1961. Comparative In Vivo Efficacy of Human-Simulated Exposures of Tedizolid (TZD) in Neutropenic (I-) versus Immunocompetent (I+) Murine Streptococcus pneumoniae Lung Infection Model
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: Limited data exist on the efficacy of TZD in presence of neutropenia. Given that TZD exhibits substantial lung penetration, we hypothesize that TZD could achieve good efficacy against lung infections in I- model. The objective of this study was to compare the efficacy of TZD human-simulated epithelial lining fluid (ELF) exposure for the treatment of S. pneumoniae in the I- versus I+ murine lung infection model.

Methods: ICR mice (20-22 g) were rendered I- via intraperitoneal cyclophosphamide injections, and then inoculated intranasally with S. pneumoniae suspensions. TZD dose in mice that mimics the humanized ELF exposure was examined. Additionally, TZD dose that mimics the humanized ELF exposure in infected I+ CBA/J mice (7-9 weeks old) was also examined. Four S. pneumoniae isolates were used to compare the efficacy. Treatment mice were administered the TZD ELF human-equivalent doses identified intraperitoneally, while control mice were vehicle-dosed. The changes in log10CFU at 24 h compared with 0 h controls were estimated.

Results: TZD 55 mg/kg/day resulted in ELF AUC0-24 of 117 mg.h/L in I- mice, while TZD 40 mg/kg/day resulted in ELF AUC0-24 of 110 mg.h/L in I+ mice. These exposures were comparable to that achieved in humans (109 mg.h/L) following the 200 mg QD clinical dose. Human-simulated exposures were adequate to attain > 2-log reduction in bacterial burden at 24 h for 3/4 isolates in both models. Results of efficacy study and TZD MICs are illustrated in the table.

Isolate

 (MIC, mg/L)

 

Change in log10CFU at 24 h

P

I-

I+

ATCC 700905 (0.25)

Control

0.41 ± 0.46

0.18 ± 0.34

0.35

Treatment

- 2.90 ± 0.44

- 4.22 ± 1.02

0.01

ATCC 6303 (0.5)

Control

1.10 ± 0.33

1.20 ± 0.17

0.53

Treatment

- 0.74 ± 0.57

- 0.79 ± 0.16

0.81

SP 95

(0.25)

Control

0.76 ± 0.19

0.70 ± 0.16

0.55

Treatment

-2.22 ± 0.56

-4.56 ± 0.61

<0.0001

SP 102

(0.25)

Control

0.76 ± 0.51

0.30 ± 0.45

0.13

Treatment

-2.89 ± 0.78

-3.85 ± 0.52

0.03

Conclusion: The administration of humanized TZD ELF exposures resulted in a high degree of killing in both I- and I+ lung infection models. Moreover the presence of white cells in I+ mice generally enhance the antibacterial profile of TZD. These preclinical data utilizing achievable bronchopulmonary exposures supports the consideration of TZD for S. pneumoniae infection in the lung.

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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