Cardiac infections, including infective endocarditis and cardiovascular implantable electronic device infections, are associated with substantial morbidity and mortality and are commonly caused by gram-positive bacteria. Standard management typically requires prolonged courses of intravenous antibiotics and extended hospitalisation, which are costly, burdensome, and associated with complications related to long-term vascular access. People who inject drugs are disproportionately affected and often experience stigma, barriers to care, and poorer outcomes. Long-acting lipoglycopeptides such as oritavancin maintain therapeutic serum concentrations for prolonged periods and may offer an alternative to conventional intravenous antibiotic regimens. Oritavancin is not TGA-registered in Australia and is accessed as an unregistered medicine (for example, via SAS or clinical trials). It is approved in other jurisdictions, including the United States and European Union, for acute bacterial skin and skin structure infections. Prospective data in cardiac infections remain limited, and optimal dosing strategies, including the role of therapeutic drug monitoring, are uncertain. This multicentre, open-label pilot study will assess the feasibility, pharmacokinetics, safety, acceptability, and preliminary efficacy of oritavancin for gram-positive cardiac infections using both standard fixed dosing and TDM-guided dosing strategies. Findings will inform PK/PD modelling, the potential role of TDM, and the design of future larger-scale trials and models of care, including alternatives to prolonged inpatient intravenous therapy.

Inclusion Criteria:

1. Age ≥18 years
2. Hospitalised for management of a cardiac infection (infective endocarditis or cardiovascular implantable electronic device infections)
3. Gram-positive organism identified in blood or tissue culture, that in the opinion of the investigator is the cause of cardiac infection and would be treatable with a finite antibiotic duration (e.g., 4-6 weeks)
4. Afebrile for at least 24 hours at screening
5. Clearance of blood cultures for at least 24 hours at screening
6. Receiving effective antibiotic therapy for at least 24 hours and no more than 14 days at screening
7. Willingness of both treating provider and participant to proceed with oritavancin therapy
8. Able to provide written informed consent
9. Willingness and ability to participate in study procedures, including follow-up visits and drug monitoring

Exclusion Criteria:

1. History of severe allergic reaction or hypersensitivity to oritavancin or any of its components
2. Severe renal impairment (eGFR < 30 mL/min/1.73 m²) or currently receiving dialysis
3. Severe hepatic impairment (Child-Pugh class C)
4. Current infection involving the central nervous system, including septic emboli, ischemic or haemorrhagic stroke, epidural abscess, or meningitis (excluding prior/unrelated central nervous system events).
5. Presence of prosthetic heart valve
6. Culture negative endocarditis
7. Presence of any other active infection requiring concurrent antibiotic treatment that could interfere with study outcomes
8. Infection with Gram positive organism not susceptible to oritavancin or vancomycin (vancomycin MIC > 2 μg/mL).
9. Use of contraindicated medications (see Section 8)
10. Participation in another interventional clinical trial that may confound study outcomes
11. Pregnant or breastfeeding people, or those planning to become pregnant during the study period (people of childbearing potential must have a negative pregnancy test during hospitalization and use effective contraception for trial duration and for 3 months after last infusion of study medication).
12. Immunosuppression (defined as active chemotherapy expected to cause absolute neutrophil count <100 cells/mm3 lasting >7 days during the study period, bone marrow transplantation in the preceding 90 days, solid organ transplantation within prior 3 months or receipt of augmented immunosuppression for rejection within 3 months, chronic granulomatous disease, HIV with a CD4 count <50 cells/mm3 based on last known measure).
13. Any condition (e.g. severe cognitive impairment, psychiatric illness, active withdrawal) that, in the opinion of the investigator, would limit the participant's ability to comply with study procedures or give informed consent
14. Medically unstable in opinion of treating clinician that would preclude participation
15. Cases in which the investigator deem curative or finite antibiotic treatment unlikely (e.g., long term indefinite suppressive antibiotics are likely such as retained hardware).