Staphylococcus Aureus Bacteremia Antibiotic Treatment Options

• 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.

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:

• MSSR: penicillinase-resistant penicillins (e.g. flucloxacillin, cloxacillin), β-lactam plus β-lactamase-inhibitors (e.g. ampicillin+sulbactam, piperacillin+tazobactam), cephalosporins (except ceftazidime), carbapenems, clindamycin, fluoroquinolones, trimethoprimsulfamethoxazole, doxycycline, tigecycline, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, ceftobiprole, and macrolides.
• MRSA: vancomycin, teicoplanin, telavancin, fluoroquinolones, clindamycin, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, linezolid, daptomycin, macrolides, ceftaroline, and ceftobiprole.

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:

• deep-seated focus: e.g. endocarditis, pneumonia, undrained abscess, empyema, and Osteomyelitis
• septic shock, as defined by the AACP criteria (23), within 4 days before randomization
• prolonged bacteremia: positive follow-up blood culture more than 72h after the start of adequate antimicrobial therapy
• body temperature >38 °C on two separate days within 48h before randomization
• Presence of the following non-removable foreign bodies (if not removed 2 days or more before randomization):

• prosthetic heart valve
• deep-seated vascular graft with foreign material (e.g. PTFE or dacron graft). Hemodialysis shunts are not considered deep-seated vascular grafts.
• 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 (as defined below), 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 (as defined below), 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 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:

• 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 (as defined below), 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

• 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 biologicals within the previous year
• 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:

• oral hormonal contraception ('pill')
• dermal hormonal contraception
• vaginal hormonal contraception (NuvaRing®)
• contraceptive plaster
• long-acting injectable contraceptives
• implants that release progesterone (Implanon®)
• tubal ligation (female sterilisation)
• intrauterine devices that release hormones (hormone spiral)
• double barrier methods
• 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