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Original Research: Critical Care |

Efficacy of Single-Dose Antibiotic Against Early-Onset Pneumonia in Comatose Patients Who Are VentilatedPreventing Pneumonia in Comatose Patients FREE TO VIEW

Jordi Vallés, MD, PhD; Raquel Peredo, MD; Maria Jose Burgueño, MD, PhD; A. Patrícia Rodrigues de Freitas, MD; Susana Millán, MD; Mateu Espasa, MD; Ignacio Martín-Loeches, MD, PhD; Ricard Ferrer, MD, PhD; David Suarez, PhD; Antonio Artigas, MD, PhD
Author and Funding Information

From the Critical Care Center (Drs Vallés, Peredo, Burgueño, Millán, Martín-Loeches, Ferrer, and Artigas), Hospital Sabadell, Consorci Hospitalari Universitari Parc Taulí, CIBER Enfermedades Respiratorias, Sabadell, Spain; Emergency Medicine Service (Dr Rodrigues de Freitas), Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal; Microbiology Laboratory (Dr Espasa), UDIAT, Consorci Hospitalari Universitari Parc Taulí, Sabadell, Spain; and Epidemiology and Assessment Unit (Dr Suarez), Fundació Parc Taulí, Universitat Autònoma de Barcelona, Sabadell, Spain.

Correspondence to: Jordi Vallés, MD, PhD, Critical Care Center, Parc Taulí Hospital-Sabadell, Parc Tauli s/n. 08208 Sabadell, Spain; e-mail: jvalles@tauli.cat


For editorial comment see page 1195

Funding/Support: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(5):1219-1225. doi:10.1378/chest.12-1361
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Background:  Comatose patients present a high risk of early-onset ventilator-associated pneumonia (EO-VAP) for which antibiotic prophylaxis has been proposed. Comatose patients were studied to evaluate the efficacy of a single-dose of antibiotic prophylaxis at intubation against EO-VAP.

Methods:  A prospective cohort of comatose patients (Glasgow Coma Score ≤ 8) who were admitted in 2009-2010 and administered a single-dose of antibiotic within 4 h of intubation was compared with comatose patients (admitted ≥ 4 h after intubation in 2009-2010 or admitted in 2007-2008) who did not receive antibiotic prophylaxis. We analyzed the incidence of EO-VAP, late-onset VAP, and ventilator-associated tracheobronchitis in both groups. Propensity scores for receiving antibiotic prophylaxis were derived on the basis of patients’ characteristics (eg, age and severity) to assess its impact on EO-VAP development.

Results:  We included 129 patients (71 in the prophylaxis group and 58 in the control group). The global incidence of VAP and incidence of EO-VAP were lower in the prophylaxis group: 10.8 vs 28.4 episodes/1,000 days on mechanical ventilation (P = .015) and 4.4 vs 23.1 episodes/1,000 days on mechanical ventilation (P = .02), respectively. The incidence of late-onset VAP did not differ. The prophylaxis group tended toward lower incidence of ventilator-associated tracheobronchitis (15.5% vs 25.9%, P = .14). No differences in mortality were found between groups. The propensity-score regression analysis confirmed that a single dose of antibiotic prophylaxis was independently associated with lower incidence of EO-VAP (OR, 0.11; 95% CI, 0.02-0.58; P = .009).

Conclusions:  A single dose of antibiotic prophylaxis at intubation might lower the incidence of EO-VAP. However, a randomized clinical trial should be conducted to confirm our findings.

