like acquisition
could be insufficient. In an endemic ICU without
obvious epidemic acquisition, it is arguable that a
reduction in antibiotic selective pressure and improvement in
hygiene standards should be combined. The second
conclusion is that invasive devices remain an important
determinant in P. aeruginosa acquisition. Whether
invasive devices are a surrogate of patients severity (an
already known acquisition risk factor) or a step for
bacteria in the chain linking the environment to the
patients cannot be inferred from the results of this
In our study, the classical binary endogenous/exogenous
scheme [12,22] is transcended by the interaction of both
factors, which confirms that P. aeruginosa acquisition is
complex. In the past, some molecular epidemiology
7.66 (2.88 to 20.36)
7.72 (2.32 to 25.70)
2.54 (0.89 to 7.24)
4.61 (1.67 to 12.72)
2 (0.76 to 5.27)
1.02 (0.95 to 1.10)
4.91 (1.47 to 16.39)
1.14 (0.27 to 4.90)
2.37 (0.96 to 5.89)
3.79 (1.26 to 11.44)
4.63 (1.37 to 15.65)
70 years (vs. <70)
Equal to or more than nine cumulated days since admission
(vs. less than nine days)
Antibiotic treatment not active against P. aeruginosa
More than three days (vs. zero to two days)
Antibiotic treatment active against P. aeruginosa**
per cumulated day since admission
Previous patient-induced environmental pressure
Equal to or more than one colonized patient on the same
ward on the previous day (vs. zero)
Equal to or more than one colonized patient on the ICU on
the previous day (vs. zero)
Previous tap water-induced environmental pressure
Equal to or more than one colonized tap water on the same
ward on the previous day (vs. zero)
Equal to or more than one colonized tap water on the ICU
on the previous day (vs. zero)
Equal to or more than one colonized tap water in shared
rooms on the previous day (vs. zero)
Interaction between previous patient-induced environmental
pressure and inactive antibiotics:
If equal to or more than three days of inactive antibiotics
- no colonized patient on the same ward on the
- equal to or more than one colonized patient on the
same ward on the previous day
If zero to two days of inactive antibiotics
- no colonized patient on the same ward on the
- equal to or more than one colonized patient on the
same ward on the previous day
studies have reported a significant role of exogenous
colonization [4-7,18], whereas others have predominantly
identified the role of endogenous colonization [11,13].
Genotypic methods may detect an epidemic context
where exogenous sources are the most important  and
potentially overestimate its role. Hence, the same group
has described two different levels of exogenous P.
aeruginosa cross-transmission [9,11]. It is also likely that strains
spread rapidly from patients to the environment and
viceversa, complicating environmental and patient screening
because screening at distinct time intervals could
misclassify some cases of exogenous acquisition . Special
1.99 (0.67 to 5.88)
3.07 (0.93 to 10.16)
1.00 (0.26 to 3.87)
attention should also be paid to so-called endogenous
P. aeruginosa acquisition. P. aeruginosa is not generally
considered to be part of the normal human flora , and
in most patients admitted to hospital for the first time,
P. aeruginosa is not usually isolated from bacteriological
specimens until the patient has been in the hospital for
several days [22,24,25]. In these cases it is unclear if P.
aeruginosa is really endogenous (that is, present on admission
but undetected by screening and only revealed by
antibiotic selective pressure) [17,18]. On the other hand, despite
being absent from the flora on admission, P. aeruginosa
could be acquired from the environment through
repetitive daily healthcare procedures. Sequential cultures
with P. aeruginosa isolation from oropharyngeal samples
before the gastrointestinal tract support this hypothesis
. Moreover, Johnson et al.  recently observed that
50% of imipenem-resistant P. aeruginosa acquisition
corresponded to neither the classical endogenous nor
exogenous route. The question of an undiscovered environmental
source was raised. This is the case in some endemic ICU
contexts . In our ICU the endemic context was
suggested by the fact that one-third of the strains shared the
same genotypic profile without an obvious exogenous
source of acquisition or epidemic profile .
