The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared to that of vancomycin and linezolid against methicillin-resistant Staphylococcus aureus (MRSA) in a murine pneumonia model. Telavancin produced greater reductions in lung bacterial titer and mortality than did vancomycin and linezolid at human doses equivalent to those described by the area under the concentration-time curve. These results suggest the potential utility of telavancin for treatment of MRSA pneumonia.Nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) has been reported with increasing frequency over the past 2 decades (13). Vancomycin and linezolid, two drugs that are slowly bactericidal and bacteriostatic, respectively, are frequently used in the treatment of nosocomial pneumonia caused by Staphylococcus aureus, including MRSA. However, overall clinical cure rates attained with these two drugs are less than optimal (8).Telavancin is a novel lipoglycopeptide that operates through multiple mechanisms to produce potent and rapid bactericidal activity against clinically relevant gram-positive bacteria, including MRSA (4, 5, 7). We have previously shown that telavancin exhibits potent antibacterial activity against a range of gram-positive bacteria, including MRSA, in two animal models of soft-tissue infection, with the area under the concentrationtime curve (AUC)/MIC ratio being the pharmacodynamically linked parameter (3). In the studies described here, we assessed the efficacy of telavancin in an immunocompromised murine model of MRSA-induced pneumonia.Telavancin for injection (250 mg/vial) was reconstituted in 5% dextrose in water. Vancomycin (Sigma-Aldrich, St. Louis, MO) and linezolid (Pharmacia, Kalamazoo, MI) were dissolved in 5% dextrose in water and hydroxypropyl--cyclodextrin, respectively. MRSA ATCC 33591 was obtained from the American Type Culture Collection (Manassas, VA). MICs were determined by the broth microdilution method according to protocol M7-A5 of the National Committee for Clinical Laboratory Standards (6). The MICs of telavancin, vancomycin, and linezolid against MRSA 33591 were 0.5, 1, and 1 g/ml, respectively. The doses used in pharmacodynamic studies were chosen to approximate human doses equivalent to those described by AUCs as opposed to other pharmacokinetic parameters since the AUC/MIC ratio is believed to be the key pharmacodynamically linked parameter for all three drugs against S. aureus (1, 3).All studies were approved by the Institutional Animal Care and Use Committee at Theravance, Inc. Female BALB/c mice (Harlan, Indianapolis, IN), weighing between 16 and 26 g, were rendered neutropenic by treatment with 250 mg/kg of cyclophosphamide intraperitoneally at 4 and 2 days prior to infection. Neutropenic animals were lightly anesthetized with isoflurane gas and then held in an upright position to be inoculated. Each animal was inoculated by placing 50 l of inoculum containing approximately 10 7 CFU of MRSA onto the tip of the nares. The animals were allowed to inhale t...