This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Andes, D.
Right arrow Articles by Craig, W. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Andes, D.
Right arrow Articles by Craig, W. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2002, p. 3484-3489, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3484-3489.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vivo Pharmacodynamics of a New Oxazolidinone (Linezolid)

D. Andes,1* M. L. van Ogtrop,2 J. Peng,3 and W. A. Craig1,4

Section of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine,1 Hospital Diagnostic Laboratory, Leiden, The Netherlands,2 Pharmacia Upjohn, Kalamazoo, Michigan,3 Section of Clinical Pharmacology, Department of Medicine, William S. Middleton VA Hospital, Madison, Wisconsin4

Received 20 November 2000/ Returned for modification 29 April 2001/ Accepted 5 August 2002

Linezolid is a new oxazolidinone with activity against gram-positive cocci. We determined the in vivo activity of linezolid against four strains of Staphylococcus aureus (two methicillin-susceptible S. aureus [MSSA] strains and two methicillin-resistant S. aureus strains) and one penicillin-susceptible Streptococcus pneumoniae (PSSP) strain, two penicillin-intermediate S. pneumoniae strains, and five penicillin-resistant S. pneumoniae strains. The mice had 106.3 to 107.7 CFU/thigh before therapy and were then treated for 24 h with 5 to 1,280 mg of linezolid/kg divided into 1, 2, 4, 8, or 16 doses. The killing activities after 4 h of therapy ranged from 2.4 to 5.0 log10 CFU/thigh against S. pneumoniae and 1.35 to 2.2 log10 CFU/thigh against S. aureus. Increasing doses produced minimal concentration-dependent killing; doses of 20 and 80 mg/kg produced no in vivo postantibiotic effects (PAEs) with PSSP and modest PAEs (3.4 and 3.2 h) with MSSA. Pharmacokinetic studies at doses of 20 and 80 mg/kg by high-pressure liquid chromatography analysis exhibited peak dose values of 0.68 and 0.71 and elimination half-lives of 1.02 and 1.00 h. Linezolid MICs ranged from 0.5 to 1.0 µg/ml for S. pneumoniae and from 1.0 to 4.0 µg/ml for S. aureus. A sigmoid dose-response model was used to estimate the dose required to achieve a net bacteriostatic effect over 24 h. Static doses against S. pneumoniae ranged from 22.2 to 97.1 mg/kg/24 h and from 133 to 167 mg/kg/24 h for S. aureus. The 24-h area under the concentration-time curve (AUC)/MIC ratio was the major parameter determining the efficacy of linezolid against PSSP (R2 = 82% for AUC/MIC versus 57% for T>MIC and 59% for the peak level in serum/MIC [peak/MIC]). It was difficult to determine the most relevant pharmacokinetic/pharmacodynamic parameter with S. aureus, although the outcomes correlated slightly better with the 24-h AUC/MIC ratio (R2 = 75%) than with the other parameters (T>MIC R2 = 75% and peak/MIC R2 = 65%). The 24-h AUC/MIC ratio required for a bacteriostatic effect with linezolid varied from 22 to 97 (mean = 48) for pneumococci and from 39 to 167 (mean = 83) for staphylococci. Based upon a pharmacokinetic goal of a 24-h AUC/MIC of 50 to 100, a dosage regimen of 600 mg given either intravenously or orally twice daily would achieve success against organisms with MICs as high as 2 to 4 µg/ml.

