title: Pharmacokinetics and efficacy of linezolid in a gerbil model of Streptococcus pneumoniae-induced acute otitis media.
abstract: 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 micro g/ml, linezolid MIC = 1 micro g/ml) or penicillin-susceptible S. pneumoniae (PSSP; amoxicillin MIC = 0.015 micro g/ml, linezolid MIC = 1 micro g/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 ( approximately 10(6) to 10(7) 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 C(max)/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.
authors.affiliation: Pharmacia Corporation, Kalamazoo, Michigan 49007, USA. william.r.humphrey@pharmaia.com
authors.forename: William R
authors.initials: WR
authors.lastname: Humphrey
authors.forename: Mark H
authors.initials: MH
authors.lastname: Shattuck
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Zielinski
authors.forename: Ming-Shang T
authors.initials: MS
authors.lastname: Kuo
authors.forename: John J
authors.initials: JJ
authors.lastname: Biermacher
authors.forename: Donald P
authors.initials: DP
authors.lastname: Smith
authors.forename: Jana L
authors.initials: JL
authors.lastname: Jensen
authors.forename: Ronda D
authors.initials: RD
authors.lastname: Schaadt
authors.forename: Gary E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Richards
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004195:Disease Models, Animal; D005260:Female; D005849:Gerbillinae; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D010033:Otitis Media / Q000188:drug therapy*; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010403:Penicillin Resistance; D011008:Pneumococcal Infections / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid