Macrolides Versus Azalides: A Drug Interaction Update

Abstract

Objective: To describe the current drug interaction profiles for all approved and investigational macrolide and azalide antimicrobials, and to comment on the clinical impact of these interactions when appropriate. Data Sources: MEDLINE was searched to identify all pertinent studies, review articles, and case reports from 1975 to 1995. When appropriate information was not available in the literature, data were obtained from the product manufacturers. Study Selection: All available data were reviewed to give an unbiased account of possible drug interactions. Data Extraction: Data for some of the interactions were not available from the literature, but were available from abstracts or from company-supplied materials. Although the data were not always entirely explicative, the best attempt was made to deliver the pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. Data Synthesis: Since the introduction of erythromycin into clinical practice, there have been several clinically significant drug interactions identified throughout the literature associated with this drug. These interactions have been caused mostly by inhibition of the CYP3A subclass of hepatic enzymes, thereby decreasing the metabolism of any other agent given concurrently that is also cleared through this mechanism. With the development and marketing of several new macrolides, it was hoped that the drug interaction profile associated with this class would improve. This has been met with variable success. Although some of the extensions of the 14-membered ring macrolides have shown an incidence of interactions equal to that of erythromycin, others have shown improved profiles. In contrast, the 16-membered ring macrolides have demonstrated a much improved, though not absent, interaction profile. The most success in avoiding drug interactions through structure modification has been accomplished with the development of the azalide class, of which azithromycin is the first to be approved for marketing. This agent has to date produced none of the classic drug interactions that most macrolides have demonstrated in patient care. Conclusions: The introduction of new 14- and 16-membered ring macrolides appears to have had a variable effect in modifying the incidence of drug interactions associated with this class. Azithromycin, a member of the new azalide class, has to date produced fewer clinically significant interactions than other azalides with any agent that is cleared through the CYP3A system. Overall, the available data are promising, and the final test should come from conducting studies in patients who are taking potentially interacting compounds on a chronic basis, as most available data are from trials in healthy volunteers.