In vivo pharmacodynamic activity of daptomycin

Abstract

Daptomycin is a lipopeptide antibiotic with activity against a wide range of gram-positive bacteria. We used the neutropenic murine thigh model to characterize the pharmacodynamics of daptomycin. ICR/Swiss mice were rendered neutropenic with cyclophosphamide; and the thigh muscles of the mice were infected with strains of Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Animals were treated by subcutaneous injection of daptomycin at doses of 0.20 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Daptomycin exhibited linear pharmacokinetics, with an area under the concentration-time curve (AUC) from time zero to infinity/dose of 9.4 and a half-life of 0.9 to 1.4 h. The level of protein binding was 90%. Free daptomycin exhibited concentration-dependent killing and produced in vivo postantibiotic effects (PAEs) of 4.8 to 10.8 h. Nonlinear regression analysis was used to determine which pharmacokinetic (PK) or pharmacodynamic (PD) parameter was important for efficacy by using free drug concentrations. The peak concentration/MIC (peak/MIC) ratio and 24-h AUC/MIC ratio were the PK and PD parameters that best correlated with in vivo efficacy (R(2) = 83 to 87% for peak/MIC and R(2) = 86% for the AUC/MIC ratio, whereas R(2) = 47 to 50% for the time that the concentration was greater than the MIC) against standard strains of S. aureus and S. pneumoniae. The peak/MIC ratios required for a bacteriostatic effect ranged from 12 to 36 for S. pneumoniae, 59 to 94 for S. aureus, and 0.14 to 0.25 for E. faecium. The AUC/MIC ratios needed for a bacteriostatic effect ranged from 75 to 237 for S. pneumoniae, 388 to 537 for S. aureus, and 0.94 to 1.67 for E. faecium. The free daptomycin concentrations needed to average from one to two times the MIC over 24 h to produce a bacteriostatic effect and two to four times the MIC over 24 h to produce greater than 99% killing. The long PAE and potent bactericidal activity make daptomycin an attractive option for the treatment of infections caused by gram-positive bacteria.

FIG. 1.

Plasma daptomycin concentrations after administration of single subcutaneous doses of 10 and 40 mg/kg to neutropenic infected mice. Each symbol represents the mean ± standard levels in the plasma of three mice. T1/2, plasma elimination half-life (in hours); Cmax, peak level in plasma.

FIG. 2.

In vivo PAE of daptomycin against S. pneumoniae ATCC 10813 after administration of single doses of 2.5 (triangles) and 10 (squares) mg/kg. T > MIC, time that the concentration remains above the MIC.

FIG. 3.

Relationships between PK and PD parameters and number of organisms remaining in the thighs of neutropenic mice after 24 h of therapy with multiple dosing regimens of daptomycin. (a) The PK and PD parameters are the time that the concentration remains above the MIC for total and free drug; (b) the PK and PD parameters peak/MIC and 24-h AUC/MIC ratios for total drug. The dotted lines represent the log₁₀ CFU per thigh at the start of therapy.

FIG. 4.

Dose-response curves for daptomycin against various strains of S. pneumoniae.

FIG. 5.

Dose-response curves for daptomycin against various strains of S. aureus (circles) and E. faecium (squares).

FIG. 6.

AUC over 24 h for free daptomycin associated with the static dose and doses producing killing of 1 and 2 log₁₀ CFU/thigh for multiple strains of S. pneumoniae and S. aureus.