title: Novel carbapenem antibiotics for parenteral and oral applications: in vitro and in vivo activities of 2-aryl carbapenems and their pharmacokinetics in laboratory animals.
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(90)s of ≤ 1 μg/ml. Unlike tebipenem (MIC(50), 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC(50), ≥ 128 μg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren. The therapeutic efficacies of intravenous administrations 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 were equal or superior to that of tebipenem and greater than that of cefditoren, respectively, reflecting their in vitro activities. SM-295291 and SM-369926 showed intravenous pharmacokinetics similar to those of 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, showed good oral bioavailability in rats, dogs, and monkeys (4.2 to 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 therapies.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co, Ltd, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Takemoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hatano
authors.forename: Toru
authors.initials: T
authors.lastname: Nakai
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Terashita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Eriguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Eguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizudani
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Sato
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kanazawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunagawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001682:Biological Availability; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017714:Community-Acquired Infections / Q000188:drug therapy; D004150:Dipeptidases; D004285:Dogs; D004355:Drug Stability; D058851:GPI-Linked Proteins; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D058851:GPI-Linked Proteins; D004150:Dipeptidases; C549872:dipeptidase 1