Pharmacokinetic/Pharmacodynamic Evaluation of Solithromycin Against Streptococcus pneumoniae Using Data from a Neutropenic Murine-Lung Infection Model.

Solithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with community-acquired bacterial pneumonia. Using a neutropenic murine-lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with efficacy and the magnitude of such indices necessary for solithromycin efficacy against Streptococcus pneumoniae Plasma and epithelial lining fluid (ELF) samples for pharmacokinetics (PK) were collected serially over 24 hours from healthy mice administered single doses of solithromycin (0.625 to 40 mg/kg). Neutropenic CD-1 mice infected with 108 colony forming units (CFU) of one of five S. pneumoniae isolates were administered solithromycin (0.156 to 160 mg/kg/day) via oral gavage. Doses were administered in a fractionated manner for mice infected with one isolate while mice infected with the remaining four isolates received solithromycin as either a q6h or q12h regimen. A three-compartment model best described solithromycin PK in the plasma and ELF (r2 = 0.935 and 0.831, respectively). The ratio of total-drug ELF to free-drug plasma area under the concentration-time curve from time 0 to 24 hours (AUC) was 2.7. Free-drug plasma and total-drug ELF AUC to minimum inhibitory concentration ratios (AUC/MIC ratios) were most predictive of efficacy (r2 = 0.851 and 0.850, respectively). The magnitude of free-drug plasma/total-drug ELF AUC/MIC ratios associated with net bacterial stasis, and a 1- and 2-log10 CFU reduction from baseline was 1.65/1.26, 6.31/15.1, and 12.8/59.8, respectively. These data provided dose selection support for solithromycin for clinical trials in patients with community-acquired bacterial pneumonia.