title: Pharmacodynamics of vancomycin at simulated epithelial lining fluid concentrations against methicillin-resistant Staphylococcus aureus (MRSA): implications for dosing in MRSA pneumonia.
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 [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 10(8) 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 < or = 60% penetration (fAUC24/MIC < or = 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating > or = 80% penetration (fAUC24/MIC > or = 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 > or = 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (r2 > or = 0.965). Due to the emergence of vancomycin-intermediate resistance at a fAUC24/MIC of < or = 210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.
authors: 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, NY 14260, USA.
authors: Yoriko
authors: Y
authors: Harigaya
authors: Jürgen B
authors: JB
authors: Bulitta
authors: Alan
authors: A
authors: Forrest
authors: George
authors: G
authors: Sakoulas
authors: Alan J
authors: AJ
authors: Lesse
authors: Joseph M
authors: JM
authors: Mylotte
authors: Brian T
authors: BT
authors: Tsuji
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001433:Bacteriolysis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity; D008826:Microbial Sensitivity Tests; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D014640:Vancomycin / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin