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Outcome and Attributable Mortality in Critically Ill Patients With Bacteremia Involving Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus
Stijn I. Blot, RN, MSc;
Koenraad H. Vandewoude, MD;
Eric A. Hoste, MD;
Francis A. Colardyn, MD
Arch Intern Med. 2002;162:2229-2235.
ABSTRACT
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Background Staphylococcus aureus bacteremia carries high
mortality rates. The clinical impact of methicillin resistance remains controversial:
outcome comparisons between patients with bacteremia involving methicillin-susceptible
(MSSA) and methicillin-resistant (MRSA) S aureus are
difficult to perform because of important differences in severity of illness.
Methods A retrospective cohort analysis and 2 independent case-control analyses
were performed to determine and compare outcomes and attributable mortality
rates of MSSA (n = 38) and MRSA bacteremia (n = 47) in critically ill patients.
For the case-control studies, matching (1:2 ratio) was based on the APACHE
(Acute Physiology and Chronic Health Evaluation) II classification: APACHE
II score (±1 point) and diagnostic category.
Results Patients with MRSA bacteremia had more acute renal failure and hemodynamic
instability than patients with MSSA bacteremia. They had a longer intensive
care unit stay and ventilator dependency. Patients with MRSA bacteremia had
a higher 30-day mortality rate (53.2% vs 18.4%) and in-hospital mortality
rate (63.8% vs 23.7%) (P<.05). Multivariate survival
analysis demonstrated acute renal failure, length of mechanical ventilation,
age, and methicillin resistance to be independently associated with mortality
(P<.05). The attributable mortality rate for MSSA
bacteremia was 1.3%: mortality rates for cases and controls were respectively
23.7% and 22.4% (P = .94). The attributable mortality
rate for MRSA bacteremia was 23.4%: mortality rates for cases and controls
were respectively 63.8% and 40.4% (P = .02). The
difference (22.1%) between both attributable mortality rates was significant
(95% confidence interval, 8.8%-35.3%).
Conclusion In critically ill patients, after accurate adjustment for disease severity
and acute illness, we found MRSA bacteremia to have a higher attributable
mortality than MSSA bacteremia.
INTRODUCTION
THE INCIDENCE of Staphylococcus aureus bacteremia
in hospitals as well as communities has significantly increased over the past
decades.1 Staphylococcus
aureus has become the leading cause of both community-acquired and
nosocomial bacteremia.
Particularly in intensive care units (ICUs) where nosocomial bacteremia
is one of the leading cause of death associated with nosocomial infections, S aureus is a feared pathogen. Because of its ability to
cause severe infections and spread by metastatic foci, S aureus is considered extremely virulent. In general, fatality rates
range from 20% to 50%.2-8
With the emergence of methicillin resistance, S aureus has received even more attention as bacteremia involving methicillin-resistant S aureus (MRSA) are causing higher hospital costs,2, 9 and therapeutic options are limited
to the use of glycopeptides. Besides this, it is uncertain if methicillin
resistance affects the outcome.
MATERIALS AND METHODS
SETTING
The present study was conducted in the 1060-bed Ghent University Hospital
(Ghent, Belgium) and performed in a subset of critically ill patients. The
ICU has 54 beds and includes a medical and surgical ICU, a unit for cardiac
surgery, and a burn unit. An average of 3300 patients are admitted to the
ICU each year. In the global ICU population, no changes in age, length of
ICU stay, or APACHE (Acute Physiology and Chronic Health Evaluation) II scores10 were observed during the study period.
STUDY OBJECTIVE AND DESIGN
The aim of this study was to compare population characteristics, outcomes,
and attributable mortality in adult ICU patients with bacteremia involving
methicillin-susceptible S aureus (MSSA) and MRSA.
A retrospective population-based cohort study of patients with MSSA or MRSA
bacteremia from January 1992 through December 1998 was performed. All microbiologically
documented bloodstream infections were prospectively screened by the local
center for infection control. This case-based surveillance system was used
for the retrospective search for all ICU patients whose ICU stay was complicated
with S aureus bacteremia during the study period.
In addition, to adjust for differences in severity of illness, attributable
mortality rates for MSSA and MRSA bacteremia were determined and compared.
Two independent case-control studies were performed: a MSSA case-control study
and a MRSA case-control study. In each case-control study, every case patient
(defined as patient with S aureus bacteremia) was
matched with 2 other ICU patients (1:2 ratio) without clinical or microbiological
evidence of S aureus bacteremia (matched controls).
Matching was based on the APACHE II classification10:
an equal APACHE II score (±1 point) and an equal principal diagnosis
leading to ICU admission (diagnostic category). The APACHE II classification
is considered a standard for the comparison of severity of illness in ICU
patients. The APACHE II score is calculated on the basis of a long-term health
evaluation and a set of acute physiologic parameters obtained during the first
24 hours of ICU observation. Because expected in-hospital mortality rate can
be calculated with the APACHE II score and a factor attributed to a precise
diagnostic category (surgical vs nonsurgical admission diagnosis, elective
or urgent surgery, major vital organ system of failure, and the principal
diagnosis leading to ICU admission), this matching procedure resulted in an
equal expected mortality rate for cases and controls.10 Therefore,
this severity of disease scoring system has been repeatedly used for case-control
studies dealing with nosocomial infections in ICU settings.11-13 To
reduce the risk of selection bias, matching was done on a 1:2 ratio. Selection
of control subjects was obtained without knowledge of outcome. In case of
there being more than 2 potential controls, matching was based on the nearest
admission date of the case. All control patients were selected from the study
period in which the cases were detected.
DEFINITIONS
Staphylococcus aureus bacteremia is defined
as the microbiologically documented presence of S aureus in the blood. All ICU patients with at least 1 positive hemoculture
are included in the study. Hemocultures are taken on a routine basis when
infection is clinically suspected or when a patient's temperature rises above
38.4°C. In this way, only clinically significant bacteremia were included.
Hemocultures are executed following the BacT/Alert procedure (Organon Teknika
Corp, Durnham, NC), and a 10-mL blood inoculum is considered standard. Methicillin
resistance is determined according to methods recommended by the National
Committee for Clinical Laboratory Standards for disk diffusion testing.14
Staphylococcus aureus bacteremia were considered
nosocomially acquired when they appeared after 72 hours of hospital admission.
The source of the bacteremia was determined by microbiologists and intensivists
based on isolation of S aureus from the presumed
portal of entry and on clinical evaluation.
Antibiotic therapy was considered adequate if the drugs used had in
vitro activity against the isolated S aureus strain.
We considered antibiotic therapy inadequate if the drugs used did not have
in vitro activity against the S aureus strain or
if the patient did not receive antibiotic treatment. Delay in therapy was
calculated from the onset of the S aureus bacteremia.
Severity of illness was assessed by means of the APACHE II score, a
severity of disease classification system.10 Acute
renal failure was defined as dialysis dependency, acute respiratory failure
as ventilator dependency, and hemodynamic instability as the need for inotropic
or vasopressive support during the ICU stay.
The following data were recorded: age, ICU stay, length of hospital
stay prior to the onset of the bacteremia, length of ventilator dependency,
and the presence of a polymicrobial bacteremia. No study patients were neutropenic
(neutrophil count <500/µL).
OUTCOME
For the outcome comparison of patients with MSSA and MRSA bacteremia,
survival status is checked 15 days and 30 days after the onset of the bacteremia
and at the end of the hospital stay, defined respectively as 15-day, 30-day,
and in-hospital mortality. When patients with MSSA and MRSA bacteremia are
compared with their respective control groups, in-hospital mortality rates
are used. Attributable mortality is defined as the excess mortality caused
by the bacteremia. It is determined by subtracting the crude mortality rate
of the control patients from the crude mortality rate of the cases.15
STATISTICAL ANALYSIS
Continuous variables are described as mean ± SD and median (interquartile
range). Comparative tests on categorical variables are executed with the Pearsons  2 test and with the Mann-Whitney test on continuous variables.
Survival curves for patients with MSSA and MRSA bacteremia and their
respective control groups were prepared according to the Kaplan-Meier method.
