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Antimicrobial Agents and Chemotherapy, September 2009, p. 3894-3901, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.01585-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Vancomycin at Simulated Epithelial Lining Fluid Concentrations against Methicillin-Resistant Staphylococcus aureus (MRSA): Implications for Dosing in MRSA Pneumonia{triangledown}

Yoriko Harigaya,1,{dagger} Jürgen B. Bulitta,1,2 Alan Forrest,1,2 George Sakoulas,4 Alan J. Lesse,3,5 Joseph M. Mylotte,3 and Brian T. Tsuji1,6*

Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences and The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, State University of New York, Buffalo, New York,1 Ordway Research Institute, Albany, New York,2 School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York,3 Department of Medicine, Division of Infectious Diseases, New York Medical College, Valhalla, New York,4 VA Western New York Healthcare System, Buffalo, New York,5 Roswell Park Cancer Institute, Department of Medicine, Buffalo, New York6

Received 30 November 2008/ Returned for modification 24 March 2009/ Accepted 3 June 2009

Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [fAUC24]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (fAUC24/MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two agr-functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a high inoculum of 108 CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a fAUC24/MIC of 350 did not achieve bactericidal activity. At regimens of ≤60% penetration (fAUC24/MIC ≤ 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating ≥80% penetration (fAUC24/MIC ≥ 280) suppressed development of resistance. Resistant mutants amplified by suboptimal vancomycin exposure displayed reduced rates of autolysis (Triton X-100) at 72 h. Bacterial growth and death were well characterized by a Hill-type model (r2 ≥ 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (r2 ≥ 0.965). Due to the emergence of vancomycin-intermediate resistance at a fAUC24/MIC of ≤210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.

* Corresponding author. Mailing address: Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, NY 14260. Phone: (716) 881-7543. Fax: (716) 849-6890. E-mail: btsuji{at}buffalo.edu

{triangledown} Published ahead of print on 13 July 2009.

{dagger} Present address: Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3894-3901, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.01585-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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