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Treatment and Outcome of Staphylococcus aureus Bacteremia
A Prospective Study of 278 Cases
Allan G. Jensen, MD;
Carsten H. Wachmann, MSc, PhD;
Frank Espersen, MD, PhD;
Jens Scheibel, MD;
Peter Skinhøj, MD, PhD;
Niels Frimodt-Møller, MD, PhD
Arch Intern Med. 2002;162:25-32.
ABSTRACT
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Background Staphylococcus aureus bacteremia is still a
serious problem, and the optimal treatment is under debate. Only a few studies
concerning treatment are available.
Methods The study population was all patients with a positive blood culture
result for S aureus in Copenhagen County, Denmark,
from May 1994 through April 1996. Of 278 patients with S aureus bacteremia, 186 were evaluated according to outcome in a prospective,
observational follow-up study. The time above the minimum inhibitory concentration
was estimated for dicloxacillin sodium for each treatment regimen and evaluated
by logistic regression along with other potential risk factors.
Results The following variables were statistically associated with death: the
presence of an uneradicated focus (odds ratio [OR], 6.7; 95% confidence interval
[CI], 2.1-21.0); the presence of septic shock (OR, 3.7; 95% CI, 1.5-9.1);
the total daily dose of penicillinase-stable penicillin less than 4 g (OR,
3.7; 95% CI, 1.3-11.1); and age 60 years or older (OR, 2.4; 95% CI, 1.1-5.3).
The following variables were significantly associated with recurrence: the
total daily dose of penicillinase-stable penicillin less than 3 g (OR, 3.9;
95% CI, 1.6-10.0) and the presence of a secondary focus (OR, 3.2; 95% CI,
1.3-7.7). Among 155 patients with observation time longer than duration of
treatment, this factor (duration of treatment, <14 days) was significantly
related to mortality (OR, 0.84; 95% CI, 0.76-0.94).
Conclusions Focus eradication and the dosing of penicillinase-stable penicillin
are important to the outcome of S aureus bacteremia.
We recommend treatment with at least 1 g of penicillinase-stable penicillins
4 times daily for longer than 14 days.
INTRODUCTION
STAPHYLOCOCCUS AUREUS is still one of the most
important pathogens of bacteremia.1-5
Despite the availability of potent antistaphylococcal antibiotics, S aureus bacteremia (SAB) is still an important problem with a high
mortality,6-9
and studies are already available on this condition.6, 8, 10-13
Some data on the importance of focus identification and focus eradication
in the treatment of SAB are available,7, 10
and (based on primarily experimental evidence) the time the serum drug concentration
remains above the minimal inhibitory concentration (MIC) is an important pharmacokinetic
parameter for the effect of  -lactam antibiotics14-18
when determining the appropriate dosage. However, very few clinical studies
have investigated the optimal dosing strategy of -lactam antibiotics
in the treatment of SAB. One study19 showed
equal efficacy with continuous infusion compared with intermittent infusion
of 2 g of oxacillin 6 times daily; however, a significantly less amount of
the drug was used with continuous infusion.
In the present study of consecutive SAB cases, we compare outcomes in
hospital-acquired SAB vs community-acquired SAB and specifically address the
role of the bacterial focus and the administration of penicillinase-stable
penicillin in multiple regression analysis.
POPULATION, MATERIALS, AND METHODS
STUDY POPULATION, MICROBIOLOGICAL METHODS, AND COLLECTION OF DATA
The study period was from May 1, 1994, to April 30, 1996, and comprised
236 136 admissions to 4 community hospitals (2404 somatic beds), which
serve 604 762 inhabitants in Copenhagen County, Denmark. The Department
of Clinical Microbiology at Herlev University Hospital, Copenhagen, received
all clinical samples from this area. All specimens were routinely registered
in a microbiological database system (ADBakt, Autonik AB; Ramsta, Sköldinge,
Sweden) running on a digital minicomputer (model VAX 4200; Compaq Computer
Corp, Houston, Tex) with 40 connected terminals.20
The blood culture system used was Colorbact (Statens Serum Institut).21-22 All S aureus
strains isolated were phage typed according to the method of Blair and Williams23 using the current international set of typing phages.
