Abstract

Background. The prevalence of infections caused by extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae is increasing worldwide. The influx of these bacteria into hospitals has major implications for infection-control and empirical treatment strategies.

Methods. Isolates from 2 patient cohorts—patients with gram-negative bacteremia within 2 days after admission and patients screened for fecal colonization at admission—were assessed for ESBL production. ESBL phenotype was confirmed according to Clinical and Laboratory Standards Institute guidelines. Predictors of ESBL phenotype were examined by univariate and multivariate analyses.

Results. Of 80 Enterobacteriaceae isolates from blood samples obtained at admission to the hospital, 13.7% produced ESBL. Thirty-eight patients with ESBL-positive isolates and 72 with ESBL-negative isolates were included in a case-control study. Predictors of ESBL production were male sex and nursing home residence (area under receiver operator characteristic curve, 0.7). Of 241 persons screened at admission, 26 (10.8%) had fecal carriage of ESBL-producing Enterobacteriaceae. Predictors of fecal carriage were poor functional status, antibiotic use, chronic renal insufficiency, liver disease, and use of histamine2 blockers (area under receiver operator characteristic curve, 0.8). Four (15.4%) of the 26 individuals with fecal carriage had subsequent bacteremia with ceftazidime-resistant Enterobacteriaceae, compared with 1 (0.5%) noncarrier (odds ratio, 38.9; P < .001). Of 80 ESBL-producing Enterobacteriaceae isolates obtained at admission, 65 were health care associated, and 15 were community acquired. The 15 community-acquired ESBL-producing Enterobacteriaceae belonged to diverse clones. The most prevalent ESBL gene among these isolates was CTX-M-2 (found in 53.3% of the isolates).

Conclusions. We report high rates of bacteremia and colonization with ESBL-producing Enterobacteriaceae at admission to our institution, which may undermine infection-control measures and complicate the selection of empirical treatment.

Extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae are increasingly prevalent nosocomial pathogens in intensive care units [1–3], general medicine wards, and long-term care facilities [4–6]. In our institution, there is a high prevalence of ESBL-producing Enterobacteriaceae among clinical isolates: 35% of all Klebsiella species, 12% of Escherichia coli, and 35% of Proteus mirabilis produce ESBL [7]. Among isolates of Enterobacteriaceae from blood at our institution, 24% produce ESBL [8]. These organisms are multidrug-resistant and pose a serious public health threat, in that only a limited number of antimicrobial agents can be reliably used against them [1, 9, 10].

Recent studies suggest that ESBL-producing Enterobacteriaceae should not be considered to be exclusively nosocomial pathogens. ESBL-producing organisms have been reported to cause urinary tract infections [11–13] and bacteremia [12–14] in nonhospitalized persons. In a recent study from Spain, ESBL-producing organisms were isolated from the stool samples of 3.7%–5.5% of nonhospitalized patients [15]. The role that these community-acquired ESBL-producing organisms may play in the epidemiology of ESBL in hospitals is currently unknown. Unrecognized influx of ESBL-producing organisms into hospitals may hinder infection-control measures. Furthermore, empirical antibiotic treatment of community-acquired infections may become inadequate if ESBL-producing organisms are highly prevalent in the community. The present study was conducted to quantify and characterize the influx of ESBL-producing Enterobacteriaceae into the hospital.

Materials and Methods

Three studies were conducted at the Tel Aviv Medical Center, a 1100-bed tertiary hospital; these included a prospective study to evaluate the prevalence of the ESBL phenotype in organisms causing bloodstream infections at the time of hospital admission, a case-control study of bloodstream infections at admission to assess for predictors of the ESBL phenotype, and screening to assess the prevalence and predictors of fecal carriage of ESBL-producing Enterobacteriaceae at the time of admission. Strains were classified as nosocomial, health care—associated, or community-acquired according to the scheme proposed by Friedman et al. [16]. The study protocol was approved by the ethics committee of the Tel Aviv Medical Center.

Non-nosocomial bacteremia. Gram-negative bacilli cultured from blood samples submitted to the clinical microbiology laboratory at our institution from June 2003 through December 2003 were examined prospectively, as previously reported [8]. Data were cross-checked with the hospital admissions database to single out cultures of blood samples obtained within 2 days after admission. Organisms identified as E. coli, Klebsiella species, or P. mirabilis were assessed for ESBL production by the double-disk diffusion assay according to Clinical and Laboratory Standards Institute guidelines [17].

Case-control study. Adults hospitalized from January 2000 through December 2003 with at least 1 blood culture positive for E. coli, Klebsiella species, or P. mirabilis from a sample obtained within 2 calendar days of admission were included. Case patients were those with ESBL-producing isolates, and control subjects were patients with non—ESBL-producing isolates. Control subjects were randomly enrolled at a ratio of 2 : 1. Case patients and control subjects were compared regarding demographic variables, comorbidities, exposure to the health care system, and antibiotic exposure before blood was cultured.

Fecal carriage at admission to the hospital. Screening was performed for a sample of patients admitted to a medical ward from December 2002 through September 2003. Demographic and clinical data were collected by interviewing patients and reviewing medical documentation.

Stool samples collected at the time of admission were inoculated into brain-heart infusion broth (Hy-Labs), incubated at 35°C overnight, and then streaked onto MacConkey agar plates containing ceftriaxone (1 µg/mL) and amphotericin B (2 µg/mL). Oxidase-negative isolates were further identified, using the Vitek-2 ID-GNB card (bioMérieux) and kept at -70°C for further analysis. Isolates identified by double-disk diffusion as ESBL-producing E. coli, Klebsiella species, and P. mirabilis were included in this study.

Bacterial isolates other than E. coli, Klebsiella species, and P. mirabilis were tested for the ESBL phenotype as described above, and if results were positive, the isolates were further evaluated by isoelectric focusing as described elsewhere [18], according to the method of Mathew et al. [19], using an LKB Multiphor II Electrophoresis System apparatus (Amersham Pharmacia Biotech). β-Lactamases with known isoelectric points were used as controls, and activity was revealed with nitrocefin.

Bacterial cultures obtained during hospital stay. To estimate the clinical consequences of fecal carriage of ESBL-producing Enterobacteriaceae, we searched the laboratory database for clinical specimens obtained from patients with fecal carriage up to 3 months after hospital admission. Resistance to ceftazidime (MIC >16 µg/mL) in E. coli, Klebsiella species, and P. mirabilis isolates was used as a marker for the ESBL-producing phenotype. Patients for whom culture of the initial stool sample yielded negative results for an ESBL-producing organism served as a control group.

Genetic characterization of community-acquired ESBL-producing strains. Community-acquired strains from all 3 cohorts were further characterized for their genetic relatedness and ESBL genes.

Genetic typing by PFGE. DNA was prepared and cleaved as described elsewhere [20, 21], using a CHEF-DR III apparatus (Bio-Rad). PFGE DNA patterns were compared between community-acquired strains and nosocomial strains of ESBL-producing organisms from the same species [22].

Detection of ESBL genes by PCR. Primers used for the PCR assays are listed in table 1. PCR reactions were performed with Hot-StarTaq DNA polymerase (Qiagen) according to the manufacturer's instructions. The resulting PCR products were analyzed in 1% agarose gels and were further sequenced using the PCR primers.

Table 1

List of oligonucleotides used for PCR amplification.

Table 1

List of oligonucleotides used for PCR amplification.

Cloning and sequencing of the PCR products. PCR products obtained with primers CTX-M-25-full and CTX-M-2 were cloned using pGEM-T (Promega) and sequenced using SP6 and T7 promoter primers. Sequences were analyzed with an ABI Prism 3100 Genetic Analyzer (PE Biosystems). The nucleotide acid and the deduced protein sequences were analyzed and compared using BLAST software (available at http://www.ncbi.nlm.nih.gov/BLAST/).

Statistical analysis. Statistics were analyzed with Stata software, version 7 (Stata). All variables were examined by univariate analysis using the χ2 test or Fisher's exact test, as appropriate. Continuous variables were analyzed by Student's t test. Variables with P < .2 in univariate analysis were included in the multivariate model. Predictors were examined using logistic regression. A final model was built including all the variables with P ⩽ .05. Variables that were not retained in the model by this procedure were then tested for confounding by adding them one at a time to the model and examining their effects on the β coefficients. Variables that caused substantial confounding (change in β coefficient of >10%) were included in the final model. Effect modification between variables was evaluated by testing appropriate interaction terms for statistical significance. Colinearity was examined by replacing variables with each other and examining the effect on the model. The area under the receiver operator characteristic (ROC) curve was calculated for the predictive models. All statistical tests were 2-tailed. P ⩽ .05 was considered to be statistically significant.

Results

Non-nosocomial bacteremia. Eighty episodes of bacteremia were studied (50 due to E. coli, 20 due to Klebsiella species, and 10 due to P. mirabilis). Eleven isolates (13.7%) possessed the ESBL phenotype; 3 were community-acquired strains (all of which were E. coli), and 8 were health care—associated strains (1 E. coli, 5 Klebsiella species, and 2 P. mirabilis) (figure 1). The proportion of ESBL-positive isolates was 8% for E. coli (4 isolates), 25% for Klebsiella species (5 isolates), and 20% for P. mirabilis (2 isolates).

