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* From the Pulmonary and Critical Care Medicine Division (Drs. Ibrahim and Kollef, and Ms. Ward), Department of Internal Medicine, Washington University School of Medicine; and the Department of Nursing (Ms. Sherman), Barnes-Jewish Hospital, Saint Louis, MO.
Correspondence to: Marin H. Kollef, MD, FCCP, Pulmonary and Critical Care Medicine, Washington University School of Medicine, Campus Box 8052, 660 South Euclid, St.Louis, MO 63110; e-mail: mkollef{at}pulmonary.wustl.edu
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Prospective cohort study.
Setting: A medical ICU and a surgical ICU from a university-affiliated urban teaching hospital.
Patients: Between July 1997 and November 1998, 3,668 patients were prospectively evaluated.
Intervention: Prospective patient surveillance and data collection.
Results: Four hundred twenty patients (11.5%) developed NP. Early-onset NP was observed in 235 patients (56.0%), whereas 185 patients (44.0%) developed late-onset NP. Among patients with early onset NP, 114 patients (48.5%) spent at least 24 h in the hospital prior to ICU admission, compared to 57 patients (30.8%) with late-onset NP (p = 0.001). One hundred eighty-three patients (77.9%) with early-onset NP received antibiotics prior to the development of NP, as compared to 162 patients (87.6%) with late-onset NP (p = 0.010). The most common pathogens associated with early-onset NP were Pseudomonas aeruginosa (25.1%), oxacillin-sensitive Staphylococcus aureus (OSSA; 17.9%), oxacillin-resistant S aureus (ORSA; 17.9%), and Enterobacter species (10.2%). P aeruginosa (38.4%), ORSA (21.1%), Stenotrophomonas maltophilia (11.4%), OSSA (10.8%), and Enterobacter species (10.3%) were the most common pathogens associated with late-onset NP. The ICU length of stay was significantly longer for patients with early-onset NP (10.3 ± 8.3 days; p < 0.001) and late-onset NP (21.0 ± 13.7 days; p < 0.001), as compared to patients without NP (3.5 ± 3.2 days). Hospital mortality was significantly greater for patients with early-onset NP (37.9%; p = 0.001) and late-onset NP (41.1%; p = 0.001) compared to patients without NP (13.1%).
Conclusions: Both early-onset and late-onset NP are associated with increased hospital mortality rates and prolonged lengths of stay. The pathogens associated with NP were similar for both groups. This may be due, in part, to the prior hospitalization and use of antibiotics in many patients developing early-onset NP. These data suggest that P aeruginosa and ORSA can be important pathogens associated with early-onset NP in the ICU setting. Additionally, clinicians should be aware of the common microorganisms associated with both early-onset NP and late-onset NP in their hospitals in order to avoid the administration of inadequate antimicrobial treatment.
Key Words: clinical outcomes • critical care • hospital mortality • ICU • infection • nosocomial pneumonia • risk factors
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Early-onset NP is most often reported to be due to antibiotic-sensitive pathogens including Haemophilus influenza, oxacillin-sensitive Staphylococcus aureus (OSSA), and Streptococcus pneumonia, while late-onset NP is frequently attributed to antibiotic-resistant pathogens such as oxacillin-resistant S aureus (ORSA), Pseudomonas aeruginosa, Acinetobacter species, and Enterobacter species.8 9 A systematic comparison of risk factors, pathogens, and clinical outcomes between early-onset and late-onset NP in the ICU setting has not been previously reported. Therefore, we performed a prospective cohort study with three goals. First, we wanted to determine the magnitude of the problem of early-onset and late-onset NP among critically ill adult patients. Second, we sought to identify potential risk factors associated with NP in each group of patients. Third, we set out to evaluate the relationship between hospital mortality and NP. It was our hope that such data would provide useful information for the clinical management of patients at risk for NP and those developing NP.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Study Design and Data Collection
One of the investigators made daily rounds in the medical and
surgical ICU to identify eligible patients and record relevant data
from patients’ medical records, bedside flow sheets, computerized
bedside nursing stations (EMTEK Health Care Systems; Tempe, AZ),
computerized radiographic reports, and reports of microbiological
studies (sputum Gram’s stains and sputum, blood, and pleural fluid
cultures). Study patients were prospectively followed for the
occurrence of early-onset and late-onset NP until they were
successfully treated and discharged from the hospital or until death.
