Importance Dalbavancin is an alternative to prolonged intravenous therapy for complicated Staphylococcus aureus bacteremia, yet its pharmacokinetics (PK) in patients with this condition are uncertain. Objective To characterize dalbavancin PK and evaluate associations of total and unbound exposures of dalbavancin with clinical success in patients with complicated S aureus bacteremia. Design, Setting, and Participants This study was an exploratory prespecified secondary analysis of PK and exposure response within Dalbavancin as an Option for Treatment of S aureus Bacteremia (DOTS), a multicenter, randomized, open-label, assessor-blinded clinical trial conducted from April 2021 to December 2023. Data analysis was conducted from January 2024 to December 2025. Adults with complicated S aureus bacteremia who achieved bloodstream clearance were randomized to dalbavancin or standard therapy; PK analyses included dalbavancin recipients with at least 1 postdose concentration measurement. Intervention Dalbavancin 1500 mg intravenously on days 1 and 8 (1125 mg for patients with severe kidney impairment not receiving dialysis). Main Outcomes and Measures Individual exposure metrics, including day 22 concentration and area under the concentration-time curve (AUC) from days 0 to 22, were derived using nonlinear mixed-effects population PK modeling. Exposure metrics were then assessed for association with clinical success at day 70 (exposure-response analysis). Results A total of 97 patients (mean SD age, 54.5 15.8 years; 69 male 71.1%) contributing 640 PK samples were included. Clearance was estimated at 0.066 L/h (95% CI, 0.062 to 0.069 L/h), and the central volume of distribution was estimated at 5.67 L (95% CI, 5.37 to 5.99 L). Interindividual variability was 22.6% (95% CI, 18.9% to 25.6%) for clearance and 19.7% (95% CI, 13.8% to 25.0%) for the central volume of distribution. Clearance increased with creatinine clearance according to a power function (exponent, 0.21; 95% CI, 0.16 to 0.30). Distribution volumes increased with body weight following power relationships, including the central volume (exponent, 0.57; 95% CI, 0.37 to 0.86), second peripheral volume (0.82; 95% CI, 0.37 to 1.46), and third peripheral volume (0.56; 95% CI, 0.30 to 0.82). Albumin was inversely associated with the second peripheral volume (exponent, −0.81; 95% CI, −1.79 to −0.32) and unbound-fraction scaling factor (exponent, −0.78; 95% CI, −0.98 to −0.54), and age was positively associated with the third peripheral volume via a power relationship (exponent, 0.63; 95% CI, 0.44 to 0.83). Among 93 evaluable patients, 72 individuals (77.4%) achieved clinical success at day 70. Patients with a day 22 concentration greater than 32 μg/mL (30 patients 32.3% of evaluable patients receiving dalbavancin) had higher clinical success compared with 63 patients with a day 22 concentration of 32 μg/mL or less (29 patients 96.7% vs 43 patients 68.3%; adjusted difference, 25.3 percentage points; 95% CI, 3.5-47.0 percentage points) and experienced similar rates of serious adverse events (8 patients 26.7% vs 27 patients 42.9%; unadjusted difference, −16.2 percentage points, 95% CI −36.2 to 3.8 percentage points). Conclusions and Relevance In this study, dalbavancin pharmacokinetics were predictably influenced by kidney function, body weight, albumin levels, and age, and higher total day 22 concentrations were associated with greater clinical success without increased serious adverse events. These findings are exploratory and support further evaluation of exposure-guided dosing strategies. Trial Registration Clinical Trials.gov Identifier: NCT04775953
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