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Clinical Outcomes for Patients with Bacteremia Caused by Vancomycin-Resistant Enterococcus in a Level 1 Trauma Center

  1. Lodise Thomas P.,
  2. McKinnon Peggy S.,
  3. Tam Vincent H.a, and
  4. Rybak Michael J.
  1. Anti-Infective Research Laboratory, Detroit Receiving Hospital, Wayne State University, Detroit, Michigan
  1. Reprints or correspondence: Dr. Peggy S. McKinnon, Dept. of Pharmacy Services and Anti-Infective Research Laboratory, Detroit Receiving Hospital, Wayne State University, 4201 St. Antoine Blvd., 1-B UHC, Detroit, MI, 48201 (pmckinno{at}dmc.org).

  1. Presented in part: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, September 2000.

  • ↵Present affiliation: Division of Clinical Pharmacology, Albany Medical College, Albany, New York.

 
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Abstract

To assess the degree of morbidity and mortality attributable to vancomycin resistance in enterococcal bacteremia (EB), a matched case-control study was conducted. Patients with bacteremia due to vancomycin-resistant enterococcus (VRE) were matched to control patients with bacteremia due to vancomycin-susceptible enterococcus. During 1996–2000, 65 patients with cases of clinically significant VRE bacteremia were identified, and 53 of these patients were successfully matched. In this group of patients, VRE bacteremia was found to be an independent predictor of crude mortality (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.2–13.3) and the infection-related mortality rate (OR, 5.2; 95% CI, 1.4–20.0). It was also an independent predictor of the rate of clinical failure at day 7 after the onset of EB (OR, 4.6; 95% CI, 1.2–17.3) and overall clinical failure (OR, 4.3; 95% CI, 1.3–14.5) and was associated with a longer mean length of hospitalization after the onset of EB, compared with that for control patients (22.7 ± 1.88 vs. 15.9 ± 1.7, P = .006). These observations indicate that vancomycin resistance in EB independently affects outcomes.

Infections due to vancomycin-resistant enterococcus (VRE) have become the focus of increased attention during the past decade. The first enterococcal strains with glycopeptide resistance were reported from France in 1986 [1]. The Centers for Disease Control and Prevention (CDC) reported that, by 1993, there had been a 20-fold increase in the percentage of nosocomial isolates of enterococci resistant to vancomycin, with greater increases in isolates recovered from intensive care units (ICUs) [2]. In 1998, the SCOPE study demonstrated an overall vancomycin resistance rate of ∼14%, and reported that the rate of vancomycin resistance among strains of Enterococcus faecium in the northeast section of the United States was 63% [3].

The lack of viable treatment options for VRE infection has contributed to the growing concern about this organism. The development of vancomycin resistance in this organism further diminishes the treatment options, which were already limited because of other intrinsic and acquired forms of resistance in enterococcus. Despite the dearth of therapeutic options, the degree of morbidity and mortality attributable to vancomycin resistance in enterococcal infections remains controversial. Although most studies that have compared VRE infections and vancomycin-susceptible enterococcus (VSE) infections have demonstrated that a higher crude mortality rate is associated with the former, it is unclear whether infection with a vancomycin-resistant strain is an independent predictor of mortality [4–15].

Previous studies have indicated that episodes of VRE bacteremia occur in patients with serious underlying diseases, high severity-of-illness scores, and various other comorbid conditions [4–10, 12–15]. This patient profile makes it difficult to determine the contribution of vancomycin resistance to the morbidity and mortality associated with enterococcal bacteremia (EB). Few studies have attempted to match patients for disease severity and other factors that are found to be predictors of mortality in order to determine the association between vancomycin resistance and mortality [5, 10]. In addition, most studies have focused on the impact of VRE infection on mortality, and little is known regarding the effect of vancomycin resistance on other clinical outcomes [5, 6, 16]. Therefore, the objective of the present study was to determine the contribution of vancomycin resistance to the rates of clinical and microbiological outcomes in a group of patients with VRE infection, while matching for disease severity and other factors known to be associated with a high mortality rate.

