Carbapenems: Past, Present, and Future

In this review, we summarize the current state of the art of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the beta-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most beta-lactamases, in some cases act as slow substrates or inhibitors of beta-lactamases, and still target penicillin binding proteins. This value-added feature of inhibiting beta-lactamases serves as a major rationale for expansion of this class of beta-lactams. We describe the initial discovery and development of the carbapenem family of beta-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.