In vivo pharmacodynamic activity of the glycopeptide dalbavancin

Abstract

Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either Streptococcus pneumoniae or Staphylococcus aureus by using the thigh infection model. The burden of organisms for S. pneumoniae was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of S. aureus but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [C(max)]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the C(max)/MIC parameters correlated well with the in vivo efficacy of treatment against S. pneumoniae and S. aureus (for 24-h AUC/MIC, R(2) = 78 and 77%, respectively; for C(max)/MIC, R(2) = 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 +/- 7 for five S. pneumoniae isolates. A similar treatment endpoint for the treatment against five strains of S. aureus required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 +/- 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log(10) in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC(90) for the target gram-positive organisms would fall within this value.

FIG. 1.

Serum PKs of dalbavancin in neutropenic infected mice following the administration of six twofold escalating doses ranging from 2.5 to 80 mg/kg intraperitoneally. Each datum point represents the mean and standard deviation for three mice. t_1/2, half-life.

FIG. 2.

Impacts of single doses of dalbavancin on organism burden in thighs of neutropenic mice infected with either S. pneumoniae ATCC 10813 (left panel) or S. aureus ATCC 29213 (right panel). Mice received either no drug or one of five twofold-increasing dose levels of dalbavancin administered via the intraperitoneal route. The microbiologic burden was determined by plate counts of thigh homogenates at selected time points over 96 h. Each symbol represents a different dose level. Each datum point represents the mean and standard deviation for four thighs.

FIG. 3.

Impact of dalbavancin dosing interval on the in vivo efficacy of dalbavancin against S. pneumoniae ATCC 10813 (left panel) or S. aureus ATCC 29213 (right panel) in neutropenic mice. Five total dose levels were fractionated over a 144-h study period. Each symbol represents one of four dosing intervals. Each datum point represents the mean and standard deviation log₁₀ CFU/thigh for four thighs.

FIG. 4.

Relationship between the free-drug 24-h AUC/MIC, C_max/MIC, and T > MIC and the efficacy of dalbavancin against S. pneumoniae ATCC 10813 (top panel) and S. aureus ATCC 29213 (bottom panel) in the thighs of neutropenic mice over a 144-h treatment period. Each symbol represents the mean log₁₀ CFU/thigh values for four thighs.

FIG. 5.

Relationship between free-drug 24-h AUC/MIC and change in log₁₀ CFU/thigh over 6 days. Each datum point represents the mean value for four thighs. Hollow symbols, data from the q72h regimens; solid symbols, data from the q24h regimens; left panel, data for five S. aureus strains; right panel, data for five S. pneumoniae strains.

FIG. 6.

Dose-response relationship for dalbavancin in the neutropenic murine thigh and lung infection models against S. pneumoniae ATCC 10813 over a 6-day treatment period. Each datum point represents the mean and standard deviation for either two mice (four thighs [triangles]) or three mice (lungs [circles]).