Carbapenems: Past, Present, and Future

Abstract

In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as "slow substrates" or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-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.Carbapenems play a critically important role in our antibiotic armamentarium. Of the many hundreds of different ␤-lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria. As a result, they are often used as "last-line agents" or "antibiotics of last resort" when patients with infections become gravely ill or are suspected of harboring resistant bacteria (23,(174)(175)(176)229). Unfortunately, the recent emergence of multidrug-resistant (MDR) pathogens seriously threatens this class of lifesaving drugs (189). Several recent studies clearly show that resistance to carbapenems is increasing throughout the world (35,64,73,123,151,155,173,200). Despite this menacing trend, our understanding of how to best use these agents is undergoing a renaissance, especially concerning their role with regard to ␤-lactamase inhibition. In this context, we view the number, type, and diversity of carbapenems as compelling reasons to explore these compounds for new insights into drug development.

Acinetobacter baumannii: biology and drug resistance — role of carbapenemases

“…Doripenem is a synthetic 1-beta-methylcarbapenem, differing from meropenem with the presence of sufamoylaminomethyl group. This modification increases doripenem activity towards non-fermentative Gram-negative bacilli [45,46]. Another carbapenem, introduced to the therapy in 2001, is ertapenem.…”

“…Carbapenem binding of PBP leads to weakening of the peptidoglycan and may result with the cell burst due to the osmotic pressure. Furthermore, one of the essential features of the carbapenems is the ability to bind to multiple different PBPs [46].…”

Molecular characterization of resistance mechanisms in Pseudomonas aeruginosa isolates resistant to carbapenems

“…However, carbapenem-resistant P. aeruginosa could be resistant to other classes of antimicrobial agents and such infections are associated with limited therapeutic options and high rates of mortality and morbidity especially in hospitalized and immunocompromised patients [3][4].…”

Antimicrobial Susceptibility and Microorganisms Isolated from Blood Cultures of Hospitalized Patients in Intensive Care Units

“…Kan dolaşımı sistemi enfeksiyonlarının tedavisinde çoğul dirençli mikroorganizmalardan özellikle GSBL üretenler sorunlar oluşturmaktadır (4,(21)(22)(23). Karbapenemler GSBL üreten ve çoğul dirençli mikroorganizmaların tedavisinde en etkili antibiyotikler olmasına rağmen sık kullanımları durumunda bunlara karşı da direnç gelişimi oluşmaktadır (22,24,25). Çalışmamızda Acinetobacter spp.…”