Introduction
Pseudomonas aeruginosa infections on the ICU are a constant concern [
1]. Colonization with this organism often precedes infection [
2] and its prevention is, therefore, extremely important.
P. aeruginosa colonization has been reported to originate from exogenous sources such as tap water [
3], 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 patient's 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 issue.
In a previous study [
3], 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 [
3]. 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.
Results
Study population
Of the 415 patients admitted to the ICU during the 29-week 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 patient-days. 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)
Age (years) | 57 ± 17 |
Male/female | 72/54 |
SAPS II | 45 ± 18 |
Hospitalization before admission | 88 (70.0%) |
Underlying conditions | 0.7 ± 0.7 |
immunosuppression | 29 (23.0%) |
chronic respiratory failure | 24 (19.0%) |
diabetes | 22 (17.5%) |
heart disease | 4 (3.2%) |
renal disease | 4 (3.2%) |
cirrhosis | 2 (1.6%) |
Invasive device | |
Mechanical ventilation (%) | 78 |
Duration (days) | 6 (2 to 10) |
Central venous catheter (%) | 65 |
Duration (days) | 5 (0 to 10) |
Nasogastric tube (%) | 72 |
Duration (days) | 6 (0 to 10) |
Enteral nutrition (%) | 93 |
Duration (days) | 6 (4 to 9) |
Foley catheter (%) | 79 |
Duration (days) | 6 (2 to 11) |
Length of stay (days) median | 8 (6 to 12) |
ICU mortality | 29 (23%) |
Microbiological screening
During the study, microbiological screening yielded 807 samples: 166 sputum or bronchoalveolar cultures, 144 blood cultures, 114 nasal, 111 rectal, 109 throat, 108 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 peritoneal sample.
Acquired colonization/infection
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.
Antibiotic treatment
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.
Table 2
Distribution of antibiotic treatment according to acquisition group*
Antibiotics active against
P. aeruginosa
|
10 (50)
|
57 (54)
|
67 (53)
|
Aminosides | 6 (30) | 17 (16) | 23 (18) |
Ureido/carboxypenicillins | 5 (25) | 19 (18) | 24 (19) |
Piperacillin-tazobactam | 5 (25) | 12 (11) | 17 (13) |
Ticarcillin-clavulanic acid | 0 (0) | 7 (7) | 7 (6) |
Antipseudomonal cephalosporins | 3 (15) | 13 (12) | 16 (13) |
Ceftazidime | 3 (15) | 6 (6) | 9 (7) |
Cefepime | 0 (0) | 7 (7) | 7 (6) |
Carbapenems | 4 (20) | 12 (11) | 16 (13) |
Fluoroquinolones | 7 (35) | 33 (31) | 40 (32) |
Others | 1 (5) | 3 (3) | 4 (3) |
Fosfomycin | 0 (0) | 2 (2) | 2 (2) |
Colomycin | 1 (5) | 1 (1) | 2 (2) |
Antibiotics not active against
P. aeruginosa
|
14 (70)
|
85 (80)
|
99 (79)
|
Glycopeptides | 5 (25) | 30 (28) | 35 (28) |
Non-antipseudomonal penicillins | 4 (20) | 43 (41) | 47 (37) |
Penicillin G | 0 (0) | 1 (1) | 1 (1) |
Penicillin M | 0 (0) | 2 (2) | 2 (2) |
Amoxicillin | 1 (5) | 3 (3) | 4 (3) |
Amoxicillin-clavulanic acid | 3 (15) | 37 (35) | 40 (32) |
Non-antipseudomonal cephalosporins (cefotaxim; cefuroxim; ceftriaxon) | 10 (50) | 23 (22) | 33 (26) |
Macrolides | 5 (25) | 12 (11) | 17 (13) |
Other | 2 (10) | 18 (17) | 20 (16) |
Pristinamycin | 0 (0) | 3 (3) | 3 (2) |
Metronidazole | 0 (0) | 10 (9) | 10 (8) |
Cotrimoxazole | 1 (5) | 1 (1) | 2 (2) |
Rifampicin | 1 (5) | 4 (4) | 5 (4) |
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 patient's 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).