Figures in this Article

Ventilator-associated pneumonia (VAP) is the most common acquired infection in ICUs1 and results in substantial morbidity and mortality.25 VAP is associated with an increased length of mechanical ventilation (MV), ICU stay, hospital stay, and costs.6

Time of onset of pneumonia is an important variable and risk factor for specific pathogens in patients with VAP. Early-onset VAP (EO-VAP), which occurs during the first 4 days of MV in patients who have not received prior antibiotics or who have not had prior hospitalization, is usually caused by antibiotic-sensitive bacteria, and late-onset VAP (LO-VAP), which occurs from the fifth day, is more likely to be caused by more-resistant pathogens.7

Patients with head injury have high risk of EO-VAP.8,9 In comatose patients, EO-VAP develops due to microaspirations caused by glottic dysfunction before intubation and high bacterial inoculum introduction into the lower airway during the intubation procedure.1012 The most commonly isolated pathogens are methicillin-sensitive Staphylococcus aureus (MSSA), Haemophilus influenzae, and Streptococcus pneumoniae.5,10

Some guidelines recommend different strategies to prevent VAP.7,1316 The latest American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines7 conclude, from level 1 evidence based on a single, prospective, randomized, clinical trial,9 that prophylactic administration of a systemic antibiotic for 24 h at the time of emergent intubation may be useful to prevent VAP in patients with closed head injury. However, the ATS/IDSA guidelines have not yet recommended the prophylactic use of systemic antibiotics, pending availability of more data. In 2005, Acquarolo et al17 demonstrated a 64% relative risk reduction of EO-VAP in comatose patients receiving ampicillin-sulbactam for 3 days. Furthermore, selective digestive decontamination with topical antibiotics combined with IV antibiotics during the first days can also help prevent VAP.18 However, a European consensus document on hospital-acquired pneumonia opined that more research is necessary to conclude that prophylactic antibiotic administration immediately after intubation reduces EO-VAP.19

We aimed to evaluate the efficacy of an intervention protocol with a single dose of antibiotic at intubation in reducing EO-VAP in comatose patients. We also analyzed the impact on the incidence of LO-VAP and ventilator-associated tracheobronchitis (VAT) on the length of MV, ICU stay, and hospital stay, and on mortality.

Selection of Patients

This comparative cohort study was conducted in a single, 16-bed, adult medical and surgical ICU in a university hospital. The study was approved by the Corporació Sanitaria Parc Taulí ethics committee (institutional review board approval number 2012/535). The ethics committee waived the requirement for informed consent since confidentiality was guaranteed and because the intervention protocol with antibiotic at intubation was introduced as a measure to reduce EO-VAP in comatose patients according the latest ATS/IDSA guidelines.7

The present study compared two groups of patients. A prospective cohort of comatose patients on mechanical ventilation (Glasgow coma score ≤ 8) who were admitted in 2009-2010 and who received a single dose of antibiotic as prophylaxis against EO-VAP within the first 4 h of intubation (the prophylaxis group) was compared with a control group comprising a historical cohort of comatose patients who were mechanically ventilated admitted in 2007-2008 and patients admitted in 2009-2010 to the ICU > 4 h after intubation and who did not receive antibiotic prophylaxis.

Prophylaxis Against VAP

Patients in the prophylaxis group received a single dose (2 g) of ceftriaxone within 4 h of intubation. Patients with known hypersensitivity to β-lactams received a single 1-g dose of ertapenem, and patients with known anaphylaxis to β-lactams received a single 500-mg dose of levofloxacin.

Other evidenced-based measures to prevent VAP16,19 used in our ICU during the study period (2007-2010) were monitoring endotracheal-tube cuff pressure, continuous subglottic suctioning, semirecumbent position, and oral cleaning with chlorhexidine. No new preventive measure was introduced during the study period.

Definitions

VAP was suspected if new or progressive infiltrates or consolidation appeared on chest radiographs in the presence of two of the following: leukocytes ≥ 11,000/mm3 or ≤ 4,000/mm3, fever ≥ 38°C or hypothermia < 36°C, or new onset of purulent endotracheal secretions or change in character of sputum. Pneumonia was considered definite in the presence of either a quantitative culture of tracheal aspirate ≥ 106 colony forming units (cfu)/mL or a quantitative culture of a protected specimen brush ≥ 103 cfu/mL or a quantitative culture of BAL ≥ 104 cfu/mL. VAP was defined as early onset when it developed in the first 4 days of MV and as late onset when it appeared after the fourth day.7

VAT was suspected if purulent endotracheal secretions were present along with one of the following criteria: leukocytes ≥ 11,000/mm3 or ≤ 4,000/mm3 and fever ≥ 38°C or hypothermia < 36°C in absence of new and/or progressive chest radiographic infiltrates and the presence of a quantitative culture of tracheal aspirate (≥ 106 cfu/mL).20 Microorganisms were classified as primary or secondary endogenous flora.18

Statistical Analysis

Frequencies and percentages or means and SD were used as appropriate to describe patient characteristics. Student t, Mann-Whitney, and χ2 tests were used to compare the groups, as appropriate. We used Kaplan-Meier curves and the log-rank test to compare the number of pneumonia-free days during the first week between the two groups. The incidences were compared using tests based on the normal distribution or exact tests, when appropriate. A propensity-score regression analysis was applied to assess the effect of antibiotic prophylaxis on EO-VAP development. We estimated propensity scores by fitting a logistic regression with the dependent variable being antibiotic prophylaxis. The covariates included in the previous model were those with significant differences in the univariate analysis (Table 1) and those that were clinically relevant for the outcome, such as age and APACHE (Acute Physiology and Chronic Health Evaluation) II score. Finally, we fitted a logistic model for EO-VAP including the propensity score and treatment as covariates. To assess the positivity assumption, we plotted the distribution of the propensity scores for each treatment arm. The positivity assumption means that there is a positive probability for selection of each treatment of any combination of covariates. Moreover, as a sensitivity analysis, we refitted the propensity-score regression analysis excluding patients with no propensity score overlapping between treatment groups.21 For all analyses, P values < .05 were considered significant. We used SPSS version 15.0 for Windows (IBM) for all analyses.

Table Graphic Jump Location
Table 1 —Baseline and Characteristics of the Study Population

Data presented as % unless otherwise indicated. AMI = acute myocardial infarction; APACHE = Acute Physiology and Chronic Health Evaluation; GCS = Glasgow Coma Score.

Patients

We included 129 patients: 71 in the prophylaxis group and 58 in the control group. The most common reasons for endotracheal intubation were head trauma, stroke, and cardiac arrest; there were no significant differences between the two groups. Within the control group, 28 patients were admitted in the period 2007-2008 and 30 patients in the period 2009-2010. The time of intubation of these 30 patients until the admission in our ICU was between 4 and 6 h, and the delay was secondary to previous surgery, diagnostic tests, or transfer from other hospital. The incidence of intubation outside the hospital was 47.8% in the prophylaxis group and 44.8% in the control group (P = .72). Table 1 shows the baseline characteristics of the two groups making up the study population. The only differences between the two groups were an increased incidence of COPD in the control group (1.4% vs 10.3%, P = .02), a higher incidence of neurosurgical intervention in the control group (12.7% vs 29.3%, P = .01), and a higher prevalence of antibiotic use in the control group (60.3% vs 32.3%, P < .01). In the prophylaxis group, the mean time to antibiotic administration after intubation was 1.4 ± 0.8 h; 66 patients (93%) received ceftriaxone, three (4.2%) received levofloxacin, and two (2.8%) received ertapenem.

Incidence of Respiratory Infection

The incidence of microbiologically confirmed EO-VAP was two of 71 (2.8%) in the prophylaxis group compared with 13 of 58 (22.4%) in the control group (P = .001). The incidence of EO-VAP was 4.4 episodes/1,000 days of MV in the prophylaxis group and 23.1 episodes/1,000 days of MV in the control group (OR, 0.1; 95% CI, 0.02-0.46; P = .001). Further details are displayed in Table 2. The mean time of MV before the diagnosis of EO-VAP was 2 ± 0.2 days in the prophylaxis group and 2.7 ± 0.9 days in the control group (P = .3). The number of pneumonia-free days during the first week was lower in the control group than in the prophylaxis group (log-rank test, P = .02) (Fig 1).

