Staphylococcus Aureus Network Adaptive Platform Trial

• Status: Not yet recruiting
• Trial end date: 2025-12-01
• Target enrollment: 0
• Participant gender: All

Summary

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is an International Multi-Centered Randomised Adaptive Platform Clinical Trial to evaluate a range of interventions to reduce mortality for patients with Staphylococcus Aureus bacteraemia (SAB).

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Melbourne
• Collaborators: Berry Consultants; Menzies School of Health Research; Queensland University of Technology; Sunnybrook Health Sciences Centre; Tan Tock Seng Hospital; Telethon Kids Institute; The Peter Doherty Institute for Infection and Immunity; The University of Queensland
• Treatments: Anti-Bacterial Agents; Cefazolin; Clindamycin; Daptomycin; Lincomycin; Penicillin G; Penicillins; Vancomycin

Criteria

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

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 trial:

1. Time of anticipated platform entry is greater than 72 hours post collection of the index blood culture

a) 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, excluding those organisms judged to be contaminants by either the microbiology laboratory or treating clinician

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

4. Known previous participation in SNAP

5. 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

6. Treating team deems enrolment in the study is not in the best interest of the patient

7. Treating team believes that death is imminent and inevitable

8. Patient is for end-of-life care and antibiotic treatment is considered not appropriate

9. Patient <18 years of age and paediatric recruitment not approved at recruiting site

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) or severe diarrhoea from any cause

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 is penicillin-susceptible

2. For MSSA silo: Index blood culture isolate is methicillin-susceptible but penicillin resistant

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.

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)

1. Immediate severe allergy: Anaphylaxis/angioedema

2. Severe delayed allergy: Severe cutaneous adverse reaction (SCAR; including Steven Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP)), severe drug induced liver injury, proven allergic interstitial nephritis, immune-mediated haemolytic anaemia and other severe cytopenia.

3. Non-severe rash to cefazolin

a) 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.

4. Severe allergy or non-severe rash to both vancomycin AND daptomycin

a) 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

EARLY ORAL SWITCH DOMAIN

Inclusion Criteria:

Day 7 (+/- 2 days):

1. Clearance of SAB by platform Day 2: blood cultures negative for S. aureus from platform 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) or skin and soft tissue, AND source control achieved (for 'line-related' this means line removed; for 'skin and soft tissue' means site PI considers source control to have been achieved and any abscess more than 2cm diameter has been drained)

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

Day 14 (+/- 2 days):

1. Clearance of SAB by platform Day 5: blood cultures negative for S. aureus from platform Day 5 (+/-1 day) AND no known subsequent positive blood cultures. If the most recent blood culture from Day 2-4 is negative for S. aureus, blood cultures do not need to be repeated on Day 5 to fulfil eligibility criteria (Day 5 blood cultures 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 the treating team)

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

3. There are no appropriate oral antibiotics due to contraindications, drug availability, 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

a) In the lead-up to judging eligibility, it may be helpful to discuss with the patient the potential for continued IV treatment versus oral switch, to allow hospital discharge planning

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

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. Known presence of intravascular clot (excluding superficial peripheral IV line-related thrombophlebitis), graft or other intravascular prosthetic material

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

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