Chloramphenicol: Relation of Structure to Activity and Toxicity

The availability of an increasing number of effective broad spectrum anti­ microbials in the past decade has diminished considerably the clinical in­ dications for chloramphenicol (CAP). However, interest in this antibiotic has recently been revived both because of its antimicrobial activity and its toxic­ ity. Some factors affecting its resurgence are the emergence of ampicillin­ resistant Halmophilus influenzae, the superiority of CAP in fighting certain anaerobic infections and infections of the central nervous system, and the development of sensitive assays for the antibiotic and some of its metabolites in body fluids. Greater attention, however, has focused on hematotoxicity from CAP and its pathogenesis. The extensive use of a CAP analogue, thiamphenicol (TAP), in Europe and the Far East, without an increase in the incidence of associated aplastic anemia, has revived interest in the structure­ toxicity relationship in the CAP molecule and has focused attention on the P-N02 group as the structural feature that probably underlies the development of bone marrow aplasia in association with administration of CAP. TAP, with a similar antimicrobial spectrum, has emerged as a challenging substitute to CAP. In this chapter the comparative metabolism and toxicity of CAP and TAP are reviewed with particular emphasis on the role of the P-N02 group. For a clearer perspective, the properties of CAP, its mechanism of action, and relation of structure to activity and to bacterial resistance are briefly consid­ ered.