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

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 [ƒAUC₂₄]/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% (ƒAUC₂₄/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 ƒAUC₂₄/MIC of 350 did not achieve bactericidal activity. At regimens of ≤60% penetration (ƒAUC₂₄/MIC ≤ 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating ≥80% penetration (ƒAUC₂₄/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 ƒAUC₂₄/MIC of ≤210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.Nosocomial pneumonia remains a significant cause of morbidity and mortality. Recently the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) (1) proposed vancomycin trough concentrations of 15 to 20 mg/liter for health care- and ventilator-associated (HAP and VAP) methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) pneumonia. This recommendation is derived from evidence suggesting that the vancomycin 24-h area-under-the-concentration-time-curve-to-MIC (AUC/MIC) ratio of ≥350 is predictive of cure in patients with S. aureus pneumonia and recent concerns regarding vancomycin''s antistaphylococcal activity, such as the MIC “creep,” low rate of killing, and increasing reports of treatment failure (14, 26, 31, 32). However, there has been significant debate as to whether high-dose vancomycin is beneficial, since some studies have shown that greater exposure is not correlated with a more favorable hospital outcome and is associated with increased nephrotoxicity in patients receiving high-dose vancomycin regimens (9, 11, 22).Additionally, little is known regarding the degree of penetration of vancomycin into epithelial lining fluid (ELF) from plasma. Although an earlier study by Lamer et al. (19) provided evidence that vancomycin penetrates poorly into ELF (free vancomycin in ELF/plasma was less than 30%), a recent study by G. L. Drusano et al. (7a) suggests that ELF penetration may be higher (free vancomycin in ELF/plasma was approximately 100%). Adding to this discrepancy is the lack of information regarding vancomycin''s killing activity and ability to suppress resistance at clinically achievable concentrations at the site of infection and the relationship between the early physiologic changes in S. aureus that occur due to suboptimal exposure.The objective of this investigation was to simulate human concentration-time profiles of vancomycin in ELF and determine the proclivity toward developing reduced glycopeptide susceptibility, tolerance, and phenotypic alterations using an in vitro pharmacodynamic model of MRSA infection and mathematical modeling.(This work was presented in part at the 47th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 2007.)