This is a sub-study of the S. aureus Network Adaptive Platform (SNAP) trial (NCT05137119) wherein we will evaluate whether not giving rifampin in patients with probable or definite prosthetic valve endocarditis due to S. aureus is non-inferior to giving rifampin.

Inclusion Criteria:

1. Probable or definite prosthetic valve endocarditis involving the tricuspid, pulmonic, mitral and/or aortic valves by the 2023 Duke-ISCVID Criteria (including Cardiac PET evidence if applicable);
2. Patient or healthcare proxy provide informed consent.

Exclusion Criteria:

1. Death deemed imminent and inevitable within days or patient will be receiving palliative care and has prognosis < 90 days according to the treating team;
2. Patient requires intensive care but has a do not resuscitate order precluding transfer;
3. Polymicrobial bacteremia (not including skin commensals or other recognized contaminant);
4. Organism tests as rifampin resistant;
5. History of hypersensitivity/anaphylaxis or severe adverse reaction to rifampin;
6. Category X or other important drug-drug interaction with rifampin which cannot be safely mitigated [with as-needed consultation from experts from pharmacy and/or internal medicine/geriatrics for potential deprescribing];
7. Child Pugh Class C cirrhosis;
8. Clinician deems rifampin to be mandatory;
9. Patient has already received >3 days of rifampin at time of screening or >10 days of total therapy
10. Pregnancy or breast feeding

Administrative exclusions:

1. No reliable means of outpatient contact (telephone/email/text);
2. Previously enrolled;
3. Prior S. aureus bacteremia within the preceding 180 days

Data sharing policies are dependent on the policies of the SNAP Platform (NCT05137119)

The trial analyst will also be blinded.