Nosocomial bloodstream infections caused by Klebsiella pneumoniae: impact of extended-spectrum β-lactamase (ESBL) production on clinical outcome in a hospital with high ESBL prevalence
BMC Infectious Diseases
Nosocomial bloodstream infections caused by Klebsiella pneumoniae: impact of extended-spectrum -lactamase (ESBL) production on clinical outcome in a hospital with high ESBL prevalence
Alexandre R Marra 2
Srgio B Wey 2
Adauto Castelo 2
Ana Cristina Gales 1 2
Ruy Guilherme R Cal 0
Jos R do Carmo Filho 1
Michael B Edmond 3
Carlos Alberto P Pereira 2
0 Intensive Care Unit, Hospital Israelita Albert Einstein , Sao Paulo , Brasil
1 Clinical Microbiology Laboratory, Universidade Federal de Sao Paulo, Brasil (UNIFESP-EPM)/Hospital Sao Paulo (HSP) , Brasil
2 Division of Infectious Diseases, Universidade Federal de Sao Paulo, Brasil (UNIFESP-EPM)/Hospital Sao Paulo (HSP) , Brasil
3 Department of Internal Medicine, Medical College of Virginia Campus, Virginia Commonwealth University , Richmond, Virginia , USA
Background: The frequency of ESBL producing Klebsiella pneumoniae bloodstream infections (BSI) is high in Brazilian hospitals, however little is known regarding what role, if any, resistance plays in the expected outcome in hospitals with a high prevalence of these pathogens. Methods: From 1996 to 2001, hospital acquired K. pneumoniae BSI were evaluated retrospectively. Each patient was included only once at the time of BSI. ESBL producing strains were identified using the E-test method. The association of variables with the mortality related to bacteremia was included in a stepwise logistic regression model. Results: One hundred and eight hospital acquired K. pneumoniae BSI met criteria for inclusion. Fifty two percent were due to ESBL producing strains. The overall in-hospital mortality was 40.8%. Variables independently predicting death by multivariate analysis were the following: mechanical ventilation (p = 0.001), number of comorbidities (p = 0.003), antimicrobials prescribed before bacteremia (p = 0.01) and fatal underlying disease (p = 0.025). Conclusion: Bacteremia due to ESBL producing K. pneumoniae strains was not an independent predictor for death in patients with BSI. An increased mortality in hospital-acquired BSI by K. pneumoniae was related to the requirement for mechanical ventilation, more than two comorbidities, the previous use of two or more antibiotics, and the presence of a rapidly fatal disease.
Klebsiella pneumoniae is an important cause of many
infections . It ranks among the top ten pathogens that cause
bloodstream infection (BSI) in the United States and
Canada . In Latin America, it is the third most prevalent
pathogen isolated in the respiratory tract of hospitalized
patients with pneumonia and corresponds to 12% of all
pathogens isolated .
Extended-spectrum -lactamase (ESBL) producing
organisms were first isolated in Germany in 1983  and in the
United States in 1989 . ESBLs are plasmid-mediated
enzymes that hydrolyze broad-spectrum -lactams .
The emergence of ESBL-producing K. pneumoniae has been
reported as an important cause of nosocomial infection in
the United States and Europe. The prevalence of
ESBLproducing K. pneumoniae strains in hospitals, ranges from
5 to 25% in several parts of the world [7,8]. In Brazilian
hospitals, the frequency of ESBL-producing K. pneumoniae
is higher than those observed in many European and
American hospitals, accounting for 45% of K. pneumoniae
It has been shown that a poor outcome occurs when
patients with serious infections due to ESBL-producing
organisms are treated with antibiotics to which the
organism is highly resistant . The mortality rate in such
patients is significantly higher than those observed in
patients treated with antibiotics to which the organism is
susceptible. In addition, a suboptimal clinical outcome
occurs when cephalosporins are used for the treatment of
serious infections due to ESBL-producing organisms,
which may appear to be susceptible on the basis of
cephalosporin MICs of 2 to 8 g/mL .
