Title In vivo efficacy and pharmacokinetics of tomopenem ( CS - 023 ) , a novel carbapenem ,

Objectives; Tomopenem (CS-023) is a novel parenteral carbapenem with broad spectrum activity against Gram-positive and -negative bacteria, as well as potent activity against drug resistant pathogens, including penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. We compared the in vivo activity of tomopenem and that of meropenem in a chronic lower respiratory infection mouse model of P. aeruginosa. Methods; Mice with chronic airway infection of P aeruginosa were treated with saline (as the control, twice daily), tomopenem (100 mg/kg, twice daily) or meropenem (100 mg/kg, twice daily) for seven days. After treatment, the number of viable bacteria in lungs and histopathological findings were analyzed. The pharmacokinetics of tomopenem and meropenem were also analyzed after initial treatment. Results; The number of viable bacteria in lungs treated with saline, tomopenem or meropenem was 4.21±1.28, 2.91±0.87 and 3.01±1.00 log10 cfu/lung (mean ± SEM), respectively (p<0.05, control vs. tomopenemor meropenem-treated groups). In the histopathological examination of lung specimens, control group revealed the features of chronic bronchial infection, however, tomopenemand meropenem-treated groups had fewer inflammatory cells compared to control group. The pharmacokinetic parameters of % time above MIC for tomopenem and meropenem were 16% and 17% in sera, and 15% and 18% in lungs, respectively. Conclusions; Tomopenem significantly reduced the number of viable bacteria in a murine model of chronic airway infection of P. aeruginosa, compared to the control. Considering the longer half-life of tomopenem in humans compared to most other carbapenems, tomopenem treatment of chronic airway infection with P. aeruginosa is expected to be efficacious. Key words; chronic respiratory infections, meropenem, pharmacokinetics Morinaga et al., Page 3 of 15