Teicoplanin pharmacodynamics in reference to the accessory gene regulator (agr) in Staphylococcus aureus using an in vitro pharmacodynamic model.
OBJECTIVE
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 (> or = 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.
Rose
Warren E
WE
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA;
Kaatz
Glenn W
GW
Sakoulas
George
G
Rybak
Michael J
MJ
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017334:Teicoplanin / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015534:Trans-Activators; D017334:Teicoplanin