Figure 1

Overview of patient cohorts in a study of extended-spectrum β-lactamase (ESBL)–producing organisms at hospital admission

Figure 1

Overview of patient cohorts in a study of extended-spectrum β-lactamase (ESBL)–producing organisms at hospital admission

Case-control study. The case-control study included 110 patients: 38 case patients with ESBL-positive isolates (15 E. coli, 17 Klebsiella species, and 6 P. mirabilis) and 72 randomly selected control patients with non—ESBL-producing isolates (21 E. coli, 41 Klebsiella species, and 10 P. mirabilis). Of the 38 patients with ESBL-producing blood isolates, 7 (18.4%) had community-acquired bacteremia, and 31 had health care—associated bacteremia (figure 1). Mean age, functional status, McCabe score, and the number and types of comorbid conditions were similar for case patients and control subjects. Univariate predictors of ESBL-positive bacteremia were admission from a long-term care facility, current use of antibiotics, and male sex (table 2).

Table 2

Univariate and multivariate predictors of extended-spectrum β-lactamase production by Enterobacteriaceae causing bacteremia in patients newly admitted to the hospital.

Table 2

Univariate and multivariate predictors of extended-spectrum β-lactamase production by Enterobacteriaceae causing bacteremia in patients newly admitted to the hospital.

On multivariate analysis, male sex (OR, 2.57; 95% CI, 1.08–6.12; P = .03) and admission from a long-term care facility (OR, 4.76; 95% CI, 1.82–12.40; P = .001) remained significant predictors of bacteremia associated with an ESBL-producing organism (table 2). Area under the ROC curve for the multivariate model was 0.7, indicating moderate prediction.

Fecal carriage at admission to the hospital. A total of 241 patients were screened for fecal carriage of ESBL-producing organisms at admission to a medical ward. The median age was 76 years (interquartile range, 66–82 years); 52% were male. Two hundred and eleven patients (87.6%) were admitted from home, and 30 (12.4%) were admitted from a long-term care facility. Ninety-four patients (39.0%) were hospitalized, and 83 patients (34.4%) received antibiotic treatment in the 3 months before their current admission.

Twenty-six patients (10.8%) were identified as having fecal carriage of 31 ESBL-positive isolates (figure 1). ESBL-producing isolates from stool included E. coli (17 isolates), P. mirabilis (6), Klebsiella species (5), Providencia species (2), and Enterobacter species (1). On univariate analysis, fecal carriage of ESBL-producing organisms was significantly associated with admission from a long-term care facility, recent hospitalization (within the previous 3 months), a dependent functional state, presence of decubitus ulcer(s), presence of an indwelling bladder catheter, chronic renal insufficiency, hemodialysis, use of histamine2 (H2) receptor antagonists, and current antibiotic use. There was a tendency for carriage of ESBL-producing organisms to be associated with male sex (OR, 2.2; P = .07) (table 3).

Table 3

Univariate and multivariate predictors of fecal carriage of extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae at admission to the hospital.

Table 3

Univariate and multivariate predictors of fecal carriage of extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae at admission to the hospital.

Although antibiotic use at the time of admission was significantly associated with carriage of ESBL-producing Enterobacteriaceae, earlier antibiotic use (i.e., within 3 months before hospital admission) was not (table 3). Specifically, current use of a penicillin or a cephalosporin (30.8% of patients with fecal carriage vs. 10.2% of patients without; OR, 3.9; 95% CI, 1.5–10.0; P = .003) and trimethoprim-sulfamethoxazole (7.7% vs. 0.5%; OR, 17.8; 95% CI, 1.6–204.0; P = .002) was associated with carriage of ESBL-producing Enterobacteriaceae.

On multivariate analysis, 5 variables were significantly associated with fecal carriage of ESBL-producing organisms; these included dependent functional state (OR, 4.2; P = .004), current use of antibiotics (OR, 3.4; P = .015), chronic renal insufficiency (OR, 2.8; P = .03), liver disease (OR, 11.1; P = .02), and use of a H2 receptor antagonist (OR, 2.8; P = .03). Six (60%) of 10 patients with >2 predictors had carriage of ESBL-producing organisms at admission, compared with 9 (28.1%) of 32 patients with 2 predictors and 11 (5.5%) of 199 patients with 0 or 1 predictor (OR, 15.8; P < .0001, for comparison of patients with >2 and ⩽2 predictors). The area under the ROC curve for this model was 0.81, indicating good prediction.

Clinical isolates obtained during hospital stay. Of the 26 patients found to have fecal carriage of ESBL-producing Enterobacteriaceae at admission, 4 (15.4%) had subsequent bacteremia with a ceftazidime-resistant isolate of the same species up to 3 months after admission, compared with 1 (0.5%) of those patients without carriage (OR, 38.9; P < .001). Bacteremia associated with ESBL-producing isolates occurred 7, 10, 38, and 73 days after hospital admission. Seven ceftazidime-resistant Enterobacteriaceae from any source were isolated from 5 (19.2%) of those patients who had fecal carriage at admission; all isolates belonged to the same species as the isolate from the stool sample found on screening. In comparison, 16 drug-resistant Enterobacteriaceae were isolated from 12 (5.6%) of the patients who had negative results of stool screening at admission (P = .02).

