Effects of Prophylactic Antibiotic Therapy With Mezlocillin
Plus Sulbactam on the Incidence and Height of Fever
After Severe Acute Ischemic Stroke
The Mannheim Infection in Stroke Study (MISS)
Stefan Schwarz, MD; Frank Al-Shajlawi, MD; Christian Sick, MD;
Stephen Meairs, MD; Michael G. Hennerici, MD
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Background and Purpose—Fever after stroke is a strong predictor for a negative outcome with infections as the most
common cause. The aim of this pilot study was to evaluate the effects of prophylactic antibiotic therapy on the incidence
and height of fever after acute ischemic stroke.
Methods—This is a randomized, controlled study of antibiotic prophylaxis in patients with ischemic stroke enrolled within
24 hours from clinical onset who presented bedridden (modified Rankin score ⬎3) with no significant infection.
Interventions included prophylactic mezlocillin plus sulbactam (3⫻2 g/1 g for 4 days) or conventional management.
Over 10 days, body temperature was continuously monitored, and the presence of infection was daily assessed. Primary
end points were incidence and height of fever; secondary end points included rate of infection and clinical outcome.
Results—Sixty patients were included (mean, 75 years; median National Institutes of Health Stroke Scale score, 16). Over
the first 3 days, patients in the intervention group showed lower mean body temperatures as well as lower daily peak
temperatures (P⬍0.05). Throughout the observation period, 15 of 30 patients in the intervention group but 27 of 30
patients in the conventionally treated group developed an infection (P⬍0.05). Mean interval until the diagnosis of
infection was 5.1 days in the intervention group and 3.3 days in the control group (P⬍0.05). Clinical outcome was more
favorable in patients with prophylactic therapy (P⫽0.01).
Conclusions—In patients with acute severe stroke, prophylactic administration of mezlocillin plus sulbactam over 4 days
decreases body temperature, lowers the rate of infection, and may be associated with a better clinical outcome. (Stroke.
2008;39:1220-1227.)
Key Words: acute stroke 䡲 antibiotic prophylaxis 䡲 fever 䡲 hyperthermia 䡲 infection
T
the limitations of its present symptomatic treatment options, it
appears reasonable to ascertain and treat the causes of fever,
and, if possible, to prevent its occurrence altogether.
The etiology of fever after stroke is not always evident. In
some patients, even a rigorous search for the cause of fever
remains unsuccessful, leading to the assumption of “central”
or “neurogenic” fever in these patients.10 However, systemic
infections are the main origin of fever after stroke. The
incidence of infection after stroke varies remarkably depending on the observation period, definitions of infection, and
patient selection.1 Infections have been extensively discussed
as a risk factor11 but, to a lesser extent, also as a complication
of stroke due to immobilization, dysphagia, or catheterizations.10 More recently, it has been hypothesized that alleged
“brain-induced immunodepression” could also contribute to
the occurrence of infection after stroke.12
Considering that (1) fever is a common finding after acute
stroke; (2) fever is associated with a negative outcome; (3) the
he prognostic importance of body temperature during the
acute phase of ischemic stroke has been increasingly
recognized. Several clinical studies have consistently shown
that in the early phase after stroke, fever (⬎37.5°C) is very
common, occurring in up to 61% of patients, and is a strong
predictor of an unfavorable outcome.1 A multitude of different biochemical and inflammatory mechanisms for the detrimental effects of fever during the acute phase of stroke have
been identified.2 Consequently, present guidelines recommend lowering fever in patients with acute stroke.3
However, in many patients, symptomatic treatment of
fever remains frustrating.4 –7 Invasive catheter-based heatexchange systems influence the body temperature more
effectively but may not be suitable for the general stroke-unit
setting due to technical and staff requirements, possible
complications, and the substantial costs of this invasive
technique.8,9 Given the prognostic significance of fever and
Received July 22, 2007; final revision received September 5, 2007; accepted September 13, 2007.