For the analysis between patients with MSSA and MRSA bacteremia, survival
was compared from the onset of the bacteremia. For cases and controls, survival
curves are compared from the time of ICU admission. The log-rank test and
Wilcoxon test were used to determine significance between survival curves.
To assess relationship between mortality and a set of variables, multivariate
survival analyses were executed following the Cox proportional hazards model.
In this multivariate analysis, continuous variables are handled as such. Hereby,
hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. Variables
with a P value greater than .10 were removed from
the equation.
For differences between observed mortality and expected mortality rates,
as assessed on the basis of the APACHE II classification, 95% CIs are reported.
The z test was used to compare attributable mortality rates of MSSA and MRSA
bacteremia. Statistical analyses were performed with STATISTICA 4.5 (Statsoft
Inc, Tulsa, Okla) and SPSS 9.0 (SPSS Inc, Chicago, Ill) software. All tests
are 2-tailed, and statistical significance is defined as a P value less than .05.
RESULTS
During the 7-year study period, 22 431 patients were admitted to
the ICU. In 85 patients a microbiologically documented S aureus bacteremia was diagnosed. This represents a prevalence of
3.8 cases of S aureus bacteremia in 1000 ICU admissions.
Fifteen patients developed S aureus bacteremia
within 72 hours of hospital admission. Of these, 12 were MSSA and 3 MRSA bacteremia.
In our opinion, these specific S aureus bacteremias
could not be considered community acquired because none of these patients
had septicemia as a principal diagnosis at time of admission and the S aureus bacteremia was diagnosed after surgery or placement
of central venous catheters in all patients.
THE COHORT STUDY (MSSA VS MRSA)
Thirty-eight patients had S aureus bacteremia
involving MSSA. An MRSA bacteremia was diagnosed in 47 patients. Population
characteristics for both groups are given in Table 1.
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Table 1. Population Characteristics for Intensive Care Patients With
MSSA and MRSA Bacteremia*
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There was a significant difference between both groups in ICU stay,
time of hospitalization prior to the onset of the S aureus bacteremia, and length of ventilator dependency. Patients with MRSA
bacteremia also had more acute renal failure and hemodynamic instability.
However, both of these comorbidities were also more present in this group
before the onset of the bacteremia. The APACHE II scores and related expected
in-hospital mortality rates were significantly higher in the MRSA group.
Figure 1 shows the survival
curves for patients with bacteremia involving MSSA and MRSA. At the end of
the hospital stay, mortality rates for patients with MSSA and MRSA bacteremia
were respectively 23.7% and 63.8% (P<.001). Multivariate
survival analysis demonstrated acute renal failure (HR, 4.13; 95% CI, 1.99-5.58; P<.001), methicillin resistance (HR, 1.93; 95% CI, 1.18-3.18; P = .009), length of mechanical ventilation (HR, 1.02;
95% CI, 1.00-1.03; P = .01), and age (HR, 1.02; 95%
CI, 1.00-1.03; P = .01) to be independent predictors
of in-hospital mortality.
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Figure 1. Survival curves for intensive
care patients with bacteremia involving methicillin-susceptible Staphylococcus aureus (MSSA) (n = 38) and methicillin-resistant S aureus (MRSA) (n = 47) (log-rank test, P = .001; Wilcoxon test, P<.001).
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THE MSSA BACTEREMIA CASE-CONTROL STUDY
Population characteristics of cases and controls are shown in Table 2. Compared with their control subjects,
patients with MSSA bacteremia had a longer ICU stay, a longer ventilator dependency,
and more acute respiratory failure. Despite these differences, the attributable
mortality rate for MSSA bacteremia was only 1.3% (95% CI, -15.2% to
17.8%) as in-hospital mortality rates for cases and controls were respectively
23.7% and 22.4% (P = .94). Figure 2 demonstrates the survival curves for both groups. The mortality
rate observed in the control group (22.4%) did not differ from the expected
mortality rate (26.0%) as assessed on basis of the APACHE II classification
system (95% CI, 13.0%-31.8%).
