Methods: Male Syrian hamsters received 30 mg/kg MXF subcutaneously oad for 5 days (at H0 from D1 to D5), and were orally infected at D3 with 104 C. diff spores. Animals received DAV131A bid from D1 to D8 at various daily doses (0, 200, 600, 1200 or 1800 mg/kg/d) with various dosing schedules (H-4/H1, H0/H5 or H2/H7); some animals received an additional dose of DAV131A at H-10 at D1.In addition, some animals were treated with a tid administration at the highest dose, and also received an initial dose of DAV131 at H-10. Conc were determined at D3 and mortality was evaluated at D10. We separately modelled the evolution of Conc vs DAV131A daily dose using a nonlinear regression model and death vs Conc using a logistic model. We then developed a joint model and estimated parameters by maximum likelihood. Results of the joint model were used to derive Conc and DAV131A daily dose leading to 90% survival. Confidence intervals (CI) were computed using the delta method.
Results: Data from 210 animals were obtained, 56 of which died before D10. Mortality rates were 100%, 100%, 10%, 0% and 0% in groups receiving DAV131A doses of respectively 0, 200, 600, 1200 and 1800 mg/kg/d. Highly significant reduction of Conc by DAV131A doses was best described by a full sigmoid Imax model (p<10-15). Logit of death probability significantly decreased with Conc (p<10-15). DAV131A intake at H-10 decreased DAV131A D50 (p<10-13). Decreasing Conc from 58 µg/g (95%CI, 50-66) in the absence of DAV131A to 17 µg/g (95%CI, 14-21) in the presence of DAV131A was required to reach 90% survival. The DAV131A dose necessary to reach such concentrations was 703 mg/kg (596-809).
Conclusion: The co-administration of DAV131A provides dose dependent protection from MXF-induced lethal C. diff colitis. The joint model allows to quantify the reduction in free fecal MXF concentration and hence the DAV131A dose needed for 90% survival.
N. Saint-Lu, Da Volterra: Employee , Salary
S. Sayah-Jeanne, Da Volterra: Employee , Salary
A. Andremont, Da Volterra: Consultant and Scientific Advisor , Consulting fee
F. Mentré, Da Volterra: Consultant and Research Contractor , Consulting fee and Research support
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