Intra- and Extracellular Activities of Dicloxacillin against Staphylococcus aureus In Vivo and In Vitro

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 intraand 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 (R 2 ¼ 55%) than with the fT .MIC parameter (R 2 ¼ 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.