Relationship between digestive tract colonization and subsequent ventilator-associated pneumonia related to ESBL-producing Enterobacteriaceae
Relationship between digestive tract colonization and subsequent ventilator- associated pneumonia related to ESBL- producing Enterobacteriaceae
Marion Houard 0 1
Anahita RouzeÂ 0 1
Geoffrey Ledoux 0 1
Sophie Six 0 1
Emmanuelle Jaillette 0 1
Julien Poissy 0 1
SeÂ bastien PreÂ au 0 1
FreÂ deÂ ric Wallet 1
Julien Labreuche 1
Saad Nseir 0 1
Benoit Voisin 0 1
0 CHU Lille, Critical Care Center, Lille, France, 2 Univ. Lille, Faculty of Medicine, Lille, France , 3 CHU Lille , Centre de Biologie et de Pathologie, Lille, France , 4 CHU Lille , Clinique de Sant eÂ Publique, Plateforme d'Aide M eÂthodologique , Lille , France
1 Editor: Yu Ru Kou, National Yang-Ming University , TAIWAN
Ventilator-associated pneumonia (VAP) is the most common ICU-acquired infection. Recently, the incidence of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBLE) has substantially increased in critically ill patients. Identifying patients at risk for VAP related to ESBLE could be helpful to improve the rate of appropriate initial antibiotic treatment, and to reduce unnecessary exposure to carbapenems. The primary objective was to identify risk factors for VAP related to ESBLE. Secondary objective was to determine the impact of ESBLE on outcome in VAP patients.
Data Availability Statement: All relevant data are
within the paper.
Funding: The authors received no specific funding
for this work.
Competing interests: SN: Bayer (advisory board),
and MSD (lecture); other authors: none. This does
not alter our adherence to PLOS ONE policies on
sharing data and materials.
This retrospective study was conducted in a single mixed intensive care unit (ICU), during a
4-year period. All patients with confirmed VAP were included. VAP was defined using
clinical, radiologic and quantitative microbiological data. VAP first episodes were prospectively
identified using the continuous surveillance data. Exposure to different risk factors was
taken into account until the diagnosis of ESBLE VAP or until ICU discharge, in patients with
ESBLE VAP and VAP related to other bacteria, respectively. In all patients, routine
screening for ESBLE (rectal swab) was performed at ICU admission and once a week. Patients
with ESBLE VAP were compared with those with VAP related to other bacteria using
univariate analysis. All significant factors were included in the multivariate logistic regression
Among the 410 patients with VAP, 43 (10.5%) had ESBLE VAP, 76 (19%) patients had
polymicrobial VAP and 189 (46%) had VAP related to multidrug resistant bacteria. Multivariate
analysis identified prior ESBLE colonization of the digestive tract as the only independent
risk factor for ESBLE VAP (OR [95% CI] = 23 [10±55], p < 0.001). Whilst the positive
predictive value of ESBLE digestive colonization was low (43.6%), its negative predictive value
was excellent (97.3%) in predicting ESBLE VAP. Duration of mechanical ventilation (median
[IQR], 28 [
] vs 23 [
] d, p = 0.4), length of ICU stay (31 [
] vs 29 [
] d, p =
0.6), and mortality rates (55.8% vs 50%, p = 0.48) were similar in ESBLE VAP, compared
with VAP related to other bacteria.
Digestive tract colonization related to ESBLE is independently associated with ESBLE VAP.
Its excellent negative predictive value suggests that patients without ESBLE colonization
should not receive carbapenems as part of their initial empirical treatment to cover ESBLE.
Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in the
intensive care unit (ICU) [1±3]. VAP is associated with high morbidity and attributable
mortality, ranging from 10 to 30% in different studies [4±7]. VAP also leads to prolonged duration
of mechanical ventilation and length of stay [7±9].
As inappropriate initial antimicrobial treatment is an important risk factor for mortality,
the choice of empiric antimicrobial treatment for critically ill patients is often challenging
]. Infections involving multidrug-resistant (MDR) bacteria are common in ICU and a
negative impact on mortality is reported in patients with severe infections related to these
]. Among MDR bacteria, extended-spectrum beta-lactamase producing
Enterobacteriaceae (ESBLE) became a serious threat. A recent meta-analysis of thirteen studies reported
a rate of ICU-acquired ESBLE ranging 5±10% in the United States and Europe [
use of beta-lactam/beta-lactamase or carbapenems and recent hospitalization were identified
as risk factors for ESBLE colonization. In addition, digestive tract colonization was associated
with significantly higher frequency of ESBLE subsequent infection and increased mortality
According to the current guidelines, patients with risk factors for pneumonia related to
MDR bacteria should receive broad-spectrum antimicrobial treatment [
]. Given the recent
spread of ESBLE, this strategy leads to an increased use of carbapenems, considered as the
treatment of choice in ESBLE infections [15±17]. Due to the risk of antimicrobial resistance,
empirical treatment should be selected with caution. Thus, identifying patients at risk for VAP
related to ESBLE could be useful to reduce the spectrum of initial antibiotic treatment.
We performed this retrospective study to identify risk factors for VAP related to ESBLE in
the ICU. The secondary objective was to determine the impact of ESBLE on outcome of VAP
Patients and methods
This retrospective observational study was conducted during a 4-year period, From January
2008 through January 2011, in a 30-bed mixed ICU, located in the University Hospital of Lille,
France. All patients with confirmed VAP were included. Only first episodes of VAP were
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included and were prospectively identified using surveillance of nosocomial infections. The
local IRB approved the study (ComiteÂ de Protection des Personnes Nord Ouest IV, NÊ HP04).
According to the French law, no informed consent was required because of the observational
and retrospective design of the study.
VAP was defined as pneumonia diagnosed after 48 hours of intubation and mechanical
ventilation. The diagnostic criteria for VAP included a new infiltrate on chest X-rays in conjunction
with at least two of the following: core temperature 38,5ÊC or < 36ÊC, leukocyte count 10
x 109/L or < 1,5 x 109/L, and purulent tracheal aspirate or sputum. In addition, a
microbiological confirmation was required for all patients (positive endotracheal aspirate culture 106
colony-forming units (cfu)/mL or positive bronchoalveolar lavage culture 104 cfu/mL) [
The following microorganisms were defined as MDR bacteria: ceftazidime or
imipenemresistant Pseudomonas aeruginosa, Acinetobacter baumannii, û-lactamase-producing
Gramnegative bacilli (ESBL) and methicillin-resistant Staphylococcus aureus.
The characteristics of all study patients were prospectively recorded at ICU admission: age,
male gender, severity of illness based on Simplified Acute Physiology Score (SAPS) II, Logistic
Organ Dysfunction (LOD) score, McCabe score, comorbidities (diabetes, chronic obstructive
pulmonary disease (COPD), restrictive respiratory failure, chronic heart disease, cirrhosis,
chronic renal failure requiring dialysis, or immunosuppression), risk factors for MDR bacteria
(prior antibiotic exposure defined as antibiotic treatment received for at least 48h within the
30 days preceding ICU admission, hospitalization prior to ICU > 48 h, nursing-home
], infection at admission, location before ICU admission, admission category, main
admission diagnosis (recent surgery, acute exacerbation of COPD, acute respiratory distress
syndrome (ARDS), shock, pneumonia, congestive heart failure, neurologic failure, poisoning,
cellulitis, cardiac arrest, and others). During ICU stay, the following data were prospectively
collected: occurrence of VAP, duration of mechanical ventilation, length of ICU stay and ICU
mortality. Data related to antibiotic exposure and ESBLE digestive tract colonization were
retrospectively collected. The use of broad-spectrum antibiotics was defined by at least 24h of the
following antibiotics: Piperacillin/Tazobactam, Cefepime, Ceftazidime, quinolones active
against P. aeruginosa, and Carbapenems, from ICU admission to VAP diagnosis. Selective
digestive decontamination was not used during the study period.
