Cellular Pharmacodynamics of the Novel Biaryloxazolidinone Radezolid: Studies with Infected Phagocytic and Nonphagocytic cells, UsingStaphylococcus aureus,Staphylococcus epidermidis,Listeria monocytogenes, andLegionella pneumophila

Abstract

Radezolid is a novel biaryloxazolidinone in clinical development which shows improved activity, including against linezolid-resistant strains. In a companion paper (29), we showed that radezolid accumulates about 11-fold in phagocytic cells, with ϳ60% of the drug localized in the cytosol and ϳ40% in the lysosomes of the cells. The present study examines its activity against (i) bacteria infecting human THP-1 macrophages and located in different subcellular compartments (Listeria monocytogenes, cytosol; Legionella pneumophila, vacuoles; Staphylococcus aureus and Staphylococcus epidermidis, mainly phagolysosomal), (ii) strains of S. aureus with clinically relevant mechanisms of resistance, and (iii) isogenic linezolid-susceptible and -resistant S. aureus strains infecting a series of phagocytic and nonphagocytic cells. Radezolid accumulated to similar levels (ϳ10-fold) in all cell types (human keratinocytes, endothelial cells, bronchial epithelial cells, osteoblasts, macrophages, and rat embryo fibroblasts). At equivalent weight concentrations, radezolid proved consistently 10-fold more potent than linezolid in all these models, irrespective of the bacterial species and resistance phenotype or of the cell type infected. This results from its higher intrinsic activity and higher cellular accumulation. Time kill curves showed that radezolid's activity was more rapid than that of linezolid both in broth and in infected macrophages. These data suggest the potential interest of radezolid for recurrent or persistent infections where intracellular foci play a determinant role.Intracellular infections are difficult to treat because bacteria are shielded from many of the humoral and cellular means of natural defenses while being also partially protected from the action of most antibiotics (7,12,47,58). While intracellular survival is part of the pathogenic cycle of obligatory or facultative intracellular bacteria like Listeria monocytogenes or Legionella pneumophila (7,38,51), it contributes to the recurrent or persistent character of infections caused by opportunistic intracellular bacteria like staphylococci (16). The treatment of such intracellular infections, therefore, requires the use of antibiotics that can express their activity at the site of infection. This, however, cannot be predicted simply on the basis of the ability of drugs to accumulate in cells, as several other factors may play a critical role in enhancing or impeding their local antimicrobial properties (7, 58). For example, previous work in our laboratory using a model of Staphylococcus aureus-infected THP-1 cells showed that ␤-lactams, which do not accumulate in these cells, nevertheless display significant intracellular activity provided their extracellular concentration is brought to sufficiently high but still clinically meaningful levels (31). Conversely, azithromycin, which is known to accumulate in large amounts in cells (6, 18), proves only marginally active against S. aureus phagocytosed by macrophages (1, 32). This occurs despite the fact tha...

Pharmacodynamic Evaluation of the Activity of Antibiotics against Hemin- and Menadione-Dependent Small-Colony Variants of Staphylococcus aureus in Models of Extracellular (Broth) and Intracellular (THP-1 Monocytes) Infections

“…This is in line with what we have repeatedly described for S. aureus of different origins and resistance phenotypes and for most antibiotics tested in this in vitro model of THP-1 monocytes as well as in other models of phagocytic and nonphagocytic cells (7,27,29,31,38). The present data, however, expand those observations in two main directions.…”

Investigational Antimicrobial Agents of 2013

“…It displayed MIC 90 values against cfr-containing linezolid-resistant S. aureus isolates that were 4-to 8-fold lower than those of linezolid (103). Another attractive property of this compound is higher intrinsic activity than linezolid in infected cells, with phagocytic cell internal concentrations increased 11-fold over extracellular concentrations (104,105). The compound has recently successfully completed two phase 2 clinical trials for community-acquired pneumonia (CAP) and for uncomplicated skin and skin structure infections (uSSSI) (http://www.clinicaltrials.gov).…”

Pharmacodynamic Evaluation of the Intracellular Activity of Antibiotics towards Pseudomonas aeruginosa PAO1 in a Model of THP-1 Human Monocytes

“…The aim of the present study was therefore to set up a model of intracellular P. aeruginosa infection allowing a comparative evaluation of the activities of antipseudomonal antibiotics. We selected THP-1 human monocytes as host cells because these have proven useful in obtaining reproducible levels of intracellular infection with other bacteria and in quantitatively assessing the activities of antibiotics by a pharmacodynamic approach (19,20,(24)(25)(26). We included in our study most of the currently used antipseudomonal agents (27) and tested them against reference strain PAO1.…”