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 ifpatient has died, they were admitted to this site anytime from the time of bloodculture 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 theindex blood culture (Where the time of culture collection is not recorded, the timeof laboratory registration of the sample will be used as an alternative)

2. Polymicrobial bacteraemia, defined as more than one organism (at species level) inthe index blood cultures OR in any subsequent blood culture reported between thecollection of the index blood culture and platform eligibility assessment, excludingthose organisms judged to be contaminants by either the microbiology laboratory ortreating 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 thepatient

6. Treating team believes that death is imminent and inevitable

7. Patient is for end-of-life care and antibiotic treatment is considered notappropriate

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 thisdomain unless they meet any of the following exclusions listed.

2. Patients are eligible for this domain regardless of S. aureus susceptibility testingresults 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 theMicrobiology Appendix. In short, this will require phenotypic disc testing withEUCAST (a P1 disc diffusion with zone >=26mm OR a P1 disc diffusion with zone >=26mmand 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 theMicrobiology 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. thetime of collection of the first positive blood culture from the patient during thisepisode)

2. History of type I hypersensitivity reaction (i.e. anaphylaxis or angioedema) to anypenicillin or cephalosporin

3. History of severe delayed reaction (e.g. allergic interstitial nephritis, cutaneousvasculitis, Stevens-Johnson, DRESS, etc.) to any penicillin or cephalosporin

4. PSSA silo: Non-severe rash to any penicillin (unless patient has been subsequentlyde-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 subsequentlyde-labelled); (Nausea, diarrhoea, headache, and other non-specific symptoms are NOTallergies, they are drug intolerance, and they are not exclusion criteria.Similarly, a vague history of an allergy of unclear nature, or a family history ofallergy are not exclusions.)

5. Treating team deems enrolment in this domain is not in the best interest of thepatient

6. Currently receiving maintenance dialysis (haemodialysis or peritoneal dialysis); (Acute renal replacement therapy (including CRRT, haemodialysis or peritonealdialysis) are not exclusions. Such patients are eligible as long as appropriatevascular access is available or can be arranged.)

7. Polymicrobial bacteraemia (defined as more than one organism [at species level] inblood cultures, excluding those organisms judged to be contaminants by either themicrobiology laboratory or treating clinician) reported between collection of theindex blood culture and backbone domain eligibility assessment

8. Patient currently being treated with a systemic antibacterial agent that cannot beceased or substituted for interventions allocated within the platform (unlessantibiotic is listed in Table 1 of the DSA, which specifies allowed antibiotics withlimited absorption from the gastrointestinal tract or negligible antimicrobialactivity against S. aureus)

MRSA TREATMENT DOMAIN (backbone)

Inclusion Criteria:

1. MRSA confirmed microbiologically

Exclusion Criteria:

1. Time to allocation reveal is >72 hours from time of index blood culture collection

2. Severe allergy to any beta-lactam (including cefazolin) Immediate severe allergy:Anaphylaxis/angioedema Severe delayed allergy: Severe cutaneous adverse reaction (SCAR; including Steven Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Rash withEosinophilia and Systemic Symptoms (DRESS) and acute generalised exanthematouspustulosis (AGEP)), severe drug induced liver injury, proven allergic interstitialnephritis, immune-mediated haemolytic anaemia and other severe cytopenia.

3. Non-severe rash to cefazolin Nausea, diarrhoea, headache and other non-specificsymptoms are NOT allergies, they are drug intolerance, and they are not exclusioncriteria. Similarly, a vague history of an allergy of unclear nature, or a familyhistory of allergy are not exclusions.)

4. Severe allergy or non-severe rash to both vancomycin AND daptomycin Vancomycin infusion reaction (formerly known as "red man syndrome") is due to direct histamine release and is not generally an allergy, and therefore is not considered an exclusion.

5. Treating team deems enrolment in the domain is not in the best interest of the patient

6. Polymicrobial bacteraemia (defined as more than one organism [at species level] in blood cultures, excluding those organisms judged to be contaminants by either the microbiology laboratory or treating clinician) reported between collection of the index blood culture and backbone domain eligibility assessment.

