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(Chest. 2003;123:1208-1213.)
© 2003 American College of Chest Physicians

Evaluation of Outcome in Critically Ill Patients With Nosocomial Enterobacter Bacteremia*

Results of a Matched Cohort Study

Stijn I. Blot, MA; Koenraad H. Vandewoude, MD and Francis A. Colardyn, MD

* From the Intensive Care Department, Ghent University Hospital, Ghent, Belgium.

Correspondence to: Stijn I. Blot, MA, Intensive Care Department, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium; e-mail: stijn.blot{at}rug.ac.be


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To evaluate the clinical impact of nosocomial Enterobacter bacteremia in critically ill patients.

Design: Retrospective (January 1992 to December 2000) matched cohort study.

Setting: Fifty-four-bed ICU (including medical, surgical, cardiosurgical ICU, and burns unit) from a university hospital.

Patients: Sixty-seven ICU patients with Enterobacter bacteremia (case patients) and 134 control patients.

Intervention: Matching of control patients (1:2 ratio) was on the basis of the APACHE (acute physiology and chronic health evaluation) II system. As expected, mortality can be derived from this severity-of-disease classification system; this matching procedure results in an equal expected mortality rate for patients with Enterobacter bacteremia and control patients.

Results: The overall rate of appropriate antibiotic therapy in patients with Enterobacter bacteremia was high (96%) and initiated soon after the onset of the bacteremia (0.5 ± 0.9 days). Patients with Enterobacter bacteremia had more hemodynamic instability (p = 0.015), longer ICU stay (p < 0.001), and ventilator dependence (p < 0.001). No differences between case and control patients were found in age (52 years vs 53 years, p = 0.831), prevalence of acute renal failure (16% vs 16%, p = 0.892), and acute respiratory failure (93% vs 84%, respectively; p = 0.079). In-hospital mortality rates for case and control patients were not different (34% vs 39%, respectively; p = 0.536).

Conclusion: After accurate adjustment for severity of underlying disease and acute illness, no difference was found between ICU patients with Enterobacter bacteremia and matched control patients. In the presence of fast and appropriate antibiotic therapy, Enterobacter bacteremia does not adversely affect the outcome in ICU patients.

Key Words: acute physiology and chronic health evaluation • bacteremia • Enterobacter • intensive care • outcome


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ICU patients often have a decreased immune status due to a strongly debilitated physical condition or immunosuppressive therapy, and are exposed to a high number of invasive procedures. This combination makes these patients extremely vulnerable for nosocomial bloodstream infections.1 In ICUs, Gram-negative bacteremia is considered a serious event associated with a grim prognosis.2 However, for decades it has been assumed that the clinical impact of Gram-negative bacteremia is low in comparison with the severity of underlying disease in these patients.3 4 Consequently, the prognosis for these patients should not significantly alter when bacteremia occurs. In previous reports, we described surprisingly low excess mortality rates in ICU patients with nosocomial Acinetobacter and Pseudomonas bacteremia when compared with control subjects carefully matched for underlying disease and acute illness.5 6 The objective of the present study was to investigate the clinical impact of nosocomial Enterobacter bacteremia in critically ill patients.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Setting and Study Design
The study was conducted at the Ghent University Hospital, a 1,060-bed tertiary care center with a 54-bed ICU, including a surgical and medical ICU, an ICU for cardiac surgery, and a burn unit. No significant changes in age, length of ICU stay, or APACHE (acute physiology and chronic health evaluation) II scores7 were observed during the study period.

We conducted a retrospective, matched-cohort study (1:2 ratio) in which all ICU patients with nosocomial, microbiologically documented Enterobacter bacteremia were defined as case patients. In patients who had more than one episode of Enterobacter bacteremia, only the first episode was considered. Every case patient was matched with two other ICU patients (matched control patients) without clinical or microbiological evidence of bloodstream infection (with the exception of those caused by coagulase-negative staphylococci). The study was performed in adult, critically ill patients admitted to the ICU over a 9-year period (January 1992 to December 2000).

A hospital-wide, case-based surveillance program for bloodstream infections was used for the retrospective search for ICU patients with nosocomial Enterobacter bacteremia. Every patient whose ICU stay was complicated with Enterobacter bacteremia was used in the analysis.

Control patients were selected from the same period. Matching was based on the APACHE II classification system: an equal APACHE II score (± 1 point) and an equal principal diagnosis leading to ICU admission.7 The APACHE II score is calculated on the basis of a chronic health evaluation and a set of acute physiologic parameters obtained during the first 24 h of ICU observation. The APACHE II-expected in-hospital mortality can be calculated with the APACHE II score and a factor attributed to a precise diagnostic category. As expected mortality can be derived from the APACHE II system (APACHE II score and diagnostic category), this matching procedure resulted in an equal expected mortality for case and control patients. Therefore, this severity-of-disease scoring system has been repeatedly used in case-control analyses dealing with nosocomial infections in ICU settings.8 9 10 11 12 13 Selection of control patients was obtained without knowledge of outcome. In case of more than two potential control patients, matching was based on the nearest ICU admission date of the case.

