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A Reference Broth Microdilution Method for Dalbavancin In Vitro Susceptibility Testing of Bacteria that Grow Aerobically
Published on: September 9, 2015
Optimizing dalbavancin dosing for complicated methicillin-resistant Staphylococcus aureus infections: a multicentre
Manjunath P Pai1, Pier Giorgio Cojutti2, Riccardo De Paola2
1Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
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.
Insights
New dalbavancin dosing strategies improve treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections in obese patients and those with preserved kidney function. These optimized regimens increase the probability of target attainment for prolonged therapy.
Area of Science:
- Pharmacology and Infectious Diseases
- Clinical Pharmacokinetics
- Antimicrobial Stewardship
Background:
- Dalbavancin is increasingly used for complicated methicillin-resistant Staphylococcus aureus (MRSA) infections requiring extended treatment.
- Current dalbavancin dosing may be suboptimal for patients with obesity or normal to high kidney function, potentially leading to inadequate drug exposure.
Purpose of the Study:
- To develop and evaluate practical dalbavancin dosing strategies for prolonged therapy (4-8 weeks) in patients with MRSA infections.
- To optimize dosing based on population pharmacokinetic modeling, considering body size (BMI) and kidney function (eGFR).
Main Methods:
- Multicenter cohort study of 311 adults treated with dalbavancin.
- Population pharmacokinetic modeling using nonlinear mixed-effects methods.
- Monte Carlo simulations to estimate probability of target attainment (PTA) for maintaining dalbavancin concentrations ≥8.04 mg/L.
Main Results:
- Patients with obesity had significantly higher dalbavancin clearance and volume of distribution.
- Standard regimens achieved only 50-60% 4-week PTA in obese patients, especially those with eGFR ≥120 mL/min.
- Modified two- and three-dose strategies achieved ≥90% PTA for 4 weeks under 93% protein binding, but PTA decreased with higher protein binding assumptions (≥97%).
Conclusions:
- Body size, kidney function, and protein-binding assumptions critically impact dalbavancin PTA during prolonged use.
- Simulation-informed regimens offer a practical outpatient approach for extended dalbavancin therapy.
- Higher protein-binding assumptions necessitate cautious interpretation and individualized dosing assessments for high-risk patients.
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