Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Abstract

Background:

Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system.

Methods:

The mice were treated for 5 min, once daily, with placebo, 3, 10 or 30 mg/mL ME1100 or 30 mg/mL amikacin.

Results:

In the survival study, the survival rate was significantly improved in the 10 and 30 mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30 mg/mL ME1100 treatment group at 6 h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30 mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2 mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin.

Conclusions:

The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin.

• Authors: Norihito Kaku, Yoshitomo Morinaga, Kazuaki Takeda, Kosuke Kosai, Naoki Uno, Hiroo Hasegawa, Taiga Miyazaki, Koichi Izumikawa, Hiroshi Mukae, Katsunori Yanagihara
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 72 Issue 4 Pg. 1123-1128 (04 01 2017) ISSN: 1460-2091 [Electronic] England
• PMID: 27999047 (Publication Type: Comparative Study, Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Anti-Bacterial Agents
• Dibekacin
• Amikacin
• arbekacin

Topics

• Administration, Inhalation
• Amikacin (administration & dosage, pharmacokinetics, therapeutic use)
• Animals
• Anti-Bacterial Agents (pharmacokinetics, therapeutic use)
• Dibekacin (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)
• Disease Models, Animal
• Drug Compounding
• Lung (microbiology)
• Mice
• Microbial Sensitivity Tests
• Pneumonia, Ventilator-Associated (drug therapy)
• Pseudomonas Infections (drug therapy, microbiology)
• Pseudomonas aeruginosa (drug effects)