The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.
The neurotoxicity of meropenemwas muchlower than that of both imipenemand panipenem after intraventricular administration to mice. To clarify the majorstructural features responsible for the induction of convulsions by carbapenemantibiotics, the structure-activity relationship on convulsant activity was investigated in iV-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compoundswith strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gammaaminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediatedinhibitory transmission. However, the in vivo convulsant activity of some of these compoundsdid not correlate with their in vitro inhibitory effect on GABAA receptor binding.
The in vitro and in vivo antibacterial activities of SM-17466, a new 1-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 g/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 g/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillinbinding protein 2 in a methicillin-resistant strain (50% inhibitory concentration, 5.9 g/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 I, to an extent comparable to the resistance shown by meropenem.
To investigate combinations of antibiotics against Pseudomonas aeruginosa, the in vitro effects of combinations of meropenem with each of three aminoglycosides, arbekacin, amikacin and netilmicin, were evaluated using an agar dilution chequerboard technique. The combinations of meropenem and aminoglycosides were effective against almost all P. aeruginosa strains tested, which included meropenem-resistant strains. Increased synergic effects were observed in combinations that included arbekacin or amikacin. None of the combinations had an antagonistic effect. Most of the synergic and additive effects were achieved at clinically relevant concentrations.
The anti-i/. influenzae activity of meropenem(la) was muchhigher than those of imipenem (4), panipenem (2b) and biapenem (7). To clarify the major structural features responsible for the anti-i/. influenzae activity of carbapenem compounds,the structure-activity relationship to the anti-//. influenzae activity was investigated. The anti-//. influenzae activities of meropenem(la) and l/?-methyl-panipenem (2a) were much higher than those ofdesmethyl-meropenem (lb) and panipenem (2b), respectively. Two carbapenems (5, 6) and imipenem (4), that have a strong basic C-2 side chain, showed lower anti-//. influenzae activity than meropenem(la) having a weakly basic C-2 side chain and iV-acetyl thienamycin (3) having a neutral C-2 side chain, respectively. As a result, we found that the introduction of the 1^-methyl group or the reduction of the basicity (cationic character) of the C-2 side chain increased the antimicrobial activity and bactericidal activity of carbapenems against H. influenzae due to their increased affinity for PBP-4 and PBP-5. Haemophilus influenzae is an important pathogen that causes purulent meningitis in infants and severe infections in immunocompromisedadults1}. Meropenemis a carbapenemantibiotic that has been accepted for clinical use, and its potency against H. influenzae is markedly higher than those of other carbapenems such as imipenem and panipenem2~6). The anti-i/. influenzae activity of meropenemis equivalent to those of thirdgeneration cephems2'3'6), and sufficient for clinical use. Although imipenem-highly-resistant H. influenzae strains were isolated from clinical sources in recent years, meropenemhas maintained sufficient activity against clinical isolates3'5'6*, and meropenem-resistant H. influenzae
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