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Patients and Methods

Setting

We performed the study at Detroit Receiving Hospital (DRH), which is a 279-bed level 1 trauma center in Detroit, Michigan. DRH is part of the Detroit Medical Center and is a major teaching facility for the health sciences at Wayne State University. Medical specialties include trauma, critical care, surgery, cardiology, neurology, and internal medicine. The hospital is the regional burn center and has a spinal-cord injury unit.

Study Population

The study focused on episodes of EB identified from 1996 through 2000. Only episodes of EB that met the CDC criteria for bloodstream infection were included in the analysis [17]. When a patient had µ1 episode of EB, only the first episode was considered.

Study Design

To evaluate the effect of vancomycin resistance on the clinical and microbiologic outcomes associated with EB, a retrospective matched case-control study was performed. Patients with VRE bacteremia were designated “case patients” and patients with VSE bacteremia were designated “control patients.” Case and control patients were matched in 1 : 1 ratio with use of a stepwise method similar to one described elsewhere [18–21]. Matching criteria included the following: age; Acute Physiology and Chronic Health Evaluation (APACHE) II score [22] at the onset of EB; admitting service (i.e., medicine vs. surgery); hospital unit at the onset of EB (ICU vs. non-ICU); and length of hospital stay prior to the onset of EB (stratified into 4 time categories, as follows: ⩽3, 4–8, 9–28, and µ28 days).

Matching Process

To select the most suitable control patient for every patient with VRE bacteremia, a 15-point scoring system was used, similar to that described elsewhere [18–21]. The matching score was calculated in the following manner: for age, 4 points were given if the age difference was ±5 years, and 2 points were given if the age difference was ±10 years; for APACHE II score at the onset of EB, 4 points were given if the difference in the APACHE II scores was ±4, and 2 points were given if the difference in the APACHE II scores was ±8; for the admitting service (i.e., medicine vs. surgery), 2 points were given in case of concordance; for the hospital unit at the onset of EB, 2 points were given in case of concordance; and, for the length of hospital stay prior to the onset of EB, 3 points were given if the duration was in the same time category. A score of 12 was the minimum accepted score for a control patient. Control patients were selected without knowledge of patients' outcome status.

Data Collection

Clinical data. Data for each patient were extracted from medical records. Data obtained included the following: age, sex, admitting service (i.e., medicine vs. surgery), ward of admission (i.e., ICU vs. non-ICU), comorbidities, receipt of prior antibiotic therapy, origin of infection (i.e., community-acquired or hospital-acquired), length of hospitalization prior to the onset of EB (total and in the ICU), hospital unit at the onset of EB (ICU vs. non-ICU), presence of a central venous or urinary catheter, receipt of total parenteral nutrition or mechanical ventilation at the onset of EB, source of bacteremia, and severity of illness at the onset of EB (as calculated by means of the APACHE II score).

Definitions of terms. A comorbidity was defined as a disease, therapy, or procedure that could predispose patients to infection, alter defensive mechanisms, or cause functional impairment [21]. The presence of the following comorbid conditions was documented: diabetes mellitus, heart failure (defined as New York Heart Association class I–IV) [23], chronic obstructive pulmonary disease, hepatic dysfunction, renal insufficiency (as indicated by a baseline creatinine level of µ2.0 mg/dL or the necessity for dialysis), malignancy, HIV infection, presence of decubitus ulcers (stage II–IV), paraplegia/quadriplegia, administration of immunosuppressive drugs (receipt of prednisone, µ20 mg/day for ⩾14 days before the onset of EB, or receipt of any antineoplastic chemotherapy in the 3 months before the onset of EB), surgery (gastrointestinal or nongastrointestinal) within 30 days of the onset of EB, and presence of burn over µ30% of the body surface area.

Prior antibiotic use was defined as the administration of antimicrobials for µ72 h in the 30 days before the onset of EB. Bloodstream infections were considered to be hospital acquired if they occurred µ72 h after admission to the hospital, or ⩽72 h after admission if the patient was transferred from an outside hospital or nursing home or had been hospitalized for µ72 h in the 30 days before admission [17, 20, 24].

Microbiologic data. Microbiologic data collected included all positive enterococci culture results. Results of repeat blood cultures were documented to determine the time to organism eradication. Results of susceptibility testing were recorded, as well as MICs for ampicillin, vancomycin, and gentamicin and streptomycin synergy panels, as reported by the microbiology laboratory. Susceptibility testing was performed by use of the microtiter well method, and MICs were reported and interpreted according to the National Committee for Clinical Laboratory Standards guidelines [25]. Synergy was determined by use of a standard microtiter technique, with a high concentration of aminoglycosides.

Treatment data. Any antimicrobials administered in response to EB were noted. Therapy was considered appropriate if the following criteria were met: (1) one or more of the antibiotics administered had in vitro activity against the enterococcus isolate, (2) the dosage and route of administration were adequate, and (3) the agent(s) were administered within 96 h after the onset of EB and the treatment was maintained for µ48 h. Any use of combination therapy with an aminoglycoside was recorded. Data regarding other interventions to manage the infection were also collected; this included intravenous catheter removal and surgical drainage and/or debridement of infected tissues.

Outcomes Assessment

Clinical outcomes. The following clinical outcomes were assessed: death due to any cause (to calculate the crude mortality rate), death related to infection (to calculate the infectionrelated mortality rate), clinical response at days 3 and 7 after the onset of EB, final clinical outcome, and the length of hospital stay after the onset of EB (total length of stay in the hospital [LOS-EB] and length of stay in the ICU [ICU-LOS]). Calculation of the length of stay (LOS-EB and ICU-LOS) excluded patients who died ⩽7 days after the onset of EB, to ensure that the LOS-EB value was not artificially shortened.

On the basis of daily vital signs, WBC count, mechanical ventilation status, and use of vasopressors for maintenance of blood pressure, the patients' clinical status was classified as resolution, improvement, treatment failure, death, or indeterminate outcome. “Resolution” and “improvement” were classified as “clinical success.” “Treatment failure” and “death” were classified as “clinical failure.” Cases with indeterminate outcome were not considered in clinical outcome determination. Investigators involved in the outcomes assessments were blinded to organism susceptibility, to prevent bias.

Definition of terms. Death was considered to be related to EB if ⩾1 of the following criteria was present: (1) blood cultures were positive for enterococci at the time of death, (2) death occurred before resolution of signs and symptoms of EB, (3) death occurred ⩽7 days after the onset of bacteremia and there was no other explanation for it, (4) autopsy findings indicated EB was a cause of death, and (5) EB was indicated as a cause of death on the death certificate [20].

Clinical status classifications were defined as follows: “resolution,” complete resolution of signs of infection; “improvement,” resolution of a majority of the signs of infection; “failure,” persistence or progression of signs of infection or a change in antimicrobial regimens based on lack of response or clinical deterioration; “death,” death associated with enterococcal infection; and “indeterminate outcome,” circumstances precluded classification. LOS-EB was defined as the time from the first culture positive for EB until discharge or death.

Microbiologic outcomes data. Microbiologic outcomes were classified as eradication, presumed eradication, persistence, presumed persistence, or indeterminate. “Eradication” and “presumed eradication” were classified as “clinical success.” “Persistence” and “presumed persistence” were classified as “clinical failure.” Indeterminate cases were not considered in the final outcome determination.

Definition of terms. Microbiologic outcomes were defined as follows: “microbiologic eradication,” elimination of original causative organism(s) during therapy or on completion of therapy; “presumed eradication,” no repeat cultures were obtained with clinical improvement; “persistence,” failure to eradicate the original causative organism(s); “presumed persistence,” a second set of cultures was not done with clinical deterioration assessed as attributable to EB; and “indeterminate outcome,” inability to classify as any of the above because of extenuating circumstances.

Statistical Analysis

Qualitative variables were compared by use of Pearson χ2 or Fisher's exact test, and quantitative variables were compared by Student's t or Mann-Whitney U test. When necessary, continuous variables were log transformed to more closely approximate a normal distribution. Multivariate analyses were performed to adjust for the clinical characteristics that still differed between case and control patients after matching. All variables with P ⩽ .2 in the univariate case-control analysis were considered for inclusion in the explanatory model. Dichotomous outcomes (e.g., mortality and clinical status) were analyzed with standard logistic regression. LOS-EB was evaluated by means of analysis of covariance (ANCOVA). ANCOVA was selected to analyze LOS-EB because it measures mean group differences (in this case, adjusted mean LOS-EB) while controlling for confounding variables. To satisfy the data assumptions of ANCOVA, it was necessary to create composite variables from the characteristics that differed between case and control patients, because ANCOVA requires covariates to be on a continuous measurement scale [26]. Factor analysis (principal factor extraction and varimax rotation) was used to construct the composite variables. P < .05 was considered significant for 2-tailed tests. SPSS version 10.0 software (SPSS) was used for all calculations.

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Results

During the 4-year study period, 74 episodes of VRE bacteremia were identified. Clinically significant episodes were identified in 65 patients, and 53 of these case patients could be successfully matched. Matching results are shown in table 1. The mean matching score (±SD) was 13.8 ± 1.1. Case and control patients were equivalent with respect to age, APACHE II score at the onset of EB, admitting service, hospital days prior to onset of EB, and treatment in the ICU at the onset of EB.

Table 1
Table 1

Comparison of matching criteria between patients with vancomycin-resistant enterococcus (VRE) bacteremia and patients with vancomycin-susceptible enterococcus (VSE) bacteremia.

A comparison of demographic characteristics and comorbid conditions is presented in table 2. After matching for the above characteristics, patients with VRE bacteremia were still more likely than patients with VSE to have renal dysfunction or decubitus ulcers, and to have received antibiotics previously. Case and control patients were similar with respect to all other parameters shown in table 2.

Table 2
Table 2

Comparison of demographic characteristics and comorbid conditions of patients with vancomycin-resistant enterococcus (VRE) bacteremia and of patients with vancomycin-susceptible enterococcus (VSE) bacteremia.

Microbiologic comparisons are shown in table 3. E. faecium bacteremia was more common in the VRE group. Ampicillin susceptibility was significantly lower in patients with vancomycin-resistant E. faecium bacteremia. However, there was no difference in ampicillin susceptibility between case and control patients with Enterococcus faecalis bacteremia. The prevalence of polymicrobial bacteremia was similar between case and control patients. Although there was no significant difference in the source of bacteremia between case and control patients, intravenous catheter–related bacteremia was more common among patients with VRE bacteremia (P = .1), and VSE bacteremia originated more frequently from skin and soft tissue infections (P = .06).

Table 3
Table 3

Comparisons of microbiologic data for patients with vancomycin-resistant enterococcus (VRE) bacteremia and patients with vancomycin-susceptible enterococcus (VSE) bacteremia.

A comparison of treatment regimens is shown in table 4. A significantly greater percentage of patients with VRE bacteremia received inappropriate treatment (regardless of the infecting species of enterococcus) than did patients with VSE bacteremia. Of the case and control patients who received appropriate treatment, a similar proportion received combination therapy that included an aminoglycoside. In addition, similar numbers of case and control patients had intravenous catheters removed and underwent surgical interventions to manage the bacteremia.

Table 4
Table 4

Comparison of treatment for patients with vancomycin-resistant enterococcus (VRE) bacteremia and patients with vancomycin-susceptible enterococcus (VSE) bacteremia.

