Newer Carbapenems

The extended spectrum of antibacterial activity associated with the carbapenems together with their resistance to inac-tivation by most S-lactamases make this class of S-lactams an attractive target for drug development. In the design of new carbapenems, structural variations are being investigated with the objective of developing analogs with advantages over imipenem. Improvements that are particularly desired include stability to hydrolysis catalyzed by DHP-I,62 stability to bacterial metallo-jS-lactamases ("carbapene-mases")56 that hydrolyze imipenem, activity against MRSA,31 and increased potency against P. aeruginosa, especially imipenem-resistant strains. Enhanced pharmacokinetic properties, such as oral bioavailability and a longer duration of action, have heretofore received little emphasis in car-bapenem analog design.

Early structure-activity studies established the critical importance of the A2 position of the double bond, the 3-carboxyl group, and the 6-a-hydroxyethyl side chain for both broad-spectrum antibacterial activity and S-lactamase stability in carbapenems. Modifications, therefore, have concentrated on variations at positions 1 and 2 of the carbapenem nucleus. The incorporation of a S-methyl group at the 1-position gives the carbapenem stability to hydrolysis by renal DHP-I.64,65 Substituents at the 2-position, however, appear to affect primarily the spectrum of antibacterial activity of the carbapenem by influencing penetration into bacteria. The capability of carbapenems to exist as zwitterionic structures (as exemplified by imipenem and biapenem), resulting from the combined features of a basic amine function attached to the 2-position and the 3-carboxyl group, may enable these molecules to enter bacteria via their charged porin channels.

Meropenem

Meropenem is a second-generation carbapenem that, to date, has undergone the most extensive clinical evaluation.66 It has recently been approved as Merrem for the treatment of infections caused by multiply-resistant bacteria and for empirical therapy for serious infections, such as bacterial meningitis, septicemia, pneumonia, and peritonitis. Meropenem exhibits greater potency against Gram-negative and anaerobic bacteria than does imipenem, but it is slightly less active against most Gram-positive species. It is not effective against MRSA. Meropenem is not hydrolyzed by DHP-I and is resistant to most ^-lactamases, including a few carbapenemases that hydrolyze carbapenem.

Meropenem

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