Imipenem thienamycin derivative

Both of these antibiotics are notable. Imipenem is derived from a natural product, thienamycin. 

Thienamycin and its derivatives are exciting new antibiotics. Then-clinical use is limited, however, by their susceptibility to the kidney enzyme dehydropeptidase I. Reversible inhibition of this enzyme is provided by cilastatin [11]. The preparation of the S-cyclopropane portion [10] of cilastatin is achieved (16) by decomposition of ethyl diazoacetate in isobutylene [9] in the presence of the chiral copper catalyst R-7644. The product [10] is obtained in 92% e.e. and then further processed to cilastatin. Cilastatin is now marketed in combination with the thienamycin derivative imipenem as a very-broad-spectnim antibiotic. 

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

Meropenem (Merrem IV) is a dimethylcarbamoyl pyro-lidinyl derivative of thienamycin. It does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar to that of imipenem except that it may be less likely to cause seizures (0.5% of meropenem- and 1.5% of imipenem-treated patients seized). Its in vitro activity is similar to that of imipenem, with activity against some imipenem-resistant P. aeruginosa but less activity against Gram-positive cocci. Chnical experience with meropenem demonstrates therapeutic equivalence with imipenem. 

MEROPENEM Meropenem (merrem iv) is a derivative of thienamycin that does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity and clinical efficacy are similar to imipenem, except that it may be less likely to cause seizures. 

Case Study 4 Imipenem monohydrate (18, Scheme 23.7), which is the Af-formimidoyl derivative of thienamycin, is the first clinically available member of a new class of P-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species, which is due partly to its high stabiUty in the presence of P-lactamases. 

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