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Updated: Jun 10, 2026
Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Pharmacodynamic effect of clinical vancomycin exposures on cell wall thickness in heterogeneous
Warren E Rose1, Ryan M Knier, Paul R Hutson
1Pharmacy Practice Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA. werose@pharmacy.wisc.edu
Objectives:
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.
Methods:
In an in vitro pharmacokinetic/pharmacodynamic model, we simulated 125-2000 mg of vancomycin every 12 h (ƒAUC/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.
Results:
Bactericidal activity occurred in hVISA only with vancomycin ƒAUC/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 ƒAUC/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.
Conclusions:
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.
Insights
Vancomycin exposure thickens Staphylococcus aureus cell walls, increasing resistance. High-dose vancomycin (≥1500 mg q12h) may help manage heterogeneous VISA, but long-term use should be avoided.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) strains are prone to developing vancomycin resistance.
- Vancomycin exposure can lead to increased cell wall thickness (CWT) in hVISA.
- The relationship between clinical vancomycin dosing and hVISA CWT/resistance is not well understood.
Purpose of the Study:
- To investigate the impact of simulated clinical vancomycin doses on CWT and resistance in hVISA.
- To determine the pharmacodynamic thresholds for vancomycin activity against hVISA.
- To assess the emergence of vancomycin resistance in hVISA under simulated therapeutic conditions.
Main Methods:
- An in vitro pharmacokinetic/pharmacodynamic model was used.
- Simulated vancomycin doses ranged from 125-2000 mg every 12 hours (ƒAUC/MIC 24-225) over 72 hours.
- Three clinical hVISA strains and two control strains were tested; CWT and susceptibility were assessed.
Main Results:
- Vancomycin exposure, even at high doses (ƒAUC/MIC 225), significantly increased CWT in hVISA (24.4% vs. 3.3% in controls).
- Regrowth of hVISA occurred after 24 hours, irrespective of initial bactericidal activity.
- Vancomycin exposure led to increased MICs (≥3 mg/L, up to 8 mg/L) and a more resistant VISA population profile.
Conclusions:
- High-dose vancomycin cannot prevent cell wall thickening in hVISA.
- Therapeutic strategies using doses ≥1500 mg every 12 hours (AUC/MIC ≥364) may reduce susceptibility.
- Avoiding prolonged vancomycin exposure is crucial to prevent further resistance development.
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