Pharmacokinetic-pharmacodynamic modeling of dalbavancin, a novel glycopeptide antibiotic.
Dalbavancin is a novel glycopeptide with a 2-dose, once-weekly dosing regimen that is being developed for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Monte Carlo simulations were performed for dalbavancin using population pharmacokinetic data and minimum inhibitory concentrations (MICs) for clinical trial isolates. The time-dependent target was the maintenance of free drug concentrations above the MIC for 14 days (t>MIC). The concentration-dependent target was an area under the concentration-time curve (AUC)/MIC ratio of approximately 1000 for Staphylococcus aureus and 100 for Streptococcus sp. These targets were used to estimate susceptibility breakpoints for dalbavancin. For S aureus, the estimated susceptibility breakpoint was <or=0.5 microg/mL using AUC(14 days)/MIC and <or=1 microg/mL using t>MIC. For Streptococcus sp, the estimated susceptibility breakpoint was at least 2 mug/mL. Because dalbavancin MIC(90)s for these species are well below these values, the analysis supports the use of once-weekly dosing regimens of dalbavancin in the treatment of complicated skin and skin structure infections.
Dowell
James A
JA
Vicuron Pharmaceuticals, USA
Goldstein
Beth P
BP
Buckwalter
Mary
M
Stogniew
Martin
M
Damle
Bharat
B
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D004334:Drug Administration Schedule; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D017192:Skin Diseases, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development; D017334:Teicoplanin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014640:Vancomycin / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D017334:Teicoplanin; D014640:Vancomycin; C469289:dalbavancin