Definitions
Enterobacter bacteremia is defined as the presence of Enterobacter in the blood, documented with at least one positive blood culture result. Blood culture specimens are obtained on a routine basis when the patient’s temperature rises > 38.4°C or when infection is suspected on clinical grounds, and are processed following the BacT/Alert (Organon Teknika; Durham, NC) procedure. Antibiotic susceptibility patterns are determined according to methods recommended by the National Committee for Clinical Laboratory Standards for disk diffusion testing.14 The source of the bacteremia was determined by both intensivists and microbiologists and based on isolation of Enterobacter from the presumed portal of entry and by clinical evaluation.

Acute respiratory failure is defined as ventilator dependence, acute renal failure is defined as dialysis dependence, and hemodynamic instability is defined as the need for vasopressors or inotropics during the ICU stay.15 16 17 Outcome evaluation was based on the in-hospital mortality of case and control patients.

Statistical Analysis
For reporting statistics, continuous variables are described as mean ± SD and median (interquartile range). Comparative analyses are executed with Mann-Whitney U test or {chi}2 test when appropriate. Comparison of observed vs expected mortality rates are executed with {chi}2 for observed vs expected frequencies. Survival curves are prepared by the Kaplan-Meier method, and univariate survival distributions are compared with the log-rank test. A multivariate survival analysis is evaluated according to the Cox proportional hazards model; hazard ratios and 95% confidence intervals are reported. To avoid spurious associations, only variables with a plausible relationship with mortality were entered in this model. All used tests are two tailed, and p < 0.05 is considered significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
During the study period, 29,727 patients were admitted to the ICU. In 68 patients, the ICU stay was complicated with an Enterobacter bacteremia, representing an incidence of 2.3 cases of Enterobacter bacteremia per 1,000 ICU admissions. Forty-three bacteremias were caused by Enterobacter aerogenes, and 24 were caused by Enterobacter cloacae. In one patient, both Enterobacter species were isolated from the same bottle. Table 1 summarizes the antibiotic susceptibility patterns of all episodes of Enterobacter bacteremia during the study period (n = 76). E cloacae strains were more likely to be ceftazidime susceptible than E aerogenes strains (51.4% vs 29.3%, p = 0.049). Twenty-seven bacteremias were polymicrobial (39.7%). Twenty-one bacteremias were primary in origin (30.9%). In the other bacteremias, the following sources were detected: lower respiratory tract infection (22.1%), urinary tract infection (20.6%), intra-abdominal infection (17.6%), wound infection (5.9%), and nasal sinusitis (4.4%). In nine bacteremias, more than one presumed source was found (13.2%). The median lengths of stay in the ICU and the hospital prior to the bacteremia were 13 days and 14 days, respectively. Bacteremias were treated appropriately in 96% of the patients. The mean ± SD delay for the start of antibiotic therapy was 0.5 ± 0.9 days. Mortality rates at 14 days and 28 days after the onset of the Enterobacter bacteremia were 20.6% and 26.5%, respectively. In-hospital mortality was 35.5%.


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  		Table 1. Antibiotic Susceptibility Patterns of 76 Enterobacter Species Cultured From the Blood*

 
For the matched-cohort study, one patient who died within 14 days after onset of the bacteremia was excluded because of incomplete medical files. For all other ICU patients with Enterobacter bacteremia, matching was successful, leading to a study population of 201 ICU patients: 67 patients with Enterobacter bacteremia (case patients) and 134 matched control patients.

Nonsurvivors vs Survivors
Population characteristics for in-hospital nonsurvivors vs survivors are shown in Table 2 . Nonsurvivors were older, had higher APACHE II scores and related expected mortality, and had more organ derangements. Survivors had a longer ICU stay and a longer period of ventilator dependence.


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  		Table 2. Population Characteristics for ICU Patients Distributed for Hospital Nonsurvivors and Hospital Survivors

 
Patients With Enterobacter Bacteremia vs Matched Control Patients
Characteristics of case and control patients are summarized in Table 3 . Patients with Enterobacter bacteremia had more hemodynamic instability, longer ICU stay, and received mechanical ventilation for a more extended period. Survival curves for case and control patients are shown in Figure 1 . Survival distributions for both groups were not different (p = 0.145). In-hospital mortality rates for case and control patients were 34.3% and 38.8%, respectively (p = 0.536). Observed in-hospital mortality rates were not different from the APACHE II-related expected mortality rates for case (p = 0.112) and control patients (p = 0.999). In a multivariate survival analysis, APACHE II-related expected mortality was identified as the only variable independently associated with in-hospital mortality (hazard ratio, 3.7; confidence interval, 2.0 to 6.7; p < 0.001).


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  		Table 3. Population Characteristics for ICU Patients With (Cases) and Without Enterobacter Bacteremia (Matched Control Patients)

 


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  		Figure 1. Survival curves for ICU patients with Enterobacter bacteremia (case patients, n = 67; solid line) and without Enterobacter bacteremia (control patients, n = 134; dashed line) [log-rank test, p = 0.145].

