JAC Advance Access published online on August 13, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg337
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Center for Anti-infective
Research and Development, Hartford Hospital, Hartford, CT 06102, USA
* Corresponding author. E-mail: dnicola{at}harthosp.org.
Received 18 December 2002
; revised 12 May 2003
; accepted 18 May 2003
Objective: To describe the pharmacodynamic
profile of daptomycin against methicillin-resistant Staphylococcus
aureus (MRSA) and Enterococci species based
on bacterial density in an immunocompromised mouse thigh infection
model. Materials and methods: The pharmacodynamic (PD)
profile of daptomycin was determined against two MRSA, one vancomycin-resistant Enterococcus faecium, and one vancomycin-susceptible Enterococcus faecalis using the immunocompromised
murine thigh model. Efficacy was assessed by the change in log10 cfu
in thighs after 24 h of drug treatment. Results: Daptomycin produced a maximal kill
of 4.5-5 log10 cfu against the MRSA and 1.5-2
log10 for the Enterococcus species.
AUC/MIC was the most predictive of the PD parameters. Utilizing
MICs determined in serum or broth in the calculation of the PD parameters
had minimal effect on this correlation. AUCfree/MICbroth required
for static effects with MRSA and Enterococcus species
were 12-36 and 5-13, whereas 99% of maximal
kill was achieved at ratios of 171-442 and 38-157,
respectively. Conclusions: These data reveal the potent in vivo bactericidal activity of daptomycin against
MRSA and Enterococcus species using clinically
achievable drug exposures (dose 4-6 mg/kg per day) currently
under investigation in man.
Keywords: pharmacodynamic profiles, lipopeptides, Gram-positive
organisms
Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection
model
2 Center for Anti-infective
Research and Development, and Office of Research Administration,
Hartford Hospital, Hartford, CT 06102, USA
3 Center for Anti-infective
Research and Development, and Division
of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA
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