Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections

Background: Vancomycin is commonly used to treat staphylococcal infections, but there has not been a definitive analysis of the pharmacokinetics of this antibacterial in relation to minimum inhibitory concentration (MIC) that could be used to determine a target pharmacodynamic index for treatment optimisation. Objective: To clarify relationships between vancomycin dosage, serum concentration, MIC and antimicrobial activity by using data gathered from a therapeutic monitoring environment that observes failures in some cases. Methods: We investigated all patients with a Staphylococcus aureus lower respiratory tract infection at a 300-bed teaching hospital in the US during a 1-year period. Clinical and pharmacokinetic information was used to determine the following: (i) whether steady-state 24-hour area under the concentration-time curve (AUC(24)) divided by the MIC (AUC(24)/MIC) values for vancomycin could be precisely calculated with a software program; (ii) whether the percentage of time vancomycin serum concentrations were above the MIC (%Time>MIC) was an important determinant of vancomycin response; (iii) whether the time to bacterial eradication differed as the AUC(24)/MIC value increased; (iv) whether the time to bacterial eradication for vancomycin differed compared with other anti-bacterials at the same AUC(24)/MIC value; and (v) whether a relationship existed between time to bacterial eradication and time to significant clinical improvement of pneumonia symptoms. Results: The median age of the 108 patients studied was 74 (range 32-93) years. Measured vancomycin AUC(24)/MIC values were precisely predicted with the A.U.I.C. calculator in a subset of our patients (r(2) = 0.935). Clinical and bacteriological response to vancomycin therapy was superior in patients with higher ( greater than or equal to400) AUC(24)/MIC values (p = 0.0046), but no relationship was identified between vancomycin %Time>MIC and infection response. Bacterial eradication of S. aureus (both methicillin-susceptible and methicillin-resistant) occurred more rapidly (p = 0.0402) with vancomycin when a threshold AUC24/MIC value was reached. S. aureus killing rates were slower with vancomycin than with other anti staphylococcal antibacterials (p = 0.002). There was a significant relationship (p < 0.0001) between time to bacterial eradication and the time to substantial improvement in pneumonia score. Conclusions: Vancomycin AUC(24)/MIC values predict time-related clinical and bacteriological outcomes for patients with lower respiratory tract infections caused by methicillin-resistant S. aureus.