Pharmacokinetic modeling and efficacy of ceftobiprole medocaril against pneumonic tularemia in cynomolgus macaques.

Francisella tularensis is the etiologic agent of tularemia, and there are few FDA-approved antibiotics to treat infections. Ceftobiprole medocaril has potential for being developed as a therapeutic for the treatment of inhalational tularemia, as it has previously demonstrated efficacy in vivo. Pharmacokinetic modeling of ceftobiprole in cynomolgus macaques was used to predict an efficacious dose of ceftobiprole medocaril against inhalational tularemia in the disease model based on the measured exposures and human clinical exposure data. The efficacy of ceftobiprole medocaril against inhalational tularemia was then evaluated in the cynomolgus macaque disease model using three doses designed to mimic the human mean clinical exposure of ceftobiprole medocaril (including the predicted efficacious dose). Treatments of 0.00 (placebo), 1.33, 6.67, or 20.0 mg/kg ceftobiprole medocaril (q8h for 10 days) were administered to cynomolgus macaques by intravenous infusion after animals were exposed to aerosolized F. tularensis and exhibited a fever. Control animals exhibited a 12.5% survival rate, a median time to death of 11.63 days post-challenge, and significantly elevated tissue burdens. By comparison, animals receiving 1.33 mg/kg treatments with ceftobiprole medocaril exhibited a 50% survival rate, and animals receiving either of the higher doses exhibited an 87.5% survival rate. Evidence of adaptive immunity (seroconversion) was identified in all surviving animals, though detection of F. tularensis with sensitivity to ceftobiprole in vitro in a limited number of treated and surviving animals indicates that the clinical efficacy of ceftobiprole medocaril may be enhanced by treatment durations greater than 10 days.