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

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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 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 (∼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.