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.