Article Figures & Data
Figures
- Fig 1
Concentrations for linezolid (A) and TR-700 (B) in plasma after administration of single oral doses of 0.625, 2.5, 10, and 40 mg/kg in neutropenic infected mice. Each symbol represents the geometric mean ± standard deviation (error bar) of the levels measured in three mice. Cmax, peak level in plasma; AUC, plasma AUC0–∞; T1/2, plasma elimination half-life (in hours). PK parameters were not determined for the lowest dose of linezolid, as there were too few data points to estimate these parameters.
- Fig 2
Dose-response relationships for linezolid (A) and TR-701 (B). Mice received one of a series of 2-fold increasing doses of linezolid or TR-701 every 12 h over a 24-hour treatment period. Each symbol represents the mean organism burden in the lungs of three mice. The error bars represent the standard deviations. The dashed horizontal line represents the organism burden at the start of therapy. Symbols below the line represent organism reduction compared to the start of therapy. Symbols above the line represent organism growth.
- Fig 3
Relationship between linezolid (A) and TR-700 (B) plasma 24-h fAUC/MIC ratios and in vivo efficacy against multiple strains of S. aureus (5 and 11 strains, respectively). Mice were treated with 2-fold increasing concentrations of either linezolid or TR-701 given every 12 h over a 24-h treatment period. Each symbol represents the geometric mean in the change of organism burden from the start of therapy in the lungs of three mice. The dashed horizontal line represents the burden in the lungs at the start of therapy. Symbols below the line represent organism reduction compared to the start of therapy. Symbols above the line represent organism growth. The sigmoid lines represent the best-fit curves. R2 is the coefficient of determination.
Tables
- Table 1
In vitro activity of linezolid and TR-700 against select S. aureus isolates
Organism MIC (mg/liter)a Lineage Linezolid TR-700 Methicillin MSSA ATCC 25923 2 0.06 0.25 ATCC 29213 2 0.25 0.125 ATCC 6538P 0.125 0.5 ATCC Smith 0.5 0.125 MRSA 04-045 2 0.125 >16 04-154 2 0.25 >16 MW2 2 0.5 >16 USA400 307109 0.25 >16 ATCC 33591 0.25 >16 USA200 R2527 0.125 >16 USA300 05-051 0.25 >16 ↵a The MICs are reported as the median values of three MIC tests.
- Table 2
In vivo activity of linezolid against select S. aureus isolatesa
S. aureus isolate or parameter MIC (mg/liter) SD (mg/kg/24 h) 24-h SD tAUC/MIC 24-h SD fAUC/MIC 1-log-unit kill dose (mg/kg/24 h) 24-h 1-log-unit kill tAUC/MIC 24-h 1-log-unit kill fAUC/MIC S. aureus isolates ATCC 25923 2 18.8 21.6 15.1 50.1 70.3 49.2 ATCC 29213 2 35.1 48.2 33.7 61.6 86.5 60.5 MW2 2 30.3 40.4 28.3 52.6 73.8 51.7 04-154 2 13.6 13 9.1 39.8 55.8 39 04-045 2 13.4 12.7 8.9 31.8 42.7 28.9 Mean 2 22.2 27.2 19 47.2 65.8 46.1 Median 2 18.8 21.6 15.1 50.1 70.3 49.2 SD 0 9.9 16.3 11.4 11.6 16.9 11.9 ↵a SD, static dose; tAUC/MIC, total drug AUC/MIC; fAUC/MIC, free drug (non-protein-bound) AUC/MIC. The means, medians, and static doses are shown in boldface type.
- Table 3
In vivo activity of TR-701 or TR-700 against select S. aureus isolatesa
S. aureus isolate or parameter MIC (mg/liter) TR-701 SD (mg/kg/24 h) TR-700 24-h SD tAUC/MIC TR-700 24-h SD fAUC/MIC TR-701 1-log-unit kill dose (mg/kg/24 h) TR-700 24-h 1-log-unit kill tAUC/MIC TR-700 24-h 1-log-unit kill fAUC/MIC S. aureus isolates ATCC Smith 0.5 9.1 86.8 13 14 148.3 22.2 UW 307109 0.25 6.4 124.6 18.7 9.5 181 27.3 MW2 0.5 11 108.1 16.2 15.9 173.2 26 ATCC 29213 0.25 14.3 303.7 45.5 20.3 461 69.2 ATCC 33591 0.25 7.5 144.2 21.6 15.3 331.1 49.7 ATCC 6538P 0.125 3.7 145.9 21.9 6.3 242.9 36.4 R2527 0.125 7.2 277.3 41.6 13.9 588.2 88.2 05-051 0.25 3.4 67.7 10.1 5.1 99.3 14.9 ATCC 25923 0.06 1.4 116.2 17.4 1.8 147.3 22.1 04-154 0.125 0.8 27.6 4.1 1.8 70.4 10.6 04-045 0.25 3.1 61.9 9.29 4.7 91.2 13.7 Mean 0.24 6.2 133.1 20 9.9 230.4 34.6 Median 0.25 6.4 116.2 17.4 9.5 173.2 26 SD 0.14 4.2 85.9 12.9 6.3 165.2 24.8 ↵a SD, static dose; tAUC/MIC, total drug AUC/MIC; fAUC/MIC, free drug (non-protein-bound) AUC/MIC. The means, medians, and static doses are shown in boldface type.
