Pharmacodynamics of telavancin (TD-6424), a novel bactericidal agent, against gram-positive bacteria.
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.
Hegde
Sharath S
SS
Theravance, Inc., South San Francisco, California 94087, USA. shegde@theravance.com
Reyes
Noe
N
Wiens
Tania
T
Vanasse
Nicole
N
Skinner
Robert
R
McCullough
Julia
J
Kaniga
Koné
K
Pace
John
J
Thomas
Roger
R
Shaw
Jeng-Pyng
JP
Obedencio
Glen
G
Judice
J Kevin
JK
D000081:Acetamides / Q000627:therapeutic use; D000617:Aminoglycosides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D023381:Endpoint Determination; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D000069349:Linezolid; D000077427:Lipoglycopeptides; D016106:Methicillin Resistance; D051379:Mice; D018482:Muscle, Skeletal / Q000382:microbiology; D009254:Nafcillin / Q000627:therapeutic use; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology; D023303:Oxazolidinones / Q000627:therapeutic use; D011485:Protein Binding; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D040521:Subcutaneous Tissue / Q000382:microbiology; D014640:Vancomycin / Q000627:therapeutic use
D000081:Acetamides; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; D023303:Oxazolidinones; D009254:Nafcillin; D014640:Vancomycin; D000069349:Linezolid; C487637:telavancin