1946. Human-Simulated Exposure and Pharmacodynamic (PD) Assessment of Tedizolid (TZD) against Streptococcus pneumoniae in an Immunocompetent Murine Lung Infection Model
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: TZD possesses potent in vitro activity against S. pneumoniae; however, the in vivo efficacy of TZD human-simulated epithelial lining fluid (ELF) exposure against S. pneumoniae lung infections has not been established. The objective of this study was to assess the PD of TZD for the treatment of S. pneumoniae over a range of exposures including a human-simulated ELF exposure in an immunocompetent murine lung infection model.

Methods: Four S. pneumoniae isolates were used in the PD study. CBA/J mice (7-9 weeks old) were inoculated intranasally with bacterial suspensions. A single daily TZD dose was administered IP 4h post-inoculation (0 h). TZD doses were varied from 0.5 and 80 mg/kg/day. Efficacy was measured as the change in log10CFU at 24 h compared with 0 h controls. Pharmacokinetics of TZD were assessed in infected mice to determine the systemic exposures of the regimens utilized. Additionally, a TZD dose in mice that mimics the humanized ELF exposure was also examined. TZD MICs were determined in triplicate for each test organisms using the broth microdilution method. Area under the free drug concentration–time curve to MIC ratios (fAUC0-24/MIC) required to achieve various efficacy endpoints against each isolate were estimated using Hill-equation.

Results: TZD 40 mg/kg/day resulted in an ELF AUC0-24 of 110 mg.h/L, which was comparable to that achieved in humans (109 mg.h/L) following the 200mg QD clinical dose. This human-simulated exposure was adequate to attain a 2-log reduction in bacterial burden at 24 h in 3/4 isolates. The plasma fAUC0-24 achieved with this dose (24.6 mg.h/L), translated to fAUC0-24/MIC ratios of 99 and 49 for MICs 0.25 mg/L and 0.5 mg/L, respectively. Results of PD studies and MICs are illustrated in the table.

Isolate

(TZD MIC, mg/L)

Penicillin Susceptibility

fAUC0-24/MIC Ratio Required to Achieve

Stasis

1-Log Reduction

2-Log Reduction

ATCC 700905

(0.25)

R

2

16

35

ATCC 6303 (0.5)

S

30

56

113

SP 95 (0.25)

S

11

23

36

SP 102 (0.25)

I

22

42

59

Conclusion: TZD showed potent in vivo efficacy against S. pneumoniae. We demonstrated killing with the humanized ELF profile and identified systemic exposures required for various efficacy targets, which will help support the clinical development of TZD for treatment of S. pneumoniae lung infections.

Kamilia Abdelraouf, Ph.D., Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT and David P. Nicolau, PharmD, FCCP, FIDSA, Center for Anti-Infective Research & Development at Hartford Hospital, Hartford, CT

Disclosures:

K. Abdelraouf, None

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

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