The Carbacephems: A New Beta-Lactam Antibiotic Class

The carbacephems are a new class of β-lactam antibiotics that are similar in structure to the cephalosporins. Carbacephems differ from cephalosporins, however, in the substitution of a sulfur atom in the dihydrothiazine ring with a methylene group to form a tetrahydropyridine ring. The result of this structural difference is the carbacephem class. Carbacephems have remarkable chemical stability that allows for structural manipulation in a manner that could not be done previously with the cephalosporin ring system. Potent broad-spectrum antibiotics result from the incorporation at the 3 position of substituents that include quaternary pyridinium or imidazole, sulfones, and heterocyclic thiazole structures. Because of the chemical stability of the carbacephems, these highly electronegative side chains can be added to the 3 or 3' position of the tetrahydropyridine ring system. Increasing the electronegativity of these side chains can increase the microbiologic activity of the compounds. In addition, utilizing the side chains that have traditionally conferred good oral absorption on the cephalosporins offers the possibility of a new series of broad-spectrum oral antibiotics. Loracarbef is the first carbacephem to undergo clinical development, and other experimental carbacephems are being produced with the aim of developing potent oral antibiotics that can be used against pathogens that cause infections commonly found in the outpatient setting.