Irrespective of the obvious, undiscovered exogenous or
true endogenous source of P. aeruginosa , it is likely
that acquisition of this microorganism by patients is
related to a third factor, namely antibiotic treatment
which could interact with the environment to facilitate
P. aeruginosa acquisition. Our study confirms this
hypothesis. It focused on individual patients with daily
recorded antibiotic treatment rather than on a
population with collective consumption data . Daily
antibiotic recording does not prevent misclassification of
antibiotic treatment as active, whereas it was eventually
inactive due to poor PK/PD optimization. Even if there
is still poor knowledge of the optimal antibiotic dosing
strategies to prevent the selection of resistance, an
antibiotic stewardship designed to limit insufficient
antibiotic doses was set up at the study period, potentially
limiting this bias. Besides, all previously known risk
factors were adjusted for, as well as widespread and
repeated patient and tap water screening (including
samples from shared rooms), which have not always
been completely (only patient-to-patient transmission)
[11,18] or properly (type and frequency of
environmental screening) [10,13] assessed. Moreover, active
antibiotics were distinguished from inactive antibiotics
(selective antibiotic pressure), which could help P.
aeruginosa become dominant in the patients flora.
In our ICU, as potentially in others with the same
endemic and antibiotic consumption profiles, the results
of this study will lead to the development of coordinated
strategies against the use of antibiotics that are inactive
against P. aeruginosa (such as a decrease in systematic
penicillin or cephalosporin treatment for aspiration
pneumonia) and against the environmental spread of
bacteria. The latter should include alcohol-based
handcleaning programmes since cross-contamination
between patients and contaminated tap water was
suspected in our study. Contaminated tap water and
patients samples were associated with P. aeruginosa
acquisition in univariate analysis but only patients
samples were significant in multivariate analysis. Positive
cultures from shared rooms were associated with
P. aeruginosa acquisition in univariate analysis and
should be interpreted as additional to ICU P. aeruginosa
There are several limitations to our study. It was a
single-centre study and the limited observations may give
reduced power to detect other contributing risk factors.
These limitations prevent its application to other ICUs
where the patient case mix, prevalence of P. aeruginosa
colonization at admission and antibiotic consumption are
different. Antibiotic selective pressure could have played
a role in revealing a pre-existing P. aeruginosa flora
shared with the patients environment without a
causeand-effect relationship (which would only have been
demonstrated by chronological acquisition of the same
genotypic strain) or in rendering the patient susceptible
to P. aeruginosa acquisition from the environment. Other
limitations include the fact that adherence to hygiene
rules was not assessed, antibiotic consumption before
admission was not recorded and P. aeruginosa screening
was not performed at the end of the ICU stay. Moreover,
the environment (patients and tap water) was screened
by intermittent samples. However, the inclusion in the
model of the most recent sample provided a closer
analysis of the time-dependent process of acquisition. Finally,
routine surveillance cultures were not obtained from 15
patients with a short stay, although this probably did not
significantly influence our findings as they accounted for
only 7% of total patient-days.
In conclusion, this study adds further support for an
interaction between the patient colonization pressure
and antibiotic selective pressure in the process of P.
aeruginosa acquisition in the ICU. These results should be
confirmed in a larger study in order to generalize their
potential implications (that is, target strategies aimed at
decreasing antibiotic treatment, where possible, and
improving hygiene protocols).
Pseudomonas aeruginosa is still a leading cause of
nosocomial infections, yet its mode of acquisition
remains the subject of debate.
In a given patient, the interaction between the
environment and the selective antibiotic treatment
he (she) just received deserves more study.
This single-centre ICU-based study shows that a
specific interaction between both patient
colonization pressure and selective antibiotic pressure is the
most relevant factor for P. aeruginosa acquisition.
Prevention of acquisition in a given patient should
include both antibiotic stewardship and
AIDS: Acquired Immunodeficiency Syndrome; CFU: colony-forming units; CI:
confidence interval; ICU: intensive care unit; OR: odds ratio; P. aeruginosa:
Pseudomonas aeruginosa; PK/PD: pharmacokinetic/pharmacodynamic; SAPS II:
Simplified Acute Physiology Score.
AB conceived the study, participated in its design and in acquisition of data,
coordinated the study and wrote the article. AD participated in the design
of the study, performed the statistical analysis, participated in the article
redaction, and contributed to this study equally with AB. RT participated in
the design of the study and coordinated the statistical analysis. AGV
participated in the design of the study. VT carried out the acquisition of
data. HB participated in the environmental acquisition of data. CB
coordinated the bacteriological study. FV participated in the acquisition of
patients data and in the conception of the study. GH participated in the
conception of the study. DG conceived the study, participated in its design
and in the article redaction. AMR conceived the study, participated in the
environmental acquisition of data, in its design and in the article redaction.
The authors declare that they have no competing interests.
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