Optimizing dalbavancin dosing for complicated methicillin-resistant Staphylococcus aureus infections: a multicentre population pharmacokinetic study.

OBJECTIVES

Dalbavancin is increasingly used off-label for complicated methicillin-resistant Staphylococcus aureus 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 modelling and simulation.

METHODS

We conducted a multicentre cohort study of adults treated with dalbavancin for presumed or documented methicillin-resistant Staphylococcus aureus infections across five centres. Dalbavancin plasma concentrations were measured using a validated liquid chromatography- tandem mass spectrometry (LC-MS/MS) assay. Population pharmacokinetic modelling 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 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 labelled regimens achieved 4-week PTA in only 50-60% of obese patients, with the lowest attainment observed among those with eGFR ≥120 mL/min. body mass index- 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.