Impact of Vancomycin Resistance on Mortality among Patients with Neutropenia and Enterococcal Bloodstream Infection

Carlos A. DiazGranados 0 1 John A. Jernigan () 0 1 0 Received 14 May 2004; accepted 18 August 2004; electronically published 17 January 2005. Presented in part: 40th Annual Meeting of the Infectious Diseases Society of America , 24-27 October 2002, Chicago (abstract 551). Promotion , Centers for Disease Control and Prevention , Mailstop E-68, 1600 Clifton Rd., NE, Atlanta, GA 30333 1 Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, and Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention , Atlanta , Georgia We performed a retrospective cohort study to measure the impact of vancomycin resistance on clinical outcome for 83 episodes of enterococcal bloodstream infection (BSI; 22 with vancomycin-resistant enterococci [VRE] and 61 with vancomycin-susceptible enterococci [VSE]) in 77 patients with neutropenia. Cox proportional hazards models showed that vancomycin resistance was an independent predictor of mortality, after controlling for severity of illness, enterococcal species, gram-negative copathogens, sex, race, duration of neutropenia before bacteremia, and early administration of active antibiotics. This effect was evident only 10 days after the onset of bacteremia (P p .0263; hazard ratio [HR], 4.969) but not after adjustment for duration of bacteremia. The median duration of bacteremia was 4.5 days for VRE BSI and !1 day for VSE BSI (P p .0001). The only independent predictor of bacteremia duration was vancomycin resistance (P p .0284; HR, 3.863). Vancomycin resistance is associated with increased mortality in patients with neutropenia, possibly because of prolonged duration of bacteremia. - The rate of enterococcal bloodstream infections (BSIs) in US hospitals has increased during the past decade [1, 2]. Enterococci are the third or fourth most common cause of nosocomial BSIs [13]. In addition, the prevalence of vancomycin resistance among enterococcal infections has increased rapidly to 14%25% of all enterococcal infections in US hospitals [35]. The impact of vancomycin resistance on clinical outcomes among patients with enterococcal BSI has been difficult to establish. Edmond et al. [6] found an attributable mortality of 37% in a study that compared 27 patients with BSI with vancomycin-resistant enterococci (VRE) with matched control subjects, but those researchers did not perform a multivariate analysis and did not control for severity of illness. Studies that have controlled for severity of illness have yielded conflicting results. Two single-institution studies1 in a livertransplantation unit [7] and the other in a trauma unit [8]and 2 recent multicenter studies [9, 10] found vancomycin resistance to be a predictor of mortality among patients with enterococcal BSI, independent of severity of illness. In contrast, 5 additional studies did not demonstrate that vancomycin resistance is an independent risk factor for mortality [1115]. The impact of vancomycin resistance on the clinical outcome of enterococcal bacteremia may not be uniform among patient populations. Hematology-oncology patients may be at a particularly high risk because of sustained periods of neutropenia resulting from treatment of their underlying malignancies. These patients frequently have multiple risk factors for VRE infection [11, 12, 16, 17], and VRE have emerged as an important pathogen in this patient population. Outbreaks of VRE BSI among patients with neutropenia have been well documented [1620], but there are no published studies that have compared the mortality of VRE BSI with that of vancomycin-susceptible enterococci (VSE) BSI in this clinical setting. We conducted a retrospective cohort study to measure the impact of vancomycin resistance on clinical outcomes among patients with neutropenia and enterococcal BSI. PATIENTS AND METHODS Patient selection and design. Emory University Hospital is a 587-bed tertiary-care teaching hospital in Atlanta. The first case of VRE BSI in our institution was diagnosed in November 1994 in a patient with neutropenia. We reviewed all episodes of enterococcal BSI among patients with neutropenia from November 1994 to January 2001 at Emory University Hospital. A systematic procedure was used for patient selection. Initially, a list of patients having at least 1 blood culture that grew an Enterococcus species was obtained from computerized clinical microbiology laboratory records. Absolute neutrophil counts (ANCs) for each patient on the list were obtained from electronic medical records, and those patients with an ANC !500 neutrophils/mm3 at the time of the onset of bacteremia were included in the study. Patients with concomitant VRE and VSE bacteremia and patients with BSI caused by enterococcal isolates with intermediate susceptibility to vancomycin were excluded. Most patients were enrolled before the approval of quinupristin/dalfopristin and linezolid; therefore, these agents were not widely available for initial therapy during the study period. Medical records for each study patient were reviewed. The data obtained for each patient included age, sex, race, hospital location, admission date, discharge date, date of the onset of neutropenia, date of the resolution of neutropenia, date of the onset of bacteremia, ANC within 24 h of the onset of bacteremia, the presence or absence of documented VRE colonization, results of all blood cultures performed during the hospital stay, the result of all catheter-tip cultures performed during the hospital stay, survival status, date of death (if applicable), underlying diseases and comorbidities, administration of chemotherapy during the hospital stay or within 15 days of admission, administration of other immunosuppressive therapies during the hospital stay (corticosteroids, cyclophosphamide, and other cytotoxic agents), administration of antimicrobial agents before and after the onset of bacteremia, history of bonemarrow transplantation, the presence of a central line at the onset of bacteremia, and severity of illness scores (APACHE II) calculated before (as close as possible to the fifth day before the onset of bacteremia) and at the onset of bacteremia. Definitions. Enterococcal BSI was defined as the isolation of an Enterococcus species from 1 blood culture obtained from a patient who met the criteria for BSI as defined by the Centers for Disease Control and Prevention (CDC; Atlanta) [21]. Enterococcal bacteremia occurring 160 days after a previous episode was considered to be a separate BSI. Nosocomial BSI was defined as a BSI in which the first positive blood culture was obtained 172 h after admission. VRE colonization was defined as the isolation of VRE in surveillance or clinical cultures obtained before or within 5 days of the onset of the enterococcal BSI. A copathogen was defined as any bacterial pathogen other than enterococci isolated from 1 blood culture within 60 days of the onset of enterococcal BSI. Polymicro (...truncated)