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Enterobacter species are increasingly emerging nosocomial pathogens.18 19 Because antibiotic-resistant susceptibility patterns easily develop in these pathogens, high attention has been given to these organisms in recent years.18 20 21 Previously reported mortality rates associated with Enterobacter bacteremia are approximately 23 to 32%.2 19 23 24 However, causality remains unclear, as the clinical impact in terms of survival of Enterobacter bacteremia is unexplored.

An important pitfall when investigating the clinical consequences of Gram-negative bacteremia is the very important severity of illness of these patients, providing a considerable confounding impact.8 9 For decades, it has been assumed that the excess mortality caused by Gram-negative bacteremia should not be exaggerated, as most of these patients die as a consequence of their overwhelming severity of underlying conditions.3 4 In order to distinguish mortality due to underlying condition from mortality due to the bacteremia, careful adjustment for severity of disease must be taken into account.

We compared ICU patients with Enterobacter bacteremia with control patients, matched on the basis of APACHE II, a severity-of-disease classification system.7 This matching procedure results in an equal predicted prognosis for case and control patients and is therefore recommended for matched cohort studies in ICU settings.8 9 10 11 12 13 After this accurate adjustment for severity of underlying disease and acute illness, no difference was found between patients with Enterobacter bacteremia and control patients. Mortality in case patients as well as in control patients is high but in accordance with mortality as assessed by the APACHE II system. The group of patients with Enterobacter bacteremia showed no excess mortality at all, indicating that mortality in these patients is mostly due to severity of underlying disease and acute illness. Yet, the proportion of patients who died directly due to the bacteremia remains uncertain. However, as mortality in the control group was equally high, we conclude that if some of the deceased case patients did not die due to the bacteremia, they would have died due to their undermined physical conditions and acute illnesses.

A possible comment on the matching procedure might be that matching was based on severity of illness at time of ICU admission, while bacteremia developed in case patients after a median ICU stay of 13 days. This is noteworthy, as the median ICU stay of the control group was only 7 days. Generally, length of hospitalization prior to nosocomial infection is considered as a major confounder in epidemiologic analysis. It is assumed that patients with a considerably longer hospitalization are sicker and consequently have a worse prognosis. However, patients with a longer ICU stay might have better outcomes, as they have already survived the acute phase at ICU entry. Our data demonstrate that differences in hospitalization prior to the infectious event do not necessarily confound outcome studies. APACHE II scores calculated at ICU admission remain an adequate predictor of in-hospital mortality irrespective of length of ICU stay. Consequently, matching on APACHE II seems justified in patient groups with different ICU stays.

Analogous to the length of ICU stay, case patients had a much longer ventilatory dependence than control patients. It is uncertain what the clinical impact of length of ventilatory support on outcome might have been in the population studied. Yet, because of the absence of a difference in mortality between case and control patients, we feel that this is of minor importance in the present study.

Ibrahim et al25 demonstrated the negative consequences of inadequate antimicrobial treatment in ICU patients with bloodstream infection. In this way, fast initiation and an overall high rate of appropriate antibiotic therapy might have contributed (at least in part) to the absence of an excess mortality in patients with Enterobacter bacteremia. In our ICU, first-line empiric antibiotic therapy consists of a second-generation cephalosporin (cefuroxime). In this study population, however, bacteremia occurred after a median ICU stay of 2 weeks, which requires a second-line empiric therapy. Perhaps the short delay in the start of antibiotic therapy is reached by an intensive screening policy. Thrice-weekly, site-specific surveillance culture specimens are obtained from every ICU patient. When clinical infection occurs, empirical antibiotic therapy is initiated on the basis of the presumed septic focus and the reported antibiotic susceptibility patterns of microorganisms in surveillance cultures. In the present study, 64% of Enterobacter bacteremia pathogens were preceded by colonization with Enterobacter with an identical antibiogram as the species recovered from the blood culture. In the absence of useful surveillance culture results in patients with a considerable ICU stay (> 5 days), broad-spectrum antibiotic therapy is initiated with an antipseudomonal penicillin (piperacillintazobactam). Carbapenems are strictly restrained for patients with microbiologically documented colonization with extended-spectrum, ß-lactamase-producing microorganisms.

Bertrand et al26 and Langer et al27 showed surveillance cultures to have a high specific and negative predictive value, as colonization preceded infection in almost all cases of Pseudomonas aeruginosa infection in an ICU. Yet, the clinical benefits of this strategy, in comparison with blind initiation of broad-spectrum antibiotics, remains unexplored. In addition, routine surveillance sampling is rather expensive. Because of the paucity of data showing clinical advantage, the associated costs and the fear of treating colonization surveillance sampling remains a controversial issue in the ICU.

In summary, mortality associated with Enterobacter bacteremia in ICUs is high; but after accurate adjustment for severity of underlying disease and acute illness, no difference in mortality was found between ICU patients with Enterobacter bacteremia and matched control patients. In the presence of prompt initiation of adequate antibiotic therapy, Enterobacter bacteremia does not adversely affect the outcome.


   Footnotes
 
Abbreviation: APACHE = acute physiology and chronic health evaluation

Mr. Blot is supported by a Special Doctoral Grant of the Fund for Scientific Research, Flanders, Belgium.

Received for publication January 2, 2002. Accepted for publication July 16, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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