* Corresponding author. Mailing address: Department of Medicine, Section of Infectious Diseases, University of Wisconsin School of Medicine, Room H4/570, 600 Highland Ave., Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail: drandes{at}facstaff.wisc.edu.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3484-3489, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3484-3489.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hilliard, J. J., Fernandez, J., Melton, J., Macielag, M. J., Goldschmidt, R., Bush, K., Abbanat, D. (2009). In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457. Antimicrob. Agents Chemother. 53: 2028-2033 [Abstract] [Full Text]  
  • Choi, S., Isaacs, A., Clements, D., Liu, D., Kim, H., Scott, R. W., Winkler, J. D., DeGrado, W. F. (2009). De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers. Proc. Natl. Acad. Sci. USA 106: 6968-6973 [Abstract] [Full Text]  
  • Baldoni, D., Haschke, M., Rajacic, Z., Zimmerli, W., Trampuz, A. (2009). Linezolid Alone or Combined with Rifampin against Methicillin-Resistant Staphylococcus aureus in Experimental Foreign-Body Infection. Antimicrob. Agents Chemother. 53: 1142-1148 [Abstract] [Full Text]  
  • Pea, F., Viale, P., Lugano, M., Baccarani, U., Pavan, F., Tavio, M., Adani, G. L., Della Rocca, G., Furlanut, M. (2009). Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients. J Antimicrob Chemother 63: 167-169 [Abstract] [Full Text]  
  • Wang, L., Wismer, M. K., Racine, F., Conway, D., Giacobbe, R. A., Berejnaia, O., Kath, G. S. (2008). Development of an integrated semi-automated system for in vitro pharmacodynamic modelling. J Antimicrob Chemother 62: 1070-1077 [Abstract] [Full Text]  
  • Louie, A., Heine, H. S., Kim, K., Brown, D. L., VanScoy, B., Liu, W., Kinzig-Schippers, M., Sorgel, F., Drusano, G. L. (2008). Use of an In Vitro Pharmacodynamic Model To Derive a Linezolid Regimen That Optimizes Bacterial Kill and Prevents Emergence of Resistance in Bacillus anthracis. Antimicrob. Agents Chemother. 52: 2486-2496 [Abstract] [Full Text]  
  • LaPlante, K. L., Leonard, S. N., Andes, D. R., Craig, W. A., Rybak, M. J. (2008). Activities of Clindamycin, Daptomycin, Doxycycline, Linezolid, Trimethoprim-Sulfamethoxazole, and Vancomycin against Community-Associated Methicillin-Resistant Staphylococcus aureus with Inducible Clindamycin Resistance in Murine Thigh Infection and In Vitro Pharmacodynamic Models. Antimicrob. Agents Chemother. 52: 2156-2162 [Abstract] [Full Text]  
  • Moise, P. A, Castro, R. S, Sul, C., Forrest, A., Sakoulas, G. (2008). Relationship of Linezolid Minimum Inhibitory Concentration and Time to Bacterial Eradication in Treatment for Methicillin-Resistant Staphylococcus aureus Infection. The Annals of Pharmacotherapy 42: 592-593 [Full Text]  
  • Ambrose, P. G., Forrest, A., Craig, W. A., Rubino, C. M., Bhavnani, S. M., Drusano, G. L., Heine, H. S. (2007). Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model. Antimicrob. Agents Chemother. 51: 4351-4355 [Abstract] [Full Text]  
  • Stein, G. E., Schooley, S., Peloquin, C. A., Missavage, A., Havlichek, D. H. (2007). Linezolid tissue penetration and serum activity against strains of methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility in diabetic patients with foot infections. J Antimicrob Chemother 60: 819-823 [Abstract] [Full Text]  
  • Gill, C. J., Abruzzo, G. K., Flattery, A. M., Misura, A. S., Bartizal, K., Hickey, E. J. (2007). In Vivo Efficacy of a Novel Oxazolidinone Compound in Two Mouse Models of Infection. Antimicrob. Agents Chemother. 51: 3434-3436 [Abstract] [Full Text]  
  • Turnidge, J., Paterson, D. L. (2007). Setting and Revising Antibacterial Susceptibility Breakpoints. Clin. Microbiol. Rev. 20: 391-408 [Abstract] [Full Text]  
  • Moreillon, P., Wilson, W. R., Leclercq, R., Entenza, J. M. (2007). Single-Dose Oral Amoxicillin or Linezolid for Prophylaxis of Experimental Endocarditis Due to Vancomycin-Susceptible and Vancomycin-Resistant Enterococcus faecalis. Antimicrob. Agents Chemother. 51: 1661-1665 [Abstract] [Full Text]  
  • Boak, L. M., Li, J., Rayner, C. R., Nation, R. L. (2007). Pharmacokinetic/Pharmacodynamic Factors Influencing Emergence of Resistance to Linezolid in an In Vitro Model. Antimicrob. Agents Chemother. 51: 1287-1292 [Abstract] [Full Text]  
  • Beer, R., Engelhardt, K. W., Pfausler, B., Broessner, G., Helbok, R., Lackner, P., Brenneis, C., Kaehler, S. T., Georgopoulos, A., Schmutzhard, E. (2007). Pharmacokinetics of Intravenous Linezolid in Cerebrospinal Fluid and Plasma in Neurointensive Care Patients with Staphylococcal Ventriculitis Associated with External Ventricular Drains. Antimicrob. Agents Chemother. 51: 379-382 [Abstract] [Full Text]  
