Linezolid pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model

To describe the relationship between the ratio of the 24-h area under the concentration–time curve (AUC24) to minimum inhibitory concentration (MIC) as well as the effect of linezolid on Staphylococcus aureus, the killing kinetics of three S. aureus strains was studied by in vitro simulation of 5-day antibiotic dosing over a wide range of AUC24/MIC ratios. Similarly susceptible meticillin-resistant S. aureus ATCC 43300 and S. aureus 479 and vancomycin-intermediate S. aureus ATCC 700699 (Mu50) at a starting inoculum of 108 colony-forming units (CFU)/mL were exposed to multiple-dose pharmacokinetics of twice-daily linezolid for 5 days. The simulated AUC24/MIC ratios varied from 30 h to 1200 h (S. aureus ATCC 43300), from 30 h to 600 h (S. aureus 479) and from 50 h to 400 h (S. aureus ATCC 700699). The cumulative antimicrobial effect was expressed by its intensity (IE) measured from the start of treatment to the time after the last antibiotic dose when numbers of antibiotic-exposed bacteria reached ≥108 CFU/mL. With each organism, bacterial re-growth followed a pronounced reduction of the starting inoculum that occurred at each simulated AUC24/MIC ratio except for the lowest value (30 h). This reduction was AUC24/MIC-dependent: the minimum numbers of surviving organisms decreased with increasing AUC24/MIC ratios. A sigmoid relationship was established between IE and the simulated AUC24/MIC ratio. This relationship was bacterial strain-independent; a logistic function fits the combined data with r2 = 0.95. The established AUC24/MIC–IE relationship is useful to predict the antistaphylococcal effects of linezolid at clinically attainable AUC24/MIC values.