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

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Abstract
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 [fAUC(24)]/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% (fAUC(24)/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 10(8) CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a fAUC(24)/MIC of 350 did not achieve bactericidal activity. At regimens of <= 60% penetration (fAUC(24)/MIC <= 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating >= 80% penetration (fAUC(24)/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 (r(2) >= 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (r(2) >= 0.965). Due to the emergence of vancomycin-intermediate resistance at a fAUC(24)/MIC of <= 210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.

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