JAC Advance Access published online on July 12, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm263
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Pharmacokinetics of dalbavancin in plasma and skin blister fluid
1 Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA 2 Division of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA 3 Vicuron Pharmaceuticals, King of Prussia, PA 19406, USA
Received 4 January 2007; returned 9 March 2007; revised 21 May 2007; accepted 23 June 2007
* Correspondence address. Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102-5037, USA. Tel: +1-860-545-3941; Fax: +1-860-545-3992; E-mail: dnicola{at}harthosp.org
Objectives: Dalbavancin is a novel lipoglycopeptide antibiotic in development for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria. The aim of the present study was to assess the penetration of dalbavancin into skin blister fluid.
Methods: Nine healthy subjects (five males; ranging in age from 26 to 57 years) were administered a single 30 min intravenous infusion of dalbavancin at a dose of 1000 mg. Skin blisters were induced by application of cantharidin ointment. Plasma and blister fluid samples were collected over 7 days post-dose, and concentrations of dalbavancin were assessed by a validated LC/MS/MS assay. Pharmacokinetics were determined by non-compartmental methods, and drug penetration was assessed based on the ratio of area under the curve (AUC) in the blister fluid versus plasma for each subject.
Results: The mean (SD) peak concentration of dalbavancin in plasma and blister fluid was 285 (31.1) and 67.3 (18.2) mg/L, respectively; the corresponding AUCDay 7 values were 10 806 (1926) and 6438 (1238) mg·h/L, respectively. The mean (SD) penetration of dalbavancin into blister fluid was 59.6% (6.3%). By Day 7, the mean concentration of dalbavancin in plasma and blister fluid was 46.5 and 30.3 mg/L, respectively.
Conclusions: Dalbavancin concentrations in blister fluid remained well above the MIC90 values for pathogens commonly implicated in cSSSIs such as Staphylococcus aureus, including methicillin-resistant S. aureus (MIC90 = 0.06 mg/L) and ß-haemolytic streptococci (MIC90 = 0.03 mg/L) through Day 7. These pharmacokinetic data support the use of dalbavancin in the treatment of cSSSIs caused by susceptible Gram-positive pathogens.
Key Words: lipoglycopeptides , infections , cSSSIs