Antibiotic susceptibility patterns. ESBL-producing isolates obtained within 2 days after hospital admission were mostly multidrug-resistant (table 4). The proportions of isolates resistant to gentamicin, trimethoprim-sulfamethoxazole, ciprofloxacin, and piperacillin-tazobactam were 61%, 64%, 64%, and 24%, respectively. Similar rates of coresistance to antimicrobial agents were seen in community-acquired and health care—associated strains.

Table 4

Antibiotic-resistance patterns of extended-spectrum β-lactamase—producing Enterobacteriaceae obtained within 2 days after hospital admission.

Table 4

Antibiotic-resistance patterns of extended-spectrum β-lactamase—producing Enterobacteriaceae obtained within 2 days after hospital admission.

Community-acquired ESBL-producing Enterobacteriaceae. Of a total of 80 ESBL-producing isolates obtained from all 3 cohorts, 65 were health care-associated and 15 were community-acquired (figure 1). The 15 community-acquired isolates included 8 E. coli, 4 Klebsiella pneumoniae, and 3 P. mirabilis; 5 were isolated from stool samples, and 10 were isolated from blood samples. These 15 isolates were further studied for genetic relatedness, and their ESBL enzymes were characterized.

Genetic relatedness. PFGE did not demonstrate clonality among E. coli or K. pneumoniae isolates. A single E. coli isolate had a PFGE pattern identical to that of a nosocomial ESBL-producing E. coli clone recognized at our hospital, whereas all other E. coli and K. pneumoniae isolates were genetically unrelated to each other and to nosocomial strains. Two of the 3 community-acquired ESBL-producing P. mirabilis strains belonged to the same clone, which is also abundant among nosocomial ESBL-producing strains of P. mirabilis at our hospital (figure 2).

Figure 2

PFGE profiles of community-acquired extended-spectrum β-lactamase (ESBL)–producing clones. DNA was restricted with 20 U of SpeI endonuclease for Escherichia coli and Klebsiella pneumoniae isolates and with SmaI (New England Biolabs) for Proteus mirabilis isolates. Lane 1, λ DNA ladder molecular weight marker; lanes 2–8, E. coli isolates belonging to diverse genetic clones; lanes 9–12, K. pneumoniae isolates belonging to diverse genetic clones; lanes 13–15, P. mirabilis isolates, 1 unique clone and 2 genetically related clones, which are identical to the predominant P. mirabilis ESBL-producing clone in our institution (lane 16).

Figure 2

PFGE profiles of community-acquired extended-spectrum β-lactamase (ESBL)–producing clones. DNA was restricted with 20 U of SpeI endonuclease for Escherichia coli and Klebsiella pneumoniae isolates and with SmaI (New England Biolabs) for Proteus mirabilis isolates. Lane 1, λ DNA ladder molecular weight marker; lanes 2–8, E. coli isolates belonging to diverse genetic clones; lanes 9–12, K. pneumoniae isolates belonging to diverse genetic clones; lanes 13–15, P. mirabilis isolates, 1 unique clone and 2 genetically related clones, which are identical to the predominant P. mirabilis ESBL-producing clone in our institution (lane 16).

ESBL genes. The most common ESBL genes carried by community-acquired ESBL-producing organisms were members of the CTX-M group, which were identified in 11 isolates (73.3%); 8 of these 11 enzymes were CTX-M-2. Three isolates (20%) had ESBL genes belonging to the SHV group. We were unable to identify the ESBL genes carried by 2 isolates with an ESBL-producing phenotype (table 5).

Table 5

Extended-spectrum β-lactamases (ESBLs) produced by 15 community-acquired Enterobacteriaceae.

Table 5

Extended-spectrum β-lactamases (ESBLs) produced by 15 community-acquired Enterobacteriaceae.

Discussion

ESBL-producing Enterobacteriaceae are emerging worldwide and present a major challenge to clinicians, public health professionals, and hospital infection-control teams. Recent reports on the occurrence of ESBL-producing Enterobacteriaceae in nonhospitalized persons [11, 12, 14, 15, 31] imply that important reservoirs of these pathogens exist outside of hospitals. Failure to consider the emergence of drug-resistant organisms in the community could undermine infection-control efforts in hospitals and render empirical antibiotic therapy inadequate. However, the influx of ESBL-producing organisms into hospitals is poorly understood. In the present study, we assessed the prevalence and clinical predictors of bacteremia and fecal carriage involving ESBL-producing Enterobacteriaceae in newly admitted patients, the association of fecal carriage with later invasive infection, and genetic characteristics of community-acquired ESBL-producing strains.