A routine screening for ESBLE digestive colonization was performed by rectal swab at ICU
admission and repeated once a week. All samples were placed on a standardized selective agar
medium (Mueller-Hinton). During the study period, the technique for standard antibiotic
susceptibility testing in our microbiology laboratory was a disc diffusion method. Antibiotic discs
containing a cephalosporin were then added by technicians. After a 24h-incubation, the
susceptibility of bacteria to antibiotics was determined by reading the diameter of inhibition.
Confirmation of ESBLE was obtained with a MAST phenotypic test. An aspect of champagne
cork was characteristic of extended spectrum beta-lactamase. Patients were considered as
ESBLE carriers when a rectal swab returned positive.
SPSS software (SPSS, Chicago, IL, USA) was used for data analysis. Results are presented as
numbers (percentage) for categorical variables. The distribution of quantitative variables was
tested and was abnormal, results are presented as median (25th-75th interquartile). In order to
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determine factors associated with ESBLE VAP, patients with ESBLE VAP were compared with
those with VAP related to other bacteria using univariate analysis. The Pearson's chi-square
test was used to compare qualitative variables. The Mann-Whitney U test was used to compare
quantitative variables. The statistical significance was set at p < 0.05.
Multivariate analysis was used to determine risk factors independently associated with
ESBLE VAP. All data from univariate analysis with p values < 0.05 were included in the
multivariate logistic regression model. Potential interactions were tested and the
Hosmer-Lemeshow goodness-of-fit was calculated.
The odds ratio (OR) and 95% confidence interval (CI) were calculated for all significant
variables in univariate and multivariate analysis. Exposure to potential risk factors for ESBLE
VAP was taken into account until the occurrence of ESBLE VAP or until ICU discharge in
patients with ESBLE VAP or VAP related to other bacteria, respectively.
Sensitivity, specificity, positive, and negative predictive values were calculated by standard
statistical methods for identified independent factors.
During the study period, 1570 patients received mechanical ventilation for more than 48 hours
and 469 patients had a suspected VAP. Forty-two patients were excluded from analysis because
VAP was not documented by microbiological results. Data were not available for 17 patients.
Among the 410 remaining patients with confirmed VAP, 43 (10.5%) were related to ESBLE.
Among the 43 patients with ESBL VAP, 13 (30.2%) had a positive blood culture related to
ESBL. No outbreak occurred during the study period. Patient characteristics at ICU admission
are presented in Table 1. No significant difference was found in age, SAPS II, comorbidities
and risk factors for MDR bacteria.
VAP was polymicrobial in 76 patients (19%) and related to MDR bacteria in 189 patients
(46%). Pseudomonas aeruginosa was the most common microorganism isolated in the cultures
of VAP related to MDR bacteria. Enterobacter and Klebsiella were the main ESBLE (Table 2).
VAP related to ESBL represented 11.9% of all VAP related to Gram-negative bacilli. VAP was
confirmed by quantitative endotracheal aspirate, and BAL in 96% and 4% of patients,
respectively. No significant difference was found between different types of bacteria and duration of
mechanical ventilation (data not shown).
During ICU stay, 297 patients (72.4%) acquired MDR bacteria. Among them, digestive
tract colonization with ESBLE was found in 125 patients (30.5%). 79% of ESBLE VAP occurred
in patients previously identified as ESBLE carriers (Table 3). The median [IQR] time from
digestive tract colonization to VAP related to ESBL was 8 [
Risk factors for ESBLE VAP
Exposure to different risk factors for ESBLE VAP during ICU stay is reported in Table 4. No
significant difference was found in median duration of mechanical ventilation before VAP
occurrence (median [IQR], 13 [
] vs 14 [
] d, p = 0.4), percentage of patients with prior
broad-spectrum antibiotics (84% vs 68%, p = 0.3), or percentage of patients with prior use of
carbapenems (26% vs 19%, p = 0.33), between patients with ESBLE VAP, and those with VAP
related to other bacteria.
