Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin.

The discovery of Streptomyces cattleya and its antibiotic product, thienamycin, has ushered in a new era of beta-lactam agents, the carbapenems. Numerous carbapenems were subsequently discovered; however, none had the potency, broad-spectrum activity, and lack of cross-resistance exhibited by thienamycin. Chemical instability encountered with thienamycin was overcome by the N-formimidoyl derivative, imipenem. Imipenem is distinguished from other beta-lactams by its outstanding activity against gram-positive organisms as well as against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides. However, development was hindered by extensive renal metabolism of imipenem, resulting in low urinary concentrations of antibiotic. A renal dipeptidase, dehydropeptidase-I, was responsible for hydrolyzing imipenem and other carbapenems. To counter its action, a specific inhibitor, cilastatin, was developed. Coadministered with imipenem in a one-to-one ratio, cilastatin provides prolonged, reversible blockade of imipenem metabolism, dramatically improving urinary recoveries to therapeutically significant levels. Cilastatin also contributes to the safety of imipenem, since its coadministration prevents proximal tubular necrosis which has been observed in sensitive animals receiving imipenem alone in high doses. Thus, the combination imipenem and cilastatin overcame the pharmaceutical and metabolic challenges presented by thienamycin, and allowed for the evaluation in humans of the outstanding antimicrobial activity of this new class of beta-lactam antibiotics.