The phages were used in concentrations of routine dilution: 100x and
1000x routine dilution. The subdivision into phage groups and complexes
was done according to Parker.24
Susceptibility to antibiotics of the infecting strains was determined
by a disk diffusion method.25 The testing comprised
susceptibility to penicillin, streptomycin, tetracycline, erythromycin, methicillin,
and gentamicin. When a blood culture was detected as positive for S aureus in the clinical microbiology laboratory, the patient was seen
by one of us (A.G.J.), in most cases within 24 hours. After receiving informed
consent, the patient was examined at bedside, and clinical data were obtained
from the chart. From reviewing medical records, the following data were extracted:
source of infection, sex, age, underlying disease and/or condition, type and
time of symptoms, and clinical findings (ie, primary and secondary foci; hospital
investigations, such as echocardiography, radiography, bone scintigraphy,
and computed tomography scanning; and type, duration, and daily dosage of
antibiotic treatment). All medical records were reviewed by the same person
(A.G.J.) 3 months after a blood culture was found positive for S aureus to establish time of hospital admission and 3-month survival
and recurrence outcome.
DEFINITIONS
Based on the history of the patient, physical examination findings,
body temperature, clinical course, and results of cultures from other body
sites, it was decided whether the bacteremia was a true bacteremia or if it
had to be regarded as a contamination according to Weinstein et al.26 True bacteremia cases were subdivided into hospital-
and community-acquired cases. A hospital-acquired bacteremia was defined as
a patient with a positive blood culture result and clinical evidence of infection
that developled later than 48 hours after admission.26
Episodes in patients with infections of implanted foreign bodies were considered
hospital acquired. Underlying condition was any disease and/or underlying
condition recorded prior to or at admission. Onset of infection was the time
of first appearance of symptoms. Primary focus of infection was based on evident
clinical signs and/or symptoms that were later confirmed by the cultivation
of a bacterial strain with the same resistance pattern as the blood culture
strain. Endocarditis, osteomyelitis, arthritis, and meningitis were considered
secondary foci if the patients had not received surgical intervention prior
to the onset of SAB. Finding S aureus in the urinary
tract was considered secondary to SAB if the patient did not have signs and/or
symptoms of urinary tract infection and a primary focus of infection other
than in the urinary tract was demonstrated. Foci of infection were divided
into identified and not identified. Identified foci were further subdivided
into eradicable and not eradicable, and eradicable foci were further subdivided
into eradicated and not eradicated. Eradicable foci included drainable abscesses
and foci with indwelling foreign bodies, such as peripheral and central intravenous
catheters, urinary tract catheter, subcutaneous arteriovenous fistula, transvenous
pacemaker, pleural drain, Hoffmann apparatus, and endoprosthesis. Noneradicable
foci included skin, respiratory tract, urinary tract, gastrointestinal tract,
endocarditis, osteomyelitis, meningitis, and arthritis. Eradicated foci included
foci in which cases abscesses and indwelling foreign bodies, such as intravenous
catheters, urinary tract catheters, had been drained or removed, respectively.
Unknown foci were considered not eradicable. Septic shock included both severe
sepsis and septic shock as defined by Muchardt et al.27
Death was considered attributable to SAB if the patient died within 5 weeks
after a blood culture was found positive or if the patient died in connection
with recurrence of SAB. Recurrence was defined as a new blood culture result
positive for S aureus with the same resistance pattern
and phage type within 3 months from the onset of SAB and after antibiotic
treatment had been stopped.
TREATMENT
Patients who died within 3 days after a blood culture was found positive
for S aureus and patients who survived without treatment
were excluded from the analysis. To evaluate the importance of dose and dosing
interval, only patients (n = 186) treated with dicloxacillin sodium were included
in the present statistical analysis.
Based on simple pharmacokinetic principles and under the assumption
that the dicloxacillin sodium kinetics fit an open 2-compartment model, the
time above the MIC (T>MIC) was estimated for dicloxacillin sodium
for each treatment regimen. In accordance to Löfgren et al,28
the MIC of dicloxacillin sodium for S aureus was
0.4 mg/L and peak concentrations of dicloxacillin 30 minutes after intravenous
administration (1 hour after oral administration) were 100 mg/L(oral, 30 mg/L)
and 200 mg/L (oral, 60 mg/L) for 1 and 2 g, respectively. The serum elimination
half-life was estimated to be 2 hours with a 3% free concentration of dicloxacillin
sodium assumed throughout. Set in relation to the total time of treatment
(Ttotal), the T>MIC/Ttotalof the protein-free
fraction was estimated to be 78% for intravenous dicloxacillin sodium, 1 g
three times daily, and 100% for intravenous dicloxacillin sodium, 1 g four
times daily and 2 g three times daily. Similarly, the area under the free
serum dicloxacillin concentration curve (AUC) above the MIC (AUC/MIC) was
estimated for the 3 dosage regimens (data not shown).