Table Graphic Jump Location
Table 2 —Incidence of Pneumonia and Mortality in Treatment and Control Groups

Data given as % unless otherwise indicated. LOS = length of stay; MV = mechanical ventilation; VAP = ventilator-associated pneumonia; VAT = ventilator-associated tracheobronchitis.

Figure Jump LinkFigure 1. Comparison of the cumulative proportion of patients remaining free of ventilator-associated pneumonia during the first week of hospitalization between the prophylaxis and the control groups (log-rank test, P = .02).Grahic Jump Location

There were six episodes of LO-VAP, representing an incidence of 6.5 episodes/1,000 days of MV in the prophylaxis group and 5.3 episodes/1,000 days of MV in the control group (P = .72). The incidence of VAT did not differ between groups (Table 2), and the mean time of MV prior to diagnosis was 5.8 ± 5.9 days in the prophylaxis group and 4.6 ± 5.2 days in the control group (P = .68).

Etiology of Respiratory Infection

In the two patients with EO-VAP in the prophylaxis group, MSSA was isolated in one and Peptostreptococcus species in the other; both patients had received ceftriaxone as prophylaxis. The mean time to antibiotic administration after intubation was 2.1 ± 1.6 h in the two patients with EO-VAP, whereas in the patients without EO-VAP, it was 1.48 ± 0.9 h (P = .35). Among the 13 patients in the control group with EO-VAP, S aureus, H influenzae, and S pneumoniae were the predominant microorganisms (Table 3). Table 3 also shows the etiologies of LO-VAP and VAT in the two groups.

Table Graphic Jump Location
Table 3 —Isolated Microorganisms in Patients With VAP

MSSA = methicillin-sensitive S aureus. See Table 2 legend for expansion of other abbreviations.

Morbidity and Mortality

The mean duration of MV was 6.4 ± 6.5 days in the prophylaxis group and 9.7 ± 9.6 days in the control group (P = .02). The mean ICU stay was 9.7 ± 9.8 days in the prophylaxis group and 14.9 ± 13.9 days in the control group (P = .01).

A total of 39 patients (30.9%) died, 21 of 71 (29.6%) in the prophylaxis group and 18 of 58 (31%) in the control group (P = .85). The main causes of death were cerebral anoxia (32.4%), brain death (29.7%), cerebral hemorrhage (19%), shock (13.5%), and sepsis (5.4%).

The propensity-score regression analysis confirmed that antibiotic prophylaxis was independently associated with lower incidence of EO-VAP (OR, 0.11; 95% CI, 0.02-0.58; P = .009). The overlap between the distributions of the propensity scores for treated and untreated patients was good, reinforcing the validity of these results (Fig 2). Moreover, the sensitivity analysis excluding the patients with no propensity-score overlapping gave very similar results (OR, 0.12; 95% CI, 0.02-0.60; P = .010).

Figure Jump LinkFigure 2. Distribution of propensity scores for treated and untreated groups. The propensity scores estimate the probability of receiving antibiotic prophylaxis for all the patients.Grahic Jump Location

Our results demonstrate the effectiveness of a single dose of antibiotic for prophylaxis against EO-VAP in this specific group of comatose patients, without increasing incidence of infection by multiresistant microorganisms. It is important to highlight that the incidence of EO-VAP in comatose patients is higher than in the general MV population. In our study, the reported incidence of EO-VAP was 22% in the control group and is in agreement with other authors, such as Sirvent et al9 (36% baseline EO-VAP), Acquarolo et al17 (57.9% baseline EO-VAP), and Perbet et al22 (64% baseline EO-VAP) in a population of unconscious patients with cardiac arrest. The high incidence of EO-VAP in patients with altered level of consciousness seems to be related to impaired swallowing, and gag and cough reflexes, which all facilitate aspiration. Moreover, these patients are nearly always intubated in emergency conditions outside the hospital, where of the lack of aseptic conditions makes it easier for microorganisms to enter the respiratory tract. In a study evaluating the risk factors for developing pneumonia within 48 h of intubation, Rello et al12 found that patients with respiratory/cardiac arrest and coma had the highest incidence of pneumonia in the first 48 h, that antibiotic use reduced the incidence of pneumonia within this period, and that other preventive measures such as the aspiration of subglottic secretions were ineffective because these patients had already aspirated microorganisms while being intubated.

