Drug chirality: a consideration of the significance of the stereochemistry of antimicrobial agents

Abstract

Approximately 25% of drugs are marketed as either racemates or mixtures of diastereoisomers. Such stereoisomers frequently differ in terms of their biological activity and pharmacokinetic profiles and the use of such mixtures may contribute to the adverse effects of the drug particularly if they are associated with the inactive or less active isomer. In recent years drug stereochemistry has become a significant issue for both the pharmaceutical industry and the regulatory authorities. The significance of stereoisomerism in antimicrobial agents is addressed in this review using examples drawn from the beta-lactams, as being representative of semisynthetic agents, and the quinolones, as examples of synthetic agents. Within these two groups of compounds it is clear that stereochemical considerations are of significance for an understanding of concentration effect relationships, selectivity in both action and inactivation and for an appreciation of the mode of action at a molecular level. In the case of some agents the use of a single isomer is precluded due to their facile epimerization, e.g. carbenicillin, in the case of others there are potential advantages with the use of single isomers, e.g. ofloxacin. However, in the case of latamoxef, a compound which undergoes in-vivo epimerization with a half-life similar to its apparent serum elimination half-life the situation is by-no-means clear cut. These agents emphasise the importance of considering each compound individually, i.e. on a case-by-case basis, before deciding to use a single isomer or stereoisomeric mixture.