JAC Advance Access first published online on February 8, 2008
This version published online on March 15, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn037
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Original research |
Teicoplanin pharmacodynamics in reference to the accessory gene regulator (agr) in Staphylococcus aureus using an in vitro pharmacodynamic model
1 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; 2 Detroit Receiving Hospital and University Health Center, Detroit, MI, USA; 3 University of Wisconsin School of Pharmacy, Madison, WI 53705, USA; 4 School of Medicine, Wayne State University, Detroit, MI, USA; 5 John D. Dingell Department of Veteran’s Affairs Medical Center, Detroit, MI, USA; 6 Department of Medicine, Division of Infectious Diseases, New York Medical College, Munger Pavilion 245, Vahalla, NY 10595, USA
Received 3 August 2007; returned 7 January 2008; revised 8 October 2007; accepted 13 January 2008
* Corresponding author. Tel: +1-313-993-4673; Fax: +1-313-577-8915. E-mail: m.rybak{at}wayne.edu
Objectives: The accessory gene regulator (agr) has been identified as playing a role in the expression of reduced glycopeptide susceptibility in Staphylococcus aureus. Previous studies indicate that strains with agr dysfunctional group II polymorphism have a higher propensity for reduced vancomycin activity. We investigated this relationship in agr groups I–IV using another glycopeptide, teicoplanin, in an in vitro pharmacodynamic model.
Methods: Teicoplanin doses ranging from 1.88 to 30 mg/kg daily (fAUC/MIC 26.1–380.7) were simulated and evaluated for activity and the development of reduced susceptibility over 72 h.
Results: A dose–response relationship in activity was noted as doses escalated up to 30 mg/kg daily, but regrowth was identified with all doses. Teicoplanin doses of 3.75 and 1.88 mg/kg daily resulted in isolates with intermediate teicoplanin susceptibility (MIC = 16 mg/L) in agr groups II, IV (MIC = 16 mg/L) and III (MIC = 24 mg/L), regardless of function of the agr operon. Resistance to teicoplanin (
32 mg/L) occurred in agr group I functional and dysfunctional isolates. Minimal changes in MIC were noted with 7.5 mg/kg daily doses in agr groups II–IV. However, this dose resulted in variable susceptibility (4–24 mg/L) in agr group I+/– isolates. Higher doses of 15 and 30 mg/kg daily did not produce changes in MIC in any isolate tested.
Conclusions: Agr function did not determine teicoplanin resistance proclivity and is consistent with the previously described higher mutation rate in S. aureus to teicoplanin. Further investigation of agr group and function is warranted for all glycopeptides and compounds with a similar mechanism of action.
Key Words: quorum sensing , glycopeptides , resistance