Sirvent et al9 conducted a randomized trial to evaluate the effectiveness of two doses of cefuroxime administered within 24 h of intubation in reducing the incidence of EO-VAP in patients with closed head injury (Glasgow Coma Score < 12). Acquarolo et al17 also showed that 3 days’ treatment with amoxicillin-clavulanate reduced the incidence of pneumonia in comatose patients. Along the same line, Zandstra and Van Saene18 suggested that the IV administration of systemic antibiotic (cefotaxime) in selective decontamination of the digestive tract during the first 5 days was largely responsible for the reduced incidence of VAP and improved survival observed in these patients.18 However, in these cases, the use of antibiotics may be more akin to a short course of treatment than true prophylaxis, and the administration of antibiotics for prolonged periods might increase the risk of subsequent infection with antibiotic-resistant microorganisms.23,24 For this reason, we decided to use a single dose of an antibiotic that has a long half-life and is effective against the primary endogenous flora responsible for most EO-VAP.

We chose ceftriaxone because it has proven useful for prophylaxis in patients undergoing thoracic surgery and because serum levels during 24 h to 48 h were higher than the minimal inhibitory concentration to prevent the growth of S aureus, which is the most common organism isolated in comatose patients who develop EO-VAP.9,12,25 In addition, a study of the intrapulmonary pharmacokinetics of cefuroxime in volunteer subjects demonstrated that cefuroxime was not detected within cells or in the epithelial lining fluid at any time between 6 h and 24 h after a single 0.5 g dose.26 This could explain in part why the cefuroxime group in the Sirvent et al9 study still had an incidence of EO-VAP of 16% despite the significant reduction in the incidence of EO-VAP. In cases of known allergy or anaphylaxis to β-lactams, we used ertapenem or levofloxacin to achieve long-lasting antibiotic coverage in a single dose as early as possible after intubation because both these antibiotics achieve adequate levels in the lung.2730

One of the dangers of overusing antibiotics is the selection for multiresistant organisms. In our study, surveillance cultures were not obtained; however, we could not find differences in antibiotic resistance patterns for LO-VAP episodes between patients who did or did not receive antibiotic prophylaxis. This finding suggests that a single dose of antibiotic would not be a risk factor for generating resistance.

Despite the significant reduction in the incidence of pneumonia, we found no differences in mortality between the prophylaxis and control groups. The most likely explanation is that the reduction occurs only in the incidence of EO-VAP, which is produced by less-virulent microorganisms and causes less mortality. In fact, in a previous study in our ICU, we found no pneumonia-related mortality in patients with EO-VAP and significantly higher pneumonia-related mortality in patients with LO-VAP, in whom more-resistant organisms were more prevalent.5 However, in the present study we found a significant reduction in the duration of MV and ICU stay in the prophylaxis group that could be attributed to the reduction in the incidence of pneumonia. On the other hand, in the control group, we observed an increase in the antibiotic use secondary, in part, to the higher incidence of pneumonia.