Table 3
Summarization of environmental screening data according to acquisition group
Cumulative patient-induced environmental pressure* | | | |
From the same ward | 1.2 (0.6 to 1.8) | 0.8 (0 to 1.7) | 1 (0.1 to 1.8) |
From the ICU | 4.8 (3.6 to 5.6) | 4.7 (3.3 to 5.6) | 4.7 (3.3 to 5.6) |
Cumulative tap water-induced environmental pressure* | | | |
From the patients' wards | 0.1 (0 to 0.7) | 0 (0 to 0.6) | 0 (0 to 0.6) |
From the ICU | 1.9 (1.1 to 2.3) | 1.6 (0 to 3) | 1.8 (0 to 2.9) |
From shared rooms | 1 (0.7 to 2.3) | 0.8 (0 to 1) | 1 (0 to 1) |
Patient-induced environmental pressure** | | | |
≥1 colonized patient on the same ward | | | |
yes | 20 | 79 | 99 |
no | 0 | 27 | 27 |
≥1 colonized patient on the ICU | | | |
yes | 20 | 106 | 126 |
no | 0 | 0 | 0 |
Tap water-induced environmental pressure** | | | |
≥1 colonized tap water on the same ward | | | |
yes | 10 | 51 | 61 |
no | 10 | 55 | 65 |
≥1 colonized tap water on the ICU ¤ | | | |
yes | 18 | 68 | 86 |
no | 2 | 38 | 40 |
≥1 colonized tap water in shared rooms | | | |
yes | 17 | 70 | 87 |
no | 3 | 36 | 39 |
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 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.Table 4
Risk factors for P. aeruginosa acquisition in the ICU (n = 126)
SAPS II | | | | |
≥43 (vs. <43) | 2.54 (0.89 to 7.24) | 0.08 | * | |
Age | | | | |
≥70 years (vs. <70) | 4.61 (1.67 to 12.72) | 0.14 | * | |
Nasogastric tube | | | | |
Equal to or more than nine cumulated days since admission (vs. less than nine days) | 7.66 (2.88 to 20.36) | <0.0001 | 7.72 (2.32 to 25.70) | 0.001 |
Antibiotic treatment not active against P. aeruginosa | | | | |
More than three days (vs. zero to two days) | 2 (0.76 to 5.27) | 0.16 | *** | |
Antibiotic treatment active against P. aeruginosa** | | | | |
per cumulated day since admission | 1.02 (0.95 to 1.10) | 0.54 | **** | |
Previous patient-induced environmental pressure | | | | |
Equal to or more than one colonized patient on the same ward on the previous day (vs. zero) | 4.91 (1.47 to 16.39) | 0.01 | *** | |
Equal to or more than one colonized patient on the ICU on the previous day (vs. zero) | 1.14 (0.27 to 4.90) | 0.86 | **** | |
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) | 2.37 (0.96 to 5.89) | 0.06 |
$
| |
Equal to or more than one colonized tap water on the ICU on the previous day (vs. zero) | 3.79 (1.26 to 11.44) | 0.02 | 1.99 (0.67 to 5.88) | 0.21 |
Equal to or more than one colonized tap water in shared rooms on the previous day (vs. zero) | 4.63 (1.37 to 15.65) | 0.01 | 3.07 (0.93 to 10.16) | 0.07 |
Interaction between previous patient-induced environmental pressure and inactive antibiotics: | | | | 0.03$$ |
If equal to or more than three days of inactive antibiotics | | | 1 | |
- no colonized patient on the same ward on the previous day | | | 10.26 (1.83 to 57.43) | 0.01 |
- 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 previous day | | | 1 | |
- equal to or more than one colonized patient on the same ward on the previous day | | | 1.00 (0.26 to 3.87) | 0.99 |
Discussion
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 patient's 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 study.
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 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 [
23] 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 vice-versa, complicating environmental and patient screening because screening at distinct time intervals could misclassify some cases of exogenous acquisition [
16]. Special 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 [
16], 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 [
26]. Moreover, Johnson
et al.
[
22] 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 [
27]. 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 [
3].
Irrespective of the obvious, undiscovered exogenous or true endogenous source of
P. aeruginosa
[
28], 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 [
29]. 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 hand-cleaning 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 colonization pressure.
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 patient's environment without a cause-and-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.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
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.