Risk factors associated with infections caused by ESBL
producing organisms include central venous catheters
, tracheostomy , and cephalosporin use ,
however little is known regarding what role, if any,
resistance plays in the expected outcome in hospitals with a
high prevalence of these pathogens.
The aim of this study was to evaluate whether ESBL
producing K. pneumoniae is associated with a high mortality
rate in a hospital with a high ESBL prevalence.
A retrospective cohort study was carried out at the
Universidade Federal de So Paulo, a 624-bed university
hospital, located in the state of So Paulo, Brazil. The study was
approved by the Hospital Ethics Committee. All patients
for whom blood culture results were positive for K.
pneumoniae from January 1996 to May 2001 were eligible for
inclusion in the study. Each patient was included only
once. If multiple blood cultures from the same patient
were positive for the above organism, only the first
episode was reviewed and recorded. Pseudobacteremia
caused by K. pneumoniae, defined as the presence of a
positive blood culture without clinical manifestations of
sepsis (fever, hypotension, tachycardia, tachypnea and
leukocytosis or leukopenia), and cases with incomplete
data in the medical record were excluded.
Clinical and laboratory characteristics of patients
Potential risk factors for mortality due to K. pneumoniae
infection were ascertained by means of a review of
medical charts. Data obtained included age, sex, ward, number
of hospital days prior to infection, the presence of a
central venous line, haemodyalisis, Swan-Ganz and urinary
catheters, draining tubes and mechanical ventilation. The
presence of septic shock was defined by a systolic blood
pressure 90 mmHg or a reduction of 70 mmHg in
systolic blood pressure in hypertensive patients. The severity of
illness at the time of bacteremia was classified by the
Simplified Acute Physiology Score (SAPS) . The presence
of the following comorbid conditions was documented:
cardiovascular diseases, solid or hematologic
malignancies, neurological diseases, renal failure (indicated by a
creatinine level >2.0 mg/dL or the requirement of
dialysis), diabetes mellitus, hepatic dysfunction, chronic
obstructive pulmonary disease, intravenous drug use, and
HIV infection. Previous antibiotic treatment was defined
as an antibiotic prescribed for at least 48 hours during the
fifteen-day period prior to the onset of BSI .
Underlying diseases were classified according to the
McCabe classification . Nosocomial infections and
sources of infection were defined according to Centers for
Disease Control and Prevention (CDC) criteria .
Inadequate empiric antimicrobial treatment was defined as
therapy administered within 24 hours after blood cultures
were obtained that included the administration of an
antimicrobial agent to which the K. pneumoniae isolate was
resistant . Antimicrobial agents were considered
adequate if the organism was susceptible, except when
cephalosporins were used for the treatment of ESBL infections
. A group of five infectious disease specialists
responsible for BSI surveillance at our hospital assessed the
adequacy of antimicrobial therapy (including the dosage and
route of administration) for patients infected with K.
pneumoniae BSI. We inform doctors (generally residents or
fellows) about the blood culture results daily (in two
periods, generally in the morning and in the afternoon). We
based our adequacy of antimicrobial treatment for
ESBLproducing K. pneumoniae on guidelines that were written
and followed by these five infectious diseases specialists.
Each case was reviewed by all five physicians,
independently. Rarely, when there was any discordance among us,
the final decision was made after further discussion with
the majority deciding on the adequacy of antimicrobial
LOS = Length of hospital stay
therapy. Mortality was defined as death from any cause
within 15 days from the date of the first positive blood
culture for K. pneumoniae.
