Table 1 Inclusion and exclusion criteria

• Age at least 18 years

• 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

• Not legally incapacitated

• Written informed consent from the trial subject has been obtained

• Blood culture positive for Staphylococcus aureus not considered to represent contamination

• At least one negative follow-up blood culture obtained within 48 to 72 hours after the start of adequate antimicrobial therapy to rule out persistent bacteremia

• Recent history (within 3 months) of prior S. aureus bloodstream infection

• Five to 7 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:

• In vitro resistance of S. aureus to all oral or all i.v. study drugs

• Contraindications in reference document for all oral or all i.v. study drugs

 - Antimicrobial therapy has to be initiated within 72 h after the first positive blood culture was drawn.

• Previously planned treatment with active drug against S. aureus during intervention phase (for example, cotrimoxazole prophylaxis)

 - Provided in-vitro susceptibility and adequate dosing (as judged by the principal investigator) preferred agents for pre-randomization antimicrobial therapy are: flucloxacillin, cloxacillin, vancomycin, and daptomycin. However, the following parenteral antimicrobials are allowed: MSSA: penicillinase-resistant penicillins (for example, flucloxacillin and cloxacillin), β-lactam plus β-lactamase-inhibitors (for example, ampicillin + sulbactam, piperacillin + tazobactam), cephalosporins (except ceftazidime), carbapenems, clindamycin, fluoroquinolones, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, vancomycin, teicoplanin, linezolid, daptomycin, ceftaroline, and macrolides. MRSA: vancomycin, teicoplanin, fluoroquinolones, clindamycin, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, linezolid, daptomycin, macrolides, and ceftaroline

• Signs and symptoms of complicated SAB as judged by an ID physician. Complicated infection is defined as at least one of the following:

 - deep-seated focus: for example, endocarditis, pneumonia, undrained abscess, empyema, and osteomyelitis

 - septic shock, as defined by the AACP criteria [32], within 4 days before randomization

 - prolonged bacteremia: positive follow-up blood culture more than 72 h after the start of adequate antimicrobial therapy

 - body temperature > 38 °C on 2 separate days within 48 h before randomization

• Presence of a non-removable foreign body (if not removed two days or more before randomization):

 - prosthetic joint

 - prosthetic heart valve

 - vascular graft

 - pacemaker

 - automated implantable cardioverter-defibrillator

 - ventriculo-atrial shunt

• 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

• End-stage renal disease

• Severe immunodeficiency:

 - primary immunodeficiency disorders

 - neutropenia (<500 neutrophils/μl) at randomization or neutropenia expected during intervention phase due to immunosuppressive treatment

 - uncontrolled disease in HIV-positive patients

 - high-dose steroid therapy (>1 mg/kg prednisone or equivalent doses given for > 4 weeks or planned during intervention)

 - immunosuppressive combination therapy with two or more drugs with different mode of action

 - hematopoietic stem cell transplantation within the past 6 months or planned during treatment period

 - solid organ transplant

 - treatment with biological

• 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.

• 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