Finally, some limitations of the study should be noted. First, this is a nonrandomized study, so there may be a bias in the choice of patients for the control group. In fact, the higher incidence of COPD in the control group could allow greater colonization of the airway before intubation; however, a study has demonstrated that intubated patients with nonexacerbated COPD were not exposed to a higher risk of VAP.31 On the other hand, the higher incidence of chronic renal failure and immunosuppression in the prophylaxis group could also favor previous airway colonization. Moreover, more patients in the control group required neurosurgical intervention. This difference in the distribution of patients partly resulted from including in the control group patients admitted during the period in which we administered antibiotic prophylaxis and whose admission to the ICU was delayed > 4 h by surgery. However, the other measures applied to prevent nosocomial infection in our ICU were the same for all patients in both cohorts. Moreover, the goal of propensity score analysis was to balance observed covariates between subjects from the study to mimic what happens in a randomized study, creating a quasi-randomized experiment from a nonrandomized observational study. Second, the study was performed in a single ICU without endemic multiresistant organisms such as methicillin-resistant S aureus or Acinetobacter baumannii, in which other measures are used to prevent pneumonia; therefore, it may limit the broader applicability of our results.

In summary, based on our data, a single dose of antibiotic significantly reduced the incidence of EO-VAP in comatose patients undergoing MV; it also reduced the duration of MV and ICU stay, and had no impact on the mortality and the incidence of infection by multiresistant microorganisms. However, a randomized clinical trial needs to be conducted to confirm our findings in a larger population.

Author contributions: Dr Vallés had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Vallés: contributed to the design of the study, coordinated patient recruitment, analyzed and interpreted the data, assisted in writing and revising the paper, read and approved the final manuscript, and served as principle author.

Dr Peredo: contributed to the design of the study, coordinated patient recruitment, analyzed and interpreted the data, assisted in writing the paper, and read and approved the final manuscript.

Dr Burgueño: contributed to the acquisition and analysis of data and read and approved the final manuscript.

Dr Rodriques de Freitas: contributed to the acquisition and analysis of data and read and approved the final manuscript.

Dr Millán: contributed to the acquisition and analysis of data and read and approved the final manuscript.

Dr Espasa: contributed to the design of the study, coordinated patient recruitment, analyzed and interpreted the data, assisted in writing the paper, and read and approved the final manuscript.

Dr Martín-Loeches: contributed to the conception and design of the study, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and read and approved the final manuscript.

Dr Ferrer: contributed to the design of the study, coordinated patient recruitment, analyzed and interpreted the data, assisted in writing the paper, and read and approved the final manuscript.

Dr Suarez: contributed to the conception and design of the study, analysis and interpretation of data, revision of the final manuscript, and read and approved the final manuscript.

Dr Artigas: contributed to critical revision of the manuscript for important intellectual content, and read and approved the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

ATS/IDSA

American Thoracic Society/Infectious Diseases Society of America

cfu

colony forming units

EO-VAP

early-onset ventilator-associated pneumonia

LO-VAP

late-onset ventilator-associated pneumonia

MV

mechanical ventilation

VAT

ventilator-associated tracheobronchitis

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Figures

Figure Jump LinkFigure 1. Comparison of the cumulative proportion of patients remaining free of ventilator-associated pneumonia during the first week of hospitalization between the prophylaxis and the control groups (log-rank test, P = .02).Grahic Jump Location
Figure Jump LinkFigure 2. Distribution of propensity scores for treated and untreated groups. The propensity scores estimate the probability of receiving antibiotic prophylaxis for all the patients.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline and Characteristics of the Study Population

Data presented as % unless otherwise indicated. AMI = acute myocardial infarction; APACHE = Acute Physiology and Chronic Health Evaluation; GCS = Glasgow Coma Score.

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Table 2 —Incidence of Pneumonia and Mortality in Treatment and Control Groups

Data given as % unless otherwise indicated. LOS = length of stay; MV = mechanical ventilation; VAP = ventilator-associated pneumonia; VAT = ventilator-associated tracheobronchitis.

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Table 3 —Isolated Microorganisms in Patients With VAP

MSSA = methicillin-sensitive S aureus. See Table 2 legend for expansion of other abbreviations.

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