STATISTICAL METHODS
The following potential risk factors associated with survival and recurrence
in this study were evaluated by logistic regression analysis: age, sex, the
origin of infection, the time from onset of symptoms to SAB, underlying malignancy,
the presence of a septic shock, the eradication of a primary focus, the presence
of a secondary focus, the total daily dose, the T>MIC/Ttotal, and the total AUC. Statistical analysis was performed with computer
software (SAS/STAT; SAS Institute Inc, Cary, NC), using the GENMOD procedure
to account for overdispersion and PHREG procedure for Kaplan-Meier estimates
of survival and recurrence functions.
RESULTS
INCIDENCE
From 236 136 patients admitted to the 4 hospitals during the study
period, 296 episodes of SAB were detected. Of these, 18 (6%) were regarded
as contaminations, and of the remaining 278 true bacteremia cases, 147 (53%)
were hospital acquired and 131 (47%) community acquired. Thus, the total incidence
rate of true bacteremia cases was 1.18 per 1000 admissions (0.62 for hospital-acquired
cases and 0.56 for community-acquired cases).
PHAGE TYPING AND ANTIBIOTIC RESISTANCE
Strains belonging to phage type group II and type 95 were isolated most
frequently (65 [23%] and 54 [19%], respectively). Of 278 S aureus strains isolated, 57 (21%) were susceptible to all antibiotics
tested, 186 (67%) were resistant to penicillin alone, and 35 (13%) were resistant
to more than 1 antibiotic. Only 3 (1%) of the isolated S aureus strains were resistant to methicillin. Community-acquired
strains did not differ significantly from hospital-acquired strains in accordance
to phage type distribution or resistance pattern (data not shown). Thus, no
strains seemed especially related to hospital infection in this study.
PATIENT CHARACTERISTICS
The median age (70 years) for patients with community-acquired SAB was
higher than the median age (62 years) for patients with hospital-acquired
SAB; however, the sex distribution was not significantly different (Table 1). Patients with malignancies and
patients receiving immunosuppressive therapy were most frequently found among
the hospital-acquired cases (Table 1).
These patients and patients receiving hemodialysis more often had hospital-acquired
SAB, while intravenous drug abusers had primarily community-acquired infection
compared with other patients.
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Table 1. Clinical Data for Patients With Community-Acquired SAB Compared
With Hospital-Acquired SAB*
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SYMPTOMS AND INFECTIOUS FOCI
Fever was registered in nearly all patients (97%) (Table 1). Septic shock was recorded in 70 cases (25%), and when
further analyzed it did not relate to source of infection or primary foci
(Table 1, data not shown).
PORTAL OF ENTRY
Intravenous catheters and postoperative wounds were most often the primary
foci of SAB infection (90 [61%]) in hospital-acquired cases, while skin lesions
predominated in community-acquired cases (53 [40%]) (Table 1). The number of cases with an unknown portal of entry was
much higher for community-acquired cases vs hospital-acquired cases (Table 1). Patients with community-acquired
SAB had a higher frequency of secondary infection, especially endocarditis
and osteomyelitis (Table 1).
TREATMENT
Patients who died within 3 days after a positive blood culture finding
(n = 38) and patients who survived without treatment (n = 5) were excluded
from the analysis. Of the resulting 235 patients, 186 (79%) were treated with
penicillinase-stable penicillin (dicloxacillin sodium); 24 (10%), with penicillin
G or ampicillin sodium; 13 (6%), with a second-generation cephalosporin; 8
(3%), with vancomycin hydrochloride; and 2 (0.85%), with aminoglycoside either
alone or with erythromycin base. None of the patients were treated with a
third-generation cephalosporin.
Of the 186 patients treated with dicloxacillin sodium, 162 were treated
with dicloxacillin sodium intravenously followed by oral treatment. Of these
patients, 16 (10%) received less than 3 g/d; 101 (62%), 3 g/d; 22 (14%), 4
g/d; and 23 (14%) above 4 g/d. Of the resulting 24 patients (13%) who received
oral dicloxacillin sodium only, most received 1.5 g/d or 3 g/d (11 [46%] and
10 [42%], respectively).