From the Departments of Neurology (S.S., C.S., S.M., M.G.H.) and Internal Medicine (F.A.-S.), Klinikum Mannheim, University of Heidelberg,
Mannheim, Germany; and the Central Institute of Mental Health (S.S.), University of Heidelberg, Mannheim, Germany.
Correspondence to Stefan Schwarz, MD, Central Institute of Mental Health, J 5, Mannheim 68159, Germany. E-mail [email protected]
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.107.499533
1220
Schwarz et al
Table 1.
Fever
Standardized Protocol for Symptomatic Treatment of
Prophylactic Antibiotic Therapy After Stroke
Table 2.
1221
Definitions of Significant Infection*
Pneumonia
Start treatment immediately as soon as the temperature exceeds 37.5°C
Step 1: 1000 mg acetaminophen per rectum or orally; may be repeated
(maximum daily dose 4 g)
Step 2: 400 mg metamizole orally or IV; may be repeated (maximum daily
dose 2 g)
Step 3: External cooling with cooling blankets
Step 4: Consider additional therapy with opiates (5 to 10 mg pethidine
subcutaneously or IV) or neuroleptics (25 to 50 mg levopromazine orally or IV)
Evidence of a new infiltrate on the chest x-ray compatible with the
diagnosis of infection plus at least one of the following findings:
Fever (temperature ⬎38.0°C)
Leukocytosis ⬎12 000/␮L or leukopenia ⬍3000/␮L
Purulent tracheal secretions
Tracheobronchitis
Purulent tracheals secretions or sputum plus at least one of the following
findings:
Fever (temperature ⬎38.0°C)
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symptomatic treatment of fever often remains ineffective; and
(4) infections are the most common cause of fever after
stroke, prophylactic antibiotic therapy to prevent fever after
stroke emerges as an appealing concept.
The aim of this phase II, randomized pilot study was to test
the primary hypothesis that prophylactic antibiotic treatment
with mezlocillin and sulbactam over 4 days decreases the
incidence, duration, and height of fever in the first 10 days
after acute, severe ischemic stroke. Secondary objectives
included the effects of antibiotic prophylactic treatment on
the rate of infection and clinical outcome parameters.
Leukocytosis ⬎12 000/␮L or leukopenia ⬍3000/␮L
Urinary tract infection
Evidence of ⬎25 leukocytes/␮L in the urine if not explained by other
findings (eg, blood contamination); each urinary tract infection in this
patient group is considered significant
Bacteremia
Evidence of bacteria in blood cultures
Sepsis
Clinical evidence of an infection with at least two of the following
findings:
Temperature ⬎38°C or ⬍35°C
Materials and Methods
Tachycardia ⬎90/min
Over a period of 2 years, 60 patients with acute ischemic stroke were
enrolled in this study. All patients were being treated at the Stroke
Unit of the Klinikum Mannheim of the University of Heidelberg
according to present American Heart Association guidelines.3 Fever
was treated using a standardized protocol (Table 1). Physiotherapy,
early mobilization, and breathing exercises were performed on a
regular basis.
We included patients in whom the diagnosis of an ischemic stroke,
with onset of symptoms less than 24 hours ago, had been established
and who were bedridden on time of inclusion (modified Rankin score
[mRS] ⬎3). We deliberately used the criterion of being bedridden
because these patients carry the greatest risk of infection and because
this simple clinical criterion would facilitate the implementation of
study results into future treatment regimes. Other eligibility criteria
were age ⱖ18 years, stable deficit as well as an estimated premorbid
mRS ⬍2.
Exclusion criteria included evidence of a significant systemic
bacterial or viral infection on inclusion, renal insufficiency (serum
creatinine ⬎2 mg/dL), immunosuppressive medication, expected life
expectancy of ⬍90 days, and intolerance to penicillin antibiotics or
sulbactam. Women of childbearing potential were also excluded.
