Combined effects of meropenem and aminoglycosides on Pseudomonas aeruginosa in vitro.

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.

[Antipseudomonal activity of carbapenem antibiotics].

To date, three carbapenem antibiotics have been introduced for clinical use, and they can be structurally classified into two types. One is a natural type that has the naturally-occurring carbapenem skeleton and a strongly basic (cationic) moiety in the C-2 side chain, like imipenem or panipenem. The other is a new generation carbapenem, meropenem, which has the 1 beta-methyl carbapenem skeleton and a less basic group in the C-2 side chain.

Structure-activity relationships of carbapenems to the antagonism of the antipseudomonal activity of other beta-lactam agents and to the beta-lactamase inducibility in Pseudomonas aeruginosa: effects of 1beta-methyl group and C-2 side chain.

The antagonism of the antipseudomonal activity of ceftazidime by meropenem (1a) was much less than those by imipenem (2a) and panipenem (2b). To reveal the major structural features of carbapenem compounds responsible for the antagonism, we investigated the structure-activity relationships of carbapenems to their antagonism of the antipseudomonal activity of ceftazidime and to their beta-lactamase-inducibility in P. aeruginosa.

Structure-activity relationships of carbapenem compounds to anti-Haemophilus influenzae activity and affinity for penicillin-binding proteins. Effect of 1 beta-methyl group and C-2 side chain.

The anti-H. influenzae activity of meropenem (1a) was much higher than those of imipenem (4). panipenem (2b) and biapenem (7).

[Neurotoxicity of carbapenem compounds and other beta-lactam antibiotics].

The neurotoxic potencies are considerably different among various beta-lactam antibiotics. Some carbapenem antibiotics, a new class beta-lactam antibiotic, also induce convulsion in human and laboratory animals. This article reviews the structure activity relationship for the neurotoxicity of beta-lactam antibiotics, especially carbapenems.

Structural features resulting in convulsive activity of carbapenem compounds: effect of C-2 side chain.

The neurotoxicity of meropenem was much lower than that of both imipenem and panipenem after intraventricular administration to mice. To clarify the major structural features responsible for the induction of convulsions by carbapenem antibiotics, the structure-activity relationship on convulsant activity was investigated in N-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, compounds with strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds.

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 1 beta-methyl carbapenem, were evaluated against a wide range of clinical bacterial isoaltes 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.

Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I.

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.

Relationship between lipophilicity and binding affinity with human serum albumin for penicillin and cephem antibiotics.

Relationship between structure and binding affinity to human serum albumin (HSA) has been studied for penicillin and cephem antibiotics. For penicillin analogs, a good correlation between the apparent affinity constants, Kapp, for HSA binding and the partition coefficient, Papp, determined in isobutyl alcohol-pH 7.4 phosphate buffer system was observed, indicating that the hydrophobic interaction of 6-substituent of penicillins with amino acid of HSA would play an important role for the binding.

Selective analysis of mutual displacement effects at the primary binding sites of phenoxymethylpenicillin and cephalothin bindings to human serum albumin.

In order to analyze the mutual displacement effects on the protein binding of beta-lactam antibiotics, binding experiments with the human serum albumin (HSA) were performed for cephalothin (CET) and phenoxymethylpenicillin (PCV) by using the centrifugal ultrafiltration method. The numbers of primary and secondary binding sites, n1 and n2, and the affinity constants for the primary and secondary binding sites, K1 and K2 were determined for CET to be 1.00 +/- 0.

Beta-lactamase stability and inhibitory activity of meropenem combined with a potent antibacterial activity.

The affinity of meropenem for various known types of beta-lactamases and its stability to them were tested in comparison with other beta-lactams, including imipenem. Meropenem exhibited a marked stability to all beta-lactamases tested and was only hydrolyzed by Xanthomonas maltophilia beta-lactamase, as were other beta-lactams. This was responsible for the potent antibacterial activities of meropenem against beta-lactamase-producing strains.