The hypothesis is that a switch from intravenous to oral antimicrobial therapy is non-inferior to standard intravenous therapy in patients with low-risk SAB. Therefore, the primary objective of the trial is to demonstrate, that oral switch therapy (…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint measure, SAB-related complication, reflects the failure
rate of antimicrobial therapy in preventing late complications. This includes
both, relapsing SAB and deep-seated S. aureus infection within 90 days and is
thus the most appropriate clinical outcome measure.
Microbiological success is sometimes demonstrated by a negative blood culture
as a test of cure at EOT. Since patients in this trial have already been
treated for seven days with antimicrobials before randomization, >99% of blood
cultures obtained at EOT are expected to yield a negative result. Therefore,
microbiological success has not been chosen as an endpoint. Death unrelated to
SAB is expected at about 5% within 30 days. It was not included in the primary
endpoint because this would compromise the power of the trial by variance
inflation. However, SAB-related and all-cause mortality will be carefully
assessed and compared (secondary/safety endpoints).
Secondary outcome
The secondary endpoint, length of hospital stay, reflects the potential
benefits for patients who have been switched to oral medication. Furthermore,
14- and 30-day survival and complications related to i.v. therapy, e.g.
chemical or septic (thrombo-)phlebitis will be measured.
The safety of study drugs is assessed by monitoring Clostridium difficile
associated diarrhea (CDAD), AEs and SAEs.
Background summary
Increasing resistance to antimicrobial agents has been recognized as a major
health problem worldwide that will even aggravate due to the lack of new
antimicrobial agents within the next decade. This threat underscores the need
to maximize clinical utility of existing antimicrobials, through more rational
prescription, e.g. optimizing duration of treatment. Staphylococcus aureus
bloodstream infection (SAB) is a major cause for prolonged antimicrobial
therapy. With an approximate incidence of 25 cases per 100,000, about 200,000
cases occur annually in Europe. Recent data for Western Europe demonstrate a
crude mortality of 20-30% (in-hospital or 30-day mortality) in patients with
SAB. In many cases SAB can be cured by antimicrobial therapy. However, SAB
differs from other bloodstream infections with respect to SAB-related
complications: relapses, local extension and distant metastatic foci are
relatively common events and occur in about 2-25% of infections. Therefore,
antbiotic therapy is considered to be especially important in this disease and
standard treatment schedules are significantly longer than in other bloodstream
infections. A course of at least 14 days of intravenous antimicrobials is
considered standard therapy in *uncomplicated SAB*. Generally, *uncomplicated
SAB* is defined by absence of: community acquisition, skin examination findings
suggesting acute systemic infection, positive follow-up blood cultures and
persistent fever at 72h. Shorter courses of intravenous treatment are currently
not recommended due to the lack of sound clinical evidence. The SABATO trial
will specifically address this issue and examine the effectiveness and safety
of an abbreviated course of intravenous therapy in patients that have a
low-risk of SAB-related complications. This trial poses specific risks for the
patient. A shorter course of effective antimicrobial therapy may lead to
relapsing SAB, local spread of the infection, or hematogenous
dissemination of S. aureus with resulting deep-seated infection. To minimize
the risk, a population of patients with a very low-risk of SAB-related
complications is described by inand exlusion criteria. This population has been
validated by using data from two prospective cohort studies. Data from the
INSTINCT (Invasive Staphylococcus aureus Infection Cohort) study (10) shows a
low incidence of SAB-related complications in low-risk patients (3%; 4 of 135
patients). A pilot study for the SABATO trial with 236 SAB patients from 10
German study centers provided further evidence for a very low risk of
complications in these patients: Only 1 of 89 patients had a SAB-related
complication. Abbreviated or early i.v. to oral switch treatment strategies
have been successfully applied to other infectious diseases such as nosocomial
pneumonia, meningococcal disease, and febrile neutropenia. These strategies
allow shorter intravenous antimicrobial therapy and offer options for early
discharge from hospital. This, in turn, increases the patients* quality of
life, decreases treatment costs, reduces the risk of nosocomial infections and
may help to diminish antimicrobial resistance development and spread. The
SABATO trial is the first randomized controlled trial addressing early oral
switch therapy in SAB.
Study objective
The hypothesis is that a switch from intravenous to oral antimicrobial therapy
is non-inferior to standard intravenous therapy in patients with low-risk SAB.
Therefore, the primary objective of the trial is to demonstrate, that oral
switch therapy (OST) is as safe and effective as intravenous standard therapy
(IST). This will be achieved by comparing the rate of SABrelated complications
(relapsing SAB, deep-seated infection with S.aureus, or mortality attributable
to SAB) within 90 days. Low-risk SAB manifests itself typically in patients
with comorbidities. Therefore, survival is
largely determined by the underlying disease (18) and was not chosen as a
primary endpoint. However, death related to SAB is comprised in the primary
endpoint. Death unrelated to SAB will be carefully evaluated and compared.
The secondary objective is to measure the potential benefit for the patient.