All patients with suspected early-onset and late-onset NP were
prospectively and independently reviewed by one of the investigators
(MHK), who confirmed the diagnosis of NP based on predetermined
criteria (see below). Patients could not be entered into the study more
than once, and only the first episode of NP was evaluated.
For all study patients, the following characteristics were prospectively recorded at the time of study entry: age, gender, concomitant diseases, hospital admitting diagnosis, indication for mechanical ventilation, the ratio of PaO2/fraction of inspired oxygen (FIO2), severity of illness based on APACHE II (acute physiology and chronic health evaluation),10 and the patient’s diagnostic category (medical vs surgical). Specific processes of medical care examined during the period of ICU admission as potential risk factors for the development of NP included the administration of antacids, histamine type-2 receptor antagonists, sucralfate, corticosteroids, or vasopressors, tracheostomy, dialysis, reintubation, the presence of central venous or urinary tract catheters and their duration, and mechanical ventilation and its duration. In addition to the occurrence of early-onset or late-onset NP, secondary outcomes evaluated included hospital mortality, the lengths of ICU and hospital stay, and the number of acquired organ system derangements.
Definitions
All definitions were selected prospectively as part of the
original study design. APACHE II scores were calculated based on
clinical data available from the first 24 h of ICU admission.
Acquired organ system derangements were defined using the modified
criteria of Rubin and coworkers.11
One point was given for
acquired dysfunction of each organ system using the following
definitions: renal, a twofold increase in the baseline creatinine level
by 2.0 mg/dL (176.8 µmol/L); hepatic, a rise in the total bilirubin
level to > 2.0 mg/dL (34.2 µmol/L); pulmonary, requiring mechanical
ventilation for a diagnosis of pneumonia, COPD, asthma, pulmonary edema
(cardiogenic or noncardiogenic), a
PaO2 < 60 mm Hg while receiving an
FIO2 
0.50, or the use of 10 cm
H2O or more of positive end-expiratory pressure;
hematologic, the presence of disseminated intravascular coagulation,
WBC count < 1,000 cells/µL (1.0 x 109
cells/L), or platelet count
< 75 x 103/µL
(75 x 109/L); neurologic, new focal deficit
(eg, hemiparesis following cerebral infarction) or new
generalized process (eg, seizures or coma); GI, GI
hemorrhage requiring transfusion, or new ileus or diarrhea lasting
> 24 h and unrelated to prior bowel surgery; and cardiac, acute
myocardial infraction, cardiac arrest, or the new onset of congestive
heart failure.
The diagnostic criteria for NP used in this study were modified from
those established by the American College of Chest
Physicians.12
Early-onset NP (ie, NP occurring
within the first 96 h of ICU admission) and late-onset NP
(ie, NP occurring after the first 96 h of ICU
admission) were prospectively defined as the occurrence of new and
persistent radiographic infiltrates in conjunction with one of the
following: positive pleural/blood cultures for the same organism as
that recovered in the tracheal aspirate or sputum; radiographic
cavitation; histopathologic evidence of pneumonia; or two of the
following: fever, leukocytosis, and purulent tracheal aspirate or
sputum. Persistence of an infiltrate was defined as having the
infiltrate present radiographically for at least 72 h. Fever was
defined as an increase in the core temperature 1°C and a core
temperature > 38.3°C. Leukocytosis was defined as a 25% increase
in the circulating leukocytes from the baseline admission value and a
value > 10 x 103/µL
(10 x 109/L). Tracheal aspirates were
considered purulent if abundant neutrophils were present per high-power
field using Gram’s stain (ie, > 25 neutrophils per
high-power field). Additionally, when available, bronchoscopic and
nonbronchoscopic BAL cultures with appropriate quantitative thresholds
were employed to support the diagnosis of NP.13
Hospital
mortality was defined as those patient deaths occurring during the
initial hospital admission during which they were studied.