Blood cultures (consisting of a pair of blood culture
bottles including aerobic and anaerobic resin-containing
media) obtained from adult patients were processed using
the BACTEC 9240 blood culture system (Beckton
Dickinson, USA). Organisms were identified according to
routine bacteriological procedures. Susceptibility testing was
performed by the disk diffusion method, following the
National Committee for Clinical Laboratory Standards
(NCCLS) recommendations . K. pneumoniae isolates
were screened for the ESBL phenotype according to the
NCCLS guidelines . The ESBL phenotype was
confirmed using the E-test ESBL (AB BIODISK, Solna,
The association of variables was compared by the use of
the 2 or Fisher's exact tests as appropriate. Significance
probabilities (p values) were defined for entry and
removal of variables in the logistic regression model: p
value <0.05 (deaths from the univariate analysis) and p
value <0.10, respectively. All tests of significance were two
When colinearity existed between two variables, only the
one that had the greatest clinical relevance associated with
mortality within 15 days was included in the multivariate
analysis. Odds ratios were calculated for independent
variables associated with 15-day mortality. The association of
independent variables was expressed as odds ratios with
95% confidence intervals. A p value of <0.05 was
considered statistically significant. All statistical calculations
were performed using SPSS for MS Windows software
(SPSS 11.0 for Windows).
During the study, 115 patients with K. pneumoniae BSI
isolates were identified, of whom 108 met criteria for
inclusion. ESBL-producing K. pneumoniae was detected in 56 of
108 patients (51%). We excluded two patients with
pseudobacteremia by K. pneumoniae and five patients were
excluded because the data in medical records were
The average age was 27.3 years (range: 078 years).
Fortyseven patients (43.5%) were less than 20 years. The most
frequent diagnoses responsible for hospitalization were
solid and hematologic malignancies (21.3%), abdominal
diseases (14.8%), neonatal diseases (premature,
congenital and genetic anomalies) (13.9%), renal failure (11%)
and respiratory infections (10%). The most frequent
sources of infection were pulmonary (38%), abdominal
(26%), central venous catheter (14%) and urinary (11%).
The median duration of hospitalization was 15.5 days.
BSI occurred in 15.7%, 10.2%, and 11.1% in the first,
second and third week of hospitalization, respectively. Most
BSI (63.0%) occurred after 21 days of hospitalization,
which can be seen in Table 1. The antibiotic therapy was
considered adequate in 63.9% (69/108) of the cases and
inadequate in 36.1% (39/108).
The proportions for the different variables in the two
groups of patients in stratified by ESBL production are
listed in Table 2. There were no age (<1 year or >60 years)
or gender differences between the two groups (p = 0.693,
p = 0.561 and p = 0.339, respectively). A higher
proportion of patients with ESBL-producing strains were in
intensive care units and had central venous catheters (p =
0.031 and p = 0.044, respectively). There was also a trend
towards more than 10 days of hospitalization in patients
ESBL (n = 56)
Non-ESBL (n = 52)
NUMBER OF COMORBIDITIES
TIME TRENDS IN MORTALITY 19961998 21 19992001 35
with ESBL-producing strains when compared to patients
with non-ESBL-producing strains BSI (p = 0.051). There
was no relevant difference in other therapeutic procedures
(pulmonary artery catheter, hemodialysis, urinary
catheter, drainage tubes and the use of any class of
antimicrobials) prior to Klebsiella BSI between the two groups.
However, case patients were significantly more likely to
need mechanical ventilation (p = 0.013). No statistically
significant difference was observed for the McCabe
classification, number of comorbidities, or sources of infection
between the two groups (p = 0.623, p = 0.662 and p =
0.343, respectively). Septic shock was present in
approximately one-quarter of the cases (p = 0.501) and
thrombocytopenia (<80.000/mm3) was present in two-quarters of
the cases (p = 0.438). Inadequate antimicrobial therapy
was more common prescribed for case patients (41.1% vs.
30.8%), however this was not statistically significant (p =
0.265). Mortality at 15 days was more common in cases
than in controls (p = 0.042). No time trends in mortality
were observed (p = 0.601).
Mortality up to fifteen days after the BSI occurred in
24.1% (26/108) of the patients. The 30-day mortality and
in-hospital mortality was 31.5% (34/108) and 37.0%
(40/108), respectively. It was also observed that 15-day
mortality was higher in patients hospitalized in intensive
care units (p = 0.019), those with urinary catheters (p =
0.009), those mechanically ventilated (p = 0.001), and
those with drainage tubes (p = 0.012).