This is achieved by evaluating the length of hospital stay after the first
positive blood culture and complications of intravenous therapy. A considerable
number of patients on OST are expected to be discharged earlier from hospital,
since hospital stay due to intravenous therapy is no longer required. This will
reduce the risks associated with hospitalization and i.v. therapy
(catheter-related infection, venous thrombosis, and septic thrombophlebitis)
and is likely to improve patients* quality of life.
Study design
Phase III, multicenter, open-label, randomized, controlled, non-inferiority
trial with a total of 430 patients enrolled.
The trial starts with the first patient visit and ends with the last visit of
the last patient. Individual patients go through a screening, intervention and
follow-up phase.
Intervention
First, patients with SAB are reported from the microbiological department to
the principle investigator. Then, individual patients with SAB are screened for
possible enrolment by the principle investigator. The intervention phase (7-9
days) starts when patients have given informed consent and all in- and
exclusion requirements are fulfilled.The length of the intervention phase
depends on how long patients have received appropriate pre-randomization
antimicrobials. All patients will receive an overall course of 14 days
appropriate antimicrobial therapy, e.g. patients having received five days of
appropriate pre-randomization antimicrobials will receive nine days of OST or
IST. Patients on OST can be discharged before end of therapy (EOT) according to
clinical and psychosocial criteria. Patients on IST can only be discharged when
an OPAT (outpatient parenteral antimicrobial therapy) service is in operation
at the local study site. The follow-up phase starts at EOT and ends 90 days
after the first positive blood culture. Patients that are still in hospital
will be visited on the ward to collect follow-up information. Discharged
patients are followed by a structured telephone interview at day 85-99.
Study burden and risks
This trial poses specific risks for the patient. A shorter course of effective
antimicrobial therapy may lead to relapsing SAB, local spread of the infection,
or hematogenous dissemination of S. aureus with resulting deep-seated
infection. To minimize the risk, a population of patients with a very low-risk
of SAB-related complications is described by inand exlusion criteria.
In turn, the patients' increases quality of life, decreases treatment costs,
reduces the risk of nosocomial infections and may help to diminish
antimicrobial resistance development and spread.
Universitätsstr. 1
Düsseldorf 40225
DE
Universitätsstr. 1
Düsseldorf 40225
DE
Listed location countries
Age
Inclusion criteria
> 18 years, not legally incapacitated, written consent, blood culture positive for S. aureus not considered to represent contamination
Negative follow-up blood culture within 24-96 hours after start of adequate antimicrobial therapy
5-7 full days of appropiate i.v. antimicrobial therapy prior to randomization
Exclusion criteria
Polymicrobial bloodstream infection
Recent history of prior SAB (within 3 months)
In vitro resistance of S.aureus to all oral or all i.v. drugs
Previously planned treatment with active drug against S. aureus during intervention phase (e.g. cotrimoxazol prohylaxis)
Signs and symptoms of complicated SAB (deep-seated focus, septic shock within 4 d, prolonged bacteremia, fever(>38C) twice within 48h before randomization
Presence of the following non-removable foreign bodies (if not removed 2 days or more before randomization): prosthetic heart valve, ascular graft, ventriculo-atrial shunt
Presence of a prosthetic joint (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled:prosthetic joint was implanted at least 6 months prior and catheter-related infection, skin and soft tissue infection or surgical wound infection is present and joint infection unlikely (no clinical or imaging signs)
Presence of a pacemaker or an automated implantable cardioverter defibrillator (AICD) device (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled: pacemaker or AICD was implanted at least 6 months prior, and
catheter-related infection, skin and soft tissue infection or surgical wound infection is present and no clinical signs of infective endocarditis, and infective endocarditis unlikely by echocardiography (preferably TEE), and pocket infection unlikely (no clinical or imaging signs)
• Failure to remove any intravascular catheter which is present when first positive blood culture was drawn within 4 days of the first positive blood culture.
• Severe liver disease. This is not an exclusion criterion, if the following condition is fulfilled:
catheter-related infection, skin and soft tissue infection or surgical wound infection is present.
End-stage renal disease. This is not an exclusion criterion, if all of the following conditions are fulfilled: catheter-related infection, skin and soft tissue infection or surgical wound infection is present and no clinical signs of infective endocarditis, and infective endocarditis unlikely by echocardiography (preferably TEE), and in patients with a hemodialysis shunt with a non-removable foreign body (e.g. synthetic PTFE loop): no clinical signs of a shunt infection
Severe immunodeficiency (e.g. neutropenia, high dose steroid therapy, immonusuppresive combination therapy, biological (last year), hematopoietic stem cell transplant, solid organ transplant)
Life expectancy < 3 months
Inability to take oral drugs
Expected low compliance with drug regimen
Participation in other interventional trials
Pregnancy/nursing
For included women: Failure to use highly-effective contraceptive methods
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-000577-77-NL |
| ClinicalTrials.gov | NCT01792804 |
| CCMO | NL48081.041.14 |