In vivo pharmacodynamics of a new oxazolidinone (linezolid)

Abstract

Linezolid is a new oxazolidinone with activity against gram-positive cocci. We determined the in vivo activity of linezolid against four strains of Staphylococcus aureus (two methicillin-susceptible S. aureus [MSSA] strains and two methicillin-resistant S. aureus strains) and one penicillin-susceptible Streptococcus pneumoniae (PSSP) strain, two penicillin-intermediate S. pneumoniae strains, and five penicillin-resistant S. pneumoniae strains. The mice had 10(6.3) to 10(7.7) CFU/thigh before therapy and were then treated for 24 h with 5 to 1,280 mg of linezolid/kg divided into 1, 2, 4, 8, or 16 doses. The killing activities after 4 h of therapy ranged from 2.4 to 5.0 log(10) CFU/thigh against S. pneumoniae and 1.35 to 2.2 log(10) CFU/thigh against S. aureus. Increasing doses produced minimal concentration-dependent killing; doses of 20 and 80 mg/kg produced no in vivo postantibiotic effects (PAEs) with PSSP and modest PAEs (3.4 and 3.2 h) with MSSA. Pharmacokinetic studies at doses of 20 and 80 mg/kg by high-pressure liquid chromatography analysis exhibited peak dose values of 0.68 and 0.71 and elimination half-lives of 1.02 and 1.00 h. Linezolid MICs ranged from 0.5 to 1.0 micro g/ml for S. pneumoniae and from 1.0 to 4.0 micro g/ml for S. aureus. A sigmoid dose-response model was used to estimate the dose required to achieve a net bacteriostatic effect over 24 h. Static doses against S. pneumoniae ranged from 22.2 to 97.1 mg/kg/24 h and from 133 to 167 mg/kg/24 h for S. aureus. The 24-h area under the concentration-time curve (AUC)/MIC ratio was the major parameter determining the efficacy of linezolid against PSSP (R(2) = 82% for AUC/MIC versus 57% for T>MIC and 59% for the peak level in serum/MIC [peak/MIC]). It was difficult to determine the most relevant pharmacokinetic/pharmacodynamic parameter with S. aureus, although the outcomes correlated slightly better with the 24-h AUC/MIC ratio (R(2) = 75%) than with the other parameters (T>MIC R(2) = 75% and peak/MIC R(2) = 65%). The 24-h AUC/MIC ratio required for a bacteriostatic effect with linezolid varied from 22 to 97 (mean = 48) for pneumococci and from 39 to 167 (mean = 83) for staphylococci. Based upon a pharmacokinetic goal of a 24-h AUC/MIC of 50 to 100, a dosage regimen of 600 mg given either intravenously or orally twice daily would achieve success against organisms with MICs as high as 2 to 4 micro g/ml.

FIG. 1.

Linezolid concentrations in serum after administration of single doses of 20 and 80 mg/kg in neutropenic infected mice. Symbols: □, data obtained with the 20-mg/kg dose; ○, data obtained with the 80-mg/kg dose. Each symbol represents the geometric mean ± standard deviation of the levels in the sera of three mice. t_1/2, serum elimination half-live in hours; C_max, peak level in serum; AUC_0−∞, serum AUC.

FIG. 2.

(A) In vivo PAE of linezolid after administration of single doses of 20 and 80 mg/kg against S. pneumoniae ATCC 10813. Symbols: □, data obtained with the 20-mg/kg dose; ▵, data obtained with the 80-mg/kg dose. Each symbol represents the mean ± the standard deviation for two mice. The solid bars represent the time that free-drug levels remained above the MIC. The open bars represent the time that total drug levels remained above the MIC. (B) In vivo PAE of linezolid after administration of single doses of 20 and 80 mg/kg against S. aureus ATCC 6538p. Symbols: □, data obtained with the 20-mg/kg dose; ▵, data obtained with the 80-mg/kg dose. Each symbol represents the mean ± the standard deviation for two mice. The solid bars represent the time that free-drug levels remained above the MIC. The open bars represent the time that total drug levels remained above the MIC.

FIG. 3.

Relationships between the percentage of the dosing interval that levels in serum remained above the MIC for S. pneumoniae ATCC 10813, the 24-h AUC/MIC, and the peak/MIC and the log₁₀ number of CFU/thigh after 24 h of therapy. Each symbol represents the data for two mice. The lines represent the best fit line. R² is the coefficient of determination.

FIG. 4.

Relationship between between the percentage of the dosing interval that both total and free-drug levels in serum remained above the MIC for S. pneumoniae ATCC 10813. Each symbol represents the data for two mice. The lines represent the best fit line. R² is the coefficient of determination.

FIG. 5.

Relationships between the percentage of the dosing interval that levels in serum remained above the MIC for S. aureus ATCC 6538p, the 24-h AUC/MIC, and the peak/MIC and the log₁₀ number of CFU/thigh after 24 h of therapy. Each symbol represents the data for two mice. The lines represent the best-fit line. R² is the coefficient of determination.