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Table 2. Population Characteristics for Patients With MSSA Bacteremia
(Cases) and Their Matched Control Subjects*
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Figure 2. Survival curves for intensive
care patients with methicillin-susceptible Staphylococcus
aureus (MSSA) bacteremia (n = 38) and their matched control subjects
(n = 76) (log-rank test, P = .435; Wilcoxon test, P = .44).
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A multivariate survival analysis showed acute renal failure to be independently
associated with fatal outcome (HR, 3.24; 95% CI, 1.6-6.48; P<.001). Hemodynamic instability reached a level of borderline significance
(HR, 1.54; 95% CI, 0.99-2.39; P = .06).
THE MRSA BACTEREMIA CASE-CONTROL STUDY
Population characteristics of cases and controls are given in Table 3. Compared with their controls,
patients with MRSA bacteremia had a longer ICU stay, a longer ventilator dependence,
more acute renal failure, and more hemodynamic instability. In this case-control
analysis, an attributable mortality rate of 23.4% (95% CI, 6.5%-40.3%) was
found, since mortality rates for cases and controls were respectively 63.8%
and 40.4% (P = .02). Figure 3 demonstrates the survival curves for cases and controls.
Although control subjects seem to die earlier, mortality did not significantly
differ in the first weeks of ICU stay. Once most case patients developed their
MRSA bacteremia (after a mean ICU stay of 20 days), curves cross and diverge
further on during ICU and hospital stay. The observed mortality rate in the
control group (40.4%) did not differ from the mortality rate that was expected
on the basis of the APACHE II classification system (42.4%; 95% CI, 30.5%-50.3%).
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Table 3. Population Characteristics for Intensive Care Patients With
MRSA Bacteremia (Cases) and Their Matched Control Subjects*
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Figure 3. Survival curves for intensive
care patients with methicillin-resistant Staphylococcus
aureus (MRSA) bacteremia (n = 47) and their matched control subjects
(n = 94) (log-rank test, P = .12; Wilcoxon test, P = .40).
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A multivariate analysis demonstrated the following variables to be independent
predictors of mortality: length of ICU stay (HR, 1.02; 95% CI, 1.01-1.03; P<.001), APACHE II score (HR, 1.04; 95% CI, 1.02-1.06; P<.001), hemodynamic instability (HR, 1.76; 95% CI,
1.14-2.71; P = .01), and MRSA bacteremia (HR, 1.72;
95% CI, 1.10-2.68; P = .02). Acute renal failure
reached a level of borderline significance (HR, 1.50; 95% CI, 0.97-2.34; P = .07).
COMPARISON OF THE ATTRIBUTABLE MORTALITY RATES OF MSSA AND MRSA BACTEREMIA
The difference between the attributable mortality rates of MSSA bacteremia
(1.3%) and MRSA bacteremia (23.4%) was 22.1%. This difference was statistically
significant (95% CI, 8.8%-35.3%).
COMMENT
Since methicillin resistance has become widespread, the debate whether
MRSA bacteremia is associated with higher mortality than MSSA bacteremia has
been ongoing. Because of important differences in population characteristics,
outcome comparisons are difficult to perform. Patients infected with MRSA
tend to be older, sicker, and more debilitated. In contrast with MSSA-infected
patients, they mostly have a history of prior antibiotic use and a longer
time of hospitalization.5-6,16-22
Previous studies comparing outcomes in MSSA and MRSA bacteremia revealed
some conflicting data. Most studies could not find a higher mortality rate
among patients with bacteremia involving MRSA.2, 17, 23-26 Other
investigators found significantly higher fatality rates in patients with MRSA
bacteremia.27-28 Probably the
most powerful study concerning clinical outcomes in patients with MSSA and
MRSA bacteremia was performed by Soriano et al.29 These
authors compared 225 episodes of MRSA bacteremia with 683 episodes of MSSA
bacteremia. In this cohort study, patients with MRSA bacteremia were older
and sicker and had, as a consequence, a higher intrinsic mortality rate. Methicillin
resistance was associated with shock, a variable recognized to be an independent
predictor of mortality. Besides this cohort study, Soriano et al composed
163 matched pairs of patients with MSSA and MRSA bacteremia on basis of preexisting
comorbidities, prognosis of underlying disease, and length of hospitalization
prior to the bacteremia. Notwithstanding this matching procedure, there were
still more comorbidity factors and a higher rate of shock and related mortality
in the MRSA group. In a logistic regression analysis, methicillin resistance
was not independently associated with shock and mortality. Based on this finding,
the authors concluded that cohort studies tend to magnify the relationship
of MRSA with clinical markers of microbial pathogenicity by inadequately controlling
for underlying disease and, hence, previous studies might have overestimated
the pathogenic impact of methicillin resistance. This may also account for
our cohort study wherein, notwithstanding adjustments for comorbidity factors
and APACHE II score, methicillin resistance appeared to be an independent
predictor of mortality.
