Combination Cefazolin with Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia

The participant must fulfil all inclusion and exclusion criteria for the SNAP Platform (NCT05137119) and also the following inclusion and exclusion criteria to be eligible for this sub-study:

Inclusion Criteria:

1. Adult >=18 years old

2. S. aureus bacteremia within the past 48 hours:

• with any unknown MRSA status (in centers with <15% prevalence of MRSA in theirannual blood cultures) or known negative MRSA screening swab within 90 days OR

• which has already been shown to be MSSA

3. Current receipt of cefazolin or where it would be clinically appropriate (accordingto treating ID specialist) to switch to cefazolin as the backbone therapy (openlabel, non-study drug).

NOTE: Up to an additional 12-24 hours of open label non-study VANCOMYCIN, LINEZOLID or DAPTOMYCIN may be allowed if there is sepsis and clinical concern for MRSA has not been excluded.

Exclusion Criteria:

Clinical:

1. At time of recruitment, the patient has already clinically improved with at leastone subsequent negative culture at >24 hours incubation

2. Anaphylaxis to any beta-lactam antibiotic (and any allergy to ertapenem)Polymicrobial bacteremia (not including skin commensals)

3. Known seizure disorder

4. Any receipt of valproic acid

5. Expected mortality within 48 hours

6. Need for critical care resources but "do not resuscitate" status precludes thereceipt of critical care

7. Unable to provide informed consent and no available healthcare proxy (with ethicsapproval for deferred consent in cases of severe illness)

Administrative:

1. Refusal to provide informed consent

2. Refusal of healthcare team to participate

3. No reliable means of outpatient contact (telephone/email/text)

4. Previously enrolled

5. Patients whose isolate is identified as MRSA post-enrollment will be subsequentlyexcluded (see below).

Note that because MSSA is much more common than MRSA in Canada (90% of all S. aureus bacteremia at MUHC, for example, are MSSA and in the presence of a negative MRSA screening swab or unknown MRSA status, this means that the risk of MRSA is less than 5%). We believe time to combination therapy is likely linked to benefit, therefore we will recruit the patients as soon as S. aureus is identified but potentially prior to confirmation the organism is MSSA. Where possible, rapid MRSA detection techniques will be deployed; however with conventional screening this will mean approximately a 12-24 hours delay. Organisms subsequently identified as MRSA will be excluded from the intention to treat analysis and the sample size will be adjusted accordingly to ensure the total enrollment meets study goals.