Statistical Analysis
Univariate analysis was used to compare variables for the
outcome groups of interest. Comparisons were unpaired, and all tests of
significance were two tailed. Continuous variables were compared using
Student’s t test for normally distributed variables and
Wilcoxon’s rank sum test for nonnormally distributed variables. The
2 statistic or Fisher’s Exact Test were used
to compare categorical variables. The primary data analysis compared
patients with early-onset NP to patients with late-onset NP, and both
were compared to patients without NP. We confirmed the results of these
tests, while controlling for specific patient characteristics and
severity of illness (Tables 1
, 2
), with multiple logistic regression analysis14
using a
commercial statistical package.15
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0.05 were considered to indicate
statistical significance. |
Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nosocomial Pneumonia
Univariate analysis demonstrated that there were significant
differences in the processes of care between patients with and without
NP (Table 2)
. Undergoing tracheostomy, reintubation, the use of
antacids, histamine type-2 receptor antagonists, sucralfate, or
vassopressors, the presence of a urinary tract catheter and its
duration, central venous catheter and its duration, and mechanical
ventilation and its duration were significantly associated with the
development of either early-onset NP or late-onset NP. Undergoing
surgery prior to ICU admission, tracheostomy, the use of antacids,
histamine type-2 receptor antagonists, sucralfate, or vasopressors, the
duration of urinary tract catheterization, central venous
catheterization and its duration, and mechanical ventilation and its
duration were significantly greater among patients developing
late-onset NP as compared to early-onset NP.
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Multiple logistic regression analysis for the entire study cohort demonstrated that increasing APACHE II scores, reintubation, the use of histamine type-2 receptor antagonists, longer durations of mechanical ventilation, and tracheostomy were independently associated with the development of NP (Table 3 ). COPD, increasing APACHE II scores, reintubation, and the use of antacids, vasopressors, or histamine type-2 receptor antagonists were independently associated with early-onset NP. Similarly, the use of vasopressors or histamine type-2 receptor antagonists, greater durations of mechanical ventilation, tracheostomy, and the presence of congestive heart failure were found to be independently associated with the development of late-onset NP.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The importance of these observations are that they may influence antimicrobial prescribing practices in the ICU setting. Our findings suggest that antipseudomonal antibiotics and antimicrobial agents directed against ORSA should be prescribed empirically at our institution to patients suspected of having either early-onset or late-onset NP. This may help to reduce the occurrence of inadequate antimicrobial therapy, which has been associated with poorer patient outcomes.17 18 19 20 21 The high rate of early-onset NP due to potentially antibiotic-resistant bacteria (eg, P aeruginosa, ORSA, Enterobacter species, Stenotrophomonas maltophilia) may be due, in part, to patients’ hospitalization prior to ICU admission as well as the prior use of antibiotics. Over 77% of patients with early-onset NP received antimicrobial therapy prior to the development of this nosocomial infection. Previous investigations have demonstrated a strong association between prior antibiotic use during the same hospitalization and the subsequent development of NP, particularly NP due to potentially antibiotic-resistant pathogens.8 22 23 24 25 These data also highlight the importance of having hospital-specific or unit-specific microbiological data to help guide the empiric therapy of suspected nosocomial infections.
Our findings are consistent with those reported from other countries. Heyland and colleagues26 found that patients with ventilator-associated pneumonia (VAP) in Canada had longer lengths of stay in the ICU and a greater risk of hospital mortality compared to patients without VAP. They also demonstrated that the timing of VAP defined as early-onset (< 7 days) and late-onset (> 7 days) did not influence mortality. This is also consistent with the findings of Mosconi and coworkers,27 who compared patients with early-onset and late-onset NP in Italy and found similar risks of death in both groups. One potential explanation for these findings, as suggested by our current investigation, is that patients with early-onset NP and late-onset NP may have similar rates of infection with high-risk pathogens (eg, P aeruginosa, Acinetobacter species, ORSA) that are associated with higher rates of attributable hospital mortality.23 28
According to a recent American Thoracic Society consensus statement, early-onset NP (ie, developing < 5 days after hospital admission) is most often due to core microorganisms, which include enteric Gram-negative bacilli, H influenza, and Gram-positive organisms, such as OSSA and S pneumoniae.4 Not included among these core micro-organisms are highly resistant Gram-negative organisms, such as P aeruginosa and Acintobacter species, and ORSA. These authors recommended monotherapy for the treatment of early-onset NP using either a second-generation cephalosporin, a nonpseudomonal third-generation cephalosporin, or a ß-lactam/ß-lactamase inhibitor combination.4 Our current findings suggest that at our institution, such therapeutic recommendations would result in undertreating patients with early-onset NP who are infected with ORSA or P aeruginosa.