We found a high prevalence (13.7%) of the ESBL phenotype among patients recently admitted to our institution who had bacteremia due to Enterobacteriaceae. Admission from a long-term care facility and male sex were predictors of bacteremia due to an ESBL-producing organism. However, the area under the ROC curve of 0.7 indicates only moderate prediction by the model. This finding may be explained by the heterogeneity of patients with bacteremia caused by ESBL-producing organisms at the time of hospital admission, a group that includes both community-acquired and health care—associated infections. Thus, prediction schemes that rely mostly on assessment of previous contact with the health care system are bound to be imperfect. In a separate cohort of unselected patients screened for fecal colonization at the time of hospital admission, 10.8% were carriers of ESBL-producing Enterobacteriaceae. Patients were mostly elderly individuals, reflecting the population admitted to a medical service. Poor functional status, current antibiotic use, chronic renal or liver disease, and use of H2 receptor antagonists predicted fecal carriage of ESBL-producing organisms. The multivariate model allowed better prediction of fecal carriage of ESBL-producing organisms in newly admitted patients and could help direct infection-control measures, such as selective screening of persons at risk and implementation of barrier precautions for those with confirmed carriage [32, 33]. This model should be further examined in larger populations from several institutions to refine and validate its performance.

The predictors of ESBL bacteremia and colonization identified by our multivariate models include factors associated with environmental exposure to ESBL-producing organisms, such as residence in a long-term care facility and recent hospitalization, and factors that increase the susceptibility of the gastrointestinal tract to bacterial colonization, such as use of H2 receptor antagonists and antibiotics. Long-term care facilities have repeatedly been shown to be reservoirs of ESBL-producing Enterobacteriaceae [4, 6, 34]. Interinstitutional transfer of patients allows for dissemination of these organisms, facilitating outbreaks among both hospitalized patients and nursing home residents. Poor functional status is associated with contact with the health care system and residence in long-term care facilities. However, among patients screened at admission, a debilitated state was more strongly associated with carriage of ESBL-producing organisms than was residence in a long-term care facility. This finding may indicate that bedridden patients represent a subpopulation at special risk for carriage of ESBL-producing organisms within or outside of long-term care facilities. Functional decline is increasingly recognized as a major risk factor for infection among residents of long-term care facilities [4, 6, 35, 36]. It is notable that 5 of the 12 bedridden ESBL carriers were admitted from home. Bedridden patients residing at home are cared for by home care providers, who may serve as vectors for disseminating infectious agents from hospitals into the community and among patients [37]. It may be practical to regard such patients as living in a “hospital at home” [38].

Carriers of ESBL-producing organisms at admission were at high risk for subsequent infection with ceftazidime-resistant Enterobacteriaceae, most notably bloodstream infection, which occurred in 15.4% of patients with fecal carriage (OR, 38.9 vs. patients without fecal carriage). Bacteremia caused by ESBL-producing Enterobacteriaceae has been shown to be associated with inappropriate initial antibiotic treatment and mortality [39–43]. Thus, detection of fecal carriage of ESBL-producing organisms at admission may have important implications for the management of subsequent infectious episodes.

ESBL-producing Enterobacteriaceae obtained within 2 days after hospital admission were often multidrug-resistant, and similar resistance patterns were seen in community-acquired and health care—associated isolates. These high levels of antimicrobial coresistance are comparable with those recently reported in ESBL-producing isolates from our hospital, most of which were nosocomial [10].

CTX-M–type β-lactamases were the predominant ESBLs found in 15 community-acquired strains. CTX-M ESBLs were previously shown to be the most prevalent ESBLs among nosocomial Enterobacteriaceae at our institution [26, 44, 45]. PFGE revealed 3 isolates (1 E. coli and 2 P. mirabilis) that were related to nosocomial clones found at our institution, whereas all other community-acquired ESBL producers belonged to diverse clones (figure 2). This pattern may indicate ESBL spread via plasmids from nosocomial strains of Enterobacteriaceae to community strains. It has been noted that CTX-M–encoding plasmids are often easily transmissible by conjugation in vitro, explaining their effective dissemination [46].

An alternative source for community-acquired ESBLs may be environmental bacteria (e.g., Kluyvera species) that are known to contain chromosomal CTX-M genes [46]. Genetic transfer of ESBLs from environmental bacteria may explain the occurrence of ESBLs in subjects with no prior health care contact and the widespread emergence of these ESBLs among community strains in England [47], Spain [12], and Greece [48] in nonoutbreak circumstances. The emergence of ESBLs in the community may be aided by the use of antibiotics in agriculture, whereas hospitals and other health care facilities may act as amplifiers for ESBL genes introduced into them from community reservoirs.

In conclusion, fecal carriage of ESBL-producing Enterobacteriaceae and bacteremia due to these organisms are frequent occurrences among patients admitted to our institution. Fecal carriage of ESBL-producing organisms confers an increased risk for subsequent invasive infection with the same organism. Prediction tools that aid in identifying patients at risk for fecal carriage may be useful in preventing institutional spread of these pathogens and need to be further refined and validated.

Acknowledgments

We thank Tamar Kricheli for valuable assistance in the collection of clinical data.

Financial support. United States-Israel Binational Science Foundation, Jerusalem, Israel.

