Impact of Glycopeptide Resistance in Staphylococcus aureus on the Dalbavancin In Vivo Pharmacodynamic Target

Abstract

Dalbavancin is a novel lipoglycopeptide with activity against Staphylococcus aureus, including glycopeptide-resistant isolates. The in vivo investigation reported here tested the effects of this antibiotic against seven S. aureus isolates with higher MICs, including several vancomycin-intermediate strains. Results of 1-log kill and 2-log kill were achieved against seven and six of the isolates, respectively. The mean free-drug area under the concentration-time curve (fAUC)/MIC values for net stasis, 1-log kill, and 2-log kill were 27.1, 53.3, and 111.1, respectively.

FIG 1

Plasma pharmacokinetics of dalbavancin in mice following intraperitoneal administration. Each symbol represents the mean and standard deviation from three mice. The drug concentration values presented represent total (protein-bound and unbound) drug. The AUC values represent 0 to infinity. Cmax, maximal drug concentration; T1/2, half-life.

FIG 2

In vivo dose-dependent effects of dalbavancin against seven select S. aureus isolates in a neutropenic mouse thigh model. (A) Dalbavancin exposure expressed at dose level (mg/kg/12 h). (B) Exposure expressed as fAUC/MIC. Each symbol represents the mean and standard deviation from four thighs. Dalbavancin exposure is expressed as the 24-h fAUC/MIC. The burden of organisms was measured at the start and end of therapy. The horizontal dashed line at 0 represents the burden of organisms in the thighs of mice at the start of therapy. Data points below the line represent killing, and points above the line represent growth. R² represents the coefficient of determination. The 50% effective dose (ED₅₀) represents the AUC/MIC associated with 50% of the maximal effect (E_max), and N is the slope of the relationship or the Hill coefficient. The line drawn through the data points is the best-fit line based on the sigmoidal E_max formula.