Intra- and extracellular activity of linezolid against Staphylococcus aureus in vivo and in vitro.

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 (E(max)), relative potency (EC(50)) and static concentration (C(static))] 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 C(max), AUC and half-life for total and free drug; and (iii) determination of the predictive PK/PD parameter (fT > MIC, fAUC(24)/MIC or fC(max)/MIC) for therapeutic outcome. RESULTS In vitro, linezolid showed an E(max) of approximately 1 log(10) cfu reduction compared with initial inoculum both intra- and extracellularly and an approximately 3-fold increased relative potency (lower EC(50) and C(static)) intracellularly. In vivo, the efficacy of linezolid was impaired (<0.5 log(10) reduction extracellularly; failure to reduce the cfu to less than the initial load intracellularly) with, however, an increased intracellular potency (lower EC(50)). Infection outcome correlated better with the fAUC(24)/MIC (R(2) = 55%) than with the fT > MIC parameter (R(2) = 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.