The carbapenems: new broad spectrum -lactam antibiotics

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Abstract
The carbapenems differ from the penicillins (penams) in having an unsaturated bond between C2 and C3 and a carbon atom replacing sulphur at position 1 of the thiazolidine ring. The various carbapenems differ primarily in the configuration of the side chains at C2 and C6. Carbapenems include the thienamycins, olivanic acids, carpetimycins, asparenomycins, pluracidomycins, and other natural and semi-synthetic compounds. Carbapenems vary in their stability and resistance to β -lacta-mases, ability to inhibit and to induce β -lactamases, and in-vitro spectra of activity. Many are highly unstable in solution. Some are degraded by mammalian dehydro-peptidases in vivo. The hydroxyethyl side chain in the a or trans-configuration at C6 in thienamycin provides striking resistance to β -lactamases, but this compound is highly unstable in concentrated solution and the solid state. The N -formimidoyl derivative of thienamycin (imipenem) is more stable in solution and has broad-spectrum activity against aerobic and anaerobic bacteria. However, imipenem is not stable to renal dehydropeptidases and its degradation products are nephrotoxic in certain animals. It is thus administered with the dehydropeptidase inhibitor cilas-tatin. High serum levels of imipenem (especially in patients with renal failure and central nervous system disease) have been associated with seizures. The drug is therefore not appropriate for meningitis. Meropenem is a new carbapenem which has the same side chain as imipenem at C6. Its unique side chain at C2 assures a broad spectrum of activity which includes Pseudomonas aeruginosa and other aerobic and anaerobic organisms. Only Ps. (Xanthomonas) maltophilia is generally resistant. This species is resistant also to imipenem. Meropenem is resistant to most β -lactamases and appears to have less inducer potential for certain β-lactamases than imipenem. The presence of a methyl group at C1 provides meropenem with excellent stability to human renal dehydropeptidases-1; therefore, it should not require concomitant administration of an enzyme inhibitor.

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