1397. Comparative Efficacy of Human-simulated Epithelial Lining Fluid (ELF) Exposures of Tedizolid (TZD) against Methicillin-resistant Staphylococcus Aureus (MRSA) in Neutropenic (I-) vs Immunocompetent (I+) Murine Models of Pneumonia
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • IDWeek 2018 - TZD MRSA Lung I+ vs I- 9-6-18 - Final version.pdf (885.3 kB)
  • 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 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 h 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 h 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 h were compared with 0 h controls.

    Results: The average bacterial burdens at 0 h were 5.86 ± 0.21 and 8.10 ± 0.24 log10 CFU/lungs among I- and I+ mice, respectively. At 24 h, average burdens in control mice were comparable among I- and I+ mice at 7.91 ± 0.62 and 9.01 ± 0.69 log10 CFU/lungs, respectively. Mean changes in bacterial density are reported in the table. No I+ control mice survived past 48 h.

    Change in log10 CFU/lungs (mean ± SD)

    I-

    I+

    24 h

    Control

    2.06 ± 0.62

    0.91 ± 0.69

    TZD

    -1.18 ± 0.58

    -1.23 ± 0.81

    48 h

    Control

    2.54 ± 0.31

    0.61 ± 0.17

    TZD

    -1.99 ± 0.90

    -2.17 ± 0.84

    72 h

    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.

    James M. Kidd, PharmD, BCPS, Kamilia Abdelraouf, Ph.D. and David P. Nicolau, PharmD, FCCP, FIDSA, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT

    Disclosures:

    J. M. Kidd, None

    K. Abdelraouf, None

    D. P. Nicolau, Merck: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Speaker honorarium .

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