title: Linezolid pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model.
abstract: To describe the relationship between the ratio of the 24-h area under the concentration-time curve (AUC(24)) 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 AUC(24)/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 10(8) colony-forming units (CFU)/mL were exposed to multiple-dose pharmacokinetics of twice-daily linezolid for 5 days. The simulated AUC(24)/MIC ratios varied from 30 h to 1200 h (S. aureus ATCC 43300), from 30h to 600 h (S. aureus 479) and from 50h to 400 h (S. aureus ATCC 700699). The cumulative antimicrobial effect was expressed by its intensity (I(E)) measured from the start of treatment to the time after the last antibiotic dose when numbers of antibiotic-exposed bacteria reached >or=10(8)CFU/mL. With each organism, bacterial re-growth followed a pronounced reduction of the starting inoculum that occurred at each simulated AUC(24)/MIC ratio except for the lowest value (30 h). This reduction was AUC(24)/MIC-dependent: the minimum numbers of surviving organisms decreased with increasing AUC(24)/MIC ratios. A sigmoid relationship was established between I(E) and the simulated AUC(24)/MIC ratio. This relationship was bacterial strain-independent; a logistic function fits the combined data with r(2)=0.95. The established AUC(24)/MIC-I(E) relationship is useful to predict the antistaphylococcal effects of linezolid at clinically attainable AUC(24)/MIC values.
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Strukova
authors.forename: Maria V
authors.initials: MV
authors.lastname: Smirnova
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Vostrov
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Lubenko
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D015169:Colony Count, Microbial; D000069349:Linezolid; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D008962:Models, Theoretical; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors; D020713:Vancomycin Resistance
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid