Emerging strategies in infectious diseases: new carbapenem and trinem antibacterial agents.

Beta-lactam antibiotics represent the most commonly prescribed antibacterial agents. New beta-lactams have been introduced continuously as many bacteria have developed resistance to older agents. In the late 1970s, a new class of exceptionally broad spectrum beta-lactams, the carbapenems, was identified. Despite being a very potent compound, the antibacterial activity of the first carbapenem, imipenem, was compromised because of hydrolysis by the renal dehydropeptidase enzyme (DHP-1), and it is now coadministered with a potent competitive inhibitor of the DHP-1 enzyme, cilastin. Molecular modifications in the carbapenem nucleus were able to increase stability to DHP-1 and retain the antibacterial activity. However, some important pathogenic bacteria were found to be resistant to this new class of agents. In addition, other clinically important gram-negative species, such as Pseudomonas aeruginosa, developed resistance mainly by the production of potent beta-lactamases and reduced permeability of the outer membrane. Since the discovery of imipenem/cilastatin, a great number of carbapenems have been developed, and a few of them have been marketed. Stability to hydrolysis by DHP-1 and decrease in toxicity were achieved by meropenem and biapenem. However, only a slight increase in the antibacterial potency and spectrum has been accomplished with either the new marketed or experimental parenteral compounds. In addition, compounds that can be administered orally, such as the carbapenens faropenem, CS-834 and MK-826, and the trinem sanfetrinem, have been developed. However, when compared with the parenterally administered compounds, the oral agents seem to lose some in vitro antibacterial activity, especially against P. aeruginosa.