Death in patients with potentially fatal or non-fatal
underlying disease according to the MacCabe
classification was 52.9% and 18.7%, respectively (p = 0.01).
Patients with a SAPS score >40 (at the time of bacteremia)
had a higher mortality rate than patients with a SAPS score
40, (63.3% vs. 26.2%, respectively, p = 0.014). The
mortality in patients with shock was 45.5%, whereas in
patients not requiring treatment with vasopressor drugs it
was only 18.6% (p = 0.009). Platelet counts lower than
80,000/mm3 were also associated with high mortality.
The presence of more than two comorbidities was related
to high mortality when compared to patients without any
or with one comorbidity (48.2% vs. 15.2%, p = 0.003).
Patients who received two or more antibiotics for more
than 48 hours for the fifteen-day period before the
diagnosis of BSI had higher than in those who received only
one or no antibiotic before BSI (43.2% vs. 14.1%, p =
In the subset of patients receiving adequate antibiotic
therapy, higher mortality occurred in those acquiring
ESBL-producing K. pneumoniae (36.4% vs. 11.1%, p =
0.013). On the other hand, in patients who received
inadequate antibiotic therapy, there was no difference in
15day mortality when patients with K. pneumoniae BSI with
or without ESBL production were compared (26.1% vs.
25.0%, respectively, p = 1.0). Variables found to be
statistically significant for 15-day mortality in BSI by univariate
analysis were selected for multiple logistic regression. The
following variables were independently related to death
(table 3): mechanical ventilation (OR = 5.27, IC 95% =
1.914.6, p = 0.001), two or more comorbidities, (OR =
2.39, IC 95% = 1.34.2, p = 0.003), more than two
antibiotics used before bacteremia (OR = 2.30, IC 95% = 1.2
4.3, p = 0.01), and the presence of a rapidly fatal disease
(OR = 2.14, IC 95% = 1.14.2, p = 0.025).
Of 108 patients with K. pneumoniae BSI, a high proportion
produced ESBL (51.8%). It is one of the highest ESBL
infection prevalence described in the literature comparing
with Canada (5%), United States (8%) Europe (23%) and
Pacific western region (25%) . Because of the high
incidence of this infection, we decided to investigate if the
mortality is increased in K. pneumoniae strains producing
ESBL. It is important to mention that before our study,
Gales et al.  studied 72 strains of K. pneumoniae
between January 1995 and October 1996 in the same
Greater than two comorbidities
Greater than two antibiotics
Rapidly fatal disease
institution, of which 39% were ESBL producers. However,
these authors analyzed strains that were found in
infections from many sources. Curiously, in our study, the
frequency of occurrence of ESBL-producing K. pneumoniae
was even higher than that observed by Gales et al. A
possible explanation for this fact is that there was a
dissemination of ESBL-producing strains over the years in our
institution. However, the limitations of our study should
be acknowledged. First, we do not have information
regarding the specific situation in Brazil, such as
genotyping results or type of ESBL. Only case reports were
described [20,21]. Second, we performed a retrospective
cohort study instead of a case-control study because it was
not our objective to establish the risk factors for the
acquisition of ESBL infection. Third, we did not observe a
statistically significant difference in mortality between the
ESBL producing K. pneumoniae and non- ESBL producing
K. pneumoniae BSI. The small number of cases could lead
to a type II error. And fourth we did not evaluate
co-infections or recent infections with other nosocomial bacteria
evaluated as predictors of mortality.
