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Antimicrobial Agents and Chemotherapy, April 2003, p. 1355-1363, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1355-1363.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Efficacy of Linezolid in a Gerbil Model of Streptococcus pneumoniae-Induced Acute Otitis Media

William R. Humphrey,* Mark H. Shattuck, Raymond J. Zielinski, Ming-Shang T. Kuo, John J. Biermacher, Donald P. Smith, Jana L. Jensen, Ronda D. Schaadt, Gary E. Zurenko, and Ivan M. Richards

Pharmacia Corporation, Kalamazoo, Michigan 49007

Received 28 June 2002/ Returned for modification 22 October 2002/ Accepted 13 January 2003

The oxazolidinone linezolid represents a new antibacterial class of potential benefit in managing multidrug-resistant gram-positive infections, including those caused by Streptococcus pneumoniae. In a gerbil model of acute otitis media (AOM) induced by either penicillin-resistant S. pneumoniae (PRSP; amoxicillin MIC = 8 µg/ml, linezolid MIC = 1 µg/ml) or penicillin-susceptible S. pneumoniae (PSSP; amoxicillin MIC = 0.015 µg/ml, linezolid MIC = 1 µg/ml), we explored the plasma and ear fluid levels of linezolid required to demonstrate efficacy. Threshold pathogen doses required to induce bilateral AOM (1,500 CFU/ear with PRSP; 30 CFU/ear with PSSP) were administered to gerbils by intrabullar injection on day 0. At peak infection (~106 to 107 CFU/ear flush; day 2 for PRSP-AOM and day 3 for PSSP-AOM), twice-a-day oral doses of linezolid, amoxicillin, or vehicle were administered over 4.5 days prior to collection and assay of middle ear effluents for S. pneumoniae content. Linezolid doses of >=10 mg/kg of body weight induced significant cure rates of >=72% versus both PRSP and PSSP infections, whereas amoxicillin at <=100 mg/kg was consistently effective only versus PSSP-AOM. Plasma and ear fluid levels of linezolid necessary to elicit pneumococcal eradication from the middle ear were measured by high-performance liquid chromatography-tandem mass spectrometry and found to be similar both within and between each infection protocol. The plasma-ear fluid pharmacodynamic profile associated with linezolid efficacy was a T>MIC of >=42%, a Cmax/MIC ratio of >=3.1, and a (24-h area under the curve)/MIC ratio of >=30 h. Application of this model will be useful in defining preclinical pharmacodynamic relationships of novel antibiotics necessary to cure S. pneumoniae-induced AOM.

* Corresponding author. Mailing address: Pharmacia Corporation, 7250-209-206, 301 Henrietta St., Kalamazoo, MI 49007. Phone: (269) 833-1877. Fax: (269) 833-9763. E-mail: william.r.humphrey{at}pharmacia.com.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1355-1363, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1355-1363.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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