BIN DU，MD； YUN LONG，MD； HONGZHONG LIU，MD； DECHANG CHEN，MD； DAWEI LIU，MD； YINGCHUN XU，MD1； XIULI XIE，MD1

Department of Critical Care Medicine，1Department of Clinical <?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

　　Intervention：None.

　　Measurements and Main Results： The demographic characteristics and clinical information including treatment were recorded upon review of patient record. The primary end point was hospital mortality.

　　Twenty－seven percent of isolates produced ESBLs. Previous treatment with third－generation cephalosporins was the only independent risk factor for bacteremia due to ESBL－producing pathogens （odds ratio [OR] 4.146，p ＝ 0.008）. Antibiotic treatment was considered appropriate in 71 cases （83％），and failed in 23 patients （27％）. Twenty－one patients （25％） died in the hospital. Antibiotic treatment failure was the only independent risk factors for hospital mortality （OR 15.376，p ＝ 0.001）. Inappropriate antibiotic treatment might lead to significantly higher mortality rate （7/14 vs 14/71，p ＝ 0.016）. Patients treated with imipenem were more likely to survive while those receiving cephalosporin treatment tended to have a poorer outcome （1/19 vs 14/40，p ＝ 0.023）.

　　Conclusions： More judicious use of cephalosporins，especially third－generation cephalosporins，may decrease ESBL－producing E. coli or K. pneumoniae bacteremia，and also improve patient outcome. 

　　Escherichia coli Klebsiella pneumoniae bacteremia beta－lactamasesrisk factors hospital mortality

 　　ESBL，extended－spectrum beta－lactamase； APACHE，acute physiology and chronic health evaluation； SD，standard deviation； OR，odds ratio； CI，confidence interval； ICU，intensive care unit

INTRODUCTION

　　Antimicrobial resistance among Gram－negative bacilli represents a major problem in nosocomial infection ^[1]. These organisms elaborate beta－lactamases，which can hydrolyze the amide bond in the beta－lactam ring of antibiotics. Since 1983，extended－spectrum beta－lactamase （ESBL）－producing organisms have been isolated around the world ^[2－4]. In the United States，the prevalence of Klebsiella pneumoniae and Escherichia coli resistant to third－generation cephalosporins in ICU was 8.9％ and 3.2％，respectively，and was even higher in large teaching hospitals ^[5]. ESBLs are especially dangerous because they are plasmid－associated，and the plasmids may be exchanged among a variety of bacterial species.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

　　Partly because of the difficulty to differentiate infection from colonization，a number of studies have elucidated inconsistent results concerning the risk factors and clinical significance of infections due to ESBL－producing organisms ^[6，7]. We therefore conducted a retrospective study of nosocomial bacteremia caused by ESBL－producing E. coli and K. pneumoniae，in order to identify the possible risk factor for infection and hospital mortality.

PATIENTS and METHODS

　　Setting and Design

The investigation was conducted at Peking Union Medical College Hospital，a university－affiliated teaching hospital with approximately 1200 beds. A retrospective review was performed on the records of the Clinical Microbiology Laboratory from January，1997 to December，1999 to identify all patients who had a documented episode of nosocomial bacteremia caused by E. coli or K. pneumoniae during hospitalization.

　　Each patient was included only once. If multiple blood cultures from the same patient were positive for the above organisms，only the first episode was reviewed and recorded.

　　Upon review of the patient record，the following data were recorded： age，sex，hospital location，and severity of illness，as calculated by APACHE （acute physiology and chronic health evaluation） II score ^[8]. The presence of a urinary catheter or mechanical ventilation was also assessed. In addition，all antibiotic therapy and operations performed in the 2 weeks prior to the bacteremic episode were documented.

　　The presence of the following comorbidity was documented： malignancy，diabetes mellitus，solid organ transplantation，hypertension，coronary heart disease，neutropenia （white blood cell count less than 0.5 x 109/L），corticosteroid use，use of an immunosuppressive agent within 30 days prior to bacteremic episode.

Definitions

　　Nosocomial bacteremia was defined as a recognized pathogen cultured from 1 or more blood cultures that were obtained more than 48 hours after hospital admission. Blood cultures were obtained primarily via peripheral venipuncture using a standard sterile technique. Central venous catheters were used to obtain blood cultures only if they had been freshly placed and prior to breaking the sterile field that was used for catheterization.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

　　Patients with acute leukemia or blastic relapse of chronic leukemia were classified into the category of rapidly fatal underlying disease based on the criteria described by Kreger et al ^[9]. A body site was considered to be a source of bacteremia on the basis of evidence of inflammation and isolation from local sites of the same organism as found in the blood. When no cultural confirmation of local sites of origin could be obtained，or when more than one site fulfilled these criteria，or when death occurred too rapidly to document the primary infection focus，patients were classified as of an “unknown” source.

　　Appropriate antibiotic therapy was defined if the infecting organism was subsequently found to be susceptible in vitro to the drug administered and if that antibiotic was given intravenously.

　　The success of antibiotic treatment was considered if patients had resolution or abatement of clinical manifestation related to infection，such as fever，leukocytosis，and all signs of infection. Treatment failure was defined if patients had absence of abatement or deterioration in any clinical parameters.

　　Microbiological methods

　　Susceptibilities to all antimicrobial agents were determined according to the criteria of the National Committee for Clinical Laboratory Standards by disk diffusion ^[10]. An isolate with ceftazidime inhibition zone （ 22 mm was suspicious for ESBL production. Synergy between caftazidime and clavulanate was detected by placing a disk of Augmentin （20 mcg of amoxicillin plus 10 mcg of clavulanic acid） and a disk of ceftazidime 30 mm apart （center to center）. A clear－cut extension of the edge of the ceftazidime inhibition zone toward the disk containing clavulanic acid was interpreted as synergy，which suggested the production of ESBL. The double－disk synergy test was considered positive when decreased susceptibility to ceftazidime was combined with synergy between ceftazidime and augmentin ^[11].

　　Statistical analysis

　　Values are presented as the mean （ SD （continuous variables） or as a percentage of the group from which they were derived （categorical variables）. Continuous variables were compared with the use of Student's t test. The chi－square test or Fisher's exact test was used to compare categorical variables. For determination of independent predictors for treatment failure and hospital mortality，odds ratio was estimated on the basis of multivariate logistic regression analysis. All comparisons were unpaired and all tests of significance were two－tailed. A p value less than 0.05 was considered as statistically significant.

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