Pharmacodynamics of TD-1792, a Novel Glycopeptide-Cephalosporin Heterodimer Antibiotic Used against Gram-Positive Bacteria, in a Neutropenic Murine Thigh Model
| العنوان: | Pharmacodynamics of TD-1792, a Novel Glycopeptide-Cephalosporin Heterodimer Antibiotic Used against Gram-Positive Bacteria, in a Neutropenic Murine Thigh Model |
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| المؤلفون: | Johanne Blais, Paul G. Ambrose, Olanrewaju O. Okusanya, Robert A. Skinner, Sujata M. Bhavnani, Jeng-Pyng Shaw, Sharath S. Hegde, Glenmar P. Obedencio |
| المصدر: | Antimicrobial Agents and Chemotherapy. 56:1578-1583 |
| بيانات النشر: | American Society for Microbiology, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Staphylococcus aureus, Neutropenia, Streptococcus pyogenes, medicine.drug_class, Injections, Subcutaneous, Gram-positive bacteria, Antibiotics, Cephalosporin, Colony Count, Microbial, Cmax, Microbial Sensitivity Tests, Biology, medicine.disease_cause, Drug Administration Schedule, Microbiology, Mice, Vancomycin, Staphylococcus epidermidis, Streptococcal Infections, medicine, Animals, Humans, Experimental Therapeutics, Pharmacology (medical), Pharmacology, Dose-Response Relationship, Drug, Glycopeptides, Staphylococcal Infections, biology.organism_classification, Anti-Bacterial Agents, Cephalosporins, Streptococcus pneumoniae, Infectious Diseases, Thigh, Area Under Curve, Pharmacodynamics, Female, Dimerization, medicine.drug |
| الوصف: | 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-log 10 CFU kill effective dose (ED 1-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 log 10 CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log 10 stasis dose (ED stasis ) and ED 1-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 ( r 2 = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r 2 = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r 2 = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log 10 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. |
| تدمد: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.05382-11 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b1a18ab7a2b2096e7241a2d9d9d7742a https://doi.org/10.1128/aac.05382-11 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b1a18ab7a2b2096e7241a2d9d9d7742a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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| DOI: | 10.1128/aac.05382-11 |