7. Patient currently being treated with a systemic antibacterial agent that cannot be ceased or substituted for interventions allocated within the platform (unless antibiotic is listed in Table 1 of the DSA, which specifies allowed antibiotics with limited absorption from the gastrointestinal tract or negligible antimicrobial activity against S. aureus)

EARLY ORAL SWITCH DOMAIN

Inclusion Criteria:

Day 7 (+/- 2 days):

1. Clearance of SAB by platform Day 2: blood cultures negative for S. aureus fromplatform Day 2 onwards AND no known subsequent positive blood cultures

2. Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility)

3. Primary focus is either line related (either central or peripheral IV cannula) orskin and soft tissue, AND source control achieved (for 'line-related' this meansline removed; for 'skin and soft tissue' means site PI considers source control tohave been achieved and any abscess more than 2cm diameter has been drained)

4. No evidence of metastatic foci (on clinical or radiological examination, butradiological imaging is not required to exclude metastatic foci if not clinicallyindicated)

Day 14 (+/- 2 days):

1. Clearance of SAB by platform Day 5: blood cultures negative for S. aureus fromplatform Day 5 (+/-1 day) AND no known subsequent positive blood cultures. If themost recent blood culture from Day 2-4 is negative for S. aureus, blood cultures donot need to be repeated on Day 5 to fulfil eligibility criteria (Day 5 bloodcultures will be assumed to be negative in this situation)

2. Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility)

3. Site Principal Investigator has determined that source control is adequate

Exclusion Criteria:

When judging eligibility at platform Day 7 (+/- 2 days) and at Day 14 (+/- 2 days), exclusion criteria are:

1. Adherence to oral agents unlikely (as judged by site PI in consultation with thetreating team)

2. Unreliable gastrointestinal absorption (e.g. vomiting, diarrhoea, nil by mouth,anatomical reasons)

3. There are no appropriate oral antibiotics due to contraindications, drugavailability, or antibiotic resistance

4. Ongoing IV therapy unsuitable e.g. no IV access

5. Clinician deems not appropriate for early oral switch

6. Patient no longer willing to participate in domain In the lead-up to judgingeligibility, it may be helpful to discuss with the patient the potential forcontinued IV treatment versus oral switch, to allow hospital discharge planning

7. Clinical team deems that sufficient duration of antibiotic therapy has already beenprovided

Exclusions when judging eligibility for early oral switch at trial Day 7 (+/- 2 days):

1. Presence of prosthetic cardiac valve, pacemaker or other intracardiac implant

2. Presence of intravascular clot, graft, or other intravascular prosthetic materialIntravascular clot excludes superficial peripheral IV line-related thrombophlebitis.Intravascular prosthetic material excludes coronary artery stents)

3. Intravascular/intracardiac infections (e.g. endocarditis, mycotic aneurysm)

4. Presence of other intracardiac abnormalities felt to put patient at increased riskof endocarditis (e.g., bicuspid aortic valve)

PET/CT DOMAIN

Inclusion Criteria:

1. PET/CT participating site

2. Patient is accessible for PET/CT - a patient is considered accessible if the siteteam are able to access the participant medical records, arrange for a PET/CT scanfor the patient, and discuss this domain with the patient and their treatinghealthcare providers.

Exclusion Criteria:

1. Pregnant - patients of childbearing potential should be assessed for pregnancystatus and a pregnancy test performed (if not performed within the past 10 days)

2. Currently breastfeeding

3. < 18 years of age

4. Patient has had PET/CT in the past 7 days

5. Patient needs PET/CT in the next 7 days (in the opinion of the clinical team, at thetime of eligibility assessment)

6. Clinically unstable for PET/CT (as judged by the treating clinical team, taking intoaccount need for organ support (including inotropes) and capacity to lie flat forthe PET/CT)

7. Contraindication to PET/CT (e.g., claustrophobia, persistently elevated blood sugarlevels [>12.5mmol/L] that cannot be corrected).

8. Patient no longer willing to participate in the domain - in the days leading up tojudging eligibility, it may be helpful to discuss with the patient the potential forPET/CT vs no PET/CT to allow imaging planning

9. Clinician deems participation in this domain is not in the patient's best interests