Pharmacodynamics of TD-1792, a Novel Glycopeptide-Cephalosporin Heterodimer Antibiotic Used against Gram-Positive Bacteria, in a Neutropenic Murine Thigh Model

• Published in: Antimicrobial Agents and Chemotherapy 2012-03, Vol.56 (3), p.1578-1583
• Main Authors: Hegde, Sharath S, Okusanya, Olanrewaju O, Skinner, Robert, Shaw, Jeng-Pyng, Obedencio, Glenmar, Ambrose, Paul G, Blais, Johanne, Bhavnani, Sujata M
• Format: Article
• Language: English
• Subjects: animal disease models; Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial properties; antibiotic resistance; Antibiotics. Antiinfectious agents. Antiparasitic agents; Area Under Curve; Biological and medical sciences; body weight; Cephalosporins; Cephalosporins - blood; Cephalosporins - chemistry; Cephalosporins - pharmacology; clinical trials; Colony Count, Microbial; Dimerization; dose response; Dose-Response Relationship, Drug; Drug Administration Schedule; Experimental Therapeutics; Female; Glycopeptides; Glycopeptides - blood; Glycopeptides - chemistry; Glycopeptides - pharmacology; Gram-positive bacteria; Hematologic and hematopoietic diseases; Humans; in vivo studies; Injections, Subcutaneous; Medical sciences; methicillin; Mice; microbial load; Microbial Sensitivity Tests; minimum inhibitory concentration; Neutropenia; Neutropenia - drug therapy; Neutropenia - microbiology; Other diseases. Hematologic involvement in other diseases; patients; pharmacokinetics; Pharmacology. Drug treatments; Staphylococcal Infections; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; Staphylococcus epidermidis; Staphylococcus epidermidis - drug effects; Staphylococcus epidermidis - growth & development; Streptococcal Infections; Streptococcal Infections - drug therapy; Streptococcal Infections - microbiology; Streptococcus pneumoniae; Streptococcus pneumoniae - drug effects; Streptococcus pneumoniae - growth & development; Streptococcus pyogenes; Streptococcus pyogenes - drug effects; Streptococcus pyogenes - growth & development; subcutaneous injection; Thigh - microbiology; Vancomycin; Vancomycin - blood; Vancomycin - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.05382-11

TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log10 CFU kill effective dose (ED1-log kill) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log10 CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log10 stasis dose (EDstasis) and ED1-logkill doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r2 = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r2 = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r2 = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log10 CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.