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Results by univariate analysis. Data are presented as number (%) or median (interquartile range). Some patients had more that one diagnosis at intensive care unit
ESBLE, extended-spectrum û-lactamase-producing Enterobacteriaceae; VAP, ventilator-associated pneumonia; MDR, multidrug-resistant bacteria; ICU, intensive care
unit; COPD, chronic obstructive pulmonary disease; ARDS, acute respiratory distress syndrome
The following factors were significantly associated with higher rates of ESBLE VAP by
univariate analysis: female gender (p = 0.04), medical admission (p = 0.03), ARDS (p = 0.01),
shock (p = 0.02), infection at ICU admission (p = 0.04), and digestive tract colonization related
to ESBLE (p < 0.001). Male gender, and acute exacerbation of COPD at ICU admission were
significantly associated with lower rate of ESBLE VAP by univariate analysis (Tables 1, and 3).
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At ICU admission
ESBLE digestive colonization
Before VAP occurrence
n = 43
No ESBLE VAP
n = 367
Results by univariate analysis. Data are presented as number (%).
MDR, multidrug-resistant bacteria; ICU, intensive care unit; ESBLE, extended-spectrum û-lactamase-producing
Enterobacteriaceae; VAP, ventilator-associated pneumonia.
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Multivariate analysis identified prior ESBLE colonization of the digestive tract as the only
independent risk factor for ESBLE VAP (OR [95% CI] = 23 [10±55], p < 0.001) (Table 5).
Sensitivity and specificity of prior digestive ESBLE colonization as a predictor of ESBLE VAP were
79% (95% CI = 64.0±84.0) and 88% (95% CI = 84.2±91.2). Whilst the positive predictive value
of ESBLE digestive colonization was low (43.6%), its negative predictive value was excellent
(97.3%) in predicting ESBLE VAP.
No significant difference was found in duration of mechanical ventilation (median [IQR], 28
] vs 23 [
] d, p = 0.4), length of ICU stay (31 [
] vs 29 [
] d, p = 0.6), and
mortality rates (55.8% vs 50%, p = 0.48) between the two groups (Table 6). No significant
difference was found in time from VAP diagnosis to death between patients with ESBL VAP, and
those with VAP related to other bacteria (10 [
] days (median [IQR]) versus 12 [
respectively, p = 0.48).
Our results suggest that prior digestive colonization with ESBLE is independently associated
with occurrence of VAP related to ESBLE. The negative predictive value of prior digestive
colonization to detect VAP due to ESBLE was excellent, although the positive predictive value
was low. No significant difference was found in duration of mechanical ventilation, ICU length
of stay or mortality between patients with ESBLE VAP, as compared with those with VAP due
to other bacteria.
Several previous studies identified risk factors for MDR bacteria and ESBLE colonization
[13,14,18±24]. However, few specific data are available about VAP related to ESBLE. Bruyère
et al. performed a single center retrospective study, over the same time period, to assess the
interest of screening for ESBLE rectal carriage to predict their involvement in VAP [
study included 587 patients with suspected VAP. VAP was caused by ESBLE in 20 (3.4%)
patients, and among them 17 were previously identified as ESBLE carriers. Sensitivity and
specificity of prior ESBLE colonization as a predictor of ESBLE VAP were 85.0% and 95.7%,
respectively. The negative predictive value was 99.4%. Our results confirm their findings in a
cohort with higher number (n = 43) of patients with VAP related to ESBL. Our results suggest
that patients without ESBLE colonization should probably not receive carbapenems as part of
their initial empirical treatment to cover ESBLE. Such a strategy of restricting the use of
carbapenems would be helpful to prevent subsequent resistance.
Most cases of VAP result from aspiration of oropharyngeal, or gastric secretions around the
tracheal-tube cuff into the normally sterile lower respiratory tract [
]. Digestive tract
represents a potential reservoir of nosocomial Gram-negative bacilli, which may become a source
of colonization of the respiratory tract during mechanical ventilation. Gram-negative bacilli,
such as Pseudomonas aeruginosa and Klebsiella pneumonia are the most common
microorganisms in patients with VAP [
]. Recent studies reported a substantial increase in the
incidence of ESBLE in community and in ICU patients, in several countries, including France
In our population, 297 patients (72.4%) acquired MDR bacteria during their ICU stay and
among them, digestive tract colonization with ESBLE was found in 125 patients (30.5%). This
result could be explained by the high percentage of patients with late-onset VAP (80%), the
long duration of ICU stay and mechanical ventilation in study patients, and the high
proportion of patients who received broad-spectrum antibiotic treatment.
