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Health and Economic Outcomes of the Emergence of Third-Generation Cephalosporin Resistance in Enterobacter Species
Sara E. Cosgrove, MD, MS;
Keith S. Kaye, MD, MPH;
George M. Eliopoulous, MD;
Yehuda Carmeli, MD, MPH
Arch Intern Med. 2002;162:185-190.
ABSTRACT
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Background This study evaluated the clinical and economic impact of the emergence
of third-generation cephalosporin–resistant Enterobacter species.
Methods Mortality, length of hospitalization, and hospital charges were examined
in a cohort that was selected from a group of 477 patients with initial cultures
that yielded a third-generation cephalosporin–susceptible Enterobacter species. Case patients (n = 46) had subsequent cultures
yielding a third-generation cephalosporin–resistant Enterobacter species. Control patients (n = 113) who did not develop
resistance were matched to cases on site of Enterobacter infection and length of hospitalization prior to isolation of the
initial susceptible organism. Multivariable analyses were used to adjust for
confounding.
Results Twenty-six percent of cases died vs 13% of controls (P = .06). The median total hospital stay for cases was 29.5 days (interquartile
range [IQR], 20-60) and 19 days for controls (IQR, 13-27; P<.001). The median hospital charge for cases was $79 323 (IQR,
$34 546-$161 384) and for controls was $40 406 (IQR, $18 470-$79 005; P<.001). After adjusting for comorbidities, severity
of illness, intensive care unit admission, surgery, transfer from another
hospital, sex, and age, emergence of resistance was associated with increased
mortality (relative risk, 5.02; P = .01), hospital
stay (1.5-fold, P<.001), and hospital charges
(1.5-fold, P<.001). Emergence of resistance had
a median attributable hospital stay of 9 days and an average attributable
hospital charge of $29 379.
Conclusions Emergence of antibiotic resistance in Enterobacter species results in increased mortality, hospital stay, and hospital
charges. Minimizing resistance in Enterobacter species
should be a priority.
INTRODUCTION
RESISTANCE TO antimicrobial drugs is a growing health and economic concern.
Rates of resistance in hospital-acquired gram-positive and gram-negative infections
have risen dramatically over the past decade.1-2
Infections caused by resistant organisms are thought to result in higher morbidity
and mortality, prolonged hospitalization, and increased costs compared with
infections caused by sensitive strains; however, few studies have examined
quantitatively the health and economic impact of the development of resistant
organisms.
Enterobacter species are common nosocomial
pathogens; they represent 6% of all hospital-acquired isolates and 11% of
all pneumonia isolates.1 Recent data show that
they are the most frequently isolated gram-negative organisms in intensive
care unit (ICU) bloodstream infections and they are the third most common
pathogen isolated in cases of ICU pneumonias.2
Resistance in Enterobacter isolates is common.
In US hospitals reporting to the National Nosocomial Infection Surveillance
(NNIS) System, the rate of third-generation cephalosporin resistance in ICU
infections caused by Enterobacter species between
January 1999 and December 1999 was 34%.2 Resistance
to  -lactam antibiotics is most frequently mediated by hyperproduction
of inducible chromosomal AmpC -lactamase. Enterobacter isolates initially may test susceptible to -lactam antibiotics
in vitro, but the emergence of resistance occurs during therapy because of
increased -lactamase production.3-5
The emergence of third-generation cephalosporin resistance occurs in an average
of 10% of patients receiving antimicrobial therapy and in up to 20% of patients
treated with third-generation cephalosporins.6-7
Patients from whom resistant Enterobacter species
are cultured have an increased risk of mortality.6
However, these patients represent two populations: those in whom a resistant
organism is detected in baseline cultures and those in whom resistance emerges
after the detection of a susceptible organism. In the case of Pseudomonas aeruginosa, there is evidence that outcomes of patients
who develop antimicrobial resistance during treatment are worse than those
of patients who have resistance detected in baseline cultures.8
The objective of this study was to investigate the effects of the development
of third-generation cephalosporin resistance on direct patient outcomes. We
studied the mortality, length of hospitalization, and hospital charges of
patients who had cultures positive for third-generation cephalosporin–resistant Enterobacter species after having initial cultures positive
for a susceptible strain. These patients were compared with patients from
whom third-generation cephalosporin–susceptible Enterobacter strains were recovered but where resistance did not emerge.
