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Antimicrobial Agents and Chemotherapy, May 2002, p. 1345-1351, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1345-1351.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Activity and Efficacy of Linezolid in a Rat Model of Pneumococcal Pneumonia

Martha J. Gentry-Nielsen,1,2,3* Keith M. Olsen,4 and Laurel C. Preheim1,2,3

Veterans Affairs Medical Center,1 School of Medicine, Creighton University,2 School of Medicine,3 College of Pharmacy, University of Nebraska, Omaha, Nebraska4

Received 27 December 2000/ Returned for modification 1 June 2001/ Accepted 30 January 2002

Linezolid is a new oxazolidinone antibiotic with potent activity against gram-positive bacteria, including Streptococcus pneumoniae. The pharmacodynamic activity and in vivo efficacy of linezolid were compared to those of ceftriaxone in an immunocompetent rat model of pneumococcal pneumonia. Rats infected intratracheally with 8 x 107 CFU of a penicillin-sensitive (MIC, 0.032 µg/ml) strain of S. pneumoniae were treated for 5 days beginning 18 h postinfection. Groups of rats were sham treated with oral phosphate-buffered saline or received oral liquid linezolid at 25 or 50 mg/kg of body weight twice a day (b.i.d.) or subcutaneous ceftriaxone at 100 mg/kg once daily. Mortality was monitored for 10 days postinfection; blood culturing was performed on day 1 (pretreatment) and on days 3, 5, and 10 postinfection for the determination of bacteremia. Serum also was collected for the determination of pharmacokinetic and pharmacodynamic parameters at 30 min and at 3, 5, and 12 h (linezolid) or 3, 5, and 24 h (ceftriaxone) postdose. The cumulative mortality rates were 100% for the sham-treated group, 58.3% for the low-dose linezolid group, 8.3% for the high-dose linezolid group, and 0% for the ceftriaxone group. Rats in each of the antibiotic treatment groups had significantly fewer bacteria (P < 0.00001) in their bronchoalveolar lavage fluid (BALF) on day 3 postinfection than sham-treated rats. There also were significantly fewer organisms in the BALF of rats treated with ceftriaxone than in the BALF of rats treated with either dose of linezolid. Oral linezolid at 50 mg/kg b.i.d. therefore was as effective as ceftriaxone in experimental pneumococcal pneumonia, whereas the 25-mg/kg b.i.d. dose was significantly less effective. All pharmacodynamic parameters reflected efficacy and were significantly different for the two dosage regimens of linezolid (P < 0.01). However, the free-fraction pharmacodynamic parameters predictive of outcome were a value of >39% for the percentage of time in the experimental dosing interval during which the linezolid concentration exceeded the MIC and a value of >147 for the ratio of the area under the serum concentration-time curve to the MIC.

* Corresponding author. Mailing address: Research Service (151), VA Medical Center, 4101 Woolworth Ave., Omaha, NE 68105. Phone: (402) 346-8800, ext. 3033. Fax: (402) 449-0604. E-mail: mgentry{at}creighton.edu.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1345-1351, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1345-1351.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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