Any infection with the need for antibacterial therapy was defined as
“significant.”
Randomization was performed using a computer-generated number sheet and by opening a numbered, sealed envelope. Patients were
randomized to either conventional management or prophylactic
antibiotic therapy:
Tachypnea ⬎20/min
1. Conventional treatment: Antibiotic therapy was initiated only
after the diagnosis of an infection had been established. Fever
as an isolated clinical symptom was not an indication for
antibiotic treatment. If antibiotic therapy became necessary,
the antibiotic drug was chosen by the treating physician
according to the underlying condition.
2. Prophylactic antibiotic treatment: The patients received 2 g
mezlocillin plus 1 g sulbactam over 20 minutes IV every 8
hours over a total of 4 days (12 infusions). If the diagnosis of
an infection was established during or after the 4-day treatment
phase, the antibiotic drug combination could either be continued or changed to another antibiotic drug regime at the
discretion of the treating physician.
Leukocytosis ⬎12 000/␮L or leukopenia⬍3000/␮L
Infection of unclear origin or other infections
Clinical evidence of an infection of unknown origin or any other systemic
infection
*Modified criteria of the Paul-Ehrlich-Society for chemotherapy.13,14
Core body temperature was continuously monitored in both groups.
In patients who needed a urinary catheter due to incontinence or
urinary obstruction, a bladder catheter with a temperature probe was
inserted. Bladder catheters were not inserted solely for study-related
reasons. In patients not needing a urinary catheter at the start of the
study or over the entire observation period, a rectal temperature
probe was inserted. Temperature values were documented on an
hourly basis during the entire observation period of 10 days.
Patients’ daily mean temperature as well as daily maximum
temperatures were assessed along with the length of time (hours)
when the temperature was ⱖ37.5°C (fever), ⱖ38.0°C, and ⱖ38.5°C.
The patients’ neurological status was assessed on a daily basis
using the National Institutes of Health Stroke Scale (NIHSS). Blood
and urine were daily taken for routine laboratory markers, including
C-reactive protein, blood cell count, and urine sediment. Radiological examinations, blood cultures, and additional assessments
to ascertain the cause of a suspected infection were only done
when clinically indicated.13,14
Because the treatment team was not blinded, an internist blinded
to the study medication assessed the evidence of significant infection
(ie, with the need for antibacterial therapy) in both treatment groups
using all available data along with standardized criteria for infections
according to present guidelines (Table 2) on a daily basis during the
study period.13,14
The final infarct location was determined using cranial CT or
MRI. Combined with other data acquired during the routine workup,
the infarct was categorized according to the TOAST15 and OCSP16
classifications.
The mRS was used to determine patients’ outcome at the end of
the observation period at day 10 and again after 90 days. The
follow-up examination at day 90 was performed by a telephone
interview.
1222
Stroke
April 2008
Table 3.