PARTICIPANTS AND METHODS
HOSPITAL SETTING AND STUDY DESIGN
Beth Israel Deaconess Medical Center, West Campus, is a 320-bed urban
tertiary care teaching hospital in Boston, Mass. It has 24 ICU beds and approximately
11 000 patient admissions per year; there are no pediatric or obstetric
patients.
We conducted a nested matched cohort study of patients who had clinical
cultures positive for Enterobacter species and who
were treated with antimicrobial agents. The cohort was drawn from a group
of 477 patients admitted to the hospital between September 1, 1994, and August
31, 1997, from whom an Enterobacter species that
was susceptible to third-generation cephalosporin antibiotics was cultured.
This group of patients has been described elsewhere.7
The 49 patients who had subsequent cultures that grew an Enterobacter species that was resistant to third-generation cephalosporins
were classified as cases and entered our cohort at the time that the third-generation
cephalosporin–resistant Enterobacter species
were cultured. Controls were chosen from the original 428 patients who had
cultures positive for a susceptible Enterobacter
species strain but no subsequent cultures that yielded a resistant strain.
Controls were individually matched to cases on 2 parameters: the anatomic
site from which the Enterobacter species was isolated
and the length of hospital stay prior to detection of the initial susceptible
organism. In addition, controls were required to have stayed in the hospital
for at least the same duration as the time to isolation of a resistant strain
for the matched cases. Up to 3 controls were matched to each case; only exactly
matched controls were included. Three outcomes were studied: in-hospital mortality,
length of hospital stay, and hospital charges.
DATA COLLECTION AND MICROBIOLOGY
Patient characteristics and microbiology data were prospectively collected
in the hospital data repository. Variables relating to comorbidities, hospital
events, and cost were extracted from administrative, accounting, and laboratory
databases. All recorded hospital events occurred prior to the patients' entry
into the cohort. Severity of illness was classified by the criteria of McCabe
and Jackson9 and was assessed at the time of
cohort entry. Patients were categorized into 3 groups: those with rapidly
fatal illnesses who were expected to die within 2 weeks (score = 1), those
with ultimately fatal diseases who were expected to live less than 5 years
(score = 2), and those with nonfatal illnesses (score = 3). This information
was extracted from patient charts. Data were then compiled into a single data
set using a relational database management system (Access; Microsoft Corp,
Redmond, Wash).
Clinical Enterobacter isolates were collected
by the clinical microbiology laboratory between September 1, 1994, and August
31, 1997. Enterobacter species were identified using
the Gram-Negative Identification Panel Type II (Dade International Inc, West
Sacramento, Calif). In vitro susceptibility was tested by microbroth dilution
(MicroScan, Dade International Inc).
Emergence of resistance was defined as the subsequent detection of a
positive culture for a third-generation cephalosporin–resistant Enterobacter species from a patient with previous cultures
from the same site yielding a susceptible Enterobacter
isolate. The organisms had a change in interpretive class and at least a 4-fold
increase (2 dilutions) in minimal inhibitory concentration (MIC) relative
to the baseline isolate. The National Committee for Clinical Laboratory Standards
susceptibility thresholds for third-generation cephalosporins were used as
breakpoints to classify strains as susceptible or resistant to third-generation
cephalosporins. Isolates with MIC values indicative of intermediate susceptibility
(MIC = 16-32 for ceftriaxone and MIC = 16 for ceftazidime) were considered
resistant.10
STATISTICAL ANALYSIS
Statistical analyses were performed with SAS software (version 7; SAS
Institute Inc, Cary, NC). Comparison of case and control variables was performed
using the 2-sided Wilcoxon rank sum test for continuous variables, the Cochran-Mantel-Haenszel
estimate for matched data for binary variables, and the  2
trend test for ordinal variables.
Univariate analysis of the association between individual variables
and the 3 outcomes studied was performed using matched regression models that
examined the individual variable of interest. Mortality was analyzed with
conditional logistic regression. Hazard ratios from the conditional logistic
regression models are presented as relative risks (RRs). Length of stay and
hospital charges were log transformed to achieve a normal distribution and
analyzed with linear regression models with an absorbed variable to account
for matching. The coefficients were converted to RRs using an exponential
transformation. The discharge date used for the length of stay analysis for
patients who died was the date of death.
