In vivo efficacy and pharmacokinetics of tomopenem (CS-023), a novel carbapenem, against Pseudomonas aeruginosa in a murine chronic respiratory tract infection model.
OBJECTIVE
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.
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Yoshitomo
Y
Morinaga
Katsunori
K
Yanagihara
Shigeki
S
Nakamura
Kazuko
K
Yamamoto
Koichi
K
Izumikawa
Masafumi
M
Seki
Hiroshi
H
Kakeya
Yoshihiro
Y
Yamamoto
Yasuaki
Y
Yamada
Shigeru
S
Kohno
Shimeru
S
Kamihira
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D006801:Humans; D008168:Lung / Q000737:chemistry / Q000382:microbiology / Q000473:pathology; D008297:Male; D000077731:Meropenem; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D044967:Serum / Q000737:chemistry; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; C492232:tomopenem; D000077731:Meropenem