Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus

The in vitro and in vivo antibacterial activities of SM-17466, a new 1β- methyl carbapenem, were evaluated against a wide range of clinical bacterial isolates and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 μg/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin- resistant S. aureus. In contrast, SM-17466 was less active against gram- negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteroides fragilis. SM- 17466, at a 50% inhibitory concentration of less than 1 μg/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillin-binding protein 2' in a methicillin- resistant strain (50% inhibitory concentration, 5.9 μg/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM- 17466. The subcutaneous injection of SM-17466 in mice revealed that the half- life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase 1, to an extent comparable to the resistance shown by meropenem.