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TR-700, a novel methyltetrazolyl-oxazolidinone, accumulates extensively within human macrophages cells and shows activity towards intraphagocytic linezolid-sensitive and linezolid-resistant S.aureus

Abstract number: P1092

Lemaire S., Kosowska-Shick K., Appelbaum P., Van Bambeke F., Tulkens P.

Background: Treatment of intracellular infections requires that antibiotics reach their intracellular target and express activity therein. Linezolid accumulates poorly within cells, and shows only modest intracellular activity against S. aureus or S. epidermidis (Barcia-Macay et al, AAC, 2006; Pascual et al, AAC, 2002). The aim of this study was to examine the cellular pharmacokinetic properties and intracellular activity of TR-700 towards S. aureus, in light of the higher lipophilicity and intrinsic activity of this molecule vs linezolid.

Methods: Human THP-1 macrophages were used throughout this study. Accumulation of both oxazolidinones was measured by microbiological assay, using S. aureus ATCC 25923 as test organism. The phenotypes of the strains used are shown in Table 1. MICs were determined in MHB. Intracellular activity was determined over a large range of extracellular concentrations (typically 0.01 to 100-fold the MIC to obtain full description of concentration-effect relationships) against bacteria phagocytised by human THP-1 macrophages (see details in Barcia-Macay et al, AAC, 2006). Results are expressed here as (i) bacteriostatic concentration (SC), and (b) maximal effect (Emax) at 24 h compared to time 0 h (post-phagocytosis) as calculated from the Hill functions fitted to the data by non-linear regression.

Results: TR-700 accumulated quickly and extensively in macrophages, within 15 minutes reaching an apparent cellular to extracellular concentration ratio of about 13 vs 1–2 for linezolid. MICs in broth (mg/L) and intracellular activities are shown in Table 1.

Conclusions: Compared to linezolid, TR-700 shows increased potency (lower bacteriostatic concentrations) towards intraphagocytic S. aureus (unaffected by resistance of the strain to linezolid), probably in relation with its extensive accumulation within cells and its higher intrinsic activity (lower MIC values).

OrganismsLinezolidTR-700
 MICintracell. activityMICintracell. activity
 (broth)SCaEmaxb(broth)SCaEmaxb
ATCC 259232~4.5-0.4±0.10.25~1.0-0.6±0.1
SA 238 c2~5.8-0.3±0.10.25–0.5~0.5-0.7±0.1
SA 238 c16>100*+0.2±0.11~1.0-0.6±0.1
CM-05 d8~21.3-0.5±0.30.25–0.5~0.7-0.6±0.1
aExtracellular antibiotic concentration (mg/L) yielding no apparent change in cfu after 24 h compared to post-phagocytosis inoculum.
bMaximal decrease in intracellular cfu (log scale) compared to the post-phagocytosis inoculum.
cStrains selected in the laboratory, dlinezolid-resistant MRSA clinical isolate carrying the cfr methyltransferase gene.
*Bacterial growth in all conditions.

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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