OUTCOME
The overall mortality rate was 34% and was nonsignificantly higher in
patients with community-acquired SAB compared with patients with hospital-acquired
SAB (Table 1). The overall recurrence
rate was 12% and possibly higher for hospital-acquired SAB (Table 1). Neither the mortality rate nor the recurrence rate was
statistically associated to the type of primary or secondary focus (data not
shown). The respiratory tract as the portal of entry was associated with a
relatively high mortality (27 [63%] of 43 patients), especially for hospital-acquired
SAB (14 [74%] of 19 cases), compared with community-acquired SAB (13 [54%]
of 24 cases); however, this finding was not significant (P = .32). The mortality rate of patients with no secondary infection
was 36% (79 of 218 patients). For these patients, the mortality rate was higher
for community-acquired SAB compared with hospital-acquired SAB (41 [49%] of
83 vs 38 [28%] of 135; P = .002). Mortality was higher
in patients with septic shock (46 [66%] of 70) compared with patients without
septic shock (49 [24%] of 208; P<.001), and patients
receiving hemodialysis had a lower mortality rate (3 [10%] of 30) than the
remaining patients (92 [37%] of 248; P = .002). However,
mortality rates for patients with malignancy (24 [36%] of 67), patients receiving
immunosuppressive therapy (26 [40%] of 65), and patients who abuse alcohol
(17 [45%] of 38) did not differ significantly from patients without these
characteristics (Table 1). The
recurrence rate was higher for patients with osteomyelitis (7 [35%] of 20)
than for patients without a secondary focus (19 [9%] of 218; P = .002). Patients with endocarditis also had a higher recurrence
rate (3 [14%] of 22) than patients without a secondary focus; however, this
finding was not significant (P = .45).
OUTCOME VS FOCUS IDENTIFICATION, REMOVABILITY, AND REMOVAL
The mortality and recurrence rates related to focus identification,
eradicability, and eradication are given in Table 2. Of the remaining 235 patients, the mortality rate and the
recurrence rate of patients with an identified focus were not significantly
higher compared with that of patients with an unidentified focus (P = .36 and P = .43, respectively) (Table 2). The mortality rate was lower
for patients with an eradicable focus than for other patients (P = .002) (Table 2).
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Table 2. Outcome Related to Focus Treatment for Patients With SAB*
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Of the 87 patients with an eradicable focus, both the mortality rate
and the recurrence rate were significantly lower for cases in which the focus
had been eradicated compared with cases in which the focus was not eradicated
(P = .001 and P = .04, respectively)
(Table 2). The same findings were
observed when patients with endocarditis were excluded in accordance to Iannini
et al.7 The outcome was not related to time
of focus identification, type of drug administration, or time of treatment
(data not shown).
FACTORS SIGNIFICANTLY ASSOCIATED WITH OUTCOME
Factors associated with death and recurrence in a logistic regression
analysis are presented in Table 3
and Table 4, respectively. The
presence of an uneradicated focus, the presence of septic shock, age 60 years
or older, and a total daily dose of dicloxacillin sodium less than 4 g were
factors significantly associated with death (Table 3), and the presence of a secondary focus and a total daily
dose of dicloxacillin sodium less than 3 g were associated with recurrence
(Table 4). Both T>MIC/Ttotal and the AUC/MIC percentages were significantly associated with
outcome, but the logistic regression analysis did not allow the selection
of either parameter as the most important. This lack of distribution between
the 2 parameters may be explained by the high correlation between the T>MIC/Ttotal and AUC/MIC percentages. The importance of focus
eradication for patient survival and presence of a secondary focus for SAB
recurrence are illustrated by Kaplan-Meier plots in Figure 1 and Figure 2,
respectively. The importance of the latter factor could be evaluated because
the observation period was longer than the duration of treatment for 155 patients.
The mortality was 23% (17 of 74 patients) for patients treated for less than
14 days and 4% (3 of 81 patients) for patients treated for 14 days or more
(P<.001). Variation in duration of treatment among
these patients somewhat obscures these observations. Among the 155 patients,
the total daily dose of dicloxacillin sodium was no longer significant: less
than 4 g/d intravenously (mortality, 18 [16%] of 116) vs 4 g/d or more intravenously
(mortality, 2 [5%] of 39) (P = .1). If duration of
treatment was included in the logistic regression analysis with all the factors
mentioned in Table 3, only 2 factors
were significantly correlated with outcome: duration of treatment (OR, 0.84;
95% CI, 0.76-0.94; P = .001) and focus removal (OR,
15; 95% CI, 1.9-121; P = .01).