Clinical outcomes are summarized in table 5. In the univariate analysis, VRE bacteremia was found to be associated with a higher overall mortality rate and a higher infection-related mortality rate than was VSE bacteremia. The group of patients with VSE bacteremia demonstrated a higher rate of clinical success at day 7 and of final clinical success than did the group with VRE bacteremia. No differences between the groups were observed in clinical response at day 3 or in microbiologic response.

Table 5
Table 5

Univariate analysis of outcomes for patients with vancomycin-resistant enterococcus (VRE) bacteremia and patients with vancomycin-susceptible enterococcus (VSE) bacteremia.

The clinical characteristics that differed between case and control patients and were included in the multivariate analyses were as follows: origin of EB, use of mechanical ventilation, prior receipt of antibiotics, presence of renal dysfunction or decubitus ulcers, history of gastrointestinal surgery, infecting species of enterococcus, intravenous catheter–related EB, and receipt of appropriate treatment. After controlling for these characteristics, VRE bacteremia remained an independent predictor of the overall mortality and of infection-related mortality in the logistic regression analysis (table 6). VRE bacteremia was also independently associated with clinical failure at day 7 and final clinical failure.

Table 6
Table 6

Clinical features selected by standard logistic regression that were independently associated with the dichotomous outcome for patients with vancomycin-resistant enterococcus (VRE) bacteremia and patients with vancomycin-susceptible enterococcus (VSE) bacteremia.

A total of 86 patients who did not die ⩽7 days after the onset of EB were included in the LOS-EB analysis (table 5). When the 2 groups were compared, the VRE group had a greater mean LOS-EB. The mean ICU-LOS after the onset of EB was also greater for the VRE group than for the VSE group. When the entire study population was examined (N = 106), the mean LOS-EB and the mean ICU-LOS after the onset of EB were still greater for the group of case patients than for the control group (means ± SDs, 19.0 ± 2.0 vs. 12.0 ± 2.0 days [P = .003] and 6.2 ± 4.2 vs. 3.5 ± 3.2 days [P = .01], respectively).

Four composite variables were identified in the factor analysis (table 7). Individual characteristics were ordered and grouped by the size of loading (a measure of the correlation between each variable and factor) to facilitate interpretation. Loadings of <0.5 were omitted. On the basis of unifying disease characteristics, the proposed factor labels are as follows: underlying disease, inappropriate antimicrobial therapy, presence of intravenous catheter–related bacteremia, and presence of decubitus ulcers.

Table 7
Table 7

Factors and loadings for extraction of principal factors and varimax rotation of 4 factors for patients with vancomycin-resistant enterococcus (VRE) bacteremia.

In the ANCOVA analysis, the mean LOS-EB did not vary significantly between the group of patients with VRE bacteremia and the group with VSE bacteremia (16.8 vs. 14.1 days; P = .28) after adjustment for the above composite variables. When controlling for all factors except inappropriate treatment (factor 2), the adjusted mean LOS-EB was significantly greater for case patients than for control patients (17.7 vs. 13.4 days; P = .041). The adjusted mean ICU-LOS after the onset of EB did not vary significantly between the case and control groups when controlling for all factors simultaneously (5.7 vs. 4.0 days; P = .34) or all factors except appropriate treatment (5.6 vs. 4.0 days; P = .2).

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Discussion

The objective of the present study was to evaluate the contribution of vancomycin resistance to clinical and microbiologic outcomes associated with EB. It has been well described that patients with bloodstream infections due to VRE are more likely than patients with VSE bacteremia to have serious underlying medical conditions, a higher disease severity, and other comorbid conditions [4–10, 12, 15]. This patient profile makes it difficult to determine whether VRE bacteremia independently affects clinical outcomes or is merely a marker of disease severity.

