Browsing by Subject "Teicoplanin"

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    ItemOpen Access
    Dalbavancin as an option for treatment of S. aureus bacteremia (DOTS): study protocol for a phase 2b, multicenter, randomized, open-label clinical trial.
    (Trials, 2022-05) Turner, Nicholas A; Zaharoff, Smitha; King, Heather; Evans, Scott; Hamasaki, Toshimitsu; Lodise, Thomas; Ghazaryan, Varduhi; Beresnev, Tatiana; Riccobene, Todd; Patel, Rinal; Doernberg, Sarah B; Rappo, Urania; Fowler, Vance G; Holland, Thomas L; Antibacterial Resistance Leadership Group (ARLG)

    Background

    Staphylococcus aureus bacteremia is a life-threatening infection and leading cause of infective endocarditis, with mortality rates of 15-50%. Treatment typically requires prolonged administration of parenteral therapy, itself associated with high costs and potential catheter-associated complications. Dalbavancin is a lipoglycopeptide with potent activity against Staphylococcus and a long half-life, making it an appealing potential therapy for S. aureus bacteremia without the need for durable central venous access.

    Methods

    DOTS is a phase 2b, multicenter, randomized, assessor-blinded, superiority, active-controlled, parallel-group trial. The trial will enroll 200 adults diagnosed with complicated S. aureus bacteremia, including definite or possible right-sided infective endocarditis, who have been treated with effective antibiotic therapy for at least 72 h (maximum 10 days) and with subsequent clearance of bacteremia prior to randomization to study treatment. Subjects will be randomized 1:1 to complete their antibiotic treatment course with either two doses of dalbavancin on days 1 and 8, or with a total of 4-8 weeks of standard intravenous antibiotic therapy. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at day 70 for patients randomized to dalbavancin versus standard of care. Key secondary endpoints include quality of life outcomes and pharmacokinetic analyses of dalbavancin.

    Discussion

    The DOTS trial will establish whether dalbavancin is superior to standard parenteral antibiotic therapy for the completion of treatment of complicated S. aureus bacteremia.

    Trial registration

    US National Institutes of Health ClinicalTrials.gov NCT04775953 . Registered on 1 March 2021.
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    ItemOpen Access
    Determination of plasma protein binding of dalbavancin.
    (The Journal of antimicrobial chemotherapy, 2022-06) Turner, Nicholas A; Xu, Allan; Zaharoff, Smitha; Holland, Thomas L; Lodise, Thomas P

    Objectives

    Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations.

    Methods

    The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding.

    Results

    Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%.

    Conclusions

    Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.