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Table 3. Univariate and Regression Analyses of Mortality Related to
SAB in 186 Patients*
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Table 4. Univariate and Regression Analyses of Recurrence Following
SAB in 186 Patients*
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Figure 1. Kaplan-Meier estimate of the survival
function in Staphylococcus aureus bacteremia cases according
to focus removal.
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Figure 2. Kaplan-Meier estimate of the recurrence
fraction according to secondary focus.
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COMMENT
In the present study, 53% of the SAB cases were hospital acquired, which
is in the lower range compared with other studies (46%-87%).6, 8, 29-38
This is probably because of the large number of patients admitted directly
from the community in contrast to other studies from larger tertiary hospitals
or referral centers in United States.39 However,
this is similar to our previous 1-year case-control study,40
the SAB cases of which were included in this 2-year study. The total incidence
rate of bacteremia cases was 1.18 per 1000 admissions.
The role of S aureus as a potential contamination
is debated. Some larger studies have demonstrated very high frequencies of
contamination.6, 26, 41
We considered S aureus a contamination in only 6%
of our cases based on the 1983 criteria by Weinstein et al.26
Patients with S aureus contaminants had a much better
outcome compared with other patients because they fully recovered without
antibiotic treatment or after treatment with 1 dose of aminoglycoside alone.
The patient record was based on observations of the attending physicians,
ie, those participating in the daily care of the patient and not of the reviewer
only. No differences were demonstrated between hospital-acquired and community-acquired
cases according to phage type distribution and antibiotic resistance, indicating
that no special hospital strains were present during the study period. Other
studies from Denmark have similarly demonstrated that the phage type pattern
and the antibiotic resistance are now almost identical among hospital- and
community-acquired infections.38, 42-43
Only 3 (1%) of the S aureus strains isolated
were resistant to methicillin. These 3 methicillin-resistant strains were
found in the same dermatology department at the same time and were a result
of a clonal spread. The high frequency of penicillin-sensitive strains and
particularly the low frequency of methicillin is similar to findings from
previous studies in 1992 from the same area.5, 38
These findings are highly remarkable and exclusively found in the Scandinavian
countries and may be because of the strict antibiotic policy and strict infection
control policies enforced in the study area.
The median age for patients with community-acquired SAB was higher than
for patients with hospital-acquired SAB (Table 1), while patients with underlying diseases more often had
hospital-acquired SAB (Table 1),
since these conditions necessitated hospital admission in themselves. Patients
with an unknown focus most often had community-acquired SAB (Table 1), possibly because of a longer history of illness and less
precise information for patients with community-acquired SAB prior to hospital
admission.
Cases of SAB in which endocarditis and osteomyelitis developed were
rarely hospital acquired (Table 1).
Whether this is because of a longer duration of bloodstream infection without
antibiotic therapy, which would have been instituted if patients had been
in the hospital, is unknown. Of the 64 patients who underwent transthoracic
echocardiography, 42 patients (66%) had no signs of endocarditis. However,
the sensitivity of transthoracic echocardiography is only around 50%.44-45 Patients with malignancies, patients
treated with immunosuppressive therapy, and patients receiving hemodialysis
more often had nosocomial SAB (Table 1).
The high mortality of SAB associated with hospital-acquired respiratory tract
infection has already been demonstrated46-47
but may be explained by the high mortality of other conditions observed among
these patients in the present study, such as sepsis, alcohol abuse, immunosuppressive
therapy, and malignancy. Patients receiving hemodialysis had a low mortality
rate similar to findings by Quarles et al,48
probably because of the relatively good clinical conditions of patients with
renal disease and good surgical and medical intervention that was available
for these patients (eg, early initiation of antibiotic treatment and focus
removal). The recurrence rate for patients with osteomyelitis was high (35%)
compared with other patients and was even higher compared with that seen in
our previous study (10%)49; however, rates
varying from 3% to 40% have been seen in other studies9, 50-53
and is related to the duration of antibiotic treatment.49
In contrast to what might be expected, patients with an identified focus did
not have lower mortality and recurrence rates compared with other patients
(Table 2). Instead, the mortality
rate for patients with an eradicable focus was significantly lower compared
with patients with an uneradicable focus (Table 2), and both the mortality and recurrence rates were significantly
lower for patients in whom the focus was actually eradicated. Thus, the value
of identifying and treating a focus is fully demonstrated in the present study
(Table 3) and confirms results
of other studies.7, 10, 54
Our findings that patients in a septic shock and patients 60 years or older
are at an increased mortality risk (Table
3) have already been demonstrated.13, 37, 55-56
We could not differentiate between severe sepsis and septic shock. Neither
could we establish more precise measures of predicting mortality, such as
APACHE (Acute Physiology, Age, and Chronic Health Evaluation) II score because
this scoring system only evaluates patients in intensive care treatment. The
overall mortality rate was higher in patients with community-acquired SAB
than in patients with hospital-acquired SAB; however, this difference was
not significant (Table 1).