  • Myrianthefs, P., Markantonis, S. L., Vlachos, K., Anagnostaki, M., Boutzouka, E., Panidis, D., Baltopoulos, G. (2006). Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients. Antimicrob. Agents Chemother. 50: 3971-3976 [Abstract] [Full Text]  
  • Murillo, O., Domenech, A., Garcia, A., Tubau, F., Cabellos, C., Gudiol, F., Ariza, J. (2006). Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus. Antimicrob. Agents Chemother. 50: 4011-4017 [Abstract] [Full Text]  
  • Buerger, C., Plock, N., Dehghanyar, P., Joukhadar, C., Kloft, C. (2006). Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis.. Antimicrob. Agents Chemother. 50: 2455-2463 [Abstract] [Full Text]  
  • LaPlante, K. L., Rybak, M. J., Leuthner, K. D., Chin, J. N. (2006). Impact of Enterococcus faecalis on the Bactericidal Activities of Arbekacin, Daptomycin, Linezolid, and Tigecycline against Methicillin-Resistant Staphylococcus aureus in a Mixed-Pathogen Pharmacodynamic Model.. Antimicrob. Agents Chemother. 50: 1298-1303 [Abstract] [Full Text]  
  • Swoboda, S., Fritz, S., Martignoni, M. E., Feldhues, R. A., Hoppe-Tichy, T., Buchler, M. W., Geiss, H. K. (2005). Varying linezolid susceptibility of vancomycin-resistant Enterococcus faecium isolates during therapy: a case report. J Antimicrob Chemother 56: 787-789 [Abstract] [Full Text]  
  • Meyer, B., Kornek, G. V., Nikfardjam, M., Karth, G. D., Heinz, G., Locker, G. J., Jaeger, W., Thalhammer, F. (2005). Multiple-dose pharmacokinetics of linezolid during continuous venovenous haemofiltration. J Antimicrob Chemother 56: 172-179 [Abstract] [Full Text]  
  • Fortun, J., Martin-Davila, P., Navas, E., Perez-Elias, M. J., Cobo, J., Tato, M., De la Pedrosa, E. G.-G., Gomez-Mampaso, E., Moreno, S. (2005). Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother 56: 180-185 [Abstract] [Full Text]  
  • Dehghanyar, P., Burger, C., Zeitlinger, M., Islinger, F., Kovar, F., Muller, M., Kloft, C., Joukhadar, C. (2005). Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses. Antimicrob. Agents Chemother. 49: 2367-2371 [Abstract] [Full Text]  
  • Whitehouse, T., Cepeda, J. A., Shulman, R., Aarons, L., Nalda-Molina, R., Tobin, C., MacGowan, A., Shaw, S., Kibbler, C., Singer, M., Wilson, A. P. R. (2005). Pharmacokinetic studies of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother 55: 333-340 [Abstract] [Full Text]  
  • Stein, G. E, Schooley, S. L, Peloquin, C. A, Kak, V., Havlichek, D. H, Citron, D. M, Tyrrell, K. L, Goldstein, E. J. (2005). Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis. The Annals of Pharmacotherapy 39: 427-432 [Abstract] [Full Text]  
  • LaPlante, K. L., Rybak, M. J. (2004). Impact of High-Inoculum Staphylococcus aureus on the Activities of Nafcillin, Vancomycin, Linezolid, and Daptomycin, Alone and in Combination with Gentamicin, in an In Vitro Pharmacodynamic Model. Antimicrob. Agents Chemother. 48: 4665-4672 [Abstract] [Full Text]  
  • Gross, M., Clements, J., Beckett, R. P., Thomas, W., Taylor, S., Lofland, D., Ramanathan-Girish, S., Garcia, M., Difuntorum, S., Hoch, U., Chen, H., Johnson, K. W. (2004). Oral anti-pneumococcal activity and pharmacokinetic profiling of a novel peptide deformylase inhibitor. J Antimicrob Chemother 53: 487-493 [Abstract] [Full Text]  
  • Bosso, J. A., Flume, P. A., Gray, S. L. (2004). Linezolid Pharmacokinetics in Adult Patients with Cystic Fibrosis. Antimicrob. Agents Chemother. 48: 281-284 [Abstract] [Full Text]  
  • Wagenlehner, F. M. E., Wydra, S., Onda, H., Kinzig-Schippers, M., Sorgel, F., Naber, K. G. (2003). Concentrations in Plasma, Urinary Excretion, and Bactericidal Activity of Linezolid (600 Milligrams) versus Those of Ciprofloxacin (500 Milligrams) in Healthy Volunteers Receiving a Single Oral Dose. Antimicrob. Agents Chemother. 47: 3789-3794 [Abstract] [Full Text]  
  • Gross, M., Burli, R., Jones, P., Garcia, M., Batiste, B., Kaizerman, J., Moser, H., Jiang, V., Hoch, U., Duan, J.-X., Tanaka, R., Johnson, K. W. (2003). Pharmacology of Novel Heteroaromatic Polycycle Antibacterials. Antimicrob. Agents Chemother. 47: 3448-3457 [Abstract] [Full Text]  
  • Alloush, H. M., Salisbury, V., Lewis, R. J., MacGowan, A. P. (2003). Pharmacodynamics of linezolid in a clinical isolate of Streptococcus pneumoniae genetically modified to express lux genes. J Antimicrob Chemother 52: 511-513 [Abstract] [Full Text]  
  • Stalker, D. J., Jungbluth, G. L., Hopkins, N. K., Batts, D. H. (2003). Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemother 51: 1239-1246 [Abstract] [Full Text]  
  • Humphrey, W. R., Shattuck, M. H., Zielinski, R. J., Kuo, M.-S. T., Biermacher, J. J., Smith, D. P., Jensen, J. L., Schaadt, R. D., Zurenko, G. E., Richards, I. M. (2003). Pharmacokinetics and Efficacy of Linezolid in a Gerbil Model of Streptococcus pneumoniae-Induced Acute Otitis Media. Antimicrob. Agents Chemother. 47: 1355-1363 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»