Baseline Characteristics
Conventional
Management (n⫽30)
Age, years
Sex
Time until admission, hours
Prophylactic Antibiotic
Treatment (n⫽30)
P
73⫾11
77⫾8
0.29
18 men, 12 women
12 men, 18 women
0.20
4.0⫾3.5
4.5⫾4.4
0.86
Time until start of study,
hours
11.7⫾5.5
10.9⫾5.5
0.12
Median initial NIHSS (range)
15 (5–27)
16.5 (8–28)
0.66
5
6
0.74
Initial systolic blood pressure
155⫾16
156⫾22
0.60
Initial diastolic blood pressure
85⫾15
84⫾8
0.72
Heart rate, beats/min
80⫾15
81⫾16
0.56
Body mass index
26.4⫾3.8
25.7⫾2.3
0.66
Mean initial temperature, °C
37.1⫾0.5
37.1⫾0.6
0.79
Fibrinolysis, n
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C-reactive protein, mg/dL)
8.6⫾11.8
8.2⫾8.4
0.70
White blood cell count ⫻109/L
8.6⫾2.5
9.0⫾2.0
0.42
13.3⫾1.8
13.9⫾1.4
0.08
⬍0.01
Hemoglobin, g/dL
Serum creatinine, g/dL
0.96⫾0.3
1.2⫾0.3
134.8⫾30.6
146.6⫾48.0
24 (80)
25 (83)
0.49
Active smoking, %
4 (13)
6 (23)
0.73
Blood glucose
Arterial hypertension, %
0.63
Diabetes mellitus, %
8 (27)
10 (33)
0.78
Coronary heart disease, %
6 (20)
3 (10)
0.47
Previous stroke, %
6 (20)
4 (13)
0.73
OCSP classification, %
TACI⫽4 (13)
TACI⫽3 (10)
0.85
PACI⫽19 (63)
PACI⫽22 (73)
POCI⫽5 (17)
POCI⫽1 (3)
LACI⫽2 (7)
TOAST classification (%)
LACI⫽4 (13)
Microangiopathic⫽4 (13)
Microangiopathic⫽4 (13)
Macroangiopathic⫽9 (30)
Macroangiopathic⫽5 (17)
Embolic⫽15 (50)
Unclassified⫽2 (7)
0.66
Embolic⫽18 (60)
Unclassified⫽3 (10)
OCSP indicates Oxfordshire Community Stroke Project; TACI, total anterior circulation infarction; PACI, partial
anterior circulation infarction; POCI, posterior circulation infarction; LACI, lacunar anterior circulation infarction.
Statistical analysis was done with statistical software (JMP 5.1;
SAS, Cary, NC) using nonparametric tests to detect differences
between the 2 groups. For nominal data, ␹2 or Fisher exact tests
(2-tailed) were used. Continuous or ordinal data were analyzed with
the Mann-Whitney signed rank test. Differences were considered
significant at values of P⬍0.05.
This study had been approved by the institutional ethics committee
and the German Federal Drug Administration. Informed consent was
obtained from the patients or their legal substitutes.
Results
The main patient characteristics are presented in Table 3.
Significant differences between the 2 groups could not be
detected, except for the initial serum creatinine, which was
higher in the treatment group (P⬍0.01). However, absolute
creatinine values were not notably high. The NIHSS scores
indicate that most patients had a moderate to severe neurological deficit in addition to all patients being bedridden
(mRS ⬎3). The majority of patients had sustained embolic
stroke, predominantly in the anterior circulation. Intubation
and artificial ventilation was not performed in any patient.
Mean body temperature on inclusion into the study was
37.1°C in both groups. Although signs of a significant
infection could not be found in any patient at the time of
inclusion, mean initial C-reactive protein was mildly elevated
in both groups.
All patients in the treatment group completed the treatment
over 4 days without additional antibiotic drugs. Serious
adverse events related to the prophylactic antibiotic drug
combination were not noted. Two patients in the treatment
group developed minor adverse events possibly linked to the
study drug: One patient had a suspected drug-induced exanthema, whereas in another patient, we noted clinically asymptomatic, mildly elevated liver enzymes. In both patients,
various comedications and other conditions could also have
caused these symptoms. Both adverse events were mild and
self-limited, and antibiotic drug therapy was continued. With
temperature monitoring generally well tolerated, we analyzed
a total of 10 072 single temperature measurements from all
Schwarz et al
Prophylactic Antibiotic Therapy After Stroke
1223
°C
37.7
37.6
37.5
*
37.4
37.3
*
Prophylactic
antibiotic therapy (n=30)
Conventional
treatment (n=30)
*
37.2
*
37.1
p < 0.05
Figure 1. Initial temperature on start of
study and mean daily temperatures over
10 days after stroke under conventional
treatment or prophylactic antibiotic therapy. Temperatures are significantly
higher in the conventional treatment
group at days 1, 2, and 3.
