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About
Increasing resistance to antibiotic 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 [1]. This threat underscores the need to maximize clinical utility of existing antibiotics, through more rational prescription, e.g. optimizing duration of treatment.
Staphylococcus aureus bloodstream infection (SAB) is a common disease with about 200,000 cases occurring annually in Europe [2]. A course of at least 14 days of intravenous antimicrobials is considered standard therapy [3-5] in "uncomplicated" SAB. This relatively long course serves to prevent SAB-related complications (such as endocarditis and vertebral osteomyelitis) that may result from hematogenous dissemination to distant sites. However, there is insufficient evidence that a full course of intravenous antibiotic therapy is always required in patients with a low risk of SAB-related complications.
In a multicenter, open-label, randomized controlled trial we aim to demonstrate that an early switch from intravenous to oral antimicrobial therapy is non-inferior to a conventional 14-days course of intravenous therapy regarding efficacy and safety. An early switch from intravenous to oral therapy would provide several benefits such as earlier discharge, fewer adverse reactions associated with intravenous therapy, increased quality of life, and cost savings.
Full description
WHO. WHO Global Strategy for Containment of Antimicrobial Resistance.: World Health Organization, 2001. Kern WV. Management of Staphylococcus aureus bacteremia and endocarditis: progresses and challenges. Curr Opin Infect Dis 2010;23(4):346-58. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006;57(4):589-608. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52(3):e18-55. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49(1):1-45.
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Inclusion criteria
Age at least 18 years
Not legally incapacitated
Written informed consent from the trial subject has been obtained
Blood culture positive for S. aureus not considered to represent contamination
At least one negative follow-up blood culture obtained within 24-96 hours after the start of adequate antimicrobial therapy to rule out persistent bacteremia and Absence of a blood culture positive for S. aureus at the same time or thereafter.
Five to seven full days of appropriate i.v. antimicrobial therapy administered prior to randomization documented in the patient Chart. Appropriate therapy has all of the following characteristics:
Antimicrobial therapy has to be initiated within 72h after the first positive blood culture was drawn.
Provided in-vitro susceptibility and adequate dosing (as judged by the PI) preferred agents for pre-randomization antimicrobial therapy are flucloxacillin, cloxacillin, vancomycin and daptomycin. However, the following antimicrobials are allowed:
Exclusion criteria
Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. aureus from a blood culture obtained in the time from two days prior to the first positive blood culture with S. aureus until randomization. Common skin contaminants (coagulase-negative staphylococci, diphtheroids, Bacillus spp., and Propionibacterium spp.) detected in one of several blood cultures will not be considered to represent polymicrobial infection
Recent history (within 3 months) of prior S. aureus bloodstream infection
In vitro resistance of S. aureus to all oral or all i.v. study drugs
Contraindications for all oral or all i.v. study drugs
Previously planned Treatment with active drug against S. aureus during Intervention Phase (e.g. cotrimoxazol prophylaxis)
Signs and symptoms of complicated SAB as judged by an ID physician. Complicated infection is defined as at least one of the following:
Presence of the following non-removable foreign bodies (if not removed 2 days or more before randomization):
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:
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:
Failure to remove any intravascular catheter which was 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:
End-stage renal disease. This is not an exclusion criterion, if all of the following conditions are fulfilled:
Severe immunodeficiency
Life expectancy < 3 months
Inability to take oral drugs
Injection drug user
Expected low compliance with drug regimen
Participation in other interventional trials within the previous three months or ongoing
Pregnant women and nursing mothers
For premenopausal women: Failure to use highly-effective contraceptive methods for 1 month after receiving study drug. The following contraceptive methods with a Pearl Index lower than 1% are regarded as highly-effective:
Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
Persons held in an institution by legal or official order
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215 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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