For patients who develop late-onset NP (ie, after being hospitalized for 5 days), the most commonly encountered pathogens are reported to be potentially antibiotic-resistant Gram-negative bacteria including P aeruginosa and Acintobacter species, as well as S aureus.4 The recommendations of the American Thoracic Society for the empirical treatment of these pathogens include the use of combination antimicrobial therapy with drugs that are active against P aeruginosa (antipseudomonal penicillins, some third-generation cephalosporins, the monobactam aztreonam, antipseudomonal ß-lactam/ß-lactamase inhibitor combinations, aminoglycosides, and the flouroquinolone ciprofloxacin) and vancomycin for severely ill patients with suspected ORSA infection.4 Our findings suggest that these antimicrobial recommendations should also apply to patients with early-onset NP when significant rates of early-onset NP are demonstrated to be due to potentially antibiotic-resistant bacteria. Such pathogens should most commonly be observed in patients with risk factors for infection due to antibiotic-resistant bacteria including prior antibiotic therapy and prolonged mechanical ventilation.8
The observed differences in potential risk factors for patients with early-onset NP and late-onset NP appear to be markers for aspiration and aerodigestive tract colonization. Both of these processes have been linked to the pathogenesis of NP.9 Reintubation was the most important risk factor for patients with early-onset NP. This suggests that aspiration during reintubation may have contributed to the development of this infection.29 Tracheostomy was the most important risk factor for late-onset NP, which also supports a potential role for aspiration in this group of patients.30 The use of antacids in patients with early-onset NP and histamine type-2 receptor antagonists in patients with late-onset NP suggests that colonization of the stomach with pathogenic bacteria may have contributed to the development of NP in some patients. However, due to the observational design of our study, we cannot exclude the possibility that the identified risk factors for NP are simply markers of severity of illness. Interestingly, prior antibiotic therapy was not found to be an independent risk factor for NP in this cohort. This may be explained by the high overall rate of antibiotic administration in this group of patients.
Our study has several limitations. First, our patient population may not be similar to those at other institutions. Therefore, our results may not be applicable to ICUs with lower rates of NP due to ORSA and P aeruginosa. Additionally, the high incidence of hospitalization prior to ICU admission and prior exposure to antibiotics among our patients may not be representative of practices at other institutions. One recent multicenter study found significant variability among the bacterial pathogens associated with VAP within four European ICUs.31 Antibiotic-resistant bacteria, including Acinetobacter species and P aeruginosa, were associated with VAP occurring within 7 days of mechanical ventilation at two of the ICUs examined. This supports the existence of variability between hospitals in terms of the etiologic agents associated with NP and VAP. Second, we used a clinical diagnosis of NP that could be established at the bedside without requiring invasive diagnostic procedures.22 32 Although some authors have warned that the incidence of NP may be overestimated when clinical criteria alone are used,12 33 our incidence of NP was similar to that reported by other investigators employing bronchoscopic methods for the diagnosis of NP.34 35 A recent study also highlighted the limited correlation observed between quantitative cultures obtained with bronchoscopic techniques (ie, protected specimen brush, BAL) and postmortem histologic examination of the lung.36 This lack of correlation has been, in part, attributed to the influence of antimicrobial therapy resulting in both false-negative culture results in patients with NP37 38 and false-positive culture results in patients without clinical manifestations of NP who are colonized with antibiotic-resistant bacteria.39 Such discrepancies have lead some authors to suggest that clinical definitions for the presence or absence of NP can be employed for "high-quality" patient care and clinical investigations.40
Despite the above-noted limitations, our large sample size allowed us to identify potential risk factors for both early-onset and late-onset NP. More importantly, our results suggest that individual hospitals should determine their most appropriate antimicrobial regimens for the empiric treatment of early-onset and late-onset NP based on the prevailing local etiologic agents associated with NP. This is further supported by the demonstrated variability that can exist between institutions in terms of the pathogens associated with VAP or NP.31 The use of hospital-specific or unit-specific microbiological information can potentially influence local antibiotic prescribing practices in order to reduce the administration of inadequate or ineffective antimicrobial treatment.
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Footnotes |
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This investigation was supported in part by grants from the Centers for Disease Control and Prevention (UR8/CCU715087) and Dura Pharmaceuticals.
Received for publication July 13, 1999. Accepted for publication October 27, 1999.
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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