Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
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Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and In Vivo Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals
Koichi Fujimoto a, Koji Takemoto a,#, Kazuo Hatano b, Toru Nakai b, Shigeyuki Terashita b, Masahiro Matsumoto b, Yoshiro Eriguchi a, Ken Eguchi a, Takeshi Shimizudani a, Kimihiko Sato a, Katsunori Kanazawa a, Makoto Sunagawa a and Yutaka Ueda a
Author Affiliations: <SUP>a</SUP>Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; <SUP>b</SUP>Drug Discovery Research Division, Astellas Pharma Inc., Ibaraki, Japan
ABSTRACT
SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae including penicillin-resistant strains, Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae including β-lactamase negative ampicillin-resistant strains, and Neisseria gonorrhoeae including ciprofloxacin -resistant strains, with MIC for 90% of isolates of ≤1 μg/ml. Unlike tebipenem (MIC for 50% of isolates [MIC<SUB>50</SUB>], 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC<SUB>50</SUB>, ≥128 μg/ml). The bactericidal activity of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and β-lactamase negative ampicillin-resistant H. influenzae was equal or superior to tebipenem and greater than cefditoren. Therapeutic efficacy of intravenous administration of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and β-lactamase negative ampicillin-resistant H. influenzae was equal or superior to tebipenem and greater than cefditoren, respectively, reflected their in vitro activity. SM-295291 and SM-369926 showed similar intravenous pharmacokinetics to meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase-I. SM-368589 and SM-375769 which are medoxomil esters of SM-295291 and SM-369926, respectively, showing good oral bioavailability in rats, dogs, and monkeys (4.2-62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and β-lactamase negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapy.
FOOTNOTES
# Corresponding author: koji-takemoto@ds-pharma.co.jp
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Author Affiliations: <SUP>a</SUP>Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; <SUP>b</SUP>Drug Discovery Research Division, Astellas Pharma Inc., Ibaraki, Japan
ABSTRACT
SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae including penicillin-resistant strains, Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae including β-lactamase negative ampicillin-resistant strains, and Neisseria gonorrhoeae including ciprofloxacin -resistant strains, with MIC for 90% of isolates of ≤1 μg/ml. Unlike tebipenem (MIC for 50% of isolates [MIC<SUB>50</SUB>], 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC<SUB>50</SUB>, ≥128 μg/ml). The bactericidal activity of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and β-lactamase negative ampicillin-resistant H. influenzae was equal or superior to tebipenem and greater than cefditoren. Therapeutic efficacy of intravenous administration of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and β-lactamase negative ampicillin-resistant H. influenzae was equal or superior to tebipenem and greater than cefditoren, respectively, reflected their in vitro activity. SM-295291 and SM-369926 showed similar intravenous pharmacokinetics to meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase-I. SM-368589 and SM-375769 which are medoxomil esters of SM-295291 and SM-369926, respectively, showing good oral bioavailability in rats, dogs, and monkeys (4.2-62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and β-lactamase negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapy.
FOOTNOTES
# Corresponding author: koji-takemoto@ds-pharma.co.jp
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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