Potential conflicts of interest. R.B.-A. received a travel grant from Merck. Y.C. received grants, honoraria, travel support, consulting fees, and other forms of financial support from Bayer, Bristol-Myers Squibb, Merck, Neopharm, Pfizer Pharmaceuticals, Teva, Vicuron Pharmaceuticals, and XTL Pharmaceuticals. M.G. received lecture fees from Merck; travel grants from Merck, Pfizer Pharmaceuticals, and Teva; and advisory board fees from Pfizer Pharmaceuticals. All other authors: no conflicts.

References

1
Alcantar-Curiel
D
Tinoco
JC
Gayosso
C
, et al.  . 
Nosocomial bacteremia and urinary tract infections caused by extended-spectrum β-lactamase—producing Klebsiella pneumoniae with plasmids carrying both SHV-5 and TLA-1 genes
Clin Infect Dis
 , 
2004
, vol. 
38
 (pg. 
1067
-
74
)
2
Paterson
DL
Ko
WC
Von Gottberg
A
, et al.  . 
International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections
Ann Intern Med
 , 
2004
, vol. 
140
 (pg. 
26
-
32
)
3
Bradford
PA
Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat
Clin Microbiol Rev
 , 
2001
, vol. 
14
 (pg. 
933
-
51
)
4
Wiener
J
Quinn
JP
Bradford
PA
, et al.  . 
Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes
JAMA
 , 
1999
, vol. 
281
 (pg. 
517
-
23
)
5
Bonomo
RA
Rice
LB
Emerging issues in antibiotic resistant infections in long-term care facilities
J Gerontol A Biol Sci Med Sci
 , 
1999
, vol. 
54
 (pg. 
260
-
7
)
6
Schiappa
DA
Hayden
MK
Matushek
MG
, et al.  . 
Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli bloodstream infection: a case-control and molecular epidemiologic investigation
J Infect Dis
 , 
1996
, vol. 
174
 (pg. 
529
-
36
)
7
Navon-Venezia
S
Hammer-Munz
O
Schwartz
D
Turner
D
Kuzmenko
B
Carmeli
Y
Occurrence and phenotypic characteristics of extended-spectrum beta-lactamases among members of the family Enterobacteriaceae at the Tel-Aviv Medical Center (Israel) and evaluation of diagnostic tests
J Clin Microbiol
 , 
2003
, vol. 
41
 (pg. 
155
-
8
)
8
Navon-Venezia
S
Leavitt
A
Ben-Ami
R
, et al.  . 
Evaluation of an accelerated protocol for detection of extended-spectrum beta-lactamase—producing gram-negative bacilli from positive blood cultures
J Clin Microbiol
 , 
2005
, vol. 
43
 (pg. 
439
-
41
)
9
Jones
RN
Pfaller
MA
Antimicrobial activity against strains of Escherichia coli and Klebsiella spp. with resistance phenotypes consistent with an extended-spectrum beta-lactamase in Europe
Clin Microbiol Infect
 , 
2003
, vol. 
9
 (pg. 
708
-
12
)
10
Schwaber
MJ
Navon-Venezia
S
Schwartz
D
Carmeli
Y
High levels of antimicrobial coresistance among extended-spectrum-beta-lactamase—producing Enterobacteriaceae
Antimicrob Agents Chemother
 , 
2005
, vol. 
49
 (pg. 
2137
-
9
)
11
Colodner
R
Rock
W
Chazan
B
, et al.  . 
Risk factors for the development of extended-spectrum beta-lactamase—producing bacteria in nonhospitalized patients
Eur J Clin Microbiol Infect Dis
 , 
2004
, vol. 
23
 (pg. 
163
-
7
)
12
Rodriguez-Baño
J
Navarro
MD
Romero
L
, et al.  . 
Epidemiology and clinical features of infections caused by extended-spectrum beta-lactamase—producing Escherichia coli in nonhospitalized patients
J Clin Microbiol
 , 
2004
, vol. 
42
 (pg. 
1089
-
94
)
13
Pitout
JD
Hanson
ND
Church
DL
Laupland
KB
Population-based laboratory surveillance for Escherichia coli—producing extended-spectrum β-lactamases: importance of community isolates with blaCTX-M genes
Clin Infect Dis
 , 
2004
, vol. 
38
 (pg. 
1736
-
41
)
14
Borer
A
Gilad
J
Menashe
G
Peled
N
Riesenberg
K
Schlaeffer
F
Extended-spectrum beta-lactamase—producing Enterobacteriaceae strains in community-acquired bacteremia in Southern Israel
Med Sci Monit
 , 
2002
, vol. 
8
 (pg. 
44
-
7
)
15
Valverde
A