37.0
Error Bars: ± 1 Standard Error
36.9
Initial
Day
Temperature 1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day
10
Downloaded from http://stroke.ahajournals.org/ by guest on June 18, 2017
tively infrequent finding, reaching its peak on day 3 (conventional treatment group: 1.3⫾3.3 hours/day; active treatment
group 0.9⫾2.6 hours/day; P⫽0.44).
Although daily maximum temperatures were higher in the
conventional treatment group from day 1 through day 3
(P⬍0.05), after day 4, the maximum temperatures were not
longer different. In both groups, the peak of the patients’
mean maximum temperature was reached on day 3 (active
treatment: 37.8⫾0.6°C, conventional treatment: 38.1⫾0.6°C,
P⬍0.001).
Figure 4 provides an overview over patients remaining free
of fever (⬎37.5°C) who were found more frequently in the
treatment group from day 1 to day 3.
Infections were diagnosed more frequently in the conventional treatment group. Over the first 10 days, 15 patients
with prophylactic antibiotic treatment compared with 27
conventionally treated patients developed a significant infection (Fisher exact P⫽0.0015, contingency coefficient⫽0.400). Supplemental Figure I, available online at
http://stroke.ahajournals.org, shows the number of patients
remaining free from infection over the observation period. In
the conventional treatment group, most infections were diagnosed within the first few days. Although in patients receiving prophylactic antibiotic therapy, infections were also a
frequent finding, occurring in half of the total sample, half of
patients. This means that 69% of all planned temperature
measurements did actually take place. Missing measurements
were due to technical problems, death during the observation
period, temporary dislocation of the rectal probe, or transport
of the patient away from the ward for therapeutic or diagnostic interventions.
The initial temperature on inclusion into the study and the
mean daily temperatures over the first 10 days are provided in
Figure 1. In both groups, patients’ temperature increased
from the time of inclusion, reaching peak values at day 3,
after which they fell back toward normal values. Interestingly, in the active treatment group, the rise in temperature
within the first few days was markedly tapered. Throughout
day 4, the mean daily temperatures in the treatment group
were lower compared with the conventional treatment group.
After day 3, the temperature differences between the 2 groups
were no longer significant.
Figures 2 and 3 depict the duration of fever (temperature
⬎37.5°C) and temperatures ⬎38.0°C per day (hours) over the
first 10 days. The duration of both fever and temperatures
⬎38.0°C were higher in the conventional treatment group
from day 1 throughout day 4 (respectively on days 2 and 3).
Throughout day 10, the daily duration of markedly elevated pyrexia above 38.5°C did not differ between the 2
groups. However, temperatures above 38.5°C were a relahours
16
14
12
10
8
6
*
* *
*
Prophylactic
antibiotic therapy (n=30)
Conventional
treatment (n=30)
4
*
2
0
Error Bars: ± 1 Standard Error
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day
10
p < 0.05
Figure 2. Duration of fever (temperature
⬎37.5°C) per day (hours) over the first
10 days after stroke under conventional
treatment and prophylactic antibiotic
therapy. The duration of fever is significantly higher in the conventional treatment group from day 1 to day 4.
1224
Stroke
April 2008
hours
8
7
6
5
*
4
Prophylactic
antibiotic therapy (n=30)
*
3
2
Conventional
treatment (n=30)
*
1
0
p < 0.05
Figure 3. Duration of marked fever (temperature ⬎38.0°C) per day (hours) over
the first 10 days after stroke under conventional treatment and prophylactic
antibiotic therapy. The duration of fever
⬎38.0°C is significantly higher in the
conventional treatment group on days 2
and 3.
Error Bars: ± 1 Standard Error
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9
Day
10
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the infections were diagnosed during the 6 days after prophylactic antibiotic therapy was stopped. The interval before
diagnosis of the first infection was shorter in the conventional
treatment group (5.1⫾2.7 days versus 3.3⫾2.1 days,
P⫽0.003). In both groups, most infections were urinary tract
infections followed by pneumonia and tracheobronchitis
(Table 4).
