Abstract
Background
TZD is an oxazolidinone with potent in vitro activity against Gram-positive pathogens, including MRSA. Limited data currently exist on the efficacy of TZD in the presence of neutropenia. Herein, we investigate the comparative efficacy of human-simulated ELF exposures of TZD against MRSA in I− and I+ murine models of pneumonia.
Methods
Four MRSA isolates with TZD broth microdilution MICs of 0.5 mg/L were studied. BALB/c mice in I− groups were made neutropenic with cyclophosphamide. Lungs of I− mice were inoculated intranasally with bacterial suspensions of 107 CFU/mL; a higher inoculum of 109 CFU/mL was required to induce infection in I+ mice. Single daily doses of TZD simulating human ELF exposures after doses of 200 mg q24h were determined in both I+ (40 mg/kg) and I− (32 mg/kg) models. Three hours after inoculation, human-simulated doses of TZD were administered q24h for up to 72 hours while control mice were vehicle dosed. A group of control and another of treatment (n = 6) per isolate were sacrificed at 24, 48, or 72 hours for lung harvest. Bacterial densities were determined by quantitative culture and averaged across all isolates. Mice that succumbed to infection before the scheduled time of sacrifice were included in the next group due for sacrifice. Changes in log10 CFU/lungs at 24 hours were compared with 0 hour controls.
Results
The average bacterial burdens at 0 hour were 5.86 ± 0.21 and 8.10 ± 0.24 log10 CFU/lungs among I− and I+ mice, respectively. At 24 hours, average burdens in control mice were comparable among I− and I+ mice at 7.91 ± 0.62 and 9.01 ± 0.69 log10CFU/lungs, respectively. Mean changes in bacterial density are reported in the table. No I+ control mice survived past 48 hours.
| Change in Log10 CFU/Lungs (Mean ± SD) | |||
|---|---|---|---|
| I− | I+ | ||
| 24 hours | Control | 2.06 ± 0.62 | 0.91 ± 0.69 |
| TZD | −1.18 ± 0.58 | −1.23 ± 0.81 | |
| 48 hours | Control | 2.54 ± 0.31 | 0.61 ± 0.17 |
| TZD | −1.99 ± 0.90 | −2.17 ± 0.84 | |
| 72 hours | Control | 2.85 ± 0.60 | ND |
| TZD | −2.78 ± 0.74 | −3.64 ± 1.03 | |
ND, no data.
Conclusion
Human-simulated ELF exposures of TZD demonstrated substantial and sustained efficacy in both I− and I+ murine models of pneumonia. These preclinical data utilizing clinically achievable bronchopulmonary exposures suggest that the efficacy of TZD for treatment of MRSA lung infections is not compromised by neutropenic status of the host. Further validation of these findings in patients is warranted.
Disclosures
D. P. Nicolau, Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium.
Session: 145. PK/PD Studies
Friday, October 5, 2018: 12:30 PM