To overcome major differences in population characteristics and, in
particular, severity of illness, we investigated outcomes in MSSA and MRSA
bacteremia by means of 2 independent case-control studies, after which attributable
mortality rates of MSSA and MRSA bacteremia were compared. Based on a MEDLINE
search (April 2001), we assume that this study contains the largest number
of exclusive ICU patients. To our knowledge, this study is the first to investigate
outcomes between MSSA and MRSA patients by comparing attributable mortality
rates obtained by case-control studies.
Crucial for the interpretation of the results is the level of coincidence
between cases and controls. The matching procedure used in the case-control
studies was based on severity of illness and diagnostic category at the time
of ICU admission because these are the most important prognostic indicators
in ICU patients with S aureus bacteremia.7, 25-26 In both case-control
studies, the mortality rates observed in the control groups were nearly equal
to the mortality rate that was expected on the basis of the APACHE II classification
system. This indicates that we had 2 dependable control groups.
Time-dependent variables such as length of hospitalization prior to
the onset of the infection and length of hospitalization may confound outcome
studies dealing with nosocomial bloodstream infections.30 As
found in general,23, 25-29,31-33 and
also in our cohort study, length of hospitalization prior to S aureus bacteremia was significantly longer in the MRSA group (Table 1). We question, however, the confounding
impact of this variable in our study: length of stay prior to the bacteremia
was not associated with fatal outcome in the multivariate survival analysis
(cohort study).
Our data revealed that in critically ill patients, MRSA bacteremia carries
a higher attributable mortality than bacteremia involving MSSA. The MSSA case-control
study revealed a nonsignificant attributable mortality rate of 1.3%, whereas
in the MRSA case-control study, an attributable mortality rate of 23.4% was
found. In the MRSA case-control study, cases were more likely to have more
comorbidities and a longer length of stay in the ICU, as well as a longer
length of mechanical ventilation. This seems not to hamper the interpretation
of the results. First, in the MSSA case-control study, there was also more
acute respiratory failure, a longer ICU stay, and a longer length of ventilator
dependency noted in the case patients. In this case-control study, these differences
seemed not to affect the outcome. Second, a more rigorous matching procedure
taking into account more comorbidities and/or time-dependent variables might
have led to overmatching with loss of validity or statistical power.25
The fact that MRSA bacteremia carries a significantly higher fatality
rate and attributable mortality does not prove causality between methicillin
resistance and deleterious outcome. A higher clinical virulence among MRSA
strains can be suggested based on studies reporting a higher infection rate
with S aureus among nasal carriers of MRSA compared
with MSSA-colonized patients.32, 34 However,
also in this setting, MRSA carriers tend to have a more debilitated physical
condition, hampering a fair comparison. Moreover, once nasal S aureus colonization has become established, selective antibiotic
pressure promotes nasal MRSA colonization to a higher degree than colonization
with methicillin-susceptible isolates because MRSA strains are resistant to
multiple antimicrobial agents and not exclusively to  -lactams.35 Consequently, MRSA colonization leads to autoinfection
at a higher rate than does MSSA colonization.
