Pharmacodynamics of telavancin (TD-6424), a novel bactericidal agent, against gram-positive bacteria

Abstract

Telavancin (TD-6424) is a novel lipoglycopeptide that produces rapid and concentration-dependent killing of clinically relevant gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacodynamics of telavancin in the mouse neutropenic thigh (MNT) and mouse subcutaneous infection (MSI) animal models. Pharmacokinetic-pharmacodynamic studies in the MNT model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy. Telavancin produced dose-dependent reduction of thigh titers of several organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. The 50% effective dose (ED50) estimates for telavancin ranged from 0.5 to 6.6 mg/kg of body weight (administered intravenously), and titers were reduced by up to 3 log10 CFU/g from pretreatment values. Against MRSA ATCC 33591, telavancin was 4- and 30-fold more potent (on an ED50 basis) than vancomycin and linezolid, respectively. Against MSSA ATCC 13709, telavancin was 16- and 40-fold more potent than vancomycin and nafcillin, respectively. Telavancin, vancomycin, and linezolid were all efficacious and more potent against MRSA ATCC 33591 in the MSI model compared to the MNT model. This deviation in potency was, however, disproportionately greater for vancomycin and linezolid than for telavancin, suggesting that activity of telavancin is less affected by the immune status. The findings of these studies collectively suggest that once-daily dosing of telavancin may provide an effective approach for the treatment of clinically relevant infections with gram-positive organisms.

FIG. 1.

Chemical structure of telavancin.

FIG. 2.

Single-dose concentration-versus-time pharmacokinetic profile for various doses of telavancin in neutropenic mice infected in the thigh with MRSA 33591. The abscissa shows the time, and the ordinate shows the plasma drug concentration (Conc.) (n = 3 per group). Data are expressed as means ± 1 SD (error bars).

FIG. 3.

Relationship between telavancin dose and C_max (A) and dose versus AUC (B) for various doses of telavancin. The values are means (n = 3).

FIG. 4.

Effects of telavancin against MRSA 33591 on titer in thighs from mice treated with various doses of telavancin administered in one, two, three, or four divided doses. The abscissa shows the total 24-h dosage, and the ordinate shows the titer observed in thighs (n = 5 to 6 for vehicle and 5 to 10 for telavancin). Data are expressed as means ± 1 SD (error bars).

FIG. 5.

Relationship between titer observed in thigh samples and the three following pharmacodynamically linked variables: time above the MIC (A and D), 24-h AUC/MIC ratio (B and E), and C_max/MIC ratio (C and F) using total (A, B, and C) and free-drug (D, E, and F) concentrations. The organism studied was MRSA 33591.

FIG. 6.

Efficacies of telavancin, vancomycin, and linezolid against MRSA 33591 in the mouse neutropenic thigh model. The abscissa shows the total 24-h dosage, and the ordinate shows the titer observed in thighs. Vehicle (n = 16) and telavancin (n = 5 to 16 per dose) were administered q 24 h, whereas vancomycin (n = 5 per dose) and linezolid (n = 6 per dose) were administered q 12 h. n = 16 for the control pretreatment group. Data are expressed as means ± 1 SD (error bars).

FIG. 7.

Efficacies of telavancin, vancomycin, and nafcillin against MSSA 13709 in the mouse neutropenic thigh model. The abscissa shows the total 24-h dosage, and the ordinate shows the titer observed in thighs. Vehicle (n = 15) and telavancin (n = 9 to 10 per dose) were administered q 24 h, vancomycin (n = 6 per dose) was administered q 12 h, and nafcillin (n = 9 to 10 per dose) was administered q 6 h. n = 15 for the control pretreatment group. Data are expressed as means ± 1 SD (error bar).

FIG. 8.

Efficacies of telavancin and vancomycin against MRSA 33591 in the murine neutropenic thigh model at different starting inocula. (A) Control inoculum; (B) high inoculum. Vehicle (n = 5) and telavancin (n = 5 per dose) were administered q 24 h, whereas vancomycin (n = 5 per dose) was administered q 12 h (n = 5 for control pretreatment group). The abscissa shows the total (24-h) dosage, and the ordinate shows the bacterial titer in the thigh. Values represent means ± 1 SD (error bar).