Previous use of broad-spectrum antibiotics, including beta-lactam/beta-lactamase and
carbapenems was identified in many studies as a risk factor for ESBLE colonization [14,24,30±
32]. In addition, previous studies reported that digestive tract ESBLE colonization was
associated with an increased mortality [
]. In our study, no significant difference was found in
prior exposure to broad spectrum antibiotic treatment, or to carbapenems between ESBLE
VAP, as compared to VAP related to other bacteria. Further, ESBLE VAP was not associated
with negative impact on outcome. These results could be explained by the relatively small
number of patients with ESBLE VAP.
Our results also suggest that a systematic screening strategy for ESBLE digestive
colonization during the ICU stay is probably helpful to guide empirical antibiotic treatment in VAP
patients. Nine patients developed an ESBLE VAP without prior digestive tract colonization. In
three of them, ESBLE digestive colonization was detected thereafter. Screening by rectal swab
twice a week could have improved sensitivity [
]. Nevertheless, increasing the screening
frequency could overestimate the risk of ESBLE VAP and the potential use of carbapenems [
8 / 11
Our study has some limitations. First, it was a retrospective study, although VAP were
prospectively identified. It was also performed in a single center. Therefore, our results could not
be generalized. Second, only the first episodes of VAP were taken into account in our study.
Some patients were exposed to prolonged duration of mechanical ventilation and developed
several episodes of VAP requiring antimicrobial treatment. Therefore, the incidence of ESBLE
VAP might have been underestimated, as late-onset subsequent VAP episodes were not
studied. Third, because of the retrospective design, appropriateness of empirical antibiotic
treatment could not be evaluated. Fourth, we did not collect information on PaO2/FiO2 ratio in
study patients. Fifth, regarding our sample size (n = 410) and number of patients with ESBLE
VAP (n = 43), we caution that we cannot not exclude that several differences were overlooked
due to the lack of adequate statistical power, and that we cannot exclude the issue of overfitting
in multivariate analysis. Finally, one could argue that a control group including only patients
with VAP related to Enterobacteriaceae-other than ESBL could be more relevant than VAP
related to bacteria-other than ESBL. However, at the time of VAP suspicion, no information is
available on the responsible microorganism. In addition, we repeated all analyses using a
control group with VAP related to Enterobacteriaceae-other than ESBL, and found similar results
(data not shown).
Our results suggest a significant relationship between digestive tract colonization related to
ESBLE and the occurrence of ESBLE VAP. The excellent negative predictive value suggests
that patients without ESBLE colonization should not receive carbapenems as part of their
initial empirical treatment to cover ESBLE. However, further prospective studies are required to
confirm our results.
Conceptualization: Marion Houard, Saad Nseir, Benoit Voisin.
Data curation: Marion Houard, Geoffrey Ledoux, Sophie Six, FreÂdeÂric Wallet.
Formal analysis: Marion Houard, Saad Nseir, Benoit Voisin.
Methodology: Julien Labreuche, Saad Nseir.
Supervision: Saad Nseir, Benoit Voisin.
Validation: Marion Houard, Anahita RouzeÂ, Geoffrey Ledoux, Sophie Six, Emmanuelle
Jaillette, Julien Poissy, SeÂbastien PreÂau, FreÂdeÂric Wallet, Julien Labreuche, Saad Nseir, Benoit
Writing ± original draft: Marion Houard, Saad Nseir, Benoit Voisin.
Writing ± review & editing: Marion Houard, Anahita RouzeÂ, Geoffrey Ledoux, Sophie Six,
Emmanuelle Jaillette, Julien Poissy, SeÂbastien PreÂau, FreÂdeÂric Wallet, Julien Labreuche,
Saad Nseir, Benoit Voisin.
9 / 11
Respir. Crit. Care Med. 2005; 171:388±416. https://doi.org/10.1164/rccm.200405-644ST PMID:
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