In the present study, multivariate analysis concerning SAB demonstrated
that the total daily antibiotic dosage of dicloxacillin sodium is significantly
associated with death (Table 3)
and recurrence (Table 4). Both
the T>MIC/Ttotal and the AUC/MIC percentages were correlated
to outcome, but the statistical calculation did not allow the selection of
either parameter as most important. The T>MIC value has been the
most important pharmacokinetic parameter for -lactam antibiotics,14-18
which demonstrates that a dosage of dicloxacillin sodium of 1 g four times
daily or 2 g three times daily is superior to 1 g three times daily. The dosage
of 1 g three times daily theoretically provides a T>MIC for only
78% of the dosing interval in contrast to 100% for the former 2 doses. The
fact that the importance of the T>MIC could not be discerned from
the AUC/MIC percentage stems from the paucity of different dosing regimens
used. If individual pharmacokinetic measurements had been devised (ie, by
measuring serum dicloxacillin concentration in each patient) and related to
outcome, this might have allowed a more exact estimate of the most important
pharmacodynamic parameter. There was no difference in mortality between patients
treated with intravenous therapy followed by oral therapy and patients treated
with only oral therapy. Therefore, this aspect was not further evaluated.
However, the results of this study lead to the conclusion that the dosing
regimen of dicloxacillin sodium is important for outcome. A recent article
retrospectively reported excellent outcomes in 20 patients treated with continuous
flucloxacillin infusion for deep tissue infections.57
Decisions regarding dosage, interval, and duration of treatment were
made by the attending physicians in this study. Most patients were treated
with dicloxacillin sodium (1 g three times daily) because this is the conventional,
registered dosage in Denmark. The duration of antibiotic treatment was significantly
related to outcome in the present study; however, proper evaluation of this
factor is difficult in such an observational study because the patients in
many cases are treated according to clinical response and not with fixed regimens.
There was no significant relation between outcome and penicillin susceptibility
(data not shown), and the outcome of patients with methicillin-resistant SAB
could not be evaluated because there were very few patients with methicillin-resistant
SAB in the study. The outcome of patients with penicillin-sensitive S aureus strains treated with penicillin was not significantly
different from patients treated with dicloxacillin sodium (data not shown);
however, there is a need for future case-control studies. Although this is
not a controlled, randomized study and population-based pharmacokinetic calculations
may be problematic, we find our results useful and relevant. However, for
evaluation of different antibiotic treatment regimens, controlled, randomized
studies are needed in the future.
In conclusion, SAB continues to be associated with high mortality and
recurrence rates. The present study emphasizes that an uneradicated focus,
septic shock, and older age are associated with SAB-related death, and the
presence of a secondary focus is associated with the risk of recurrence. Furthermore,
the present study indicates for the first time that dicloxacillin sodium taken
1 g four times daily or 2 g three times daily seems superior to 1 g three
times daily in the treatment of SAB infection.
AUTHOR INFORMATION
Accepted for publication April 30, 2001.
Dr Jensen was supported by research fellowship 12-1621 from the Danish
Research Council, Copenhagen.
Corresponding author and reprints: Allan G. Jensen, MD, Bldg 45,
Sector for Microbiology, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen
S, Denmark (e-mail: allan.garlik{at}dadlnet.dk).
From the Sector for Microbiology (Drs Jensen, Espersen, and Frimodt-Møller)
and Biostatistical Unit (Dr Wachmann), Statens Serum Institut; the Department
of Clinical Microbiology, Herlev University Hospital (Dr Scheibel); and the
Department of Infectious Diseases, Rigshospitalet (Dr Skinhøj), Copenhagen,
Denmark.
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