Several experimental, in vitro studies tried to find stronger virulence
attributes in MRSA strains.18-19,36-42 Of
all these laboratory investigations, only 1 reported a higher production of
lipase in MRSA strains,42 and one found MRSA
strains to have a lesser ability to bind to fibronectin compared with MSSA
strains.18 These data make us conclude that
the virulence of staphylococci is more closely tied to particular strains
than to methicillin resistance. This is an interesting finding considering
that our analysis was based on single-center experience. Coincidentally, the
virulence of an MRSA strain, which is frequently isolated in our ICU, may
be very high. This might represent a bias we could not adjust for given the
retrospective fashion of our study. Besides the hypothetical differences in
clinical virulence between methicillin-susceptible and methicillin-resistant
isolates, the restriction in therapeutic options might be a reasonable explanation
for the striking difference in attributable mortality between MSSA and MRSA
bacteremia. Methicillin-resistant S aureus infections
are treated with glycopeptides (rifampicin is not licensed for this indication
in Belgium), which are less powerful antibiotics than oxacillin or cloxacillin,
drugs of choice in the treatment of MSSA infections. In fact, based on a cohort
of patients with bacteremic pneumonia involving MSSA, Gonzalez et al43 reported a significantly higher mortality rate in
patients treated with glycopeptides compared with patients treated with cloxacillin.
Based on this, we assume that the worse outcome in patients with MRSA bacteremia
might be a consequence of a less effective antibiotic therapy. With new antibiotic
agents against resistant gram-positive infections, such as linezolid, quinupristin-dalfopristin,
and telithromycin, there might be some optimism. However, compared with the
currently available glycopeptides (vancomycin and teicoplanin), their clinical
benefits in terms of survival remain unclear.
We noted a high rate (26.3%) of inappropriate antibiotic therapy among
patients with MSSA bacteremia. Of the 10 patients with inappropriately treated
MSSA bacteremia, 3 patients died (2 of whom died before MSSA bacteremia was
diagnosed). Although inappropriate treatment was not associated with important
excess mortality in our population, it is generally accepted that every S aureus bacteremia should be treated promptly. The reason
for the high rate of appropriate antibiotic treatment in the MRSA cohort might
be our intensive screening policy. In every ICU patient, site-specific surveillance
cultures are taken 3 times weekly. In our MRSA cohort, colonization preceded
bacteremia in 83% of the patients. Methicillin-susceptible S aureus colonization preceded bacteremia in 37% of the cases (data
not shown). In this way, intensivists were more often alerted by prior MRSA
colonization, resulting in a high rate of appropriate antimicrobial therapy
from onset of clinical infection.
CONCLUSIONS
Following a similar case-control matching procedure, our data revealed
that MRSA bacteremia carries a significantly higher attributable mortality
than bacteremia involving MSSA. Given the close matching on the basis of APACHE
II score and diagnostic category, the higher attributable mortality in MRSA
bacteremia cannot be solely due to differences in severity of underlying disease
and acute illness. Because there is little evidence of suspecting MRSA strains
to be more virulent, the most plausible explanation for the 22.1% higher attributable
mortality rate seems to be the less bactericidal potential of glycopeptides
compared with oxacillin or cloxacillin. From this we conclude that all efforts
to limit the endemic spread of MRSA must go on and, when possible, S aureus infections should be treated with oxacillin or cloxacillin.
AUTHOR INFORMATION
Accepted for publication February 13, 2002.
Dr Blot is supported by a Special Doctoral Grant of the Fund for Scientific
Research—Flanders (Belgium).
This study was presented in part at the 40th Interscience Conference
on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, September 17-20,
2000, and at the First International Symposium on Resistant Gram-Positive
Infections, San Antonio, Tex, December 3-5, 2000.
The authors thank D. De Bacquer, PhD, from the Department of Public
Health, Ghent University, and G. Van Maele, MA, from the Department of Medical
Informatics, Ghent University, for reviewing statistics, and K. Kint, PharmD,
from the Department of Pharmacia, Ghent University Hospital, for providing
data on antibiotic use.
Corresponding author and reprints: Stijn I. Blot, RN, MSc, Ghent
University Hospital, Department of Intensive Care, De Pintelaan 185, B-9000
Ghent, Belgium (e-mail: Stijn.Blot{at}rug.ac.be).
From the Department of Intensive Care, Ghent University Hospital, Ghent
Belgium.
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