JAC Advance Access published online on February 8, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn037
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Original research |
Relationships between vancomycin pharmacodynamics and the emergence of vancomycin-intermediate Staphylococcus aureus (VISA) from heterogeneous VISA in 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, Detroit, MI 48201, USA 3 University of Wisconsin School of Pharmacy, Madison, WI 53705, USA 4 School of Medicine, Wayne State University, Detroit, MI 48201, USA 5 John D. Dingell Department of Veteran's Affairs Medical Center, Detroit, MI 48201, USA
Received 3 August 2007; returned 7 January 2008; revised 8 October 2007; accepted 13 January 2008
* Corresponding author. Tel: +1-313-577-4376; Fax: +1-313-577-8915; E-mail: m.rybak{at}wayne.edu
Objectives: Increasing reports of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) have raised concerns over vancomycin utility in treating infections caused by this pathogen. Previous studies have demonstrated that hVISA precedes the emergence of VISA. This investigation evaluates the pharmacodynamic parameters of vancomycin in vitro against hVISA and the development of reduced susceptibility.
Methods: Two hVISA isolates (Mu3 and MRSA 1629) and one clinical non-hVISA (MRSA 3286) were evaluated at moderate and high inoculum using vancomycin simulations [750–5000 mg every 12 h; free area under the curve (fAUC)/MIC 105–799] in an in vitro pharmacodynamic model over 72 h.
Results: The activity of vancomycin was highly dependent on the bacterial inoculum. At high inoculum, all vancomycin simulations displayed initial killing up to 24 h with no additional activity beyond this time point. Increased vancomycin doses had no impact on overall activity. Although bactericidal activity was achieved in all strains, regardless of the presence of hVISA, 
105cfu/mL of organisms remained after exposure. Doses as high as 5 g every 12 h (fAUC/MIC 799) had little influence on decreasing the hVISA bacterial load. More rapid bactericidal eradication was noted at lower inoculum in the non-hVISA isolate (T99 1.9 h versus 14.1 h and 15.3 h for Mu3 and 1629, respectively; P = 0.001). A 2- to 4-fold increase in vancomycin MIC was noted with both hVISA isolates compared with no increase in non-hVISA at high inoculum.
Conclusions: Vancomycin doses 
2500 mg and 2000 mg every 12 h (fAUC/MIC 374 and 271) suppressed the emergence of MIC increases in Mu3 and 1629, respectively. Our data suggest that at high inoculum, vancomycin has minimal to no activity against hVISA and leads to further reduced susceptibility.
Key Words: resistance , Mu3 , glycopeptides