The laboratory analyses revealed an increase in daily white
blood cell count and C-reactive protein levels in both groups
but no differences between the groups. Although in the active
treatment group, maximum mean white blood cell count was
at day 1 (10.493⫾3.234⫻109/L), the control group’s maximum mean white blood cell count was observed on day 2
(10.540⫾4.117⫻109/L). In the active treatment groups,
C-reactive protein levels rose to a maximum mean of
55.6⫾63.8 mg/dL on day 8. Interestingly, the peak mean
C-reactive protein levels in the control group occurred earlier,
on day 4 (52.7⫾66.4 mg/dL), before dropping thereafter (at
day 8: 33.6⫾37.4 mg/dL).
NIHSS scores showed no differences at the beginning of
the study. However, on day 2 and 3, NIHSS scores were
lower in patients receiving antibiotic drug therapy (supplemental Figure II). This coincided with the period of time
when the temperature differences were also significant.
At the end of the study, mRS did not differ between the 2
groups (Figure 5). Three patients in the conventional treat-
ment groups and one patient in the active treatment group had
died, all of them from space-occupying stroke. During short
follow-up after 90 days, clinical outcome was better among
patients having undergone prophylactic antibiotic treatment
(P⫽0.01, Figure 5).
Discussion
In this controlled phase II study on prophylactic antibiotic
therapy with fever as the primary outcome parameter, we
could demonstrate that prophylactic antibiotic therapy with
mezlocillin and sulbactam decreases the incidence as well as
the height of fever during the acute phase within the first 3 to
4 days after stroke. Moreover, prophylactic antibiotic therapy
was associated with a lower rate of infection and an improved
outcome after 90 days.
The effect size from prophylactic treatment in our study
was by far larger than the results of previous studies on
antipyretic medication for symptomatic therapy of fever after
stroke, which had shown no or only modest temperaturelowering effects.4 –7
The concept of prophylactic antibiotic therapy for patients
with an excess risk of infection is not innovative. In selected
surgical patient collectives, prophylactic antibiotic therapy
has been the subject of various studies, yielding heterogeneous results.17–19 Only a few studies have investigated
prophylactic antibiotic therapy in patients with stroke. Al-
n
30
25
20
15
10
*
5
Conventional
therapy
Prophylactic
antibiotic therapy
(n=30)
* *
*
0
day 1
day 2
day 3
day 4
Day 1: Fisher‘s exact p = <0.0001
Day 2: Fisher‘s exact p = 0.0048
Day 3: Fisher‘s exact p = 0.0159
day 5
day 6
day 7
contingency coefficient = 0.492
contingency coefficient = 0.367
contingency coefficient = 0.317
day 8
day 9
day 10
p < 0.05
Figure 4. Patients remaining free of fever
(⬎37.5°C) under conventional treatment
or prophylactic antibiotic therapy. The
incidence of fever throughout the observation period was lower in the active
treatment group throughout the first 3
days.
Schwarz et al
Table 4. Significant Infections During the Observation Period
of 10 Days
Time to first infection,
days
Prophylactic Antibiotic
Treatment (n⫽30)
Conventional
Treatment (n⫽30)
5.1⫾2.7
3.3⫾2.1
P
0.03
⬍0.01
Any infection
15
27
Urinary tract
8
18
䡠䡠䡠
Pneumonia
5
7
䡠䡠䡠
Tracheobronchitis
2
3
䡠䡠䡠
Other/unclear origin
2
2
䡠䡠䡠
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ready in 1982, Majkowski et al20 published a controlled study
on prophylactic antibiotics in 103 patients with acute stroke.
They reported a reduced incidence of infections in the active
therapy group during the first 10 days. Yet, this study,
published in a Polish-language journal during the Cold War,
was not widely recognized at the time.
