In vivo efficacy and pharmacokinetics of tomopenem (CS-023), a novel carbapenem, against Pseudomonas aeruginosa in a murine chronic respiratory tract infection model.

Abstract

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 by 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 7 days. After treatment, the number of viable bacteria in lungs and histopathological findings were analysed. The pharmacokinetics of tomopenem and meropenem were also analysed 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 log(10) cfu/lung (mean +/- SEM), respectively (P < 0.05, control versus tomopenem- or meropenem-treated groups). In the histopathological examination of lung specimens, the control group had the features of chronic bronchial infection; however, tomopenem- and meropenem-treated groups had fewer inflammatory cells compared with the control group. The pharmacokinetic parameter of % time above MIC for tomopenem and meropenem was 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 by P. aeruginosa, compared with the control. Considering the longer half-life of tomopenem in humans compared with most other carbapenems, tomopenem treatment of chronic airway infection with P. aeruginosa is expected to be efficacious.

• Authors: Yoshitomo Morinaga, Katsunori Yanagihara, Shigeki Nakamura, Kazuko Yamamoto, Koichi Izumikawa, Masafumi Seki, Hiroshi Kakeya, Yoshihiro Yamamoto, Yasuaki Yamada, Shigeru Kohno, Shimeru Kamihira
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 62 Issue 6 Pg. 1326-31 (Dec 2008) ISSN: 1460-2091 [Electronic] England
• PMID: 18835805 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Carbapenems
• Thienamycins
• tomopenem
• Meropenem

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Carbapenems (administration & dosage, pharmacokinetics, therapeutic use)
• Colony Count, Microbial
• Humans
• Lung (chemistry, microbiology, pathology)
• Male
• Meropenem
• Mice
• Pseudomonas Infections (drug therapy)
• Pseudomonas aeruginosa (drug effects)
• Respiratory Tract Infections (drug therapy, microbiology)
• Serum (chemistry)
• Thienamycins (administration & dosage, pharmacokinetics, therapeutic use)