Preventive Antibiotics in Stroke Study

Stroke is a leading cause of death worldwide. In the Netherlands, the incidence
of acute stroke is approximately 40.000 per year. This incidence is increasing
because of the ageing population. The percentage of patients with poor outcome
is high (50%). Associated costs after stroke are substantial with mean lifetime
cost varying between 38,000 and 133,000 euro per person. Fever after stroke is
a strong predictor for poor outcome. The cause of fever in stroke patients is
most often lung or urinary tract infection. Infections occur in up to 50% of
patients with stroke and have also been associated with poor outcome. Recent
randomized studies have shown that preventive antibiotic therapy lowers
infection rate in patients after stroke. Phase III trials evaluating the effect
of preventive antibiotic therapy on clinical outcome in sufficient numbers of
patients with stroke have not been performed. ceftriaxone, an off-patent
medicine, is an antibiotic with broad action against bacteria causing the most
common infections after stroke. Recent studies have also suggested a
neuroprotective effect of ceftriaxone. The administration of ceftriaxone is
simple and safe, and can easily be incorporated in standard care. Therefore,
preventive therapy with ceftriaxone has a great potential to effectively reduce
the proportion of patients with poor outcome after acute stroke and a large
randomized clinical trial is warranted.

To investigate whether preventive use of the antibiotic ceftriaxone improves
functional health outcomes in patients with stroke by preventing infection.
This will be done in a large multi-centre randomized controlled trial. Within
this trial we will also assess the cost-effectiveness of this preventive
treatment.

We will conduct a multi-centre prospective, randomized, open-label, blinded
endpoint (PROBE) trial of standard care and preventive treatment with
ceftriaxone as compared to standard care without ceftriaxone. Adult patients
with stroke (both ischemic and haemorrhagic) and a score >= 1 on the National
Institutes of Health Stroke Scale (NIHSS) will be included. Patients will be
randomly assigned to receive ceftriaxone, at a dose of 2 g given every 24 hours
intravenously for 4 days, or no treatment against a background of best medical
management. The primary end point will be functional health at 3-month
follow-up, as assessed by the modified Rankin Scale (mRS), dichotomized as a
favourable outcome (0 to 2) or an unfavourable outcome (3 to 6). Secondary
outcome measures will be death rate at discharge and 3 months, infection rate
during hospital admission, length of hospital admission, volume of post-stroke
care, including antibiotics used during the 3 months follow-up, functional
health using the full ordinal scoring range of the mRS, quality adjusted life
years (QALYs) and costs. The sample size calculation based on the assumption
that ceftriaxone will reduce the proportion of patients with an unfavourable
outcome from 50 to 45%. A two group Chi-square test with a 0.05 two-sided
significance level will have 80% power to detect the difference between a
standard care proportion of 0.50 and a treatment group proportion of 0.45 (odds
ratio of 0.818) when the sample size in each group is 1565. We intend to enrol
a total of 3200 patients.

The study medication will be ceftriaxone 2000 mg, intravenously, 1 times daily,
for 4 days. Ceftriaxone is started within 24 hours after stroke onset. The
associated direct costs of this intervention are approximately ¤50. If patients
will be discharged before day 3 after admission, study medication will be
stopped. If the treating physician decides to withdraw active treatment in a
patient with a very poor prognosis, study medication will also be stopped. The
treating physician decides whether or not to treat a patient with suspected
infection with (additional) antibiotics. Recommendations will be made for the
treatment of infections according to the Dutch SWAB guidelines for antibiotic
policy.

After inclusion in this trial an urineanalysis will be performed in every
patient, in addition to standard care. This examination is a limited burden to
the patient.

After these examinations, patients will be randomized to receive either
standard care with ceftriaxone through an intravenous infusion or standard care
without ceftriaxone. Placement of this infusion will in a majority of cases be
included in the standard care, although if not, it will form a minor burden for
the patient. An intravenous infusion always gives (low) risks of infection at
the place of insertion.

Risks side-effects of treatment with Ceftriaxon have been discussed before
(E9). Ceftriaxon has been shown to be safe in numerous trials. Side-effects are
known and will be monitored, especially the occurrence of
hypersensitivity-reactions and diarrea.

When there is suspicion of an infection in patients during admission,
diagnostic procedures to define the focus of infection will be performed
according to a predefined algorithm. This will include a chest X-ray, a
bloodsample/culture, urine-analysis and culture and if possible a
sputumculture. These examinations are standard procedures in stroke-care and
will therefore not form an additional burden to the patient.

After 3 months patients will be interviewed telephonically by a structured
questionnaire, which will be sent to the patient one week in advance. These
activities form a low burden for the patient without further risks.