Coque
TM
Sanchez-Moreno
MP
Rollan
A
Baquero
F
Canton
R
Dramatic increase in prevalence of fecal carriage of extended-spectrum beta-lactamase—producing Enterobacteriaceae during nonoutbreak situations in Spain
J Clin Microbiol
 , 
2004
, vol. 
42
 (pg. 
4769
-
75
)
16
Friedman
ND
Kaye
KS
Stout
JE
, et al.  . 
Health care—associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections
Ann Intern Med
 , 
2002
, vol. 
137
 (pg. 
791
-
7
)
17
Clinical and Laboratory Standards Institute
Performance standards for antimicrobial susceptibility testing. Fifteenth informational supplement M100-S15 ed
 , 
2005
Wayne, PA
Clinical and Laboratory Standards Institute
18
Schwaber
MJ
Raney
PM
Rasheed
JK
, et al.  . 
Utility of NCCLS guidelines for identifying extended-spectrum beta-lactamases in non—Escherichia coli and non-Klebsiella spp. of Enterobacteriaceae
J Clin Microbiol
 , 
2004
, vol. 
42
 (pg. 
294
-
8
)
19
Mathew
A
Harris
AM
Marshall
MJ
Ross
GW
The use of analytical isoelectric focusing for detection and identification of beta-lactamases
J Gen Microbiol
 , 
1975
, vol. 
88
 (pg. 
169
-
78
)
20
Marchandin
H
Carriere
C
Sirot
D
Pierre
HJ
Darbas
H
TEM-24 produced by four different species of Enterobacteriaceae, including Providencia rettgeri, in a single patient
Antimicrob Agents Chemother
 , 
1999
, vol. 
43
 (pg. 
2069
-
73
)
21
Noller
AC
McEllistrem
MC
Stine
OC
, et al.  . 
Multilocus sequence typing reveals a lack of diversity among Escherichia coli O157:H7 isolates that are distinct by pulsed-field gel electrophoresis
J Clin Microbiol
 , 
2003
, vol. 
41
 (pg. 
675
-
9
)
22
Tenover
FC
Arbeit
RD
Goering
RV
, et al.  . 
Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing
J Clin Microbiol
 , 
1995
, vol. 
33
 (pg. 
2233
-
9
)
23
Schlesinger
J
Navon-Venezia
S
Chmelnitsky
I
, et al.  . 
Extended-spectrum beta-lactamases among Enterobacter isolates obtained in Tel Aviv, Israel
Antimicrob Agents Chemother
 , 
2005
, vol. 
49
 (pg. 
1150
-
6
)
24
Coque
TM
Oliver
A
Perez-Diaz
JC
Baquero
F
Canton
R
Genes encoding TEM-4, SHV-2, and CTX-M-10 extended-spectrum beta-lactamases are carried by multiple Klebsiella pneumoniae clones in a single hospital (Madrid, 1989 to 2000)
Antimicrob Agents Chemother
 , 
2002
, vol. 
46
 (pg. 
500
-
10
)
25
Oliver
A
Perez-Diaz
JC
Coque
TM
Baquero
F
Canton
R
Nucleotide sequence and characterization of a novel cefotaxime-hydrolyzing beta-lactamase (CTX-M-10) isolated in Spain
Antimicrob Agents Chemother
 , 
2001
, vol. 
45
 (pg. 
616
-
20
)
26
Chmelnitsky
I
Carmeli
Y
Leavitt
A
Schwaber
MJ
Navon-Venezia
S
CTX-M-2 and a new CTX-M-39 enzyme are the major extended-spectrum beta-lactamases in multiple Escherichia coli clones isolated in Tel Aviv, Israel
Antimicrob Agents Chemother
 , 
2005
, vol. 
49
 (pg. 
4745
-
50
)
27
Ouellette
M
Bissonnette
L
Roy
PH
Precise insertion of antibiotic resistance determinants into Tn21-like transposons: nucleotide sequence of the OXA-1 beta-lactamase gene
Proc Natl Acad Sci U S A
 , 
1987
, vol. 
84
 (pg. 
7378
-
82
)
28
Dale
JW
Godwin
D
Mossakowska
D
Stephenson
P
Wall
S
Sequence of the OXA2 beta-lactamase: comparison with other penicillin-reactive enzymes
FEBS Lett
 , 
1985
, vol. 
191
 (pg. 
39
-
44
)
29
Huovinen
P
Huovinen
S
Jacoby
GA
Sequence of PSE-2 beta-lactamase
Antimicrob Agents Chemother
 , 
1988
, vol. 
32
 (pg. 
134
-
6
)
30
McCabe
WR
Jackson
GG
Gram negative bacteremia: I. Etiology and ecology
Arch Intern Med
 , 
1962
, vol. 
110
 (pg. 
845
-
7
)
31
Arpin
C
Dubois
V
Coulange
L
, et al.  . 
Extended-spectrum beta-lactamase—producing Enterobacteriaceae in community and private health care centers
Antimicrob Agents Chemother
 , 
2003
, vol. 
47
 (pg. 
3506
-
14
)
32