In the present study, patients with VRE bacteremia (case patients) were matched to patients with VSE bacteremia (control patients) by age, admitting service, APACHE-II score at the onset of EB, hospital unit at the onset of EB, and length of hospital stay prior to the onset of EB. These variables were selected as matching parameters because they have been associated with VRE bacteremia and have been shown to affect morbidity and mortality [4–15]. By ensuring that the groups of case and control patients were homogenous, the confounding effect of matched variables could be minimized. Standard logistic regression was used to control for differences between case and control patients that remained after matching. The present study demonstrated that the crude mortality rate and the infection-related mortality rate were significantly higher for the group of patients with VRE bacteremia than for the group of patients with VSE bacteremia. VRE bacteremia remained an independent predictor of mortality and infection-related mortality in the multivariate analysis after adjustment for characteristics found to be different between case and control patients.

Studies that have characterized the clinical implications of VRE infection have demonstrated the difficulty of controlling for confounding variables. Most frequently, studies that have examined the impact of VRE infection on mortality rates have used stepwise logistic regression. In stepwise logistic regression, the predictor that has the strongest correlation with the outcome is entered into the model first and “gets credit” for all the variance it explains, although some of the variance is often shared with other covariates. The difficulty in using this approach is that severity-of-illness composite scores and other known predictors of mortality are highly correlated with VRE infection [4–10, 12–15]. The severity-of-illness composite will serve as a more reliable predictor of mortality because it takes into consideration multiple aspects of patients' conditions and is subject to less error. Therefore, the contribution of VRE infection to the mortality rate may not be discerned. This is often the case when a study has a limited sample size [11, 13, 14].

The study by Garbutt et al. [14] did not find a significant association between VRE infection and mortality rate when controlling for APACHE II scores and Organ System Failure Index scores. That study included a total of 69 patients in the logistic regression, and it is likely that the impact of VRE infection could not be discerned because APACHE and Organ System Failure Index scores were stronger predictors of mortality. In the 200-patient study by Lucas et al. [12], VRE infection retained a trend toward association with a higher mortality rate (P = .06) when controlling for APACHE II score and other variables associated with VRE infection and poor outcomes in the stepwise logistic regression analysis. In the multicenter study of 259 patients by Bhavnani et al. [15], VRE infection remained a significant predictor of mortality in the logistic regression when controlling for APACHE II score.

Information regarding the impact of VRE infection on clinical end points other than mortality is lacking [5, 6, 16]. The present study demonstrates that VRE bacteremia is associated with considerable morbidity. We found that VRE bacteremia was an independent predictor of clinical failure at day 7 and final clinical failure overall. VRE bacteremia was also associated with a greater mean LOS-EB in the univariate analysis. In the ANCOVA analysis, there was no difference in the adjusted mean LOS-EB between patients with VRE bacteremia and patients with VSE bacteremia when we controlled for all covariates simultaneously. However, when we controlled for all composite variables except inappropriate antimicrobial therapy, the adjusted mean LOS-EB was significantly higher for the VRE group. Therefore, it appears that the higher mean LOS-EB in the VRE group may be partially explained by lack of appropriate antimicrobial therapy.

The results demonstrated that VRE bacteremia affects the mortality rate, the clinical response rate, and the length of hospitalization. Although the present study supports the notion that vancomycin resistance is independently associated with considerable morbidity and mortality, it is not known whether vancomycin resistance is merely a surrogate marker for extremely broad antibiotic resistance. Most patients in the VRE group had E. faecium bacteremia that was highly resistant to most antibiotics, and the overwhelming majority of patients with VRE bacteremia did not receive appropriate antibiotic treatment. Although the variables of infecting Enterococcus species and receipt of inappropriate treatment were included in the multivariate models, it is difficult to ascertain the definitive impact of vancomycin resistance on clinical outcomes, because these variables are so highly correlated. As new treatment options have become available, the impact of VRE infection will need to be reassessed to determine whether providing effective therapy with these agents can improve clinical outcomes.

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Acknowledgments

We thank Dr. Andrea L. Kwa for her contribution to this study. We also thank Drs. Elaine M. Hockman and Richard Kaczynski for their statistical assistance.

  • Received August 21, 2001.
  • Revision received November 7, 2001.
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  1. Clin Infect Dis. (2002) 34 (7): 922-929. doi: 10.1086/339211
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