| Abstract
| - Background and aims. Treatment of Staphylococcus aureus infections remains problematic (slow responses and frequent recurrences). Intracellular persistence of the S. aureus could explain those difficulties because of impaired intracellular efficacy of antibiotics. Our aim was to study linezolid for its intracellular activity. Methods. (i) Pharmacodynamic (PD) analysis of intracellular activity using in vitro (THP-1 macrophages) and in vivo (mouse peritonitis) models with determination of key dose-response parameters [maximal relative efficacy (Emax), relative potency (EC50) and static concentration (Cstatic)] towards methicillin-susceptible S. aureus (ATCC 25923; clinical isolate) with linezolid MICs of 4 mg/L; (ii) pharmacokinetic (PK) analysis in uninfected mice for determination of Cmax, AUC and half-life for total and free drug; and (iii) determination of the predictive PK/PD parameter (fT > MIC, fAUC24/MIC or fCmax/MIC) for therapeutic outcome. Results. In vitro, linezolid showed an Emax of ∼1 log10 cfu reduction compared with initial inoculum both intra- and extracellularly and an ∼3-fold increased relative potency (lower EC50 and Cstatic) intracellularly. In vivo, the efficacy of linezolid was impaired (<0.5 log10 reduction extracellularly; failure to reduce the cfu to less than the initial load intracellularly) with, however, an increased intracellular potency (lower EC50). Infection outcome correlated better with the fAUC24/MIC (R2 = 55%) than with the fT > MIC parameter (R2 = 51%) for the extracellular compartment, but no parameter emerged as significant for the intracellular compartment. Conclusions. Linezolid exerts only a weak intracellular activity against the strains of S. aureus tested, even though, in contrast to most other antibiotics, its potency does not appear impaired in comparison with the extracellular activity.
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