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JAC Advance Access originally published online on September 16, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):1044-1051; doi:10.1093/jac/dkp289
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Comparative antibacterial effects of daptomycin, vancomycin and teicoplanin studied in an in vitro pharmacokinetic model of infection

Karen E. Bowker*, Alan R. Noel and Alasdair P. MacGowan

Bristol Centre for Antimicrobial Research and Evaluation (BCARE), Department of Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK

Received 11 March 2009; returned 6 May 2009; revised 22 June 2009; accepted 15 July 2009

* Corresponding author. Tel: +44-(0)1179-9595654; Fax: +44-(0)117-9593217; E-mail: karen.bowker{at}nbt.nhs.uk

Objectives: To compare the antibacterial effects (ABEs) of the free (f) drugs daptomycin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), using high and low inocula in a pharmacokinetic in vitro model. To determine the daptomycin fAUC/MIC ratio for a static effect and 3 log reduction in viable count and relate this target to the clinical breakpoint.

Methods: Five clinical MRSA isolates held at Southmead Hospital were used (SMH 15841, SMH 40289, SMH 40275, SMH 33922 and SMH 33024) together with a VRSA isolate (SMH 19898); inocula of 106 and 108 cfu/mL were used. Daptomycin (6 mg/kg once daily), vancomycin (1 g twice daily) and teicoplanin (400 mg once daily) regimens were simulated. ABEs were measured using the 24 h area-under-the-bacterial kill curve (AUBKC) and log change in viable count at 24 h ({Delta}24). For daptomycin, dose escalation was used to determine the relationship between ABE and AUC/MIC.

Results: Daptomycin was bactericidal against the MRSA strains. Daptomycin and vancomycin were active against the VRSA strain; teicoplanin had a static effect. The higher inoculum reduced the ABEs. Analysis of variance (ANOVA) indicated that daptomycin had a superior ABE to teicoplanin and vancomycin. Daptomycin fAUC/MIC was related to AUBKC and {Delta}24; the fAUC/MIC ratios for a static effect and 1 log and 3 log drop were 37.2 ± 16.5, 40.6 ± 17.8 and 49.8 ± 19.2, respectively.

Conclusions: These data define the fAUC/MIC sizes for daptomycin for bacteriostatic and bactericidal ABEs and indicate that a 6 mg/kg dose of daptomycin is superior to vancomycin and teicoplanin against MRSA and VRSA strains.

Keywords: MRSA , VRSA , lipopeptides , glycopeptides


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