The influence of Staphylococcus aureus accessory gene regulator function on the development of glycopeptide heteroresistance in an in vitro pharmacodynamic model

Abstract number: 1134_03_359

Tsuji B., Rybak M.


The development of glycopeptide heteroresistance in patients with S. aureus infections has been associated with prolonged exposure to sub-therapeutic levels of vancomycin. S. aureus which display accessory gene regulator (agr) dysfunction have been associated with persistent bacteraemia and may be predisposed to develop glycopetide resistance: sub-inhibitory concentrations of vancomycin have selected for heteroresistance in vitro in agr-null group II S. aureus. We studied the effect of administering varying exposures of vancomycin and the development intermediate-level glycopeptide resistance in agr positive and negative group II S. aureus in an in vitro pharmacodynamic model (IVPM).


One agr+ group II (RN6607) and the respective agr- group II, null derivate (RN9120) strain of S. aureus were obtained from the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA). MICs were determined by Etest & microdilution according to NCCLS. An IVPM was used to simulate regimens of vancomycin of 1 g, 750 mg, 500 mg, 250 mg and 125 mg q12 h (Targeted Peak/Trough concentrations 40/10.0, 30/7.5, 20/5.0, 10/2.5 and 5/1.2 mg/ml). Simulations were performed in triplicate and bacterial quantification occurred over 72 h. The development of vancomycin heteroresistance was evaluated at 24, 48 and 72 h.


Pre-exposure vancomycin MIC were 1.0 against both agr+ group II and agr- group II strains. Against agr+ II S. aureus, exposure to all simulated of vancomycin regimens did not result in the development of resistance over 72 h. Post-exposure MICs for all regimens were <=2.0 mg/ml. Against agr- II, over 72 h, exposure to vancomycin 1 g q12 h (24 h Area Under Concentration Curve (AUCfree24/MIC:510 mg/ml/hr) and 750 mg q12 h (AUCfree24/MIC: 382) resulted in post-exposure MICs of 1–3 mg/ml. Increased post-exposure MICs up to 3 mg/ml were noted secondary to exposure to 500 mg (AUCfree24/MIC: 264) and 250 mg (AUCfree24/MIC: 123). Exposure to 125 mg (AUCfree24/MIC:67) resulted in the development of vancomycin heteroresistance, as post-exposure MICs increased to 6 mg/ml.


Sub-optimal exposures of vancomycin resulted in the development of glycopeptide heteroresistance in agr-null group II S. aureus. These findings suggest that prolonged, low-level vancomycin concentrations or decreased vancomycin penetration in sequestered infections may provide conditions that select for glycopeptide heteroresistance.

Session Details

Date: 01/08/2007
Time: 00:00-00:00
Session name: XXIst ISTH Congress
Location: Oxford, UK
Presentation type:
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