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 10(7) CFU of a
penicillin-sensitive (MIC, 0.032 microg/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.