cThis study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. S taphylococcus aureus and Streptococcus pneumoniae are the most common causes of hospital-acquired and communityacquired bacterial pneumonia, respectively (9, 10). Resistance to currently available antibiotics can be substantial, particularly for S. aureus, as methicillin resistance has been reported in upwards of 60% of S. aureus isolates (13). With respect to methicillin-resistant S. aureus (MRSA), few antibiotics are available to treat pneumonia caused by this organism. Vancomycin and linezolid are recommended as first-line therapy by recent guidelines (16). These agents are not without limitations, including nephrotoxicity and the requirement for therapeutic drug monitoring for vancomycin and myelosuppression for linezolid (29,32). Newer agents, including telavancin and ceftaroline, are not yet approved for MRSA pneumonia.Tedizolid phosphate free acid (TR-701 FA) is the prodrug of tedizolid (TR-700), an oxazolidinone active against many common respiratory Gram-positive bacteria, including methicillinsusceptible and -resistant S. aureus and S. pneumoniae (11,17,31). MICs for MRSA and pneumococcus are approximately 8-fold lower than those of linezolid (11). Because of this spectrum of activity and near-equivalent oral and intravenous (i.v.) bioavailability (2), tedizolid phosphate is being developed as i.v. and oral agents for the treatment of pneumonia. Murine pneumonia experiment results further support the development of this drug. Against S. pneumoniae, tedizolid achieved bacteriostatic and 1-log CFU killing at a dose 4.6-to 5.5-fold lower than the linezolid dose needed to achieve the same level of bacterial reductions (4). Another murine pharmacodynamic study demonstrated that ratios of the free area under the curve (fAUC) to MIC of 10 and 25 in plasma were required for bacteriostasis and a 1-log CFU killing against S. aureus isolates, respectively (22). These pharmacodynamic exposure targets were similar for linezolid and tedizolid.While murine infection model data provide insight into the possibility of tedizolid phosphate as a potential agent for the treatment of pulmonary infections, there are currently no data describing the extent of penetration into the site of infection. For pneumonia, the epithelial lining fluid (ELF) is presumed to be the site of infection for extrac...
