Staphylococcus Aureus Network Adaptive Platform Trial

PLATFORM Inclusion Criteria: Patients must fulfil all of the following criteria to be eligible to enter the SNAP trial: 1. Staphylococcus aureus complex grown from ≥1 blood culture 2. Admitted to a participating hospital at the time of eligibility assessment (OR if patient has died, they were admitted to this site anytime from the time of blood culture collection until the time of eligibility assessment) PLATFORM Exclusion Criteria: Potentially eligible participants meeting any of the following criteria at the time of eligibility assessment for platform entry will be excluded from the randomised platform (but may still participate in the registry): 1. Time of anticipated platform entry is greater than 72 hours post collection of the index blood culture (Where the time of culture collection is not recorded, the time of laboratory registration of the sample will be used as an alternative) 2. Polymicrobial bacteraemia, defined as more than one organism (at species level) in the index blood cultures OR in any subsequent blood culture reported between the collection of the index blood culture and platform eligibility assessment, excluding those organisms judged to be contaminants by either the microbiology laboratory or treating clinician. 3. Known previous participation in the randomised SNAP platform 4. Known positive blood culture for S. aureus (of the same silo: PSSA, MSSA or MRSA) between 72 hours and 180 days prior to the time of eligibility assessment 5. Treating team deems enrolment in the study is not in the best interest of the patient 6. Treating team believes that death is imminent and inevitable 7. Patient is for end-of-life care and antibiotic treatment is considered not appropriate 8. Patient \<18 years of age and paediatric recruitment not approved at recruiting site 9. Patient has died since the collection of the index blood culture To be included in any of the following DOMAINS the participant must met eligible for the PLATFORM (as listed above) ADJUNCTIVE TREATMENT DOMAIN Inclusion Criteria: 1. All participants that met the PLATFORM eligible are eligible to be included in this domain unless they meet any of the following exclusions listed. 2. Patients are eligible for this domain regardless of S. aureus susceptibility testing results to clindamycin. Exclusion criteria: 1\. Previous type 1 hypersensitivity reaction to lincosamides 2. Currently receiving clindamycin (lincomycin) or linezolid which cannot be ceased or substituted 3. Necrotising fasciitis 4. Current C. difficile associated diarrhoea (any severity) 5. Current severe diarrhoea from any cause (defined as Grade 3 or higher) 5. Known CDAD (C.Difficile Associated Diarrhoea) in the past 3 months, or CDAD relapse in the past 12 months 6. At the time of domain eligibility assessment, more than 4 hours has elapsed since platform entry 7. Treating clinician deems enrolment in this domain is not in the best interest of the patient PSSA, MSSA TREATMENT DOMAIN (backbone) Inclusion Criteria: 1. For PSSA silo: Index blood culture isolate is penicillin-susceptible as per the Microbiology Appendix. In short, this will require phenotypic disc testing with EUCAST (a P1 disc diffusion with zone \>=26mm OR a P1 disc diffusion with zone \>=26mm and the zone edge is NOT sharp) OR CLSI (a P10 disc diffusion) defined criteria. 2. For MSSA silo: Index blood culture isolate is methicillin-susceptible as per the Microbiology Appendix. Note that where trial sites are not testing for penicillin-susceptibility, patients with MSSA/PRSA can be included in the MSSA silo, but those with MSSA/PSSA (but not confirmed with a P-disc) will be excluded from the backbone domain. The rationale for this is that patients with MSSA but not tested with a P-disc may be truly PSSA (with no blaZ). If the cefazolin inoculum effect (CIE) is a clinically relevant entity, then including patients with an organism without blaZ (and hence cannot have a CIE phenotype), will bias towards non-inferiority of cefazolin compared to (flu)cloxacillin. For PSSA, the requirement for laboratories to use an accredited phenotypic test for a penicillin-susceptible phenotype, is to ensure clinical safety according to internationally accepted guidelines. The automated antimicrobial susceptibility testing, and other phenotypic tests, have poor sensitivity for detection of blaZ compared to a gold standard of blaZ PCR. Therefore, patients could be placed at risk of treatment with benzylpenicillin when the infecting isolate is actually blaZ positive, unless these guidelines are followed. Exclusion Criteria (PSSA \& MSSA): 1. \>72 hours have elapsed since the collection of the index blood culture (i.e. the time of collection of the first positive blood culture from the patient during this episode) 2. History of type I hypersensitivity reaction (i.e. anaphylaxis or angioedema) to any penicillin or cephalosporin 3. History of severe delayed reaction (e.g. allergic interstitial nephritis, cutaneous vasculitis, Stevens-Johnson, DRESS, etc.) to any penicillin or cephalosporin 4. PSSA silo: Non-severe rash to any penicillin (unless patient has been subsequently de-labelled; this criteria does not include criteria 2 and 3 above), or MSSA silo: Non-severe rash to cefazolin or any penicillin (unless patient has been subsequently de-labelled); (Nausea, diarrhoea, headache, and other non-specific symptoms are NOT allergies, they are drug intolerance, and they are not exclusion criteria. Similarly, a vague history of an allergy of unclear nature, or a family history of allergy are not exclusions.) 5. Treating team deems enrolment in this domain is not in the best interest of the patient 6. Currently receiving maintenance dialysis (haemodialysis or peritoneal dialysis); (Acute renal replacement therapy (including CRRT, haemodialysis or peritoneal dialysis) are not exclusions. Such patients are eligible as long as appropriate vascular access is available or can be arranged.) 7. Polymi