The 15-day mortality of K. pneumoniae BSI was 24.1%, and
69.2% in patients with ESBL producing strains. Hansen et
al., in Denmark, reported similar mortality rates in
Klebsiella bacteremia . In contrast, Menashe et al., in Israel,
reported a mortality rate of 43.6% with 50% of isolates
producing ESBL . By univariate analysis, we identified
other variables associated with mortality, such as ICU
stay, urinary catheter, mechanical ventilation, fatal
underlying disease, two or more comorbidities, a SAPS score
>40, shock, thrombocytopenia (<80,000/mm3) and
previous use of two or more antibiotics, which have been
demonstrated in previous studies [22-25]. To characterize
the severity of the patients' conditions in this study, in
addition to the MacCabe classification, we utilized the
SAPS-II classification (Simplified Acute Physiology Score)
at the time of bacteremia. We decided to use this
classification method instead of the APACHE II system used in
intensive care therapy, because it provides better-defined
criteria. However, the data are collected in the first
twentyfour hours of admission and is applicable only for
patients in intensive care. In addition, the data do not
present the seriousness of the patient's condition during
the hospitalization period. Through a univariate analysis,
we found that patients with a SAPS-II score >40 have a
higher chance of mortality when compared with patients
with a SAPS-II score 40 (p = 0.014).
Multivariate analysis identified that the most important
risk factor for death was the requirement for mechanical
ventilation. The respiratory tract was the source of BSI in
38% of patients. Fifty-two percent of the patients required
mechanical ventilation. The number of comorbidities
(more than two) and the presence of fatal underlying
disease were the variables associated with death during the
fifteen days following K. pneumoniae BSI, demonstrating
the importance of the patient's underlying diseases. The
same results were obtained by Garrouste-Orgeas et al. in
their study. These authors observed that the outcome was
influenced by the severity of the underlying host
conditions, particularly with patients requiring mechanical
ventilation . The prior use of two or more antibiotics was
independently associated with death, suggesting a
possible selection of resistant antimicrobial strains, such as
ESBL-producing strains .
By multivariate analysis, previous studies [23,24,27,28]
have reported no increase in the mortality rate of
infections caused by this resistant microorganism; these studies
identified the clinical implications of extended-spectrum
beta-lactamase (ESBL) production, not only for Klebsiella
pneumoniae, but also for E. coli. Many studies have
demonstrated that inadequate antibiotic therapy is related to an
increase in the mortality rate [7,15,16,29]. The adequacy
of antibiotic therapy was similar when we compared ESBL
and non-ESBL producing strains of K. pneumoniae. We
considered as inadequate the use of cephalosporins for all
ESBL- producing K. pneumoniae BSIs cases in the hospital
. Another important consideration is that our
institution has a high rate not only of ESBL-producing K.
pneumoniae but also ceftazidime-resistant Pseudomonas
aeruginosa and Acinetobacter baumannii. It certainly
changed our clinical practice over time and contributed to
a better appropriate antimicrobial treatment for this types
of infections. We believe that it limits our ability to
generalize these findings to hospitals with lower prevalence of
ESBL-producing K. pneumoniae. In our institution the
empiric therapy for gram-negative infections is
carbapenems. Conversely, Kim et al. had more cases of
ESBL-producing K. pneumoniae than non-ESBL-producing K.
pneumoniae receiving inappropriate antibiotic therapy
before culture results were reported (54.5 vs. 3.4%; P =
0.001). In our study, inadequate empirical therapy
showed no statistically significant difference in relation to
death regardless of ESBL production (p = 0.117). It likely
reflects the severity of the patient's underlying diseases.
However, in the study of Kim et al., which evaluated 19
cases of ESBL-producing K. pneumoniae BSI, no significant
difference in mortality was observed between patients
who received appropriate empiric antibiotic therapy and
those who did not (26.3 vs. 20.8%; P = 0.67). One the
other hand, Hyle et al. observed that inadequate initial
antimicrobial therapy was an independent risk factor for
mortality in ESBL-producing K. pneumoniae BSIs .
The mortality rate of BSI remains high, despite adequate
antibiotic treatment and intensive care measures. In our
study, an increase in mortality in hospital-acquired BSI
was related to the need for mechanical ventilation, rapidly
fatal disease, more than two comorbidities and the use of
more than two antibiotics before infection. Additional
studies should be carried out to confirm the relationship
between high mortality and ESBL-producing K.
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