Infective Endocarditis, Cardiac Device Infection, Gram-positive Bacterial Infections
Conditions
Keywords
Oritavancin, Long-acting antibiotic, Lipoglycopeptide, Infective endocarditis, Cardiac device infection, Gram-positive infection, Therapeutic drug monitoring, Pharmacokinetics
Brief summary
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.
Interventions
DRUGOritavancin
Oritavancin administered by intravenous infusion using a fixed weekly dosing schedule consistent with the protocol-defined guideline-based regimen (1.2 g IV once weekly)
Sponsors
Kirby Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Desirability of Outcome Ranking (DOOR) at Day 70 | Day 70 post-enrolment | Composite ordinal outcome adapted for Gram-positive cardiac infections. Participants will be ranked from most to least desirable outcome as follows: 1. = alive with no clinical failure, infectious complication, or serious adverse event/adverse event leading to study drug discontinuation; 2. = alive with 1 of these events; 3. = alive with 2 of these events; 4. = alive with all 3 of these events; 5. = death. Within each rank, ties will be resolved using net change in EQ-5D score from baseline to Day 70, with greater improvement indicating a more desirable outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total oritavancin plasma concentration at scheduled sampling time points | From post-dose Day 1 through Day 70 post-enrolment | Observed total oritavancin plasma concentrations measured at protocol-specified sampling time points to support development of the population pharmacokinetic model. |
| Oritavancin dosing interval achieved in the therapeutic drug monitoring-guided cohort | From Day 1 to Day 70 post-enrolment | Time interval in days between consecutive oritavancin doses in participants managed using therapeutic drug monitoring-guided dosing. |
| Number of participants with treatment-emergent adverse events in the oritavancin cohorts | From enrolment to Day 180 post-enrolment | Number of participants receiving oritavancin with at least 1 treatment-emergent adverse event. |
| Number of participants with serious adverse events in the oritavancin cohorts | From enrolment to Day 180 post-enrolment | Number of participants receiving oritavancin with at least 1 serious adverse event. |
| Number of participants with infusion-related reactions in the oritavancin cohorts | From enrolment to Day 180 post-enrolment | Number of participants receiving oritavancin with at least 1 infusion-related reaction. |
| Change from Baseline to Day 70 in EuroQol 5-Dimension 5-Level Index Score | Baseline to Day 70 post-enrolment | Health-related quality of life will be assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L). The EQ-5D-5L index score is derived from participant responses across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Using the Australian EQ-5D-5L value set, possible index scores range from -0.30 to 1.00, where 1.00 represents full health, 0 represents a health state equivalent to death, and scores below 0 represent health states valued worse than death. Higher scores indicate better health-related quality of life. Change will be calculated as the Day 70 score minus the baseline score; a positive change indicates improvement. |
| Proportion of participants completing protocol-specified dosing and monitoring through Day 70 | From enrolment to Day 70 post-enrolment | Proportion of participants who complete the protocol-specified dosing schedule and planned therapeutic drug monitoring/sample collection through Day 70. |
| Recruitment rate | From study opening to completion of enrolment | Proportion of eligible participants who are enrolled into the study. |
| Retention rate at Day 70 | From enrolment to Day 70 post-enrolment | Proportion of enrolled participants who complete Day 70 follow-up. |
| Number of participants who complete planned study treatment | By Day 70 post-enrolment | Number of participants who complete their planned study treatment course as determined by the treating clinician and protocol-defined study treatment period. |
| Number of participants with clinical or microbiological failure | By Day 70 post-enrolment | Number of participants with clinical or microbiological failure, including worsening or recurrent signs of cardiac infection, need for change/addition of antibiotic therapy due to inadequate response, or relapse with the same organism following study treatment. |
| Number of participants with hospital readmission by Day 70 | By Day 70 post-enrolment | Number of participants with at least 1 hospital readmission. |
| Number of participants who die by Day 70 | By Day 70 post-enrolment | All-cause mortality. |
| Number of participants with hospital readmission by Day 180 | By Day 180 post-enrolment | Number of participants with at least 1 hospital readmission. |
| Number of participants who die by Day 180 | By Day 180 post-enrolment | All-cause mortality. |
Countries
Australia
Contacts
CONTACTHila Haskelberg
PRINCIPAL_INVESTIGATORGail Matthews, MBChB MRCP(UK) FRACP PhD FAAHM
Kirby Institute
Outcome results
None listed