1. J Antimicrob Chemother. 2010 May;65(5):962-73. Epub 2010 Mar 7.

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

Sandberg A, Jensen KS, Baudoux P, Van Bambeke F, Tulkens PM, Frimodt-Møller N.

National Center for Antimicrobials & Infection Control, Statens Serum Institut, 5
Artillerivej, DK-2300 Copenhagen S, Denmark.

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.

PMID: 20211859 [PubMed - in process]