Meyer
KS
Urban
C
Eagan
JA
Berger
BJ
Rahal
JJ
Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins
Ann Intern Med
 , 
1993
, vol. 
119
 (pg. 
353
-
8
)
33
Pena
C
Pujol
M
Ardanuy
C
, et al.  . 
Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended-spectrum beta-lactamases
Antimicrob Agents Chemother
 , 
1998
, vol. 
42
 (pg. 
53
-
8
)
34
Weller
TM
MacKenzie
FM
Forbes
KJ
Molecular epidemiology of a large outbreak of multiresistant Klebsiella pneumoniae
J Med Microbiol
 , 
1997
, vol. 
46
 (pg. 
921
-
6
)
35
High
KP
Bradley
S
Loeb
M
Palmer
R
Quagliarello
V
Yoshikawa
T
A new paradigm for clinical investigation of infectious syndromes in older adults: assessment of functional status as a risk factor and outcome measure
Clin Infect Dis
 , 
2005
, vol. 
40
 (pg. 
114
-
22
)
36
Bula
CJ
Ghilardi
G
Wietlisbach
V
Petignat
C
Francioli
P
Infections and functional impairment in nursing home residents: a reciprocal relationship
J Am Geriatr Soc
 , 
2004
, vol. 
52
 (pg. 
700
-
6
)
37
Ribu
E
Haram
R
Rustoen
T
Observations of nurses' treatment of leg and foot ulcers in community health care
J Wound Ostomy Continence Nurs
 , 
2003
, vol. 
30
 (pg. 
342
-
50
)
38
Patte
R
Drouvot
V
Quenon
JL
Denic
L
Briand
V
Patris
S
Prevalence of hospital-acquired infections in a home care setting
J Hosp Infect
 , 
2005
, vol. 
59
 (pg. 
148
-
51
)
39
Du
B
Long
Y
Liu
H
, et al.  . 
Extended-spectrum beta-lactamase—producing Escherichia coli and Klebsiella pneumoniae bloodstream infection: risk factors and clinical outcome
Intensive Care Med
 , 
2002
, vol. 
28
 (pg. 
1718
-
23
)
40
Ho
PL
Chan
WM
Tsang
KW
Wong
SS
Young
K
Bacteremia caused by Escherichia coli producing extended-spectrum beta-lactamase: a case-control study of risk factors and outcomes
Scand J Infect Dis
 , 
2002
, vol. 
34
 (pg. 
567
-
73
)
41
Kim
BN
Woo
JH
Kim
MN
Ryu
J
Kim
YS
Clinical implications of extended-spectrum beta-lactamase—producing Klebsiella pneumoniae bacteraemia
J Hosp Infect
 , 
2002
, vol. 
52
 (pg. 
99
-
106
)
42
Kim
YK
Pai
H
Lee
HJ
, et al.  . 
Bloodstream infections by extended-spectrum beta-lactamase—producing Escherichia coli and Klebsiella pneumoniae in children: epidemiology and clinical outcome
Antimicrob Agents Chemother
 , 
2002
, vol. 
46
 (pg. 
1481
-
91
)
43
Lautenbach
E
Patel
JB
Bilker
WB
Edelstein
PH
Fishman
NO
Extended-spectrum β-lactamase—producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes
Clin Infect Dis
 , 
2001
, vol. 
32
 (pg. 
1162
-
71
)
44
Chmelnitsky
I
Navon-Venezia
S
Leavitt
A
Carmeli
Y
Multiple clones carrying multiple extended-spectrum β-lactamases (ESBLs) genes among E. coli clinical isolates in Tel-Aviv
Program and abstracts of the 44th Interscience Conference on Antimicrobials and Chemotherapy (Washington, DC)
 , 
2004
Washington, DC
American Society for Microbiology
pg. 
106
 
45
Morlote
M
Navon-Venezia
S
Carmeli
Y
Venkataraman
L
Gold
H
Presence of CTX-M-2 in Proteus mirabilis isolated at an Israeli Hospital
Program and abstracts of the 43rd Interscience Conference on Antimicrobials and Chemotherapy (Chicago)
 , 
2003
Washington, DC
American Society for Microbiology
pg. 
110
 
46
Bonnet
R
Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes
Antimicrob Agents Chemother
 , 
2004
, vol. 
48
 (pg. 
1
-
14
)
47
Alobwede
I
M'Zali
FH
Livermore
DM
Heritage
J
Todd
N
Hawkey
PM
CTX-M extended-spectrum beta-lactamase arrives in the UK
J Antimicrob Chemother
 , 
2003
, vol. 
51
 (pg. 
470
-
1
)
48
Pournaras
S
Ikonomidis
A
Sofianou
D
Tsakris
A
Maniatis
AN
CTX-M-type beta-lactamases affect community Escherichia coli treatment, Greece
Emerg Infect Dis
 , 
2004
, vol. 
10
 (pg. 
1163
-
4
)

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