Pharmacodynamic effect of clinical vancomycin exposures on cell wall thickness in heterogeneous vancomycin-intermediate Staphylococcus aureus

Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) have a higher predisposition to select for VISA with thickened cell walls upon vancomycin exposure, but the pharmacodynamic relationship of this occurrence with clinical doses is unknown. This study investigates the impact of clinical vancomycin dose simulations on cell wall thickness (CWT) and the emergence of resistance in hVISA in an in vitro pharmacodynamic model. In an in vitro pharmacokinetic/pharmacodynamic model, we simulated 125-2000 mg of vancomycin every 12 h (infinity AUC/MIC 24-225) over a 72 h period against three clinical hVISA and two standard control S. aureus strains. Pharmacodynamic activity, susceptibility and resistance populations were assessed, and CWT was determined at the end of the exposure. Bactericidal activity occurred in hVISA only with vancomycin infinity AUC/MIC >= 164 exposures, but regrowth occurred after 24 h, regardless of initial activity. Following vancomycin exposure, CWT correlated with MIC increases (r = 0.66; P < 0.0001). A significant increase in CWT occurred in hVISA with any vancomycin simulation, including the high-dose infinity AUC/MIC 225 regimen (24.4% increase in hVISA versus 3.3% with control; P < 0.001). Any vancomycin exposure in two of the three hVISA strains resulted in isolates with MICs >= 3 mg/L and as high as 8 mg/L, which corresponded with a more resistant VISA population profile. High-dose vancomycin exposures in hVISA cannot prevent cell wall thickening, but prudent therapeutic strategies including treatment doses >= 1500 mg every 12 h (AUC/MIC >= 364) in conjunction with avoidance of long-term vancomycin exposure may avert further reduced susceptibility.