Objectives: Dalbavancin is increasingly used off-label for complicated methicillin-resistant Staphylococcus aureus (MRSA) infections requiring prolonged antimicrobial exposure. However, approved dosing regimens were developed for short-course therapy and may provide inadequate exposure in patients with obesity or preserved kidney function. We aimed to develop a practical dosing strategy for prolonged dalbavancin therapy using population pharmacokinetic modeling and simulation. Methods: We conducted a multicenter cohort study of adults treated with dalbavancin for presumed or documented MRSA infections across five centers. Dalbavancin plasma concentrations were measured using a validated LC-MS/MS assay. Population pharmacokinetic modeling was performed using nonlinear mixed-effects methods with evaluation of body size and kidney function covariates. Monte Carlo simulations (n=1000 per scenario) estimated the probability of target attainment (PTA) for maintaining dalbavancin concentrations ≥8.04 mg/L through 4 weeks across body mass index (BMI) and estimated glomerular filtration rate (eGFR) strata. Candidate regimens for 4-8 weeks of coverage were evaluated, with protein-binding sensitivity analyses across 93%-99%. Results: A total of 311 patients contributed 946 dalbavancin concentrations with follow-up extending beyond 8 weeks. Compared with normal-weight patients, those with obesity (n=64) exhibited 49% higher clearance and 81% higher peripheral volume of distribution. Standard labeled regimens achieved 4-week PTA in only 50-60% of obese patients, with the lowest attainment observed among those with eGFR ≥120 mL/min. BMI- and eGFR-informed two- and three-dose strategies achieved ≥90% PTA under the 93% protein-binding assumption. Sensitivity analyses showed that PTA was generally preserved at 93%-96% protein binding but declined at 97%-99%, particularly with obesity, eGFR ≥120 mL/min, lower-dose weekly regimens, and every-other-week dosing. Conclusions: Body size, kidney function, and protein-binding assumptions materially influence dalbavancin PTA during prolonged therapy. Simulation-informed regimens provide a practical outpatient framework, but higher protein-binding assumptions support cautious interpretation and consideration of individualized assessment in high-risk patients.
Pai, M.P., Cojutti, P.G., De Paola, R., Zamparini, E., Tedeschi, S., Giuliano, S., et al. (2026). Optimizing dalbavancin dosing for complicated MRSA infections: a multicenter population pharmacokinetic study. CLINICAL MICROBIOLOGY AND INFECTION, https://doi.org/10.1016/j.cmi.2026.05.049, 1-24 [10.1016/j.cmi.2026.05.049].
Optimizing dalbavancin dosing for complicated MRSA infections: a multicenter population pharmacokinetic study
Cojutti, Pier Giorgio;De Paola, Riccardo;Tedeschi, Sara;Viale, Pierluigi;Pea, Federico
2026
Abstract
Objectives: Dalbavancin is increasingly used off-label for complicated methicillin-resistant Staphylococcus aureus (MRSA) infections requiring prolonged antimicrobial exposure. However, approved dosing regimens were developed for short-course therapy and may provide inadequate exposure in patients with obesity or preserved kidney function. We aimed to develop a practical dosing strategy for prolonged dalbavancin therapy using population pharmacokinetic modeling and simulation. Methods: We conducted a multicenter cohort study of adults treated with dalbavancin for presumed or documented MRSA infections across five centers. Dalbavancin plasma concentrations were measured using a validated LC-MS/MS assay. Population pharmacokinetic modeling was performed using nonlinear mixed-effects methods with evaluation of body size and kidney function covariates. Monte Carlo simulations (n=1000 per scenario) estimated the probability of target attainment (PTA) for maintaining dalbavancin concentrations ≥8.04 mg/L through 4 weeks across body mass index (BMI) and estimated glomerular filtration rate (eGFR) strata. Candidate regimens for 4-8 weeks of coverage were evaluated, with protein-binding sensitivity analyses across 93%-99%. Results: A total of 311 patients contributed 946 dalbavancin concentrations with follow-up extending beyond 8 weeks. Compared with normal-weight patients, those with obesity (n=64) exhibited 49% higher clearance and 81% higher peripheral volume of distribution. Standard labeled regimens achieved 4-week PTA in only 50-60% of obese patients, with the lowest attainment observed among those with eGFR ≥120 mL/min. BMI- and eGFR-informed two- and three-dose strategies achieved ≥90% PTA under the 93% protein-binding assumption. Sensitivity analyses showed that PTA was generally preserved at 93%-96% protein binding but declined at 97%-99%, particularly with obesity, eGFR ≥120 mL/min, lower-dose weekly regimens, and every-other-week dosing. Conclusions: Body size, kidney function, and protein-binding assumptions materially influence dalbavancin PTA during prolonged therapy. Simulation-informed regimens provide a practical outpatient framework, but higher protein-binding assumptions support cautious interpretation and consideration of individualized assessment in high-risk patients.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
