Carbapenems: special properties contributing to their activity

Abstract

Imipenem is a beta-lactam antibiotic that inhibits most clinical isolates of staphylococci, Enterobacteriaceae, and streptococci, excluding enterococci, at 1 microgram/ml or less. Resistance can develop in methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens, albeit infrequently. Pseudomonas maltophilia is intrinsically resistant to imipenem. Many strains of Enterobacter cloacae, Clostridium freundii, and S. marcescens resistant to the aminothiazolyl cephalosporins are susceptible to imipenem, but tend to have higher minimal inhibitory concentrations. In general, imipenem inhibits organisms resistant to other beta-lactams and aminoglycosides. Imipenem binds to PBP-2 and rapidly kills most bacteria which it inhibits. Imipenem is highly stable against attack by beta-lactamases of both plasmid and chromosomal origin, and is more stable by several thousand-fold than earlier beta-lactamase stable compounds. It acts as a suicide inhibitor of beta-lactamases. Imipenem does induce beta-lactamases, but the activity of imipenem against isolates containing induced beta-lactamases is not decreased and it appears not to be susceptible to the trapping that occurs with some of the cephalosporins. Imipenem acts synergistically with aminoglycosides against a wide variety of bacteria, but this is most readily demonstrated for Streptococcus faecalis, S. aureus, and P. aeruginosa organisms which show a difference between inhibition and killing. Overall, the excellent activity of imipenem is the result of (1) the lack of a permeability barrier; (2) high affinity for PBP-2, a critical protein in cell wall synthesis in gram-negative bacteria, and for critical penicillin-binding proteins of gram-positive species; and, above all, (3) its great beta-lactamase stability.