Three separate multivariable analyses were performed for the 3 outcomes
using conditional logistic regression for the analysis of mortality and linear
regression for the analysis of length of stay and hospital charges. Variables
with a P value of less than .1 in the univariate
analysis were included in the corresponding multivariable analysis. All predictors
were checked for confounding and collinearity. Possible confounding variables
were added one by one into the model, and if this resulted in a change in
the coefficient estimate of a covariate of 10% or more, the variable was left
in the model. Effect modification between variables was evaluated by testing
appropriate interaction terms for statistical significance. The final regression
models were analyzed for overfitting by the bootstrap method (1000 bootstrap
samples of all the data were used).
All statistical tests were 2-tailed; P .05
was considered significant.
RESULTS
Of the 477 patients with initial cultures that grew a third-generation
cephalosporin–susceptible Enterobacter species,
49 had subsequent cultures that grew a third-generation cephalosporin–resistant
strain and were eligible to be cases in the cohort. For 32 cases, exactly
matched controls were found at a 1:3 ratio. For 3 cases, 2 exactly matched
controls were found for each case. For 11 cases, 1 exactly matched control
was found for each case. Three cases did not have suitable matches and were
excluded from the analysis. Thus, our nested cohort included 46 cases who
were matched to 113 controls who did not have emergence of resistance. One
hundred seven isolates were identified as Enterobacter cloacae, 47 as Enterobacter aerogenes, and 5 as Enterobacter agglomerans; there were no significant differences
in the number of each species between cases and controls (P = .87). The majority of isolates were from the respiratory tract
(44%), followed by wounds (20%), effusions (18%), blood (13%), and urine (5%).
Patient characteristics are shown in Table 1. There were no significant differences in age, sex, or comorbidities
between cases and controls. The mean age of the cohort was 63 years. Sixty-two
percent of patients were men. Both cases and controls had a median of 2 comorbidities.
Specific comorbidities occurred with similar frequencies among cases and controls.
The median length of stay prior to isolation of an Enterobacter species was similar for cases and controls (5.5 and 5.0 days, respectively; P = .76). The study population included a large proportion
of severely ill patients; 29.6% were transferred from another institution,
67.9% underwent a major surgical procedure, and 68.6% were admitted to the
ICU before inclusion in the study. Admission to the ICU was the only variable
that differed significantly between cases and controls. Eighty percent of
cases compared with 64% of controls were admitted to the ICU before entry
into the cohort (P = .02). There were no significant
differences in the McCabe9 severity of illness
scores between cases and controls. The majority of patients (63.5%) had ultimately
fatal illnesses; 6.3% had rapidly fatal illnesses and 30.2% had nonfatal illnesses.
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Table 1. Descriptive Characteristics of the Cohort*
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MORTALITY
Twenty-seven of the 159 patients in the cohort died in the hospital
(case fatality rate, 17%). Mortality was higher among patients with emergence
of resistant Enterobacter species than in patients
without resistant Enterobacter species (case fatality
rate, 26% vs 13%, respectively; OR, 2.29; P = .06). Enterobacter infection was the direct cause of death in
more than half of the cases in both groups (58% in patients with emergence
of resistance and 53% in patients without emergence of resistance). Results
of the crude analysis for the association of the cohort characteristics with
mortality are shown in Table 2.
Significant univariate predictors of mortality included underlying cardiovascular
disease (RR, 3.31; P = .02), underlying hepatic disease
(RR, 10.26; P = .04), underlying renal disease (RR,
1.36; P = .02), increased number of underlying comorbidities
(RR, 2.13; P = .01), low McCabe score (RR, 19.22; P = .005), and ICU admission during hospitalization (RR,
6.37; P = .001). The results of a multivariable analysis
for mortality are shown in Table 3.
After adjusting for confounding, emergence of resistance to third-generation
cephalosporins was a predictor of increased mortality (RR, 5.02; P = .01). Low McCabe score (RR, 34.41; P =
.02), ICU admission during hospitalization (P = .01),
and increased number of underlying comorbidities (RR, 2.53; P = .04) were also associated with increased in-hospital mortality.
