JAC Advance Access originally published online on July 17, 2008
Journal of Antimicrobial Chemotherapy 2008 62(5):1065-1069; doi:10.1093/jac/dkn288
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original research |
Telavancin and vancomycin pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model
1 Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia 2 Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia 3 Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA
Received 28 February 2008; returned 30 April 2008; revised 11 June 2008; accepted 18 June 2008
* Corresponding author. Tel: +7-495-708-3341; Fax: +7-495-245-0295; E-mail: firsov{at}dol.ru
Objectives: The aim of this study was to compare the pharmacodynamics of telavancin (TLV) and vancomycin (VAN) with Staphylococcus aureus. Their concentrations were simulated between the MIC and the mutant prevention concentration (MPC), and above the MPC.
Methods: Two strains of S. aureus, glycopeptide-intermediate S. aureus (GISA) Mu-50 and ATCC 43300, were exposed for 5 days to once-daily TLV (half-life 8 h) and twice-daily VAN (half-life 6 h). The simulated ratios of 24 h area under the curve (AUC24) to MIC varied from 30–50 to 3400 h. The cumulative antimicrobial effect was expressed by ABBC (area between the level corresponding to the starting inoculum and the time–kill curve calculated from time 0 to 144 h).
Results: With each antibiotic, the ABBC versus log AUC24/MIC relationships were bacterial strain-independent. A sigmoid model fits combined data on both organisms exposed to TLV (r2=0.78) or VAN (r2=0.85). Comparable effects of the proposed therapeutic dose of TLV (10 mg/kg) and a clinical dose of VAN (2x1 g) were predicted for MRSA ATCC 43300 (AUC24/MIC 3400 and 500 h, respectively) and a 1.6-fold greater effect of TLV for GISA Mu-50 compared with VAN (AUC24/MIC 1700 and 130 h, respectively). Mutants of S. aureus ATCC 43300 resistant to 2x and 4x MIC of VAN but not TLV were enriched in these simulations. No selection of TLV- and VAN-resistant mutants of GISA Mu-50 was observed.
Conclusions: These in vitro data suggest that the effects of clinically attainable AUC/MIC ratios of TLV are similar to those of VAN on S. aureus 43300 and 2-fold greater on GISA Mu-50.
Keywords: telavancin , vancomycin , S. aureus , pharmacodynamics , in vitro model