More recently, 2 other studies on prophylactic antibiotic
therapy have been published, both concentrating on the
prevention of infectious complications. Chamorro et al21
performed a controlled study on the effects of levofloxacin
over 3 days after acute stroke. This study was prematurely
terminated after an interim analysis made positive effects
from active treatments unlikely. Actually, outcome after 90
days was even worse in the verum group. The authors
speculated that negative central nervous system effects of
levofloxacin could have caused the unexpected negative
effects on outcome. In this study, although hyperthermia was
not their main focus, daily temperature measurements were
taken revealing no differences between the groups. However,
body temperature was assessed with measurements in the
axilla, a method that is hardly adequate to determine the
actual core body temperature. Moreover, in contrast to our
data and the results from other studies,1,22,23 the authors found
no increase in body temperature after admission. The results
of this study are difficult to compare with our study, because
Chamorro et al included patients with ischemic and hemorrhagic stroke as well as patients with an NIHSS score ⱖ5.
Most likely, these patients were not as severely ill as our
severely ill, bedridden patients. Another recent study on
Prophylactic Antibiotic Therapy After Stroke
1225
antibiotic prophylaxis after stroke has so far only been
published as an abstract with seemingly ambiguous results.24
Also in this second study, the main focus was the incidence of
infection, and despite the negative results of the previously
mentioned study with levofloxacin, another fluoroquinolone
antibiotic, moxifloxacin, was used.
The choice of the optimum antibiotic drug to be administered for this purpose and the optimum duration of preventive
therapy remain hypothetical. We selected mezlocillin plus
sulbactam, a combination of a broad-spectrum penicillin with
a ␤-lactamase inhibitor, due to its excellent efficacy against
the most common microorganisms that can be expected in
this patient population.25 Cephalosporins, which rapidly induce drug-resistant bacteria, are possibly not preferable.26
Arguably, fluoroquinolones are also not the first choice in
patients with stroke because, as a group, they impose a
well-documented risk for central nervous system complications27 and are moreover associated with QT prolongation,28
which renders these drugs not attractive in patients with
stroke.
We performed no systematic microbiological monitoring.
Microorganisms causing an infection during the first days of
treatment in a stroke unit that are particularly difficult to treat
are not expected in this population. Theoretically, the possibility for drug-resistant bacteria to develop cannot be excluded. On the other hand, this risk appears negligible given
60 additional patients treated over a period of 2 years in a
stroke unit where over 700 patients are treated per year.
Previous studies on prophylactic antibiotic treatment in other
settings did not support the assumption that short-term
prophylactic antibiotic drug treatments facilitate the development of antibiotic drug resistance.17 However, if antibiotic
prophylaxis should be implemented into the daily routine of
stroke units, and a large number of patients would be treated
with the same antibiotic drugs within a single ward, the
development of drug resistance could constitute a point of
concern.
In the present study, the incidence of infection during the
first days after stroke was high. In accordance with the literature,
urinary and respiratory tract infections were the most common
types of infection.21,29 –32 In previous studies, the incidence of
infection as a complication of stroke varied enormously,
Figure 5. Outcome (mRS) at end of
study and 90 days after conventional
treatment or prophylactic antibiotic therapy (mRS 0⫽no symptoms, mRS 6⫽
death). At the end of the observation
period, the outcomes were not different.
On follow-up at day 90, outcome was
significantly better in the treatment
group. mRS 0 to 2 were not observed.
1226
Stroke
April 2008
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heavily depending on the observation period, the definitions
for infection, and, probably, also the diagnostic verve that has
been used to search for an infection. However, the incidence
of infection after stroke is highest in severely ill patients.29,30
This was our reason for selecting only severely ill patients
who were bedridden on inclusion. In the study by Chamorro
et al discussed previously,21 the cumulative rate of infection
at day 7 was below 20% even in the control group. A very
large sample size would be necessary to demonstrate beneficial effects from a prophylactic therapy in a population with
such a small event rate, and possible side effects from the
medication would gain more weight. Thus, in future studies,
only severely ill patients should be considered as candidates
for prophylactic antibiotic treatment.
We chose fever as the primary outcome criterion for the
following reasons; first, because fever has been more consistently demonstrated as a strong negative predictor than
infection per se, and second, because we had the intention to
circumvent methodological problems associated with the
diagnosis of infection. Especially in the early phase of a
systemic infection, often characterized by a systemic response with prominent fever (systemic inflammatory response syndrome), the underlying infection may not be easy
to establish.33 This is particularly true for urinary tract
infections. It is difficult, and in many situations even impossible, to differentiate a bland, localized urinary infection from
a systemic inflammatory syndrome originating from a urinary
tract infection. We used the strict criteria of ⬎25 leukocytes/mL in urine to diagnose a urinary infection if not
otherwise explainable (for example, with blood contamination), because this finding is an indication for antibiotic
therapy in hospitalized ill patients.13,14 Moreover, infections
are an important risk factor for stroke.11 Thus, in patients in
whom an infection is diagnosed within the first 2 or 3 days
after stroke, it may be impossible to distinguish between
infections that were clinically not yet evident on admission
and infections that were actually acquired after stroke.
Beneficial effects associated with prophylactic antibiotic
therapy were present even during the first 24 hours after
inclusion and thereafter over the first 3 to 4 days only. After
the first days, significant differences between the 2 groups
could no longer be detected. At this time, the vast majority of
patients in the control group had already been receiving
antibiotic treatment due to clinical indications, which could
explain this finding, whereas in the active treatment group,
many patients developed an infection after termination of
prophylactic antibiotic therapy.
This study has limitations. Although the design was controlled and randomized, treatment was not blinded to the
treating physicians. We tried to overcome this shortcoming
by blinding the internist, who assessed the evidence of an
infection on a daily basis to the study drug. Moreover, our
primary end point, fever, was automatically assessed. As
mentioned previously, the diagnosis of infection was established using standardized criteria. Regarding the complex
problems in diagnosing an incipient infection, an area of
uncertainty cannot be excluded. Finally, this study was not
designed or powered to detect differences in patients’ outcome. The unexpected result of an improved outcome in the
active treatment group has to be viewed with caution because
probably not all of the multiple predictors of outcome after
stroke have been sufficiently taken into consideration.
Conclusions
This is the first study demonstrating that prophylactic antibiotic therapy with mezlocillin plus sulbactam over 4 days after
acute severe ischemic stroke is well tolerated; decreases the
incidence, height, and duration of fever; lowers the rate of
infection; and may even be associated with an improved
clinical outcome.
Based on these data, a large, randomized multicenter study
using simple, practical inclusion criteria and valid functional
outcome parameters is justified to test the hypothesis that
prophylactic antibiotic therapy can actually improve clinical
outcome in this patient group.
Acknowledgments
We thank our study nurse, Kathrin Paszyna, for her help with data
management and Margarethe Keilmann and her stroke unit team for
their continuous support and efforts during this study.
Source of Funding
This work was funded by an unrestricted research grant by Pfizer
Germany, Karlsruhe, Germany, the manufacturer of sulbactam.
Pfizer had no influence on the design and conduct of the study, data
analysis, or data presentation.
Disclosures
None.
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Effects of Prophylactic Antibiotic Therapy With Mezlocillin Plus Sulbactam on the
Incidence and Height of Fever After Severe Acute Ischemic Stroke: The Mannheim
Infection in Stroke Study (MISS)
Stefan Schwarz, Frank Al-Shajlawi, Christian Sick, Stephen Meairs and Michael G. Hennerici
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Stroke. 2008;39:1220-1227; originally published online February 28, 2008;
doi: 10.1161/STROKEAHA.107.499533
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