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Table 2. Univariate Analysis of Mortality, Length of Hospital Stay,
and Hospital Charges*
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Table 3. Multivariate Models for Outcomes of Emergence of Resistance*
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LENGTH OF HOSPITAL STAY
The median total length of hospital stay for the cohort was 21 days
(interquartile range [IQR], 15-33); median length of stay was longer for cases
(30 days; IQR, 20-60) than for controls (19 days; IQR, 13-27; P<.001). Results of the crude analysis for the association of patient
variables with length of stay are shown in Table 2. Emergence of third-generation cephalosporin resistance
was associated with increased length of hospital stay (RR, 2.83; P<.001). Other significant univariate predictors of increased length
of hospital stay included underlying cardiovascular disease (RR, 1.99; P = .04), underlying hepatic disease (RR, 2.47; P = .01), low McCabe score (RR, 1.32; P =
.007), ICU admission while in the hospital (RR, 6.37; P = .001), major surgical procedure while in the hospital (RR, 1.85; P = .01), and transfer from another institution (RR, 2.29; P = .003). The results of the multivariable analysis for
length of hospital stay are shown in Table
3. After adjusting for confounding, emergence of resistance to third-generation
cephalosporins remained a strong predictor of increased hospital stay. A 1.47-fold
longer hospital stay occurred in patients who had emergence of a resistant Enterobacter species compared with those who did not (P<.001). The median total length of stay for controls
in our cohort was 19 days and after adjusting for confounding, a 1.47-fold
increased hospital stay occurred; therefore, emergence of resistance had a
median attributable length of stay of 9 days. Low McCabe score (RR, 1.22; P = .02), ICU admission during hospitalization (RR, 1.43;
P = .002), and transfer from another institution (RR, 1.39; P = .001) were also strong, independent predictors of increased duration
of hospital stay.
HOSPITAL CHARGES
Median hospital charges for cohort members were $46 010 (IQR, $22 098-$96 417).
The median hospital charges were significantly higher for cases ($79 323;
IQR, $34 546-$161 385) than for controls ($40 406; IQR, $18 470-$79 005; P<.001). Results of a crude analysis for the association
of the cohort characteristics with hospital charges are shown in Table 2. Emergence of third-generation
cephalosporin resistance was associated with increased hospital charges (RR,
1.85; P<.001). Other significant univariate predictors
of increased hospital charges included underlying cardiovascular disease (RR,
1.56; P = .02), underlying hepatic disease (RR, 1.81; P = .005), low McCabe score (RR, 2.39; P = .006), ICU admission during hospitalization (RR, 3.06; P<.001), major surgical procedure during hospitalization (RR, 1.80; P<.001), and transfer from another institution (RR,
1.63; P = .003). The results of the multivariable
analysis of hospital charges are shown in Table 3. After adjusting for confounding, emergence of resistance
to third-generation cephalosporins remained a significant predictor of increased
hospital charges. A 1.51-fold increase in hospital charges occurred in patients
who had emergence of a resistant Enterobacter species
compared with those who did not (P<.001). The
average hospital charge for controls in our cohort was $57 606 and after
adjusting for confounding, a 1.51-fold increase in hospital charges occurred;
therefore, emergence of resistance had an average attributable hospital charge
of $29 379 per patient in our cohort. Underlying hepatic disease (RR,
1.35; P = .04), low McCabe score (RR, 1.35; P = .003), ICU admission during hospitalization (RR, 2.18; P<.001), having a major surgical procedure while in
the hospital (RR, 1.43; P = .001), and transfer from
another institution (RR, 1.41; P = .003) were also
significant predictors of increased hospital charges.
ICU PATIENTS
To explore the issue of whether increased mortality, length of hospital
stay, and hospital charges were driven by admission to the ICU as opposed
to the emergence of resistance, we performed a subgroup analysis of patients
who had been in the ICU before inclusion in the study. In this population
of critically ill patients, the effects of resistance on length of stay and
hospital charges remained significant. Patients with emergence of resistance
had a longer median hospital stay (36 days; IQR, 25-64) than patients without
resistance (22 days; IQR, 16-32; P<.001). They
also had higher median hospital charges ($116 182; [IQR, $61 618-$172 260]
vs $61 060; [IQR, $40 595-$96 439]; P
= .002). Mortality was higher in patients who developed resistance than in
those who did not (case fatality rate, 32% vs 21%), but this difference did
not reach statistical significance (P = .19).
