Dalbavancin as an option for treatment of S. aureus bacteremia (DOTS): study protocol for a phase 2b, multicenter, randomized, open-label clinical trial

Abstract

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.govNCT04775953. Registered on 1 March 2021

Combination of Antistaphylococcal β-Lactam With Standard Therapy Compared to Standard Therapy Alone for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia: A Post Hoc Analysis of the CAMERA2 Trial Using a Desirability of Outcome Ranking Approach

“…The recently launched Staphylococcus aureus Network Adaptive Platform (SNAP) randomized clinical trial [ 25 ], which is in the early stages of recruitment at the time of writing, assesses different treatment options for S aureus bacteremia and uses an ordinal outcome as a secondary outcome, incorporating data on functional capacity at 90 days. An ongoing study comparing dalbavancin to standard of care for complicated S aureus bacteremia (Dalbavancin as an Option for Treatment of Staphylococcus aureus bacteremia [DOTS] trial) [ 26 ] is the first to use DOOR as a primary outcome measure in a randomized clinical trial and includes the absence of bacteremia-related signs and symptoms at 70 days to define clinical success. Second, some of the DOOR components may not be clinically significant to the patient, such as a 1.5-fold elevation in creatinine level (defined as “risk” in the RIFLE criteria [ 13 ]).…”

Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Host, Pathogen, and Treatment

“…Trials on genetics, biomarkers, and novel non-antibiotic agents in persistent MRSAB should be encouraged, as well as the implementation in daily practice of those that were successful. Meanwhile, it is promising that antibiotic agents such as dalbavancin [ 157 ] and ceftobiprole [ 154 ] are being studied in randomized clinical trials for SAB. These new high-quality studies represent an important step towards better understanding and ultimately improving clinical outcomes in patients with SAB.…”

“…A potential role of dalbavancin in endovascular infections has not yet been established [ 156 ]. The superiority of dalbavancin compared to standard parenteral antibiotic therapy for the completion of treatment is currently being studied in patients with complicated SAB in a phase 2b randomized clinical trial (DOTS trial) [ 157 ]. A potential role for dalbavancin in persistent bacteremia naturally warrants more follow-up research.…”

Clinical Impact of Staphylococcus aureus Skin and Soft Tissue Infections

“…Post-marketing observational use of lipoglycopeptides has been reported for invasive S. aureus infections, including infective endocarditis, osteomyelitis, and prosthetic joint infections [ 229 ]. Prospective investigations are required to assess the value (e.g., optimal dosing, safety, and outcomes) of these agents for invasive S. aureus infection [ 230 ].…”