COMMENT
Recent epidemiologic data show an increase in the frequency of isolation
of bacteria that are resistant to antimicrobial agents.1-2
To form a rational understanding and approach to controlling the development
and spread of antimicrobial resistance, quantification of the medical and
economic consequences of antimicrobial resistance is essential. This information
is important for clinicians, infection control practitioners, and even more
so for policymakers. Several studies have demonstrated adverse health outcomes
in patients with resistant organisms although the magnitude may vary based
on the organism, the site of isolation, antimicrobial resistance patterns,
and the mechanism of resistance.6, 8, 11
Estimates of the costs of resistance are high—the US Congress has reported
that the annual additional hospital cost of resistance total at least $1.3
billion; however, data on costs of resistance attributable to individual organisms
are sparse.12
This study specifically addresses the issue of emergence of third-generation
cephalosporin resistance during hospitalization. Other studies have shown
that patients with nosocomial isolation of a resistant organism have worse
outcomes than patients who enter the hospital with a resistant organism, but
data are limited.8 Previous studies have focused
on mortality due to bacteremia, but bloodstream infection comprises less than
10% of the total infections caused by Enterobacter
species.1-2,6 Moreover,
data on other outcomes such as length of hospital stay and hospital charges
may be needed to delineate the adverse consequences of the development of
antimicrobial resistance and may provide the basis for adjusting resource
allocation to prevent resistance. In this study, we analyzed positive cultures
originating from several different anatomic sites to demonstrate that adverse
outcomes result from involvement of sites other than the bloodstream. Our
evaluation of the length and cost of hospitalization further defines the effect
of resistance on patients' health outcomes.
In this study, we have shown that emergence of resistance to third-generation
cephalosporins in Enterobacter species is associated
with severe adverse outcomes. In both univariate and multivariable analyses,
emergence of resistance was associated with increase in mortality (increased
5-fold), length of hospital stay (increased 1.4-fold), and hospital charges
(increased 1.5-fold). In this cohort, the incidence of emergence of third-generation
cephalosporin resistance was 10.3%. If the average attributable cost of resistance
was $29 379, then measures directed at preventing resistance that cost
up to an average of $2938 per patient with Enterobacter species isolated would be cost saving in our hospital.
There are several possible reasons for our findings that emergence of
resistance leads to poor outcomes. More serious or deep-seated Enterobacter species infections with a higher organism burden may provide
circumstances that are more favorable to the selection of resistant strains,
and adverse outcomes may be the consequence of a more severe initial infection.
While we believe that there is likely a correlation between the size of inoculum,
the development of resistance, and the persistence of infection, disentangling
the individual effect of these factors as causes of adverse outcomes is not
possible given the data available for this study. Another explanation, which
has been supported by other studies, is that antimicrobial resistance leads
to inadequate or delayed antimicrobial therapy, either because patients are
not changed from ineffective empiric regimens to therapies that are effective
against the resistant organism or because therapeutic options are limited.6, 13
Two factors may have caused underestimation of the effect of emergence
of resistance on outcomes. First, it is likely that the development of a resistant
organism in a given patient preceded the detection of the organism in clinical
cultures; this would decrease the number of days and charges attributable
to the development of resistance. Second, there may have been patients who
developed resistance that was not detected on repeated cultures, leading to
misclassification of cases as controls.
Differentiating between infection and colonization may be difficult
in a retrospective analysis; moreover, the state of being colonized or infected
may change over time. All patients in our study were treated with antibiotics
for presumed infection. Although it is possible that some misclassification
of infection and colonization might have occurred, by matching on the site
of isolation of the organism and including only patients treated for infection,
this bias was minimized.
There are some possible limitations to this study. First, an analysis
of hospital charges most closely reflects the hospital's perspective of the
costs of emergence of resistance. The costs to patients, third-party payers,
and society are underestimated by our analysis because we did not quantitate
the medical costs accrued beyond hospitalization or non-direct medical costs.
Second, we did not perform a molecular analysis of the Enterobacter species isolates to confirm that, for a given patient,
the susceptible and resistant Enterobacter species
strains were related. However, from a practical perspective this is of little
importance. Third, it is difficult to make generalizations regarding the effects
of the emergence of resistance in other organisms based on the results of
this study. However, effects of similar magnitudes were found for emergence
of resistance in P aeruginosa.8
Further evaluation of the effects of resistance on patient outcomes for other
organisms must be undertaken.
Given the health and economic costs associated with emergence of third-generation
cephalosporin resistance in Enterobacter species
that we have demonstrated, efforts to minimize resistance in Enterobacter species should be a priority. Because other studies have
shown that resistance is most strongly associated with exposure to third-generation
cephalosporins,6-7 we suggest
that these agents be used with caution in the treatment of infections caused
by susceptible Enterobacter species In addition,
patients with Enterobacter species infections should
be monitored carefully with frequent clinical cultures to detect the emergence
of resistance. How the use of combination therapy or of individual advanced -lactams
might affect rates of emerging resistance to third-generation cephalosporins
remains to be fully elucidated.5-6,14-17
We conclude that the emergence of antibiotic resistance in Enterobacter species is associated with significant adverse outcomes.
Efforts should be directed at early detection of development of third-generation
resistance in hospitalized patients through careful clinical monitoring and
at prevention of development of resistance through judicious use of antimicrobial
agents.
AUTHOR INFORMATION
Accepted for publication May 8, 2001.
This study was supported in part by an unrestricted educational grant
from Merck & Co, Inc, Whitehouse Station, NJ.
This work was presented in part at the 40th Interscience Conference
on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, September 19,
2000.
Corresponding author: Sara E. Cosgrove, MD, MS, Department of Medicine,
The John Hopkins Hospital, 1830 E Monument St, Room 9020, Baltimore, MD 21287
(e-mail: scosgro1{at}jhmi.edu).
From the Division of Infectious Diseases, Beth Israel Deaconess Medical
Center, and Harvard Medical School, Boston, Mass (Drs Cosgrove, Eliopoulous,
and Carmeli); Division of Infectious Diseases, Department of Medicine, Duke
University Medical Center, Durham, NC (Dr Kaye); and Division of Infectious
Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (Dr Carmeli).
Dr Cosgrove is now with the Department of Medicine, The John Hopkins Hospital,
Baltimore, Md. Dr Eliopoulous has relationships with the following corporations:
Aventis (speaker, contract, consultant), Bayer (consultant, speaker), Bristol
Myers Squibb (consultant), Ortho McNeil Pharmaceuticals (speaker, consultant,
contract), SmithKline Beecham (consultant), and Wyeth-Ayerst (consultant,
contract, speaker). Dr Carmeli has received grants, honoraria, travel support,
and other forms of financial support from the following companies: Bayer Corp,
Biomedicum LTD, Bristol Mayer Squib, Eli Lilly, Merck & Co Inc, Neopharm
LTD, Pharmacia Corp, SmithKline Beecham, Roche, and XTL Pharamceuticals LTD.
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An additional measure for quantifying antibiotic use in hospitals
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Extended-Spectrum Beta-Lactamases among Enterobacter Isolates Obtained in Tel Aviv, Israel
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Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia
Am. J. Respir. Crit. Care Med. 2005;171:388-416.
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Bloodstream Infections Caused by Antibiotic-Resistant Gram-Negative Bacilli: Risk Factors for Mortality and Impact of Inappropriate Initial Antimicrobial Therapy on Outcome
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Antimicrob. Agents Chemother. 2005;49:760-766.
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Relationship between ceftriaxone use and resistance to third-generation cephalosporins among clinical strains of Enterobacter cloacae
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Comparative Study of the Effects of Ceftizoxime, Piperacillin, and Piperacillin-Tazobactam Concentrations on Antibacterial Activity and Selection of Antibiotic-Resistant Mutants of Enterobacter cloacae and Bacteroides fragilis In Vitro and In Vivo in Mixed-Infection Abscesses
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A Randomized Controlled Trial of an Antibiotic Discontinuation Policy for Clinically Suspected Ventilator-Associated Pneumonia
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Chest 2004;125:1791-1799.
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Utility of NCCLS Guidelines for Identifying Extended-Spectrum {beta}-Lactamases in Non-Escherichia coli and Non-Klebsiella spp. of Enterobacteriaceae
Schwaber et al.
J. Clin. Microbiol. 2004;42:294-298.
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Population Genetics of the Nomenspecies Enterobacter cloacae
Hoffmann and Roggenkamp
Appl. Environ. Microbiol. 2003;69:5306-5318.
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The Influence of Infection on Hospital Mortality for Patients Requiring > 48 h of Intensive Care
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Treatment with a Broad-Spectrum Cephalosporin versus Piperacillin-Tazobactam and the Risk for Isolation of Broad-Spectrum Cephalosporin-Resistant Enterobacter Species
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Antimicrob. Agents Chemother. 2003;47:1882-1886.
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Trends in Antimicrobial Susceptibilities among Enterobacteriaceae Isolated from Hospitalized Patients in the United States from 1998 to 2001
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